NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
and COX-2 INHIBITORS

Aspirin and NO-Aspirin

Non-Aspirin NSAIDs

COX-2 Inhibitors

Non-Aspirin NSAIDs

I. Topical use of NSAIDs

1. In a trial in 248 pts with knee osteoarthritis randomized to topical diclofenac vs. placebo to affected site QID, at 28d the diclofenac group had sig. greater mean reduction in pain c/w placebo (CMAJ 171:333, 2004--JW)
2. In a study in 326 pts with knee OA randomized to topical diclofenac vs. placebo QID, 12wk pain and physical function scores were sig. more improved in the diclofenac group (Arch. Int. Med. 164:2017, 2004--JW)
3. In a study in 622 pts with knee OA randomized to topical vs. oral diclofenac x 12wks, there was no sig. diff @ 12wks in improvement in pain scores but the physical function scores were sig. more improved with oral diclofenac (J. Rheumatol. 31:2002, 2004--JW)
4. In a meta-analysis of 13 randomized trials involving 1,938 pts, topical NSAIDs c/w placebo were found to be sig. better for the first 2wks of tx but not in 3rd or 4th wk; c/w oral NSAIDs, they were less effective during first week of tx but no diff. seen during 2nd-4th weeks (BMJ 329:324, 2004--JW)

II. Adverse effects

1. Dyspepsia and Peptic Ulcers
   1. No conclusive evidence that there's any diff. among various NSAIDs in this regard
   2. Meta-analysis of 12 epidemiologic studies comparing frequency of "major GI side effects" between ibuprofen and at least 1 other NSAID (BMJ 312:1563, 1996-JW)

1. Ibuprofen ranked lowest in overall risk. Compared with ibuprofen, RR of "serious GI complications":
2. RR 1.0-2.0: fenoprofen, ASA, diclofenac
3. RR 2.1-3.0: sulindac, diflunisal, naproxen, indomethacin, tolmetin
4. RR 3.1-4.0: piroxicam
5. RR > 4.0: ketoprofen, azapropazone
6. n.b. low risk with ibuprofen may be related to its frequent use at LOW DOSES!

3. Prevention of NSAID-induced ulcers and ulcer-related complications
   1. Misoprostol (a PG analog)
   2. Proton-Pump Inhibitors or high-dose Histamine-2 ("H2") Blockers may decrease risk
      1. In 285 NSAID-treated arthritis pts randomized to placebo, famotidine 20mg BID, or famotidine 40mg BID, incidence of duod. ulcers significantly lower at 6 mos with either dose of famotidine; also, incidence of gastric ulcer sig. less in high-dose, but not low-dose famotidine (2%, 4%, 13% for duodenal; 8%, 13%, 20% for gastric) Sig. side f/x c/w placebo: abd. pain, diarrhea, rash (NEJM 334:1435, 1996)
      2. In 540 pts who have EGD-proven NSAID-associated gastric or duodenal ulcers and needed to remain on NSAIDs, randomized to omeprazole 20-40 QD vs. raniditine 150 BID, higher 8wk healing rates with omeprazole (80 vs. 63%); no diff. between 20 & 40mg/d of omeprazole. Also randomized to maintenance therapy w/one or the other drug; lower relapse rates w/omeprazole (28% vs. 41%). (NEJM 338:719, 1998--JW)
      3. A trial in NSAID-induced ulcer pts found omeprazole 20-40mg/d equivalent to misoprostol 200ug QID for ulcer healing and better for maintenance therapy (NEJM 338:727, 1998--JW)
      4. Lansoprazole 30mg ass'd with sig. lower risk (1.6% vs. 14.8%) of "ulcer complications" (summary doesn't specify what) c/w placebo over avg. 12mo f/u  in a randomized trial of 123 pts with healed PUD who used low-dose ASA chronically (they were on ASA when developed ulcers & on ASA 100mg/d during the course of the trial); NOTE--all pts had had H.pylori infection w/their initial ulcer and had proven eradication (NEJM 346:2033, 2002--JW)
      5. In a study of 287 pts with h/o bleeding ulcer associated with NSAID use randomized to celecoxib 200mg BID vs. (diclofenac 75mg BID + omeprazole 20mg/d).  All who had H. pylori had it eradicated.  Over 6mo f/u, incidence of recurrent ulcer bleeding was not sig. diff. between the two groups (4.9% w/celecoxib, 6.4% with diclofenac-omeprazole) (Gastroent. 127:1038, 2004--JW)
      6. In a randomized study of 320 pts with bleeding peptic ulcer while on ASA (325mg/d or less) for prophylaxis of vascular events, all of whom were treated for the ulcer with documented ulcer healing, randomized to clopidogrel 75mg/d vs. (ASA 80mg/d + esomeprazole 20mg/d), over 1y f/u, incidence of recurrent ulcer bleeding was sig. greater in the clopidogrel group (8.6% vs. 0.7%); no sig. diff. in incidence of vascular ischemic events. (NEJM 352:238, 2005--JW)
      7. In a report which pooled data from 2 trials involving a total of 1,429 pts on NSAIDs or COX-2 inhibitors for arthritis, felt to be at high risk for peptic ulcer, randomized to esomrazole 20 or 40mg or placebo, 6mo incidence of EGD-proven ulceration was sig. lower in either esomeprazole group than placebo group (5% vs. 17%); no diff.  between subgroups of NSAID users or COS-2 users (Am. J. Gastroent. 101:701, 2006--JW)
   3. 320 pts on ASA for prophylaxis of vascular events presenting s/p at least one episode of bleeding ulcer randomized to clopidogrel 75mg/d vs. (ASA 80mg/d + esomeprazole 20mg BID) x 12mos; incidence of recurrent bleeding over 12mos was sig. higher in the clopidogrel group (8.6% vs. 0.7%) (NEJM 352:238, 2005--abst)

4. Treatment of H. pylori in pts on chronic NSAIDs

1. 92 pts with musculoskeletal pain requiring tx w/NSAIDs (none w/ previous NSAID use > 1mo or previous anti-H. pylori tx) who had H. pylori infection (determined by + CLO test + histologic confirmation) but no ulcers on EGD randomized to naproxen 750 mg/d x 8wks with or without an initial 1wk course of of triple therapy for H. pylori (bismuth subcitrate 120mg, tetracycline 500mg, and metronidazole 400mg, all PO QID). Blinded repeat endoscopy done after 8wks of naproxen. H. pylori eradication occurred in 89% of triple-therapy group. 7% on triple therapy developed ulcers (most of whom had failure of H. pylori eradication) vs. 26% of naproxen-only group (sig. difference). Most ulcers were asymptomatic (Lancet 350:975, 1997)
2. 660 pts requiring long-term NSAID tx and with biopsy-proven H. pylori colonization of gastric mucosa but NO ulcer on intake EGD had NSAID tx initiated (Diclofenac 50mg BID) and were randomized to the following along w/the Diclofenac x 5wks:
   • Omeprazole 20mg/Clarithyromycin 500mg/Amox 1g, all BID, x 1wk then placebo x 4wks
   • Omeprazole 20mg/Clarithyromycin 500mg/Amox 1g, all BID, x 1wk then omeprazole 20mg QD x 4wks
   • Omeprazole 20mg QD x 5wks
   • Placebo x 5wks

   At 5wks all pts had repeat EGD. Incidence of peptic ulcer was 1.2%, 1.2%, 0%, and 5.8% respectively, all active-tx groups had sig. diff. from placebo. Also, all active tx groups had sig. lower incidence of "therapy-requiring dyspeptic symptoms" compared w/placebo (10.6%, 10.4%, 12.3%, and 19.9% respectively). (Gut 51:329, 2003--abst)

3. In a meta-analysis of data from five randomized trials in H. pylori-infected pts requiring NSAID therapy, H. pylori eradication was associated with a sig. reduced incidence of peptic ulcer (OR 0.43) (Aliment. Pharmacol. Ther. 21:1411, 2005--JW)

2. Renal effects of NSAIDs
   1. Decrease plasma renin activity
   2. Decrease renal blood flow and hence GFR
   3. Increase Na and K retention and decrease excretion of H2O
   4. Can precipitate acute renal failure in states where angiotensin II level is high (CHF, decreased intravascular volume due to hemorrhage, dehydration, or 3rd-spacing) through inhibition of PG synthesis and hence increased tone in prerenal arterioles
   5. Risk of nephrotoxicity from NSAIDs increased in pts with chronic renal failure or decreased intravascular volume e.g. due to diuretics, cirrhosis, or CHF

3. Interference with platelet function
   1. Except possibly for meloxicam and nabumetone

4. CNS side effects--Dizziness, anxiety, drowsiness, and confusion
   1. Indomethacin may cause more CNS side f/x than other NSAIDs, especially in the elderly
   2. Also, tinnitus w/high doses of salicylates
   3. Aseptic meningitis reported in pts with connective tissue diseases on ibuprofen

5. Hepatotoxicity--Usually just small increases in transaminase levels
   1. Diclofenac ass'd with more hepatotoxicity than other NSAIDs

6. Possible association with Acute MI
   1. In a case-control study of 9,218 pts with first MI and 86,349 age- and sex-matched controls, use of NSAIDs or COX-2 inhibitors in prior 3mos was associated with sig. increased risk of MI (1.32 for rofecoxib, 1.55 for diclofenac, 1.24 for ibuprofen); no sig. interactions noted with ASA (BMJ 330;1366, 2005--JW)
   2. Cessation of NSAID therapy may increase risk --In a case-control study of 8,688 pts < 90yo with first MI (and 33,923 matched controls), after adjustment for potential confounders including ASA use, there was no association between current NSAID use and first MI, but cessation of NSAID use in the prior 29 days was associated with a sig. greater risk for MI (OR 1.52); no difference noted among specific NSAIDs (Arch. Int. Med. 164:2472, 2004--JW)
   3.  
7. Other possible side effects:
   1. Cardiovascular events--Click link for details
   2. May exacerbate Hypertension
   3. Pancreatitis
   4. May be associated with colonic ulceration (case series: Am. J. Gastroent. 96:473, 2001--JW)
   5. Aplastic anemia
   6. Dermatologic reactions: Photosensitivity, Toxic Epidermal Necrolysis
   7. May interfere with the antiplatelet activity of Aspirin--see link for details
   8. May increase risk of miscarriage when used close to time of conception (RR 1.8 in a prospective cohort study of 1,055 pregnant women with first-trimester exposures; BMJ 327:368, 2004--JW)

IV. Beneficial effects of NSAIDs other than reduction of pain and inflammation

1. Some NSAIDs may reduce risk for Alzheimer's Disease
2. May reduce risk of Colorectal Cancer and Breast Cancer--Click on links for details

Cyclo-Oxygenase-2 ("COX-2") inhibitors:

I. Background

1. NSAIDs inhibit both COX-1 and COX-2; no good data exists as of 1999 as to the relative inhibition of one vs. the other in specific NSAIDs (UW Pharm. Letter)
2. COX-1 maybe involved in gastric mucosal protection and normal platelet and renal function, and thus its inhibition may be responsible for some of the side f/x of NSAIDS
3. COX-2 is expressed selectively in tissues with ongoing inflammation as well as in the CNS, uterus, and pancreas
4. Comparable analgesic efficacy to NSAIDs

II. Adverse effects

1. GI and bleeding side f/x--Less than NSAIDs
   1. Rofecoxib 25-50mg/d ass'd with sig. less incidence of gastroduodenal ulcer than ibuprofen 800mg TID over 6mo f/u in a randomized trial of 742 pts with osteoarthritis (Gastroent. 117:776, 1999--JW)
   2. Celecoxib 100mg, 200mg, or 400mg BID was ass'd with a risk of gastroduodenal ulceration (assessed by EGD at 12wks) not sig. different from placebo and sig. less than Naproxen 500mg BID in a 12wk randomized study of 1149 adults with RA; however, risk of GI sx was not sig. different in the two groups (JAMA 282:1929, 1999--abst)
   3. Rofecoxib 12.5-50mg/d was ass'd with sig. lower incidence of UGI hemorrhage (RR 0.5) than ibuprofen 800mg TID, diclofenac 50mg TID, or nabumetone 1500mg/d in a meta-analysis of 8 randomized trials in a total of 5435 pts with osteoarthritis (JAMA 282:1929, 1999--abst)
   4. In 775 pts randomized to ibuprofen 800mg TID, Rofecoxib 25-50mg QD, or placebo, x 16-24wks, incidence of gastroduodenal ulcers on EGD at 12& 24wks was sig. less in Refecoxib groups than Ibuprofen group; there was no sig. diff. between Rofecoxib 25mg/d and placebo (Arth. Rheum. 43:370, 2000--AFP)
   5. Rofecoxib 50mg/d vs. naproxen 500mg BID ass'd with RR 0.43 for GI adverse events over avg. 9mo f/u in a randomized trial of 8000+ pts with rheumatoid arthritis (NEJM 343:1520, 2000--JW)
   6. Celecoxib 400mg BID vs. ibuprofen 800mg TID or diclofenac 75mg BID ass'd with a nonsig. decrease in incidence of symptomatic upper GI ulcers (0.76%/yr vs. 1.45%/yr, p = 0.09) but sig. less incidence of combined endpoint of upper GI complication or symptomatic gastroduodenal ulcers (2.08%/yr vs. 3.54%/yr) and sig. less bleeding-related anemia (3.1% vs. 6%) and liver function test abnormalities (0.6% vs. 2.3%) in a randomized trial of 8059 adults with OA or RA; no difference noted among those pts also using ASA (Celecoxib Long-Term Arthritis Safety Study, "CLASS" JAMA 284:1247, 2000--JW)
   7. In a meta-analysis of 9 randomized trials comparing Celecoxib to other NSAIDs for at least 12wks of tx, incidence of endoscopy-detected ulcers was 71% lower in Celecoxib groups (BMJ 325:619, 2002--JW) 

2. Cardiovascular events
   1. Rofecoxib 50mg/d vs. Naproxen 500mg BID ass'd with sig. higher incidence of MI and total cardiovascular events in a 9mo randomized trial of pts with RA (0.4% vs. 0.1%).  One possible explanation was that use of ASA was not allowed during this trial; Naproxen has sig. more antiplatelet effect than rofecoxib (NEJM 343:1520, 2000--JW; see also above re: other data from this study)
   2. In another randomized trial comparing Celecoxib, ibuprofen, and diclofenac in 8,000 pts with RA or osteoarthritis, no diff. noted in incidence of adverse cardiovascular events ("CLASS" study; JAMA 284:1247, 2000--JW)
   3. In a trial in 18,325 pts > 50yo with osteoarthritis randomized to lumiracoxib 400mg QD vs. naproxen 500mg BID vs. ibuprofen 800mg TID x 52wks, (Therapeutic Arthritis Research and Gastrointestinal Event Trial ("TARGET"), among pts not on ASA, the lumiracoxib group had sig. fewer ulcer complications that others but there was no diff. among ASA users; no sig. diff. among the groups in incidence of (MI, CVA or CV death) (Lancet 364:665 and 675, 2004--JW)
   4. In a study in 2,586 pts with colorectal adenomata randomized to rofecoxib 25mg/d vs. placebo, over 3y, incidence of thrombotic events was sig. higher in the active-tx group (3.6% vs. 2.0%) ("Adenomatous Polyp Prevention On Vioxx" ("APPROVe") Trial, NEJM 352:1092, 2005--JW)
   5. In a study in 2,035 pts with colorectal adenomata randomized to celecoxib 200-400mg/d vs. placebo, over 3y, incidence of (MI, CVA, or cardiovascular death) was greater in the two celecoxib dose groups (2.2% and 3.0%) vs. placebo (0.9%); the diff. between the higher celecoxib dose & placebo was sig. ("APC" Trial; NEJM 352:1071, 2005--JW) 
   6. In a study in 1,671 pts undergoing CABG randomized to valdecoxib (or its IV prodrug parecoxib) vs. placebo, over 30d f/u, the active tx group had sig. higher incidence of cardiovacular events (2.0% vs. 0.5%) (NEJM 352:1081, 2005--JW)
   7. A meta-analysis of 114 clinical trials concluded that Rofecoxib, but not Valdecoxib, Celecoxib, or Etoricoxib, was associated with sig. increase in risk of peripheral edema, hypertension, renal dysfunction, and sudden cardiac death (JAMA 296:1619, 2006--JW)
   8. In a systematic review of 138 randomized trials comparing COX-2 inhibitors to either placebo or another NSAID (or NSAIDs to placebo), in the former case, COX-2 inhibitors were associated with sig. higher risk for serious vascular events (RR 1.42 for MI, CVA or vascular death), though there was no sig. diff. in risk for the latter case. For comparisons of NSAIDs to placebo, the risk of the same outcome was sig. increased with ibuprofen (RR 1.51) and diclofenac (RR 1.63) but not naproxen (RR 0.92) (BMJ 332:1302, 2006--JW)
   9. In a study poolinbg data from three trials in which patients were randomized to etoricoxib vs. diclofenace, over mean 18mo f/u, there was no sig. diff. in incidence of thrombotic cardiovascular events or MI; etoricoxib recipients had sig. lower incidence of upper GI events (0.67 vs. 0.97 per 100 patient-years of tx) but there was no sig. diff.  in "complicated" upper GI events (significant bleeding, perforation, ulcer, or obstruction) (Lancet 368:1771, 2006--JW)
   10. In a study in > 34,701 pts with osteoarthritis or rheumatoid arthritis not controlled on acetaminophen and no h/o MI or coronary revascularization, randomized to etoricoxib 60-90mg/d vs. diclofenac 75mg BID or 50mg TID), over mean 18mo treatment, there was no sig. diff. in incidence of thrombotic cardiovascular events, though etoricoxib recipients had sig. lower incidence of upper GI events (0.67 vs. 0.79 per 100 patient-years, HR = 0.69; NNT = 333 pts for 1y to prevent one event).  ("Multi-national Etoricoxib and Diclofenac Arthritis Long-term" ("MEDAL") study; Lancet 368:1771, 2006--AFP)
3. Abdominal pain, diarrhea, dyspepsia
4. Renal toxicity may occur (Ann. Int. Med. 133:1,2000--JW)
5. May have a prothrombotic effect (Med. Letter 42:59, 2000)
   1. This may result from the fact that COX-1 generates Thromboxane A2, which promotes platelet aggregation and vasoconstriction and COX-2 generates prostacyclin, which inhibits platelet aggregation and vasoconstriction.  Thus, selectively inhibiting COX-2 may tip the balance in favor of platelet aggregation.
6. May reduce risk of Colorectal Cancer  in patients with adenomata--Click link for details

III. Specific agents:

1. Celecoxib (Celebrex) 100-200mg BID
2. Rofecoxib (Vioxx)--Removed from U.S. market in 2004 because of concerns regarding adverse cardiovascular effects
3. Valdecoxib (Bextra)--Removed  from U.S. market 2005 or so
4. Lumiracoxib (Prexige)
5. Etoricoxib (Arcoxia)