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BackgroundOsteoarthritis is a chronic conditioninvolving degeneration of cartilage withinthe joints. It is the most common form ofarthritis and is associated with pain,substantial disability, and reduced qualityof life. About 6 percent of U.S. adults aged30 years or older have symptomaticosteoarthritis of the knee, and 3 percenthave symptomatic osteoarthritis of the hip.Osteoarthritis increases with age: theincidence and prevalence increase two- totenfold from age 30 to 65 and continue toincrease after age 65. The total costs forarthritis, including osteoarthritis, may begreater than 2 percent of the grossdomestic product, with more than half ofthese costs related to work loss.
Common oral medications forosteoarthritis include nonsteroidalantiinflammatory drugs (NSAIDs) andacetaminophen. Patients with osteoarthritisalso use over-the-counter supplements notregulated by the U.S. Food and DrugAdministration (FDA) as pharmaceuticals,including glucosamine and chondroitin, aswell as topical agents. Opioid medicationsare also used for selected patients withrefractory, chronic pain but are notrecommended for first-line treatment ofosteoarthritis and therefore not included inthis review. Each class of medication orsupplement is associated with a uniquebalance of risks and benefits. In addition,
efficacy and safety may vary for individualdrugs within a class. Nonpharmacologicinterventions (such as physical therapy,weight reduction, and exercise) also helpimprove pain and functional status inpatients with osteoarthritis.
Comparative Effectiveness and Safety ofAnalgesics for Osteoarthritis
Executive Summary
Effective Health Care
Effective Health Care Program
The Effective Health Care Programwas initiated in 2005 to provide validevidence about the comparativeeffectiveness of different medicalinterventions. The object is to helpconsumers, health care providers, andothers in making informed choicesamong treatment alternatives. Throughits Comparative Effectiveness Reviews,the program supports systematicappraisals of existing scientificevidence regarding treatments for high-priority health conditions. It alsopromotes and generates new scientificevidence by identifying gaps inexisting scientific evidence andsupporting new research. The programputs special emphasis on translatingfindings into a variety of usefulformats for different stakeholders,including consumers.
The full report and this summary areavailable at www.effectivehealthcare.ahrq.gov/reports/final.cfm
Number 4
Effective Health Care
2
A challenge in treating osteoarthritis is deciding whichmedications will provide the greatest symptom reliefwith the fewest serious adverse effects. NSAIDsdecrease pain, inflammation, and fever by blockingcyclo-oxygenase (COX) enzymes. Understanding of thepharmacology of NSAIDs continues to evolve, but it isnow thought that most NSAIDs block three differentCOX isoenzymes, known as COX-1, COX-2, andCOX-3. COX-1 protects the lining of the stomach fromacid. COX-2 is found in joint and muscle, andmediates effects on pain and inflammation. By blockingCOX-2, NSAIDs reduce pain compared to placebo inpatients with arthritis, low back pain, minor injuries,and soft tissue rheumatism. However, NSAIDs that alsoblock the COX-1 enzyme (also called “nonselectiveNSAIDs”) can cause gastrointestinal bleeding. In theUnited States, there are an estimated 16,500 annualdeaths due to NSAID-induced gastrointestinalcomplications, a higher death rate than that for cervicalcancer or malignant melanoma. Theoretically, NSAIDsthat block only the COX-2 enzyme (also called“coxibs,” “COX-2 selective NSAIDs,” or “selectiveNSAIDs”) should be safer with regard togastrointestinal bleeding, but they also appear to beassociated with increased rates of serious cardiovascularand other adverse effects. Less is known about COX-3,which is found in the cerebral cortex and cardiac tissueand appears to be involved in centrally mediated pain.
For this report, we defined the terms “selectiveNSAIDs” or “COX-2 selective NSAIDs” as drugs inthe “coxib” class (celecoxib, rofecoxib, valdecoxib,etoricoxib, lumiracoxib). We defined “partially selectiveNSAIDs” as other drugs shown to have partial in vitroCOX-2 selectivity (etodolac, nabumetone, meloxicam).Aspirin differs from other NSAIDs because itirreversibly inhibits platelet aggregation, and thesalicylic acid derivatives (aspirin and salsalate) wereconsidered a separate subgroup. We defined“nonaspirin, nonselective NSAIDs” or simply“nonselective NSAIDs” as “all other NSAIDs.”
This report summarizes the available evidencecomparing the benefits and harms of analgesics in thetreatment of osteoarthritis.
1 These drugs are currently not approved by the FDA for use in theUnited States (etoricoxib, lumiracoxib, tenoxicam, tiaprofenic acid)or have been withdrawn from the market (rofecoxib and valdecoxib).
Oral agents include:
• Acetaminophen
• Aspirin
• Celecoxib
• Choline magnesium trisalicylate
• Chondroitin
• Diclofenac
• Diflunisal
• Etodolac
• Etoricoxib1
• Fenoprofen
• Flurbiprofen
• Glucosamine
• Ibuprofen
• Indomethacin
• Ketoprofen
• Ketoprofen ER
• Ketorolac
• Lumiracoxib1
• Meclofenamate sodium
• Mefenamic acid
• Meloxicam
• Nabumetone
• Naproxen
• Oxaprozin
• Piroxicam
• Rofecoxib1
• Salsalate
• Sulindac
• Tenoxicam1
• Tiaprofenic acid1
• Tolmetin
• Valdecoxib1
3
Questions addressed in this report are:
1. What are the comparative benefits and harms oftreating osteoarthritis with oral medications orsupplements? How do these benefits and harmschange with dosage and duration of treatment, andwhat is the evidence that alternative dosagestrategies, such as intermittent dosing and drugholidays, affect the benefits and harms of oralmedication use? (Note: The only benefits consideredunder this question are improvements inosteoarthritis symptoms from long-term use.Evidence of harms associated with NSAID useinclude long-term studies of these drugs for treatingosteoarthritis or rheumatoid arthritis and for cancerprevention.)
2. Do the comparative benefits and harms of oraltreatments for osteoarthritis vary for certaindemographic and clinical subgroups of patients?
• Demographic subgroups include age, sex, andrace.
• Coexisting diseases include hypertension,edema, ischemic heart disease, heart failure;peptic ulcer disease; history of previousbleeding due to NSAIDs.
• Concomitant medication use includesanticoagulants.
3. What are the comparative effects of coprescribingof H2-antagonists, misoprostol, or proton pumpinhibitors (PPIs) on the gastrointestinal harmsassociated with NSAID use?
4. What are the comparative benefits and harms oftreating osteoarthritis with oral medications ascompared with topical preparations? Topicalpreparations include: capsaicin, diclofenac,ibuprofen, ketoprofen, and salicylate.
A summary of the findings is shown in Table A.
Conclusions
Oral NSAIDS
Benefits: improvements in osteoarthritis symptoms
• Nonselective NSAID vs. another nonselectiveNSAID
• Many trials found no clear differences betweenvarious nonaspirin, nonselective NSAIDs orpartially selective NSAIDs (meloxicam,
nabumetone, etodolac) in efficacy for painrelief or improvement in function.
• In one short-term trial, salsalate and aspirin didnot differ significantly in efficacy for painrelief or symptom improvement.
• No studies evaluated the comparative efficacyof salsalate or aspirin vs. a nonaspirin NSAID.
• COX-2 selective NSAID vs. nonselective NSAID
• COX-2 selective NSAIDs and nonselectiveNSAIDs did not clearly differ in efficacy forpain relief, based on many good-quality,published trials.
• COX-2 selective NSAID vs. different COX-2selective NSAID
• Celecoxib and rofecoxib did not differsignificantly in efficacy for pain relief atcommonly used and comparable doses, basedon consistent evidence from six good-qualitytrials.
• No studies compared efficacy of COX-2s otherthan celecoxib and rofecoxib.
Harms: gastrointestinal (GI) and cardiovascular(CV)
• Rofecoxib vs. nonselective NSAID
• In the only large, long-term trial (VIGOR),rofecoxib 50 mg daily caused fewer seriousulcer complications than naproxen 1,000 mgdaily in patients with rheumatoid arthritis butalso significantly increased the risk ofmyocardial infarction. The overall rate ofserious adverse events was higher withrofecoxib than with naproxen.
• There were about 16 fewer symptomaticulcers, including 5.2 fewer serious GIcomplications, for every 1,000 patientstreated with rofecoxib vs. naproxen after amedian of 9 months of treatment.
• There were 3.0 additional myocardialinfarctions for every 1,000 patients treatedwith rofecoxib compared to naproxen inVIGOR.
• Rofecoxib was associated with an increasedrisk of myocardial infarction relative to placeboin the most comprehensive systematic reviewof randomized controlled trials (RCTs).
• About 3.5 additional myocardialinfarctions occurred for every 1,000patients treated for 1 year with rofecoxibcompared to placebo in the systematicreview.
• Rofecoxib was withdrawn from the market inSeptember 2004, primarily because of CVrisks.
• Celecoxib vs. nonselective NSAID or placebo
• It is not clear whether celecoxib has fewerpotential harms than nonselective NSAIDswhen used longer than 3-6 months. In the onlylarge, published trial (CLASS), celecoxib at800 mg daily did not decrease predefinedserious ulcer complications overall comparedwith diclofenac and ibuprofen; the risk ofserious GI events was lower than withibuprofen, but not diclofenac, at 6 months inpatients who did not use aspirin; and there wasno reduction in serious GI events at the end offollowup. The overall rate of serious adverseevents with celecoxib was similar to the ratewith ibuprofen and diclofenac.
• In fair-quality meta-analyses of arthritis trials,most of which evaluated short-term use,celecoxib caused fewer ulcer complicationsthan nonselective NSAIDs and did not increasethe risk of myocardial infarction.
• Celecoxib 400 mg twice daily was associatedwith an increased risk of serious CV events(CV death or myocardial infarction) relative toplacebo in a long-term trial of polypprevention.
• Celecoxib was associated with an increasedrisk of myocardial infarction relative to placeboin the most comprehensive systematic reviewof RCTs. Most of the CV events with celecoxibwere reported in two large polyp-preventiontrials evaluating 200 mg or 400 mg twice daily,or 800 mg once daily.
• About 3.5 additional myocardialinfarctions occurred for every 1,000patients treated for 1 year with celecoxibcompared to placebo.
• Valdecoxib vs. nonselective NSAID or placebo
• Valdecoxib was associated with a lower risk ofupper GI complications compared with
diclofenac, ibuprofen, or naproxen in two fair-quality meta-analyses of published andunpublished trials.
• There have been too few events reported inRCTs of patients with chronic conditions toaccurately assess CV risk associated withvaldecoxib.
• Two short-term trials in a high-risk post-coronary-artery-surgery setting found thatvaldecoxib was associated with a two- tothreefold higher risk of CV events comparedwith placebo.
• Valdecoxib was withdrawn from the marketdue to life-threatening skin reactions andincreased CV risk.
• Etoricoxib vs. nonselective NSAID
• Etoricoxib was associated with fewer GIadverse events (perforations, symptomaticulcers, and bleeds) than nonselective NSAIDsin a fair-quality meta-analysis of 10 trials.
• In primarily short-term trials, systematicreviews of RCTs suggest that etoricoxib has asimilar CV safety profile compared to otherNSAIDs, with the possible exception ofnaproxen. Definitive conclusions are notpossible because of small numbers of CVevents.
• Lumiracoxib vs. nonselective NSAID
• Results from one large trial (TARGET) foundfewer adverse GI events with lumiracoxib thanwith naproxen and ibuprofen.
• There was no statistically significant differencein rates of serious CV events betweenlumiracoxib relative to naproxen or ibuprofenin TARGET.
• Too few events have been reported in RCTs toaccurately assess CV risk associated withlumiracoxib.
• Partially selective NSAID vs. nonselectiveNSAID
• Meloxicam: There were no significantdifferences in risks of serious GI events inseveral meta-analyses of up to 28 primarilyshort-term clinical trials, and no difference inCV risk in three observational studies.
4
5
• Nabumetone or etodolac: There wasinsufficient evidence to make reliablejudgments about relative GI safety and noevidence on CV safety.
• Nonselective NSAID vs. nonselective NSAID orany COX-2 selective NSAID
• No clear difference in GI safety was foundamong nonselective NSAIDs at commonlyused doses.
• The CV safety of naproxen was moderatelysuperior to that of any COX-2 selective NSAIDin a large systematic review of RCTs.
• There were 3.3 additional myocardialinfarctions for every 1,000 patients treatedwith any COX-2 inhibitor instead ofnaproxen for 1 year.
• The CV safety of nonselective NSAIDs otherthan naproxen (data primarily on ibuprofen anddiclofenac) was similar to that of COX-2selective NSAIDs in a large systematic review.
• In indirect analyses, naproxen was the onlynonselective NSAID associated with neutralCV risk relative to placebo.
• Aspirin
• Aspirin is associated with a lower risk ofthromboembolic events and a higher risk of GIbleeds compared to placebo or nonuse whengiven in long-term prophylactic doses.
• There is insufficient evidence to assess thebalance of GI and CV safety of higher doseaspirin as used for pain relief compared withnonaspirin NSAIDs.
• Salsalate
• Salsalate was associated with a lower risk ofadverse events than other selective andnonselective NSAIDs using broad compositeendpoints in older, poor-quality observationalstudies. In a more recent observational study,salsalate had a similar rate of complicationscompared with other NSAIDs.
• Almost no data are available on CV safety.
Harms: mortality
• Individual trials were not large enough to detectdifferences in mortality between the includeddrugs.
• One meta-analysis of celecoxib found nodifference between celecoxib and nonselectiveNSAIDs, but there were few events.
• In one fair-quality cohort study, nabumetone wasassociated with a lower risk of all-cause mortalitycompared with diclofenac and naproxen, but thisfinding has not been replicated.
Harms: hypertension, congestive heart failure(CHF), edema, and impaired renal function
• All NSAIDs and COX-2 inhibitors can cause oraggravate these conditions.
• There is good evidence from short-term trials that,on average, nonselective NSAIDs raise meanblood pressure by about 5.0 mm Hg (95-percentconfidence interval [CI] 1.2 to 8.7). However,similar average blood pressure changes may notnecessarily correspond with similar likelihoods ofan event requiring withdrawal, medication change,or other clinical consequences.
• Evidence from good-quality observational studiessuggests that rofecoxib is associated with greaterrisks of hypertension, CHF, and edema thancelecoxib. Indirect evidence from various meta-analyses of either rofecoxib or celecoxib vs.nonselective NSAIDs are consistent with thesefindings. Direct randomized trial evidence,however, is limited in quantity and difficult tointerpret because of possible non-equivalentdosing of drugs. Evidence regarding thecomparative risk of renal dysfunction for celecoxiband rofecoxib is sparse.
• There was weak evidence that aspirin and sulindachave less hypertensive effect than othernonselective NSAIDs.
• There were no clear differences among otherselective or nonselective NSAIDs for these adverseevents.
Harms: hepatotoxicity
• Clinically significant hepatotoxicity was rare.
• Among currently marketed NSAIDs, onlydiclofenac was associated with a significantlyhigher rate of liver-related discontinuationscompared with placebo (1 additional case forevery 53 patients treated with diclofenac).
Tolerability
• Relative to nonselective NSAIDs, COX-2 selectiveand partially selective NSAIDs were better or
6
similarly tolerated and aspirin was less welltolerated.
• There were no clear differences in tolerabilityamong COX-2 selective or nonselective NSAIDs.
• Uncertainty remains regarding the comparativetolerability of salsalate and nonselective NSAIDs.Available evidence is somewhat sparse and mixed,with two of three short-term trials suggestingsalsalate is less well tolerated than nonselectiveNSAIDs and older, flawed observational studiessuggesting that salsalate is less toxic thannonselective NSAIDs.
Other oral agents: benefits and harms
• Acetaminophen
• Acetaminophen was modestly inferior toNSAIDs for pain and function in foursystematic reviews.
• Pain severity ratings averaged less than 10points higher for acetaminophencompared to NSAIDs on 100-point visualanalog scales.
• Compared with NSAIDs, acetaminophen hadfewer GI side effects (clinical trials data) andserious GI complications (observationalstudies).
• Acetaminophen may be associated with modestincreases in blood pressure and renaldysfunction (observational studies).
• One good-quality, prospective observationalstudy found an increased risk of CV eventswith heavy use of acetaminophen that wassimilar to the risk associated with heavy use ofNSAIDs.
• Acetaminophen at therapeutic doses does notappear to be associated with an increased riskof hepatotoxicity compared to nonuse inpatients without underlying liver disease.
• Glucosamine and chondroitin
• In one large, good-quality trial the combinationof pharmaceutical-grade glucosaminehydrochloride plus chondroitin (not currentlyavailable in the United States) was not superiorto placebo among all patients studied. Neitherglucosamine nor chondroitin alone wassuperior to placebo. In an analysis of a smallsubgroup of patients with at least moderate
baseline pain, there was a modest benefit forpain relief, but this did not appear to be apreplanned analysis.
• Systematic reviews of older trials foundglucosamine modestly superior to oral NSAIDsand placebo in most trials, but there was someinconsistency between trials, most trials hadsome flaws and results may not be directlyapplicable to the United States because thepositive trials primarily evaluatedpharmaceutical-grade glucosamine available inEurope.
• Only 2 of 20 placebo-controlled trials assessedeffects of glucosamine on radiologic diseaseprogression. One fair- and one good-qualitytrial found pharmaceutical-grade glucosaminesuperior to placebo for progression of kneejoint space narrowing over 3 years.
• Glucosamine and chondroitin were generallywell tolerated and no serious adverse eventswere reported in clinical trials.
Effect of dosage and duration of treatment onthe benefits and harms of oral medication use
• We found no studies evaluating the GI or CVsafety of alternative dosing strategies (such asalternate day dosing, once daily versus twice dailydosing, or periodic drug holidays).
• The risk of GI bleeding increases with higherdoses of nonselective NSAIDs.
• The most comprehensive systematic review ofRCTs found no clear association between durationof exposure and CV risk of COX-2 inhibitors.However, estimates of CV risk with shorterduration of exposure are imprecise due to lownumbers of events.
• The most comprehensive systematic review ofRCTs found higher doses of celecoxib associatedwith increased CV risk, but could not determinethe effects of dose on CV risk associated withrofecoxib due to low numbers of events at lowerdoses. Most trials of nonselective NSAIDsinvolved high doses.
Differences in demographic and clinicalsubgroups
• GI and CV complication rates are higher amongolder patients and those with predisposingcomorbid conditions, but there is no evidence that
7
the relative safety of different NSAIDs variesaccording to baseline risk.
• Compared to nonuse of NSAIDs, oneadditional death per 1 year of use occurred forevery 13 patients treated with rofecoxib, 14with celecoxib, 45 with ibuprofen, and 24 withdiclofenac in one large, population-basedobservational study of high-risk patients withacute myocardial infarction.
• There is no evidence that the comparative safety orefficacy of specific selective or nonselectiveNSAIDs varies depending on age, gender, or racialgroup, although data are sparse.
• Among patients who had a recent episode of upperGI bleeding, there is good evidence that rates ofrecurrent ulcer bleeding are high (around 5 percentafter 6 months) in patients prescribed celecoxib ora nonselective NSAID plus a PPI.
Concomitant anticoagulant use
• Concomitant use of anticoagulants (e.g., warfarin)and any nonselective NSAID increases the risk ofGI bleeding three- to sixfold compared toanticoagulants alone.
• Reliable conclusions about the safety of selectiveNSAIDs used with anticoagulants are not possibledue to flaws in existing observational studies,although there are case reports of serious bleedingevents, primarily in the elderly.
Concomitant aspirin use
• In the CLASS studies, there was no difference inrates of ulcer complications between celecoxib andnonselective NSAIDs in the subgroup of patientswho took aspirin.
• Concomitant low-dose aspirin use increased therate of endoscopic ulcers by about 6 percent inboth patients on celecoxib and those onnonselective NSAIDs in one meta-analysis.
• Rofecoxib plus low-dose aspirin or ibuprofenalone were associated with similar risks ofendoscopic ulcers (16-17 percent), which weresignificantly higher than those for placebo (6percent) or aspirin alone (7 percent).
• The most comprehensive systematic review ofRCTs found that compared to nonuse of aspirin,concomitant aspirin use did not ameliorate theincreased risk of vascular events associated withCOX-2 selective NSAIDs.
Effects of coprescribing H2-antagonists,misoprostol, or PPIs
• Consistent evidence from good-quality systematicreviews and numerous clinical trials foundcoprescribing of PPIs to be associated with thelowest rates of endoscopically detected duodenalulcers relative to gastroprotective agents.
• Coprescribing of misoprostol is associated withsimilar rates of endoscopically detected gastriculcers as coprescribing of PPIs.
• While misoprostol offers the advantage of beingthe only gastroprotective agent to reduce rates ofperforation, obstruction, or bleeding, there is ahigh rate of withdrawals due to adverse GIsymptoms.
• The risk of endoscopic duodenal ulcers forstandard-dose H2 blockers was lower thanplacebo, similar to misoprostol, and higher thanomeprazole. Standard dosages of H2 blockerswere associated with no reduction of risk forgastric ulcers relative to placebo.
• Double (full) dose H2 blockers were associatedwith a lower risk of endoscopic gastric andduodenal ulcers relative to placebo. It is unknownhow full-dose H2 blockers compare to otherantiulcer medications because head-to-head trialsare lacking.
Comparison of oral medications with topicalpreparations
• Topical NSAIDs: efficacy
• Studies of topical NSAIDs typically evaluatedproprietary formulations not approved by theFDA.
• Topical NSAIDs were similar to oral NSAIDsfor pain relief in trials primarily of patientswith osteoarthritis of the knee, with topicaldiclofenac (often with dimethyl sulphoxide[DMSO], a drug not approved for use inhumans in the United States) best studied.
• Topical ibuprofen was superior to placebo inseveral trials.
• Topical NSAIDs: safety
• Consistent evidence from good-quality trials,systematic reviews, and observational studiesfound topical NSAIDs to be associated withincreased local adverse events compared withoral NSAIDs.
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• Total adverse events and withdrawal due toadverse events were similar.
• Data from one good-quality trial found topicalNSAIDs superior to oral NSAIDs for GIevents, including severe events, and changes inhemoglobin.
• Topical salicylates and capsaicin
• Topical salicylates were no better than placeboin higher quality placebo-controlled trials.
• Compared to placebo, one additional patientachieved pain relief for every eight that usedtopical capsaicin in a good-quality meta-analysis, but capsaicin was associated withincreased local adverse events and withdrawalsdue to adverse events.
Balance of evidence and harms
Each of the analgesics evaluated in this report wasassociated with a unique set of benefits and risks. Eachwas also associated with gaps in the evidence necessaryto determine the true balance of benefits vs. harms. Therole of selective and nonselective oral NSAIDs andalternative agents will continue to evolve as additionalinformation emerges. At this time, although theamount and quality of evidence vary, no currentlyavailable analgesic reviewed in this report wasidentified as offering a clear overall advantagecompared with the others. This is not surprising, giventhe complex tradeoffs between the many benefits (painrelief, improved function, improved tolerability, andothers) and harms (CV, renal, GI, and others) involved.
Individuals are likely to differ in how they prioritize theimportance of the various benefits and harms oftreatment. Adequate pain relief at the expense of anincrease in CV risk, for example, could be anacceptable tradeoff for some patients. Others mayconsider even a marginal increase in CV riskunacceptable. Factors that should be considered whenweighing the potential effects of an analgesic includeage (older age being associated with increased risks forbleeding and CV events), comorbid conditions, andconcomitant medication use (such as aspirin andanticoagulation medications). As in other medicaldecisions, choosing the optimal analgesic for anindividual with osteoarthritis should always involvecareful consideration and thorough discussion of therelevant tradeoffs.
Remaining Issues• The CV safety of nonselective NSAIDs has not
been well studied in large, long-term clinical trials.Naproxen, in particular, may be associated withfewer CV risks than other NSAIDs and should beinvestigated in long-term, appropriately poweredtrials.
• Large observational studies assessing the safety ofNSAIDs have been helpful for assessingcomparative benefits and harms but have generallyhad a narrow focus on single adverse events.Observational studies that take a broader view ofall serious adverse events would be substantiallymore helpful for assessing the overall tradeoffsbetween benefits and harms.
• The CV risks and GI benefits associated withdifferent COX-2 selective NSAIDs may vary.Large, long-term trials with active and placebo-controlled arms would be needed to assess thesafety and benefits of any new COX-2 selectiveanalgesic.
• Meta-analyses of the risks associated withselective COX-2 inhibitors need to continue toassess the effects of dose and duration as moredata become available; current estimates of risks atlower doses and with shorter duration of exposureare less precise than estimates at higher doses andlonger duration of exposure because of smallnumbers of events.
• Large, long-term trials of the GI and CV safetyassociated with full-dose aspirin, salsalate, oracetaminophen compared with nonaspirin NSAIDsor placebo are lacking. Recent observational datasuggesting an increased CV risk with heavy use ofacetaminophen highlight the need for long-term,appropriately powered clinical trials.
• Given the large number of patients who meetcriteria for aspirin prophylaxis for CV events,more trials evaluating the dose-related effects ofaspirin 50-1500 mg on GI benefits and CV safetyare needed.
• The effects of alternative dosing strategies such asintermittent dosing or drug holidays have not beenassessed. Studies evaluating the benefits and risksassociated with such strategies compared withconventional dosing could help clarify the effectsof these alternative dosing strategies. In addition,although there is speculation that once daily versus
9
twice daily dosing of certain COX-2 inhibitorscould reduce CV risk, this hypothesis has not yetbeen tested in a clinical trial.
• Most trials showing therapeutic benefits fromglucosamine were conducted usingpharmaceutical-grade glucosamine not available inthe United States and may not be applicable tocurrently available over-the-counter preparations.Large trials comparing currently available over-the-counter preparations of glucosamine andchondroitin with oral NSAIDs are needed, as theseare likely to remain available even if the FDAapproves pharmaceutical-grade formulations.
• No topical NSAIDs are FDA approved in theUnited States, yet compounding of NSAIDs iswidely available. Although recent trials of topicalNSAIDs are promising, most have been conductedusing a proprietary formulation of diclofenac withDMSO, which is not approved in the United Statesfor use in humans. Cohort studies using largeobservational databases may be required toadequately assess CV risk.
AddendumAs this report was going to press, two relevant meta-analyses on risks associated with NSAIDs werepublished. We were unable to fully incorporate thesestudies into this report, but found their results generallyconsistent with our conclusions:
• A fair-quality meta-analysis of arrhythmia andrenal event (peripheral edema, hypertension, orrenal dysfunction) risk from 114 randomized trialsof COX-2 selective NSAIDs found rofecoxibassociated with increased risks of arrhythmia(primarily ventricular fibrillation, cardiac arrest, orsudden cardiac death) and renal dysfunction(peripheral edema, hypertension, or renaldysfunction) relative to control treatments(placebo, other NSAIDs, or mixed/other) . Theincreased risk was equivalent to approximately 1.1additional arrhythmia events per 1,000 patientstreated with rofecoxib. Celecoxib was associatedwith lower risks of renal dysfunction andhypertension than control treatments, although
there was no difference for the prepecified,primary composite renal outcome of peripheraledema, hypertension, renal dysfunction, orarrhythmia. There was no clear associationbetween other COX-2 inhibitors(valdecoxib/parecoxib, etoricoxib, or lumiracoxib)and either arrhythmia or renal events (noarrhythmia events reported with lumiracoxib).
• A good-quality meta-analysis of cardiovascularrisk (primarily myocardial infarction) from 23observational studies was largely consistent withour qualitative assessment of the observationalliterature. It found rofecoxib associated with adose-dependent, increased risk of cardiovascularevents that was detectable during the first monthof treatment. Of the other NSAIDs, diclofenacwas associated with the highest risk, followed byindomethacin and meloxicam. Celecoxib,naproxen, piroxicam, and ibuprofen were notassociated with increased risks. Assessments ofincreased risk were modest (relative risks all
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Table
A.
Sum
mary
of
Find
ings
on C
ompara
tive
Effe
ctiv
enes
s and
Safe
ty o
f A
nalg
esic
s fo
r O
steo
art
hriti
s, w
ith S
tren
gth
of
Evid
ence
Spec
ial c
onsi
der
atio
ns in
Trea
tmen
tBen
efits
: sy
mpto
m r
elie
fH
arm
s: g
ast
roin
test
inal,
card
iova
scul
ar, a
nd o
ther
subgro
ups
CO
X-2
sel
ectiv
e•
Goo
d ev
iden
ce C
OX
-2•
GI:
Fair
to g
ood
evid
ence
of
few
er s
erio
us G
I ev
ents
with
•G
ood
evid
ence
that
N
SAID
sse
lect
ive
NSA
IDs
are
CO
X-2
sel
ectiv
e N
SAID
s co
mpa
red
to n
onse
lect
ive
NSA
IDs,
risk
of
GI
blee
ding
com
para
ble
in e
ffic
acy
at le
ast i
n th
e fi
rst 6
mon
ths
of tr
eatm
ent.
and
CV
eve
nts
incr
ease
s (p
ain
relie
f) to
non
sele
ctiv
e •
CV
:C
ompa
rativ
e da
ta o
n C
V r
isks
of
CO
X-2
sel
ectiv
e vs
.w
ith a
ge.
NSA
IDs.
no
nsel
ectiv
e an
d pa
rtia
lly s
elec
tive
NSA
IDs
are
spar
se,
•G
ood
evid
ence
that
•G
ood
evid
ence
CO
X-2
sel
ectiv
ew
ith a
few
exc
eptio
ns (
see
belo
w).
Fai
r ev
iden
ce th
at C
OX
-2ri
sk o
f G
I bl
eedi
ng is
NSA
IDs
are
com
para
ble
inse
lect
ive
NSA
IDs
are
asso
ciat
ed w
ith in
crea
sed
risk
s of
ser
ious
grea
ter
in p
atie
nts
with
effi
cacy
to e
ach
othe
r.C
V e
vent
s (p
rim
arily
myo
card
ial i
nfar
ctio
n) c
ompa
red
to p
lace
bo.
prio
r bl
eedi
ng e
piso
des.
CV
ris
ks m
ay in
crea
se w
ith g
reat
er d
osag
es a
nd d
urat
ions
of
•Fa
ir e
vide
nce
that
tr
eatm
ent,
but e
stim
ates
of
risk
s at
low
er d
oses
and
with
sho
rter
risk
s of
CV
and
ren
aldu
ratio
ns o
f tr
eatm
ent a
re im
prec
ise
due
to s
mal
l num
bers
of
even
ts.
even
ts a
re h
ighe
r in
• R
ofec
oxib
was
with
draw
n fr
om th
e m
arke
t in
Sept
embe
r 20
04,
patie
nts
with
car
diac
and
prim
arily
bec
ause
of
CV
ris
ks.
rena
l com
orbi
ditie
s.•
Cau
tions
abo
ut C
V r
isk
appl
y pr
imar
ily to
rof
ecox
ib a
nd c
elec
oxib
,as
CV
saf
ety
data
are
less
pre
cise
(du
e to
sm
all n
umbe
rs o
f ev
ents
)fo
r va
ldec
oxib
, eto
rico
xib,
and
lum
irac
oxib
. •
Oth
er•
Val
deco
xib
was
with
draw
n fr
om th
e m
arke
t due
to li
fe-t
hrea
teni
ngsk
in r
eact
ions
and
incr
ease
d C
V r
isk.
• F
air
evid
ence
sug
gest
s th
at r
ofec
oxib
is a
ssoc
iate
d w
ith g
reat
er r
isk
of h
yper
tens
ion,
CH
F, e
dem
a, a
nd c
ardi
oren
al e
vent
s th
an c
elec
oxib
.
NSA
IDs
: •
Goo
d ev
iden
ce n
onse
lect
ive
•G
I:G
ood
evid
ence
that
all
nons
elec
tive
NSA
IDs
are
asso
ciat
ed w
ith•
Goo
d ev
iden
ce th
at r
isk
ofno
nsel
ectiv
e an
d pa
rtia
lly s
elec
tive
NSA
IDs
com
para
ble,
dos
e-de
pend
ent i
ncre
ases
in r
isk
of s
erio
us G
I ev
ents
GI
blee
ding
and
CV
(inc
ludi
ng
are
com
para
ble
in e
ffic
acy
com
pare
d to
non
use.
Goo
d ev
iden
ce th
at c
opre
scri
ptio
n of
even
ts in
crea
ses
with
age
.na
prox
en),
to
eac
h ot
her.
mis
opro
stol
or
PPIs
can
atte
nuat
e th
is r
isk,
but
mis
opro
stol
is•
Goo
d ev
iden
ce th
at r
isk
ofpa
rtia
lly s
elec
tive
less
wel
l tol
erat
ed.
GI
blee
ding
is g
reat
er in
• N
o cl
ear
evid
ence
(fa
ir f
or m
elox
icam
and
poo
r fo
r et
odol
ac
patie
nts
with
pri
or
and
nabu
met
one)
that
par
tially
sel
ectiv
e N
SAID
s ar
e bl
eedi
ng e
piso
des.
asso
ciat
ed w
ith d
ecre
ased
ris
k re
lativ
e to
non
sele
ctiv
e N
SAID
s.•
CV
:D
ata
on C
V r
isks
of
nons
elec
tive
and
part
ially
sel
ectiv
e•
Fair
evi
denc
e th
at r
isks
of
NSA
IDs
are
spar
se, w
ith a
few
exc
eptio
ns:
CV
and
ren
al e
vent
s ar
e•
Fai
r ev
iden
ce th
at h
igh
dose
s of
ibup
rofe
n an
d di
clof
enac
hi
gher
in p
atie
nts
with
ca
rry
sim
ilar
risk
s of
ser
ious
CV
eve
nts
com
pare
d to
CO
X-2
card
iac
and
rena
lse
lect
ive
NSA
IDs.
com
orbi
ditie
s.
Spec
ial c
onsi
der
atio
ns in
Trea
tmen
tBen
efits
: sy
mpto
m r
elie
fH
arm
s: g
ast
roin
test
inal,
card
iova
scul
ar, a
nd o
ther
subgro
ups
• F
air
evid
ence
that
nap
roxe
n is
ass
ocia
ted
with
a lo
wer
ris
k•
Fair
evi
denc
e th
at u
sing
of C
V e
vent
s th
an C
OX
-2 s
elec
tive
NSA
IDs
and
no e
xces
sN
SAID
s co
ncom
itant
ly
risk
com
pare
d to
pla
cebo
.w
ith a
ntic
oagu
lant
s •
Oth
er:
Fair
evi
denc
e th
at d
iclo
fena
c is
ass
ocia
ted
with
hig
her
incr
ease
s G
I bl
eedi
ng r
isk
rate
s of
am
inot
rans
fera
se e
leva
tions
than
oth
er N
SAID
s.th
ree-
to s
ixfo
ld.
Asp
irin
/•
No
evid
ence
com
pari
ng•
Goo
d ev
iden
ce th
at a
spir
in 5
0-15
00 m
g (f
or th
rom
botic
eve
nt•
Goo
d ev
iden
ce th
atsa
lsal
ate
effi
cacy
of
aspi
rin
orpr
ophy
laxi
s) is
ass
ocia
ted
with
gre
ater
ris
ks o
f se
riou
s G
I co
ncom
itant
use
of
aspi
rin
sals
alat
e to
CO
X-2
s or
.ev
ents
com
pare
d to
pla
cebo
or
whe
n ad
ded
to w
arfa
rin.
atte
nuat
es o
r el
imin
ates
the
NSA
IDs
•G
ood
evid
ence
that
low
-dos
e as
piri
n is
eff
ectiv
e fo
r pr
even
ting
GI
bene
fits
of
CO
X-2
CV
eve
nts.
sele
ctiv
e N
SAID
s.•
Insu
ffic
ient
evi
denc
e to
ass
ess
GI
and
CV
ris
ks a
ssoc
iate
d•
Fair
evi
denc
e th
at
with
hig
her
dose
s of
asp
irin
for
pai
n co
ntro
l or
with
sal
sala
te.
conc
omita
nt u
se o
f lo
w-
dose
asp
irin
doe
s no
tel
imin
ate
CV
ris
ks w
hen
adde
d to
NSA
IDs
.
Ace
tam
inop
hen
•G
ood
evid
ence
that
•
Goo
d ev
iden
ce o
f lo
wer
ris
k of
GI
com
plic
atio
ns w
ithN
one
acet
amin
ophe
n is
mod
estly
ac
etam
inop
hen
com
pare
d to
NSA
IDs.
infe
rior
in e
ffic
acy
com
pare
d •
Fair
evi
denc
e of
incr
ease
d ri
sk o
f bl
ood
pres
sure
and
ren
alto
NSA
IDs.
dysf
unct
ion
with
ace
tam
inop
hen
com
pare
d to
non
use.
•Po
or e
vide
nce
(a s
ingl
e ob
serv
atio
nal s
tudy
) th
at h
eavy
use
of
acet
amin
ophe
n ca
rrie
s a
sim
ilar
CV
ris
k co
mpa
red
to h
eavy
use
of
NSA
IDs.
Glu
cosa
min
e •
Fair
evi
denc
e (s
ome
•
Goo
d ev
iden
ce th
at g
luco
sam
ine
and
chon
droi
tin a
re w
ell
Non
e(p
harm
aceu
tical
in
cons
iste
ncy
betw
een
tole
rate
d an
d do
not
app
ear
to b
e as
soci
ated
with
ser
ious
grad
e)/
clin
ical
tria
ls)
clin
ical
ad
vers
e ev
ents
.th
at p
harm
aceu
tical
-gra
de
gluc
osam
ine
and
chon
droi
tin a
re n
ot m
ore
effe
ctiv
e th
an p
lace
bo in
un
sele
cted
pat
ient
s, in
clud
ing
one
rece
nt, l
arge
, goo
d-qu
ality
tria
l fin
ding
no
bene
fici
al e
ffec
ts f
rom
gl
ucos
amin
e or
cho
ndro
itin
alon
e or
in c
ombi
natio
n.
11
12
Spec
ial c
onsi
der
atio
ns in
Trea
tmen
tBen
efits
: sy
mpto
m r
elie
fH
arm
s: g
ast
roin
test
inal,
card
iova
scul
ar, a
nd o
ther
subgro
ups
In a
n an
alys
is o
f a
smal
l su
bgro
up o
f pa
tient
s w
ith a
t le
ast m
oder
atel
y se
vere
ba
selin
e pa
in in
the
latte
r tr
ial,
ther
e ap
pear
ed to
be
a m
odes
t ben
efit
for
pain
re
lief
from
the
com
bina
tion,
bu
t thi
s di
d no
t ape
ar to
be
a pr
epla
nned
ana
lysi
s.•
Fair
evi
denc
e of
no
clea
r di
ffer
ence
in e
ffic
acy
betw
een
phar
mac
eutic
al-
grad
e gl
ucos
amin
e or
ch
ondr
oitin
and
NSA
IDs.
•N
o st
udie
s co
mpa
red
gluc
osam
ine
or c
hond
roiti
n to
ace
tam
inop
hen.
Topi
cal
•G
ood
evid
ence
they
are
•
Goo
d ev
iden
ce th
at to
pica
l NSA
IDs
are
asso
ciat
ed w
ith
NSA
IDs
com
para
ble
to o
ral N
SAID
s in
crea
sed
loca
l adv
erse
eve
nts
com
pare
d w
ith o
ral N
SAID
s.fo
r pa
in r
elie
f in
tria
ls
•G
ood
evid
ence
that
topi
cal a
nd o
ral N
SAID
s ar
e co
mpa
rabl
epr
imar
ily o
f pa
tient
s w
ith
in r
ates
of
tota
l adv
erse
eve
nts
and
with
draw
als
due
knee
ost
eoar
thri
tis.
to a
dver
se e
vent
s.•
Mos
t tri
als
of to
pica
l •
Goo
d ev
iden
ce th
at to
pica
l NSA
IDs
are
asso
ciat
ed w
ith f
ewer
NSA
IDs
eval
uate
pro
prie
tary
G
I ev
ents
, inc
ludi
ng s
ever
e ev
ents
, and
cha
nges
in h
emog
lobi
nfo
rmul
atio
ns n
ot a
vaila
ble
com
pare
d to
ora
l NSA
IDs.
in th
e U
nite
d St
ates
.
Topi
cal
•Fa
ir e
vide
nce
that
cap
saic
in,
•G
ood
evid
ence
that
topi
cal c
apsa
icin
is a
ssoc
iate
d w
ithN
one
salic
ylat
esbu
t not
topi
cal s
alic
ylat
es a
re
incr
ease
d lo
cal a
dver
se e
vent
s an
d w
ithdr
awal
s du
e to
and
caps
aici
nsu
peri
or f
or p
ain
relie
f ad
vers
e ev
ents
com
pare
d to
pla
cebo
.co
mpa
red
to p
lace
bo.
Abb
revi
atio
ns:
CH
F =
con
gest
ive
hear
t fai
lure
; CO
X =
cyc
lo o
xyge
nase
; CV
= c
ardi
ovas
cula
r; G
I =
gas
troi
ntes
tinal
; NSA
ID =
non
ster
oida
l ant
iinfl
amm
ator
y dr
ug;
PPI
= p
roto
n pu
mp
inhi
bito
r.
AH
RQ
Pub
. No.
06-
EH
C00
9-1
Sep
tem
ber
200
6
Recommended