JOURNAL OF
`L
`Pharmaceutical Care
`in Pain 8: Symptom
`Controlm
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`1
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`_____<>__..._
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`Innoaafionsin
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`Drug Development,
`Evaluation and Use
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`PHARMACY LIBRARY
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`FEB 2 3 W31
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`2130 CHAMBERLIN HALL
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`Lupin Exh. 1011
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`Lupin Exh. 1011
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`(cid:3) (cid:55)(cid:75)(cid:76)(cid:86)(cid:3)(cid:80)(cid:68)(cid:87)(cid:72)(cid:85)(cid:76)(cid:68)(cid:79)(cid:3)(cid:80)(cid:68)(cid:92)(cid:3)(cid:69)(cid:72)(cid:3)(cid:83)(cid:85)(cid:82)(cid:87)(cid:72)(cid:70)(cid:87)(cid:72)(cid:71)(cid:3)(cid:69)(cid:92)(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:79)(cid:68)(cid:90)(cid:3)(cid:11)(cid:55)(cid:76)(cid:87)(cid:79)(cid:72)(cid:3)(cid:20)(cid:26)(cid:3)(cid:56)(cid:17)(cid:54)(cid:17)(cid:3)(cid:38)(cid:82)(cid:71)(cid:72)(cid:12)(cid:3)
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Prevention and Management
`of NSAID-Induced Gastropathy
`
`Jane C. Chandramouli
`Keith G. Tolman
`
`.-
`
`ABSTRACT. Nonsteroidal antiinflarnmatory drugs (NSAIDS) are the
`most frequently prescribed medication for chronic pain. Gastrointesti-
`nal complications from NSAID treatment are a major cause of morbid-
`ity and mortality. In the majority of patients, NSAID induced gastropa—
`thy is superficial and self-limiting. However, peptic ulcers develop in
`some patients and may lead to hemorrhage, perforation, or death.
`NSAIDS can cause gastrointestinal damage via topical
`injury of the
`mucosal barrier, systemic inhibition of prostaglandin synthesis or a
`combination of both. Risk factors for NSAID related complications
`inclrrde age > 60 years, history of ulcer disease, concomitant cortico-
`steroid or anticoagulant use, high dose therapy, and multiple NSAID use.
`Identifying high-risk patients is critical in order to minimize risk. Fae»
`tors suggested to predict the safety of NSAIDs include selective COX-2
`inhibition, absence of enterohcpatic circulation, shorter lialili-life, and
`nonacidic pro-drug formulations. The COX-2 selective NSAlDs, cele-
`coxib and rofecoxib, have been recently marketed and appear to have
`less GI toxicity. Long-term studies and post marketing surveillance are
`
`
`
`neededtoconfirmthesafetyoftheCOX~2inhibitors.Protonpump
`
`Jane C. Clrandramouli, PharmD, is Drug Information Specialist, Department of
`Pharmacy Services, University Hospitals and Clinics and Clinical Assistant Profes-
`sor of Pharmacy Practice, College of Pharmacy; Keith G. Tolman, MD, ‘is Professor-
`of Medicine, Division of Gastroenlerology, I-lepatology and Nutrition, School of
`Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah.
`Address correspondence to: Dr. Jane C. Clrandramouli, University Hospital, Phar-
`macy Services, A—050, 50 North Medical Drive, Salt Lake City, UT 84132 (E-mail:
`janeclrarrtlramoulii@hsc.utah.edu).
`'i‘he authors acknowledge the contributions of Paula H. Grahrnann, Pharn1D,
`Clinical Pharmacy Specialist, Scott & White Memorial Hospital, Temple, TX, for
`lrer contrihrrtiorrs to this manuscript.
`
`Journal of Pharmaceutical Care in Pain & Symptom Control, Vol. 8(4) 2000
`© 2000 by The Hawortlr Press, Inc. All rights reserved.
`
`27
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`28
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`.l'0m'nat of_Pim.r‘mc1cettticol Care in Fair: & Symptom Comfrol
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`in
`inhibitors and misoprostol are the only agents proven beneficial
`preventing GI adverse effects from NSAIDS. [Article copies available for
`a ee from The Heworih Document Delivery Service: 1-800-342-9678. E~maii
`address.’ -<getinfo@haworthprzosinccom> Website: 4ht£,0.‘r?wwmHawo:'thP.w2s's.
`com‘; © 2000 by The Haworth Press, Inc. All t't'ght.s' reserved.]
`
`KEYWORDS. Nonsteroidal antiintlammatory drugs, gastropathy, risk
`factors, prostaglandins, COX-2 inhibitors
`
`INTRODUCTION
`
`Aspirin was the most widely used drug in the world at the turn of
`the ccntu ry. It was also known to be toxic to the stomach. In the 1950s,
`additional nonsteroidal antiinflammatory drugs (NSAIDs) became
`available with the hope of reducing the gastrointestinal (GI) and other
`side effects associated with aspirin.1 Today, NSAIDs are the most
`frequently prescribed medication for chronic pain and remain the most
`widely used drug category for the treatment of rheumatoid arthritis,
`osteoarthritis, fibromyalgia, connective tissue diseases, spor1dy1o—ar-
`thropathies, gout, musculoskeletal injuries, and dysmenorrhea.2 Twenty
`million Americans regularly use over-the-counter and prescription
`NSAIDS3 and more than 30 million people in the United States con~
`sume NSAIDs.4’5 Celeeoxib set an industry record in its first year on
`the market generating 19 million prescriptions for approximately 7
`million patients. Worldwide, 100 million prescriptions are written
`annual]
`for NSAIDS. This number accounts for 4.5% of all prescrip-
`tions. ''-= r6 In addition, over-the-counter (OTC) NSAID sales are signif~
`icantly increasing, as more products become available." Thus, the
`potential exists for patients to supplement prescribed NSAIDS with
`OTC products. Approximately 33% to 50% of patients who die of
`ulcer-related complications had recently ingested NSAIDs.7 Patients
`over the age of 60 years account for 40% to 60% of those who use
`NSAIDS and are at a higher risk of GI toxicity because of declining
`renal function, decreased endogenous prostaglandins, concomitant
`medical conditions, and polypharmacyfi
`
`EPIDEMIOLOG Y
`
`Gastrointestinal complications from NSAID treatment are a major
`cause of morbidity and mortality. In the U.S., an estimated 16,500
`
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`l‘
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`Jane C. Chandramauti and Keith G. Totmcm
`
`29
`
`deaths per year are associated with complications from NSAID use in
`arthritis patients alone.3 Patients with rheumatoid arthritis have a 1.5%
`chance of hospitalization and a 0.22% chance of death associated with
`the use of NSAIDS. Approximately 107,000 hospitalizations per year
`occur as a result of NSAID-induced gastropathy. On average, a patient
`has a 20% chance of experiencing gastrointestinal toxicity with 1% to
`3% of these patients suffering from a life-threatening GI bleed or
`perforation.5 At an average cost of $10,000 to $15,000 per hospital-
`ized patient, over $1 billion is spent annually on gastrointestinal com-
`plications a1one.3~8 The economic burden is tremendous, and aug-
`mented by additional factors including lost wages and postoperative
`care.
`
`GAS HHC MUCOSA AND PROSTAGLANDINS
`
`The gastric mucosa is continuously exposed to both endogenous
`and exogenous injurious agents such as acid, pepsin, bile acids, food
`ingredients, bacterial products, and drugs.9 These irritants induce
`“adaptive cytoprotection” by stimulating bicarbonate and mucus
`secretion, increasing mueosal blood flow, increasing mucosa] cell res— '
`titution, and inhibiting acid secrction.1 Prostaglandins (l’Gs) mediate
`i:-e;._:As;saLg;3;'afiinaxpnsnso-lifsr.s.tittP.s;::n.sacnsea=.1woa§:a3;a:r.:=;st-ars._,;een;n1s.ibl.-=:
`iat;éézréaejairegirtgr:ctiggsasrtnrseacsireniatfassaaabidegissaawis .f:;-*vi;‘:*.1~.:.'..*g{a-.‘n§‘-.a;r;s_s;=.’¢.i=vs~i-‘:.:
`—
`
`
`.
`
`y .. _c-...e_~_' _‘(;’;C35%_{;It.}—a11<iETi3§eeexjzgen:as'te'g’2;‘;{J(;‘(%’i32gI2?i’}‘?{fig_———_-_'_
`carol
`‘are I). f1O_X=1lisi32fist.itfitix%eTt;tTes:;:1binlmest-tissu-e;s;ani;Lrin‘afEea§te§E==-
`=
`'_
`bfyztsteroicis. ('3(-3X-lunaintaiias ;:flr‘ys'=iologic=fiu'neEions-sueh=as=Tgast~E-ie
`—
`rnucosa'l m,Jenahtifinefiso-n,and pIa'tgle't- lfomeostasis-. Tn getlertallii
`H'1-1JCOI1_S- andllfiearl-';I9na.te.—'secreti'on'§iiidueeilllfir sPG leli aeidl
`"
`se.eret-ion-and'in—d‘oi'11g sonrraintains hom"eostati'c balance". »1”f'i'5'-COX-2
`is;forunei_-in.a—1irni-tedsnumhe-r ofieell!t—y£,.is i-nducecliby cell injuray, is
`steroi-d’ inhibitabl-e, and_fac-ilitates prosta-glandin production in re-
`sponse to iniu1'y.2¥l0’13 The non-selective NSAiDS inhibit both COX-1
`and COX-2, but show varying affinities for the two enzymes. The
`newer agents, like celecoxib and rofecoxib, inhibit only COX-2.
`
`‘_
`
`thesis. Prostaglandins exert pain by sensitizing nerves through the
`
`NONS TEROIDAL ANTHNFLAi1/IMATORY DRUGS
`
`NSAIDS, by inhibiting cyclooxygenase, reduce prostaglandin syn-
`
`

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`30
`
`Jourrm! of PhaJ'maceutt'c(tl Care in Pain & Symptom Control
`
`FIGURE 1
`
`
`Cell Membrane Phospholipids
`
`
`
`Phosphofipase A2
`
`Arachidonie Acid
`
`
`
`5'”P°X1’99"339
`
`Cyclooxygenase
`cox-1 and com
`
`
`
`
`PGG2
`
`Epoxyeicosanoids
`
`Peroxidase
`
`PHG2
`
`Thromboxane
`A2
`
`Prostacyclin
`
`
`
`Prostaglandins
`PDG2, PGE2, PGF2
`
`
`
`Le-ukotrienes
`
`LTA4, LTB4. LTC4,
`LTE4, LTD4
`
`
`
`formation of edema and cellular exudation. NSAIDS inhibit this effect
`and in doing so reduce inflammation and pain. In addition, NSAIDS
`exert analgesic and antiinflamtnatory effects through a secondary
`mechanism of inhibition of leukotriene B4 production. All NSAIDS are
`highly protein bound, primarily to albumin, and are metabolized chief-
`ly by hepatic biotransformation and excreted 1'enally.3»7 The non—selec-
`tive NSAIDS inhibit both COX isoforms to some degree with the more
`GI toxic agents demonstrating greater COX-1 inhibition.
`The ideal NSAID would retain analgesic and antiinflammatory
`properties while sparing the toxicity associated with COX-1 inhibi-
`tion.” In fact, the specific factors that predict safety of NSAIDS. are
`selective COX-2 inhibition, shorter half-life, absence of enterohepatic
`recirculation, and nonacidic pro-drug formulations. Agents designed
`to capitalize on these properties include nabumetone and ctodolaG-
`
`

`
`Jane C. C‘harzdramoidi' and Keith G. Tolmcm
`
`31
`
`Both are preferential COX-2 inhibitors and undergo minimal to no
`enterohepatic circulation. Nabumetone is a nonacidic pro-drug and
`etodolac has a short half-life.10 Both appear to have less GI toxicity.
`While longer half-life agents are convenient for once-daily dosing,
`this property creates an increased risk of gastrointestinal complica-
`ti ons.-‘>1 NSAIDS that undergo enterohepatic recirculation have expo-
`sure to the G1 mucosa twice, thereby increasing the potential for
`injury. NSAIDS having enterohepatic recirculation include indomctha-
`cin, naproxen, diclofenac and piroxicam. Pro-drug formulations, non-
`acidic drugs, and enteric coating were designed to minimize gastric
`mucosa exposure to acidic agents. However, these formulations still
`cause NSAID-related ulcer complications since the serious gastroin-
`testinal lcsions result from the systemic effects of PGs.15 Alternative
`administration routes including intramuscular and intravenous also
`avoid topical toxicity to the gastric mucosa; however, systemic effects
`and gastric irritation still occur (e.g., ketorolac).10 Table 1 outlines the
`available NSAIDS and corresponding characteristics.
`
`PA THOPHYSIOLOG Y
`
`The effects of NSAIDS on the upper gastrointestinal tract range
`from acute superficial damage to deep ulcerations with bleeding or
`
`TABLE 1.. Risk Factors for Developing NSAID Associated Gastrointestinal
`Toxicity5
`
`Regular use of NSAID and aspirin
`
`History of previous GI bleed
`
`History of previous peptic ulcer
`
`History of prior use of Hgreceptor antagonist
`
`Concomitant use of corticosteroids
`
`Presence of an alcohol-related diagnosis
`
`High NSAID dose [>12D% average daily dose)
`
`Concomitant use of anticoagulants
`
`Concomitant use of 22 NSA|Ds
`
`Age > 60 years
`
`

`
`32
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`J0.'.u'mIt 0fPhar'maceutical Care in Pain & Symptom Corrnrot
`
`perl’oration.15 This wide spectrum of injury can be attributed to the
`various mechanisms by which NSAIDS can cause mucosa] damage.
`NSAIDS cause gastrointestinal damage via topical injury of the muco-
`sal barrier, systemic inhibition of prostaglandin synthesis, or a com-
`bination of both.” The decreased synthesis of prostaglandins has a
`predominant role.‘-7
`Topical injury includes acute superficial damage with submucosal
`hemorrhage and crosions. This occurs in most patients who have
`ingested aspirin or other NSAIDS. Most NSAIDS are weal: acids with
`a pKa of 3 to 5.‘-8 At acidic gastric pl-I of 1 to 2, NSAIDS are nonion-
`ised and freely diffuse across the lipid membrane of the epithelial
`cell.19 Once the drug enters the epithelial cell, the neutral pH promotes
`the release of H’', and the drug is trapped in its ionized form. The
`bioconcentration of ionized NSAIDS and release of H’' causes epithe-
`lial cell necrosis and sloughing exposing deeper mucosal structures to
`gastric acid, pepsin, and NSAID. Also, mast cells release multiple
`mediators of the inflammatory response, and endothelial cells induce
`adhesion of neutrophils.19 Neutrophils adhere to endothelial cells and
`migrate into the interstitium. The result is widespread parenchymal
`cell death and ulcer formation.
`The second component to the development of gastropathy is inhibi-
`tion of prostaglandins. Prostaglandins mediate mucosal blood flow
`and repair. Decreased prostaglandin synthesis appears to be the lead-
`ing factor linked to NSAID-associated ulcer formation.9 Systemic in-
`hibition of prostaglandin synthesis leads to deep ulcerations most
`common]
`in the stomach but occasionally in the small and large
`intestine.- 53-7
`'
`Acute damage is much more widespread than damage observed
`after several weeks, suggesting that the mucosa possesses adaptive
`mechanisms that compensate for NSAID injury. This probably is a
`reflection of the rapid epithelial repair of the GI mucosa. Both
`NSA_IDs and COX-2 inhibitors can impair cell replication and may
`contribute to delayed healing, especially with larger ulcers.15=20'21
`
`PRESENTATION
`
`NSAID induced gastropathy is the most frequent serious complica-
`tion of all drug therapy; however, many patients do not complain Of
`abdominal discomfort} Sixty percent of NSAID-induced ulcer com‘
`
`

`
`Jane C. Chandramoidi and Keith G. Tiblman
`
`33
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`plications are asymptomatic compared to 25% of non~NSAJD ulcers.7
`Classic peptic ulcers, such as those caused by .Helicobacter pylori, are
`usually duodenal -and frequently present in younger patients while
`NSAlD~induced ulcers occur primarily in the stomach and in the
`elderly. There is no clear correlation between symptoms or endoscopic
`findings and complications, but persistent symptoms may be more
`predictive of serious com plications.5
`
`RISK PHCTORS
`
`Several factors increase the risk of developing serious NSAID
`gastrointestinal complications. Table 2 lists the various risk factors
`for developing NSAID-associated gastrointestinal toxicity. NSAlD-in-
`duced gastropathy was originally thought to be greatest early in the
`course of treatment, but closer examination of the data indicates that the
`risk remains constant. The National Institute of Health funded the Ar~
`thritis, Rheumatism, a11d Aging Medical Information System (ARAMIS)
`for the past 25 years in order to better characterize NSAII) related
`complications in patients with rheumatoid arthritis (RA). This data-
`base contains information on more than 36,000 patients with RA.
`Analysis of the ARAMIS data showed that the risk for serious NSAID
`related Gl toxicity remains constant over time.’-3 The most important
`risk factors for NSAID-induced gastropathy include a history of peptic
`ulcer disease or G1 bleed, concomitant corticosteroid or anticoagulant
`therapy, and comorbid conditions such as diabetes mellitus, conges-
`tive heart failure, hypertension, and any chronic cardiovascular dis-
`ease? Advanced age (> 60 years) is a risk factor and may reflect an
`age—dependent decline in gastric and duodenal prostaglandin con-
`centration.5=15 This age group may have poor tolerance of ulcer com-
`plications once they develop. Several other risk factors are less well
`defined. Many have suggested that smoking, alcohol or caffeine use,
`and female gender are associated with NSAID—induced gastropathy;
`however, the evidence is marginal.3 The use of multiple NSAIDS
`compounds the risk of gastric toxicity. Another concern is the avail-
`ability of over-the-counter NSAlDs that allows patients to sclf~pre-
`scribe in addition to using prescription NSAIDS. H. pyiori may be a
`risk factor
`for NSAID-induced ulcers. However, H. pylori and
`NSAIDS are independent risk factors for the development of ulcers.
`There is no convincing evidence that they are additive or synergistic.
`
`

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`Jane C, Charzdmmouii and Keith G‘. Toiman
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`35
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`Ironically, several studies demonstrate a negative correlation implying
`that H. pylori may protect against NSAID gastropatl1y.6»22H. pylori
`eradication does not influence ulcer healing or prevent recurrences if
`NSAIDS are continued long term.
`
`NSAID SELECTION
`
`NSAIDS are similar with respect to therapeutic efficacy; however,
`responsiveness to a particular agent varies with individual patients.
`Lack of response to one NSAID does not preclude response to another
`NSAID. Physicians may prescribe newer agents because of their po-
`tential benefit in patients refractory to ibuprofen and naproxen.7
`Often choices regarding NSAIDS are based on the desired dosing
`interval, which is determined by a drug’s half-life. Short or medium
`half-life drugs allow patients to vary the dose according to severity of
`symptoms. Long half—life agents encourage compliance with once
`daily dosing and sustain drug levels in patients with significant pain
`and inflammation. When designing a dosage regimen, avoid long
`half-life agents in those more prone to gastrointestinal complications
`(e.g., elderly patients)? Patients taking anticoagulants concomitantly
`should avoid NSAIDS. It is important to educate patients given a pre-
`scription NSAID to avoid concomitant use of OTC aspirin and NSAID
`analgesics.
`Several studies have attempted to evaluate and compare the risk for
`gastrointestinal complications among the various NSAIl‘)s.1 The
`ARAMIS post marketing surveillance program prospectively fol-
`lowed patient status, outcomes, and drug side effects for > 11,000
`patients.3 Using a GI Toxicity Index, they ranked 12 NSAIDS from
`low toxicity, < 1, to higher toxicity, 4. The GI toxicity index is the sum
`of gastrointestinal symptoms per patient year of exposure weighted by
`severity and number of hospital days and adjusted for risk factors such
`as age, sex, center, disease duration, disability, educational level, dura-
`tion of NSAID use and concomitant medications. The differences in
`GI toxicity only become clinically significant between NSAIDS at the
`upper and lower end of the range. Table 3 lists select NSAIDS in order
`of their GI toxicity index.
`
`
`
` _ ¢1.__.:?J -,g?..:-J'mnu?;,----~-.——~---——:__:.....——.,
`
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`
`36
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`J’oumcIt' ofPharmaccuu'cat' Care in Pain & Symptom Coturo!
`
`TABLE 3. ARAMIS GI Toxicity Index for Select NSA|Ds3
`
`'95.
`
`*GI Toxicity index: 0 = o toxicity; 4 = highest toxicity
`
`PREVENTING NSA ID GA STROINTESTINAL TOXICITY
`
`Currently two approaches exist to reduce G1 toxicity: (1) concom-
`itant administration of a protective agent or (2) use of a safer NSAID.
`Due to the asymptomatic nature of NSAID-induced GI toxicity and
`the impracticality of routine endoscopy, prevention is crucial. The
`usefulness of gastro-protective agents often prescribed concomitantly
`is questionable. Sucralfate is ineffective.1’7=] =23 Since NSAll)—associ-
`ated G1 injury is dependent on the presence of acid, the prophylactic
`use of an H2 blocker seems reasonable. Concomitant use of these
`agents prevents duodenal ulcers, but not gastric ulcers, which are 3 to
`4 times more common than duodenal ulcers among NSAID users.
`Thus H3 blockade alone does not constitute an adequate preventive
`treatment.1»2»9=23 Proton pump inhibitors suppress acid secretion to a
`greater degree than Hg-receptor antagonists. Nevertheless, omepra-
`zole is more effective against duodenal than gastric ulceration. The
`OMNIUM study (flmeprazole versus Misoprostol for NSAID-In-
`duced Ulcer Management) concluded however that omeprazole may
`be as effective or more effective than misoprostol for the prevention of
`NSAlD—induced gasn-opathy.14»23=24
`
`

`
`Jane C. Chaudramouli and Keith G. Slblmrm
`
`37
`
`Misoprostol is a PGE1 analogue that replaces gastric prostaglandins
`depicted by NSAID use. Currently, it is the only agent labeled for
`co-therapy with NSAIDS. It prevents both gastric and duodenal ulcer-
`ation. Significant dose-related diarrhea and abdominal pain limits its
`tolerability. Misoprostol is an abortifacient; therefore, its use in women
`of childbearing potential is contraindicated. In an attempt to be more
`cost-effective, it was combined with diclofenac (A1'throtec®).
`'l'he
`combination is as effective for arthritis pain and s mptoms as diclofe-
`nac alone with a decreased incidence of ulce1's.14= 4 2
`'
`
`COX-2 SELECTIVE NSAIDS
`
`COX-2 selective 'NSAIDs appear to have comparable antiinflam-
`matory and analgesic activity to non-selective NSAIDS with minimal
`gastrointestinal toxicity. These agents inhibit COX-2 to a much greater
`degree than COX-1.. This selectivity spares the inhibition of cyto ro-
`tective prostaglandin synthesis in the gastrointestinal mucosa.25’2
`In December 1998, the Food and Drug Administration approved
`celecoxib (Celebrex®), the first COX-2 inhibitor, for the treatment of
`osteoarthritis and rheumatoid arthritis. Comparator studies with na-
`proxen, ibuprofen, and diclofenac demonstrated decreased gastroin-
`testinal bleeding.” The second COX-2-selective agent, rofecoxib
`(Vioxx®), was approved in May 1999 for osteoarthritis, acute pain,
`and dysmenorrhea in adults. Compared to ibuprofen 800 mg three
`times daily,
`rofecoxib 50 mg daily produced fewer endoscopic
`gastrointestinal ulcers (27.7% vs. 7.3% at 12 wceks).29»3° Table 4
`compares celecoxib and rofecoxib. Other COX-2 inhibitors, such as
`parccoxib and valdecoxib, are currently in Phase III clinical trials.
`Parecoxib, marketed by Pharmacia (formerly Searle) Corporation, is
`an injectable COX-2 selective NSAU.) for the management of pain in
`the hospital setting. This drug may become avialble in 2001. Parecoxib
`is actually a parenteral NSAID for the active metabolite valdecoxib.
`Valdecoxib, which will be co-marketed by Pfizer and Pharmacia, is a
`second generation oral COX-inhibitor. It probably will not be avail-
`able until several months after the introduction of parecoxib.
`GI bleeding has been reported with the COX-2 selective NSAIDS at
`a lower incidence than with nonselective NSAIDs.2“v31 COX-2 selec-
`tive agents are priced comparably to some of the more expensive
`brands of NSAIDS, but much higher than the generic NSA[Ds ibupro-
`
`

`
`38
`
`Journal ofP!:armoceuricat' Care in Pain & Symptom Carmel’
`
`TABLE 4. Comparison of Celecoxib and Flofecoxib24=25
`
`
`
`indication
`
`
`
`
`lill.etl-iotrexate—a 23% increase in
`methotrexate levels
`Flifampin-results in a 50% decrees
`in plasma rotecoxib levels
`Warfarin—lncrease in F'Ti'|NFi
`
`
`
`
`
`
`
`l nte raetion
`potential
`
`
`
`
`
` Osteoarthritis
`Osteoarthritis [OA}
`
`Acute Pain
`
`Rheumatoid Arthritis [RA]
`Dysnmenorrhea
`Familial Adenomatous Polyposls
`
`(FAP)
`Fluconazole-results in 2-fold
`Increase in celecoxlb levels
`Warfarln—no alteration in PTi'lNFl
`when celeeoxib is given with
`warfarin; however, caution should
`be used since patients treated with
`
`waifarin are at increased bleeding
`
`risk
`
`NSAID allergy
`
`NSAID allergy
` Contraindications
`Contains a non—ary|amine
`
`sutlonamids group.
`
`Possible cross—sensitivity in patients
`
`with a history oi a sulla allergy
`
`
`DA: 200 mg once daily or 100 mg
`
`twice daily
`RA‘. 100-200 mg BID
`
`
`
`OA: 12.5 mg or 25 mg once daily
`Acute Pain, Dysmenorrhea: 50 mg
`QD
`
`
`
`
`
`
`
`
`Dosage forms
`
`100 mg and 200 mg capsules
`
`12.5 or 25 mg tablets; 12.5 mg,(rnL
`or 25 mgl5 ml oral
`
`fen and naproxen. Due to their lower G1 and platelet effects, celceoxib
`and rofecoxib should prove cost-effective in high—risk populations.
`
`S UMMA RY
`
`NSAID induced gastropathy imposes considerable morbidity, cost
`and a negative quality of life. In the majority of patients, NSAID
`induced gastropathy is superficial and self-limiting. However, peptic
`ulcers develop in some patients and may lead to hemorrhage, perfora-
`tion or death. Prevention of gastrointestinal toxicity begins with the
`selection of a11 agent. Identifying high-risk patients is critical in order
`to minimize this risk of NSAID therapy. Risk factors for NSAID-re-
`lated complications include advanced age, history of ulcer disease,
`concomitant corticosteroid or anticoagulant use and use of high dose
`or multiple NSAIDs. Proton pump inhibitors and misoprostol are the
`only agents proven beneficial in preventing G1 adverse effects from
`
`

`
`Jane C. Chnndramonli and Keith G. Tolmtm
`
`39
`
`NSAlDs. The introduction of selective COX-2 inhibitors provides a
`safer alternative to currently available NSAIDS. Long-term studies
`and post-marketing surveillance should lend additional information
`regarding the safety of COX-2 inhibitors in the general population.
`
`REFERENCES
`
`1. Roth SH. NSAID Gastropathy. Arch Intern Med 1996; 15611623-8.
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`3. Lanza FL. A guideline for the treatment and prevention of NSAID-induced
`ulcers. Am J Gastroentcrol 1998; 93:203'?'—46.
`4. Singh G, Rameyu DR, Morfeld D, Shi H, Hatou I11 I-IT, Fries JF. Gastrointesti-
`nal tract complications of nonsteroidal antiinflarnmatory drug treatment in rheuma-
`toid arthritis: A prospective observational cohort study. Arch Intern Med 1996;
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`
`5. McCarthy D. Nonsteroitlal antiinflammatory drug-related gastrointestinal tox-
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`9. Peskar BM, Maricic N. Role of prostaglandins in gastroprotection. Digestive
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`10. Rothstein R. Safety profiles of leading nonsteroidal antiinflammatory drugs.
`Am J Med 1998; 1t}5:39S—43S.
`11. Needleman P, lsakson PC. The discovery and function of COX-2. J Rheuma-
`tol 1997; 24:6-7.
`12. Lipsky PE. Progress toward a new class of therapeutics: Selective COX-2 in-
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`14. Wolfe MM. Future trends in the development of safer nonsteroidal antiinflan1—
`matory drugs. AmJ Med 1998; 105:44S—52S.
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`trointestinal toxicity. Am J Med 1998; 1{l5:10S~.i.6S.
`16. McCarthy DM. Mechanisms of mucosal injury and healing: the role of non-
`steroidal antiinflammatory drugs. Seand J Gastroenterol 1.995; 30:24-9.
`17. Wolfe MM. Gastrointestinal
`toxicity of the nonsteroidal antiinflammatory
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`macology of non~steroidal antiintlammatory drugs. Pharmac. Ther 1987; 33:383-453.
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`

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`40
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`Joumat of'1’hurmc1ceutt'cat Care in Pain & Symptom Control
`
`19. Cryer B. Nonsteroidal antiinflammatory drugs and gastrointestinal disease. In:
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`eases: Pathophysiology, Diagnosis, Management. Vol. 1. Philadelphia, PA: W.B.
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`_
`20. Reuben SS, Steinherg, R. Gastric perforation associated with the use of cele-
`onxih. Anesthesiology 1999; 91:1548—9.
`2].. Levi S, Goodlad RA, Lee CY. Inhibitory effect of nonsteroidal antiinflamma-
`tory drugs on mucosa] cell proliferation associated with gastric ulcer healing. Lancet
`1990; 336:840-3.
`22. Barkin J. The relation between Het't'cobacter pylori and nonstcroidal antiin-
`flammatory drugs. Am J Med 1998; 105:22S~2."r'S.
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`
`24. Hawkcy CJ, Karrasch JA, Szcezepanski L, et al. Omeprazole compared with
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`26. Lane NE. Pain management in osteoarthritis: The role of COX-2 inhibitors.
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`_
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`29. Vioxx (rofecoxib tablets and oral suspension) product
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`
`information. West