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Non-Steroidal Anti-Inflammatory Drugs? American Medical Journal 3 (2): 115-123, 2012 ISSN 1949-0070 © 2012 Science Publications What Is The “Safest” Non-Steroidal Anti-Inflammatory Drugs? 1Patompong Ungprasert, 1 1 1 Wonngarm Kittanamongkolchai, Chrystal Price, Supawat Ratanapo, 1Napat Leeaphorn, 1Daych Chongnarungsin and 1Wisit Cheungpasitporn, 1Department of Internal Medicine, Bassett Medical Center and Columbia University, College of Physicians and Surgeons, Cooperstown, New York Abstract: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) which are widely used in clinical practice are also very well-known for their various adverse reactions. Each NSAID has its own unique safety profile and selecting an appropriate NSAID must be individualized for each patient based on his or her medical needs and risk factors. We reviewed literatures on NSAIDs, focusing on their adverse reaction profile. We reviewed and compared the incidence of adverse reaction from individual NSAIDs according to organ systems. This review includes both selective COX-2 inhibitors and non- selective NSAIDs. Based on the most up-to-date evidence, ibuprofen appears to be the preferred NSAIDs based on its favorable GI and nephrotoxicity profiles. Naproxen might be considered in patients − who have greater cardiac risk. Celecoxib, at the dose of less than or equal to 200 mg day 1, might be an option in the patients who are at high risk for GI bleeding. Key word: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), COX-2 inhibitor, adverse drug reaction, adverse reactions, safety profile, clinical practice, organ systems INTRODUCTION Table 1: Available NSAIDs in the United States and their usual dose Generic name Usual dose Selective COX-2 inhibitor Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Celecoxib 100-200 mg day −1 are the most commonly used medications in the United Non selective COX-2 inhibitor States (Laine, 2001). They are primarily used as pain Aspirin 2.6-6 g day 4-5 divided doses Diclofenac 50 mg BID killer as well as anti-inflammatory agent. Currently, there Diflunisal 0.25-0.75 g BID is nineteen NSAIDs available in the United States (Table Etodolac 200-300 mg BID-QID 1). With the continued aging of our population, the Fenoprofen 300-600 mg QID Flurbiprofen 100 mg BID-TID Center for Disease Control predicts that the prevalence of Ibuprofen 200-800 mg QID painful degenerative joint disease will increase, which Indomethacin 25-50 mg TID-QID will probably lead to an increase in the use of NSAIDs. Ketoprofen 75 mg TID NSAIDs are well-known for their adverse drug Meclofenamate 50-100 mg TID-QID Mefenamic acid 250 mg QID reaction. Approximately 30% of hospitalizations of Meloxicam 7.5-15 mg OD adverse drug reactions are caused by NSAIDs Nabumetone 500 mg BID (Pirmohamed et al ., 2004). Adverse reactions can affect Naproxen 250-500 mg BID Oxaprozin 600 mg OD various organ systems with gastrointestinal bleeding Piroxicam 10-20 mg OD and cardiovascular events being the most serious and Sulindac 150-200 mg BID sometimes fatal reaction. Tolmetin 400-600 mg TID Ketorolac IV or IM 30 mg q 6hr Most of the toxic effects of NSAIDs are a direct (max 120 mg day −1) result of their mode of action which includes suppression of prostaglandins synthesis. COX enzyme has two isoforms COX-1 and COX-2. Cyclooxygenase (COX) is the key enzyme in COX-1 is expressed in most tissues; it serves as a prostaglandin synthetic process that is inhibited by housekeeping enzyme responsible for normal cell NSAIDs. homeostasis. COX-2 is expressed in a limited number Corresponding Author: Patompong Ungprasert, Department of Internal Medicine, Bassett Medical Center and Columbia University, College of Physicians and Surgeons, Cooperstown, New York 115 Am. Med. J. 3 (2): 115-123, 2012 of organs in a normal physiologic condition but its vasoconstrictive effect leading to systemic hypertension expression is inducible with inflammation. The resulting in increased afterload (Dzau et al ., 1984). discovery of the two isoforms of the COX enzyme lead Furthermore, non-aspirin NSAIDs can interfere to the development of selective anti COX-2 NSAIDs with the beneficial anti-platelet effect of aspirin. Concomitant administration of reversible COX-1 with the hope of a reduction in adverse effects, most inhibitors may prevent irreversible platelet inhibition by specifically gastrointestinal bleeding (Flower, 2003). low-dose aspirin, due to competition between theses Naming the universal “safest” NSAID deems drug and aspirin for a common binding site on COX-1. difficult because each NSAID has its own different At least two of conventional NSAIDs (ibuprofen and adverse reaction profile; “safety” priorities should be naproxen) have been found to have this drug interaction individualized based upon patient’s concurrent in vitro. This pharmacodynamic interaction is not seen illnesses. This review will discuss the potential adverse with selective COX-2 inhibitor or with diclofenac, reactions of both conventions (non-selective) and which has some degree of COX-2 selectivity (Catella- selective NSAIDs according to specific organ systems. Lawson et al ., 2001; Capone et al ., 2005). Whether this interaction attenuates the cardioprotective benefit of Cardiovascular effect: During the last 10 years, the low-dose aspirin is unclear (Corman et al ., 2005; adverse cardiovascular effects of selective COX-2 Rodiguez et al ., 2004). inhibitors have been a highly debated issue. In October In conclusion, based on available data from the 2004, rofecoxib was withdrawn from US and world mentioned study, NSAIDs should be avoided in patients market after a randomized placebo-controlled trial with MI or heart failure. In patients with lower cardiac found that it increased the incidence of Myocardial risk, NSAIDs might be used with caution with the Infarction (MI) and sudden cardiac death (Bresalier et lowest effective dose and shortest possible duration. al ., 2005). Attention has now turned to the Diclofenac should be avoided given the clear evidence cardiovascular safety profile of the remaining selective of increase incidence of MI and sudden cardiac death. COX-2 inhibitor (celecoxib) and non-selective The only available selective COX-2 inhibitor, NSAIDs. McGettigan and Henry (2006) conducted a Celecoxib, appears to be safe with the daily dose of not − meta-analysis of an observational study and found that more than 200 mg day 1. Naproxen might be considered − celecoxib at doses of less than or equal to 200 mg day 1 for use in this group of patients given its slight appeared to be safe and did a not significantly increase cardioprotective benefit, though this consideration is the risk of MI and sudden cardiac death. Conventional based on data which lack statistical significance. NSAIDs including ibuprofen, indomethacin and piroxicam, also did not increase the cardiac risk. Of Gastrointestinal effects: Aspirin and other non-selective significant concern from this meta-analysis is, NSAIDs are well-known for their gastrointestinal diclofenac statistically increased the risk of toxicities ranging from asymptomatic mucosal injury to fatal upper GI bleeding. The toxicity comes from the cardiovascular events with a Relative Risk (RR) of 1.36 mode of action of COX-1 inhibition. COX-1 is (95% CI 1.21-1.54). A possible explanation for the constitutively expressed in gastric and duodenal mucosa disparate result is that diclofenac is the most selective and is responsible for mucoprotective prostaglandins for COX-2 compared with other conventional NSAIDs. synthesis. As a result of COX-1 inhibition and This study also showed a slight cardioprotective effect subsequent reduction of prostaglandins synthesis, gastric of naproxen but without statistical significance (Table and duodenal mucosa which appears to be more 2). Another meta-analysis which included only vulnerable to luminal acid and pepsin (Cryer and randomized data revealed the same increased cardiac Feldman, 1998; Jick, 1981). These gastrointestinal risk from diclofenac and revealed no significant toxicities result in more than 100,000 hospital admissions cardioprotective benefit from naproxen. However, this and 7,000-10,000 deaths per year in the United States. study found a significant increased risk with a daily Aspirin, which is now widely used for coronary dose of celecoxib more than or equal 400 mg (Kearnry artery disease treatment and prevention, can cause et al ., 2006). significant gastric mucosa damage even at very low Use of NSAIDs can worsen pre-existing heart doses. One study in healthy human subjects found that − disease. The risk of worsening heart failure is well aspirin at a dose of 10 mg day 1 reduced gastric illustrated in an observational study which found that mucosal prostaglandins to 40% of baseline level and all the NSAIDs in the study (rofecoxib, celecoxib, induced significant gastric mucosa injury (Cryer and ibuprofen, diclofenac and naproxen) significantly Feldman, 1999). Several epidemiological and placebo- increased the incidence of death and re-hospitalization controlled studies showed the dose-response because of heart failure and/or MI (Gislason et al ., relationship between clinically significant gastric events 2009). The mechanism by which NSAIDs can cause and the dose of aspirin (Jick, 1981; Farrell et al ., 1991; exacerbation of heart failure is related to their Weil et al ., 1995; Singh and Triadafilopoulos 1999). 116 Am. Med. J. 3 (2): 115-123, 2012 Table 2: Relative risk and 95% confidence interval on cardiovascular events for each NSAID (adapted from Mcgettigan et al ., 2006) Celecoxib Rofecoxib Meloxicam* Naproxen Diclofenac Ibuprofen Piroxicam Relative risk 1. 06 1.35 1.25 0.97 1.4 1.07 1.06 95% confidence interval 0. 91-1.23 1.15-1.59 1.00-1.55 0.87-1.07 1.16-1.70 0.97-1.18 0.70-1.59 *Data of meloxicam is largely based upon one single study and cannot reliably lead to any conclusion Table 3: Relative risk and 95% confidence interval on GI complications from two systematic reviews Study Diclofenac Ibuprofen Indomethacin Naproxen Piroxicam Sulindac Meloxicam Hernandez-Diaz and 3.3 1.9 4.6 4 6.3 3.6 NA Garcia-Rodriguez (2000) (2.8-3.9) (1.6-2.2) (3.8-5.5) (3.5-4.6) (5.5-7.2) (2.8-4.7) Richy et al .
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