Review Article
`
`Effects of Nonsteroidal Anti-inflammatory
`Drugs on EndogenousGastrointestinal
`Prostaglandins and Therapeutic Strategies
`for Prevention and Treatment of Nonsteroidal
`Anti-inflammatory Drug—Induced Damage
`
`Byron Cryer, MD, Mark Feldman, MD
`
`@ Although nonsteroidal anti-inflammatory drugs (NSAIDs)
`are effective for pain relief and treatmentofarthritis, they
`can inducegastric and duodenal ulcers andlife-threatening
`complications. The mechanismsoftheir anti-inflammatory
`action and their gastroduodenaltoxic effects are related, in
`part, to inhibition of prostaglandin synthesis. This review
`article discusses prostaglandins, their functions in the gas-
`trointestinal tract, anti-inflammatory actions of NSAIDs,
`and mechanisms by which NSAIDs producegastroduodenal
`ulcers. Also reviewed are risk factors associated with the
`development of NSAID-related ulcers and pharmacologic
`strategies for the prevention and treatment of NSAID-
`induced ulcers.
`(Arch Intern Med. 1992;152:1145-1155)
`
`NY onstroidal anti-inflammatory drugs (NSAIDs) are
`widely used for pain relief and for treatment of
`arthritis
`(including rheumatoid arthritis, ankylosing
`spondylitis, osteoarthritis, and gouty arthritis). A partial
`list of NSAIDs is shown in the Table. Although NSAIDs
`are effective as therapeutic agents, their majortoxic effect
`is induction of gastroduodenal ulcers. Mechanisms for
`their anti-inflammatory action and their gastroduodenal
`toxic effects are probably related to an inhibition of pros-
`taglandin synthesis. The purposesofthis article are to re-
`view the effects of NSAIDs on the gastroduodenal mu-
`cosa, including their effects on mucosal prostaglandins,
`and to review the effects of therapeutic agents that can be
`used to prevent and treat NSAID-induced gastroduode-
`nal damage.
`PROSTAGLANDINS AND RELATED COMPOUNDS
`
`Prostaglandins (PGs) are a family of related fatty acids
`that are produced by nearly all of the body’s cells. Pros-
`taglandins participate in a variety of activities, including
`mediation of inflammatory responses, protection of the
`
`Accepted for publication November 16, 1997.
`From the Medical Service, Department of Veterans Affairs Med-
`ical Center, and Department of Internal Medicine, University of
`Texas Southwestern Medical Center at Dallas.
`Reprint requests to Dallas VA Medical Center (111), 4500 $ Lan-
`caster Rd, Dallas, TX 75216 (Dr Feldman).
`
`Arch Intern Med—Vol 152, June 1992
`
`gastrointestinal mucosa against injury, and regulation of
`renal blood flow. The general chemical structure of PGs
`is an oxygenated, 20-carbon, unsaturated fatty acid (ei-
`cosanoid) composedofa five-carbon ring, with two car-
`bon side chains, one composed of seven carbon molecules
`and the other composedofeight.! Nomenclature used to
`describe individual PGs is based on twodistinguishing
`features. First, the letter designation of PGs (ie,
`their
`family) is determined by thestructureof the five-carbon
`ting. For example, all PGEs have a double-bonded oxygen
`(=O)at carbon 9 and a hydroxyl group (— OH)at carbon
`11, while all PGFs have a hydroxyl group at both carbon
`9 and carbon 11.? Second, the number of double bondsin
`the side chains determines PG classification as 1-, 2-, or
`3-series and is reflected by a subscript (eg, PGE, [2-series]
`or 6-keto-PGF,, [1-series}) (Figure).
`Prostaglandins are not stored within cells in any signif-
`icant quantities, but are stored as precursor molecules.
`Prostaglandins of the 2-series are the most plentiful and
`biologically important and are derived from arachidonic
`acid, a component of phospholipids presentin all cell
`membranes. In response to a mechanical or chemical per-
`turbation of the cell membrane, arachidonic acid is
`released from membrane phospholipids into the cyto-
`plasm of the cell
`through the action of a plasma
`membrane-bound enzyme, phospholipase A,. Once re-
`leased, arachidonic acid may be acted on by cyclo-
`oxygenase, a membrane-bound enzyme,
`resulting in
`synthesis of PGs; alternatively, it may be metabolized by
`another enzyme,5-lipoxygenase, to a group ofclosely re-
`lated compounds, the leukotrienes (LTs) (Figure). The
`relative
`activities
`of
`the
`cyclo-oxygenase
`and
`5-lipoxygenase pathways, and thus the relative amounts
`of eicosanoids produced, vary with cell type.’ In gastric
`and duodenal mucosa, mostarachidonicacid is converted
`into PGE,, PGF,,, and PGI,.**
`FUNCTION OF PROSTAGLANDINSIN THE
`GASTROINTESTINAL TRACT
`
`Although PGs werefirst identified in the human body
`in the 1930s, it was not until the mid-1960s that PGs were
`identified in the gastrointestinal tract.”* Theearliest rec-
`ognized effect of PGs on gastric mucosal function was an
`Effects of NSAIDs on Prostaglandins—Cryer & Feldman
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`*Available in the United States in 1991.
`
`Partial List of Nonsteroidal Anti-inflammatory Drugs
`Salicylates
`Aspirin®
`Diflunisal (Dolobid)*
`Salsalate (Disalcid)*
`Indoles
`Indomethacin (Indocin)*
`Sulindac (Clinoril}*
`Tolmetin (Tolectin}*
`Zomepirac (Zomax)
`Pyrazoles
`Apazone (Rheumox)
`Feprazone (Methrazone)
`Phenylbutazone (Butazolidin)*
`Fenamates
`Flufenamic acid (Meralen)
`Mefenamic acid (Ponstel)*
`Meclofenamate (Meclomen)*
`Tolfenamic acid (Clotam)
`Proprionic acid derivatives
`Carprofen (Rimadyl)
`Fenbufen (Cinopal, Lederfen)
`Fenoprofen (Nalfon, Fenopron)*
`Flurbiprofen (Ansaid, Froben)*
`Ibuprofen (Motrin, Advil)*
`Ketoprofen {Orudis)*
`Naproxen (Naprosyn, Anaprox}*
`Pirprofen (Rengasil)
`Phenylacetic acid derivatives
`Diclofenac (Voltaren, Voltarol)*
`Fenclofenac (Flenac)
`Oxicams
`Isoxicam {Maxicam)
`Piroxicam (Feldene)*
`
`inhibition of gastric acid and pepsin secretion."*" Intra-
`venously administered PGsof the E, F, and A classes and
`orally administered synthetic analogues of these com-
`pounds have potent antisecretory effects, PGs of the E
`class being the most potent.*”
`In the 1970s, investigators began to demonstrate that
`PGscould protect the gastric mucosa from injury and ul-
`ceration against a wide variety of damaging agents, such
`as alcohol,bile salts, acid, hypertonic saline, boiling wa-
`ter, stress, aspirin, and other NSAIDs.7**8 Robert et al”
`performed the earliest of these experiments, in which
`they demonstrated that pretreatment with PGs could
`prevent mucosal damage from various noxious agents in
`rats. It was demonstrated that mucosal protection could
`be observed at doses of PGs that did not inhibit acid se-
`cretion.” This protective property of PGs wascalled “cy-
`toprotection.”” Even though pretreatment with PGs may
`protect against macroscopic injury, there is usually mi-
`croscopic evidence of mucosal injury to surface epithelial
`cells after exposure to alcohol or other noxious agents.”
`Because of persistent surface cell damage despite PG pre-
`treatment, the term cytoprotection is not entirely accurate
`and has for the most part been replaced by mucosalprotec-
`tion. Mucosal protection by prostaglandins has not only
`been demonstrated in the stomach, but has been shown
`in the duodenum.*'* Protection has been demonstrated
`with PGsofall classes andis separate from any effects the
`compoundsmayhaveon gastric acid secretion. In fact, in
`animals, mucosal protection has been demonstrated with
`PGs, such as 6-keto-PGF,,, that have no demonstrated
`1146) Arch Intern Med—Vol 152, June 1992
`
`Thromboxane B»
`
`6-Keto-PGF 1g
`
`Leukotrienes
`
`Thromboxanes
`
`Prostaglandins
`
`
`
`Membrane Phospholipids
`
`Phospholipase Az
`Arachidonic Acid
`*Lipoxygenase___-_Cyclo-oxygenase
`5-HPETE —> 5-HETE
`PCG,
`
`LTAg
`Wh,ie
`4
`
`"+
`
`Thromboxane A,
`
`PGH2
`
`Pe
`
`PGDz
`
`PGE, PGFag
`
`LTD,
`|
`LTE,
`
`Metabolism of arachidonic acid after its release from membrane
`phospholipids. HPETE indicates hydroperoxyeicosatetraenoic acid;
`HETE, hydroxyeicosatetraenoic acid; PG, prostaglandin; and LT,
`leukotriene.
`
`effect on acid secretion.” However, in humans,it is not
`certain that the protective effects of PGs are due to mech-
`anisms separate from inhibition of gastric acid secretion,
`since PGs, at doses employed in human trials, have
`antisecretory effects as well.
`Howis mucosal protection by PGs mediated? Integrity
`of the gastroduodenal mucosa is maintained by a balance
`between aggressive factors, such as acid and pepsin, and
`protective factors, such as bicarbonate and mucus.*-”
`Whenthere is an imbalance between aggressive and pro-
`tective factors, such that the extent of mucosal protection
`is lowered in relation to the level of offending agents,
`mucosal
`injury ensues. Persistence of this imbalance
`could lead to mucosal erosions and ulceration. Some of
`several putative mechanisms proposed through which
`PGs may provide their mucosal protective effects include
`the following: stimulation of mucosal bicarbonate secre-
`tion, mucus secretion, increased blood flow, prevention
`of disruption of the gastric mucosal barrier, acceleration
`of cell proliferation, stimulationof cellular ionic transport
`processes, stimulation of cyclic adenosine monophos-
`phate production, promotion of formation of surface-
`active phospholipids, maintenance of gastric mucosal
`sulfhydryl compounds,
`stabilization of cellular lyso-
`somes, and stabilization of cell membranes.*879-4145 Soll
`et al* categorized various protective mechanisms accord-
`ing to their location with respect to the surface epithelial
`cells. They have been accordingly described as preepi-
`thelial (mucus and bicarbonate secretion), epithelial (sur-
`face epithelial cell continuity and migration), and postep-
`ithelial (mucosal blood flow).
`INFLAMMATION AND ANTI-INFLAMMATORYACTIONS
`OF NSAIDs
`
`Inflammatory cell recruitmentis achieved through the
`release of a number of chemical mediators, such as PGs,
`LTs, histamine, serotonin, kinins, complement factors,
`and other peptides.” Evidence implicating PGs in this
`process was not obtained until 1971, when Vane® pro-
`
`Effects of NSAIDs on Prostaglandins—Cryer & Feidman
`
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`posed PGsas substances that could elicit an inflammatory
`response. Prostaglandins were demonstrated to be asso-
`ciated with inflammation in a variety of experimentalsit-
`uations. For example, after subcutaneous PG administra-
`tion, edema and erythema as well as some of the
`histologic changes of inflammation were observed.” Af-
`ter administration of aspirin, biosynthesis of PGs de-
`creased in proportion to the decrease in the amountof in-
`flammation,*°"2 and then, if exogenous PGs werelater
`administered, there would be a return of inflammation.”
`Experimental administration of PGs could induce fever™®
`and potentiate pain,™ and subsequent administration of
`an NSAID could decrease fever and pain while also
`decreasing PG concentrations. It soon becameclear that
`the anti-inflammatory effects of such drugs as aspirin
`could be explained by their suppression of PG synthesis
`and that such inhibition could also explain the actions of
`these drugs as analgesics and antipyretics.
`Aspirin, an acetylated salicylate, was one of the first
`NSAIDs shown to be clinically effective as an anti-
`inflammatory agent. Although many other NSAIDs
`have since been introduced, aspirin remains one of the
`most effective anti-inflammatory agents.® It is through
`the inhibition of cyclo-oxygenase that aspirin and other
`NSAIDs decrease PG synthesis. By acetylation of cyclo-
`oxygenase, aspirin inhibits this enzyme irreversibly,
`while other NSAIDs (flufenamic acid,
`ibuprofen, and
`sulindac, for example) inhibit cyclo-oxygenase in a re-
`versible, concentration-dependent manner.%*”? When
`cyclo-oxygenaseis irreversibly inhibited within any par-
`ticularcell, the capacity for PG synthesis does not return
`to normal until new enzyme can be synthesized.* This
`may explain why aspirin,
`in comparison with other
`NSAIDs, remains one of the most potent inhibitors of PG
`synthesis. It is hypothesized that cyclo-oxygenase exists
`in multiple forms throughout the body and that each form
`has its own drug specificity,” although this has not yet
`been verified by identification of structural cyclo-
`oxygenase variants. Cyclo-oxygenases obtained from dif-
`ferent tissues have different sensitivities to inhibition by
`a particular NSAID, and different NSAIDs have variable
`abilities to inhibit a particular cyclo-oxygenase.*”* For ex-
`ample, acetaminophenis as effective as aspirin in the in-
`hibition of brain cyclo-oxygenase, but is not nearly as ef-
`fective as aspirin in the inhibition of cyclo-oxygenase from
`some peripheral sites.” This may explain why acetami-
`nophenis an effective centrally acting antipyretic and an-
`algesic but is not an effective peripherally acting anti-
`inflammatory agent. This may also explain why
`acetaminophen does not cause gastroduodenal toxic ef-
`fects.
`The LTsalso playa significant role in the inflammatory
`response. They increase vascular permeability,
`are
`chemotactic for neutrophils, vasoconstrict arteries, stim-
`ulate bronchial wall constriction and mucus secretion,
`and increaseintestinal inflammation.®.” Certain NSAIDs,
`in addition to inhibiting cyclo-oxygenase, also may inhibit
`5-lipoxygenase.™*! The NSAIDs differ in their relative
`potencies to reduce inflammation,” and their anti-
`inflammatory effects do not always correlate with their
`ability to reduce PG synthesis. These observations may
`possibly be explained bydifferent capacities of the various
`NSAIDs to inhibit cyclo-oxygenase, on the one hand, and
`5-lipoxygenase, on the other hand. An NSAID such as
`indomethacin is predominantly a cyclo-oxygenase inhib-
`Arch Intern Med—Vol 152, June 1992
`
`itor, while other experimental NSAIDs of the fenamate
`class are effective inhibitors of both enzymes.® Whether
`differences in the relative amounts of cyclo-oxygenase/5-
`lipoxygenase inhibition by NSAIDs is indeed related to
`differences in anti-inflammatory actions of NSAIDs is
`currently under investigation.
`Anti-inflammatory actions of NSAIDsare not only ex-
`plained by inhibition of eicosanoid synthesis. For exam-
`ple, NSAIDs inhibit PG synthesis in vivo and in vitro at
`concentrations much lowerthan those required to achieve
`anti-inflammatory effects.“ Moreover, somesalicylates,
`including nonacetylated salicylates, are beneficial in in-
`flammatory disease** even though they do not inhibit
`PG synthesis.*® Inhibition of neutrophil function has
`been suggested as a second mechanism by which NSAIDs
`can exert their anti-inflammatory effects.%7°7!
`MECHANISMS OF GASTRODUODENAL MUCOSAL
`INJURY BY NSAIDs
`The mechanisms by which aspirin can cause gas-
`trointestinal mucosal damage can be grouped into two
`categories: those independentof and those dependent on
`cyclo-oxygenase inhibition. Within a few minutes of
`aspirin ingestion, denudation of surface epithelial cells
`and increased mucosal permeability to sodium (Na*) and
`hydrogen (H*) ions can be observed,” reflected experi-
`mentally as a decrease in transmucosal potential differ-
`ence.”Salicylic acid, the deacetylated metabolite of as-
`pirin, does not inhibit cyclo-oxygenase activity in the
`gastric mucosa,” yet it reduces transmucosal potential
`difference as much as aspirin does.” Thus, surface
`epithelial cell disruption and a decline in potential differ-
`ence are not dependent on cyclo-oxygenase inhibition,
`and epithelial cell disruption is not prevented by pre-
`treatment with PGs.*
`Endoscopic observation of the gastric mucosaafter 1 to
`2 weeks of enteric-coated aspirin therapy” or after 1
`week of enteric-coated naproxen therapy” revealed con-
`siderably less gastric mucosal damage than with plain,
`non-enteric-coated formulations. Although gastric injury
`from a topical effect is decreased with enteric-coated for-
`mulations, their use on a long-term basis will result in
`gastric ulcers (GUs},™ presumably the result of a systemic
`rather than topical effect. Gastric ulcers can be produced
`experimentally after NSAIDs are administered intrave-
`nously* or by rectal suppository™ and without a change
`in gastric transmucosal potential difference.*)® It is likely
`that the NSAIDs were ulcerogenic because they reduced
`mucosal PG synthesis. This is supported by two observa-
`tions: (1} small nonantisecretory doses of exogenous PGs
`prevent NSAID-induced ulcers®*#* and (2) depletion of
`mucosal PGs by another mechanism, active or passive
`immunization with PG antibodies, leads to GUs.
`Although inhibition of PG synthesis contributes to
`NSAID-induced mucosal injury, it is not settled whether
`PG inhibition is the primary mechanism. In somestudies,
`there has been poor correlation between gastric mucosal
`injury and PG suppression after NSAIDs.Otherfac-
`tors probably work in combination with PG suppression
`to increase the propensity for mucosal injury by NSAIDs.
`For example, after indomethacin administration, gastric
`acid secretion has been shown to increase,” gastric mu-
`cosal blood flow to decrease,” and duodenal bicarbon-
`ate output to decrease.” Nonsteroidal anti-inflammatory
`drugs can also potentially affect mucus secretion, as
`Effects of NSAIDs on Prostaglandins—Cryer & Feldman
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`to
`they have been shown to inhibit mucus synthesis,
`reduce incorporation of radiolabeled precursors into
`mucus glycoprotein, and to alter thickness of the mu-
`cus layer.
`It has been hypothesized that, as a consequence of
`cyclo-oxygenase inhibition, arachidonic acid metabolism
`could alternatively be shunted toward the lipoxygenase
`pathway, resulting in increased LT synthesis.*” The
`postulated mechanism by which increased activity of the
`5-lipoxygenase pathway could enhance mucosalinjury is
`by LT-mediated vasoconstriction or by direct vascularin-
`jury by oxygenradicals produced in this pathway.*” The
`relative importance of LTs in NSAID-induced gastric mu-
`cosal damageis still unclear.
`Since other pathogenetic mechanismsare potentially
`operative, one may ask whether significant NSAID-
`related mucosal
`injury can occur in the absence of
`suppression of mucosal PGs. After administration of
`salsalate,
`a mnonacetylated
`salicylate
`that
`is
`anti-
`inflammatory, mucosal injury has been far less than after
`other NSAIDs.!©1Salsalate does not significantly inhibit
`cyclo-oxygenase activity or reduce mucosal PG con-
`tent.’ Thus, inhibition of PG synthesis is probably
`necessary but not sufficient for mucosal injury.
`
`SHORT-TERM VS LONG-TERM NSAID ADMINISTRATION
`
`Mucosal petechiae and erosions are comparatively triv-
`ial, transient lesions that have low risk for major unto-
`ward effects.""° Acute mucosal injury can be repaired rap-
`idly through processes of
`restitution and gastric
`adaptation. With continued and frequent aspirin admin-
`istration, the rate of mucosal injury may be greater than
`the rate of mucosal repair, ultimately resulting in a
`persistentepithelial defect."”° Consequently, an erosion or
`an ulcer may develop, the distinction between the two
`being depth of damage.” An ulcer, once formed, has the
`potential to cause significant bleeding, luminal obstruc-
`tion, or gastrointestinal perforation, all of which are
`not uncommon complications of
`long-term NSAID
`therapy.“"*8 Thus, the clinically important aspects of
`NSAID mucosal damage are primarily the consequences
`seen after long-term rather than short-term therapy.
`Although there may be considerable differences in in-
`cidences of injury after short-term administration ob-
`served between the various nonaspirin NSAIDs, these
`differences cannot be used to predict injury after longer-
`term administration. Drugs that produce slight acute
`mucosal injury can still produce ulcers when given on a
`long-term basis. For example, sulindac produceslittle
`mucosal damage when given for a short term”! but is as-
`sociated with one of the highest rates of NSAID-related
`upper gastrointestinal bleeding.'* Most data on conse-
`quences of long-term NSAID therapy come from epide-
`After short-term administration, a variety of types of
`miologic studies or from prospective trials of patients
`injury develop, ranging from petechial hemorrhages, dif-
`taking these medications for therapy for chronic rheu-
`fuse hemorrhages, superficial erosions, and, less com-
`matic diseases.
`monly, ulceration.* On the basis of such observations,
`Retrospective reviewsof records of hospital admissions
`many claims have been made asto the superiority of one
`for upper gastrointestinal bleeding have provided further
`NSAIDover another regarding the incidence of mucosal
`evidence that long-term aspirin use is associated with
`injury. Lanza’? reported the largest experience with en-
`GUs.'* With the newer, nonaspirin NSAIDs, case-
`doscopic mucosal observations after 7 days of NSAID in-
`controlled studies also suggest that gastrointestinal bleed-
`gestion. High doses of aspirin had the highest incidence
`ing from ulcers is strongly associated with NSAID
`of acute gastric mucosalinjury, while the incidenceof in-
`use.'#724131 Fiowever, the incidence of serious ulcer com-
`jury induced by other nonaspirin NSAIDs wasless but
`plications with nonaspirin NSAIDsis less than that with
`also dose dependent. Among the nonaspirin NSAIDs,it
`aspirin. Patients presenting with bleeding ulcers are three
`was not easy to compare incidences of gastric mucosal
`to five timesas likely as controls to have taken an NSAID,
`toxic effects becauseof difficulties in determining equiv-
`and 13% to 60% have a recent history of NSAID
`alent doses. By compiling all of his NSAID data, Lanza
`consumption.“*™ Among subjects without a history of
`observed a 6.7% incidence of GU and a 1.4% incidence of
`ulcer, patients taking NSAIDs have 1.5 times therisk of
`duodenal ulcer (DU)after 1 week of NSAID ingestion. The
`developing upper gastrointestinal bleeding than do con-
`largest numbers of GUs were produced by aspirin and the
`trols not taking NSAIDs.’ A dose-response relationship
`lowest numbers by lower anti-inflammatory doses of ibu-
`between NSAID consumption and development of mu-
`profen.
`cosal ulcers may also exist. Cameron’ found that a pat-
`The evolution of mucosal injury over time after short-
`tern of regular aspirin consumption (>15 aspirin tablets
`term NSAID therapy also has been an interest of investi-
`per week) hadasignificantly higher association with GUs
`gation. After a single dose of aspirin (650 mg), gastric in-
`than patterns of occasional (14 or less per week) or no as-
`tramucosal hemorrhages
`endoscopically visible
`as
`pirin consumption. On the basis of the distribution of as-
`petechiae appearin aslittle as 15 minutes and gastric ero-
`pirin use amongthese patients, it has been estimated that
`sionsin aslittle as 45 minutes." Petechial lesions become
`the relative risk of developing a GU rises dramatically
`most pronouncedby 1 to 2 hours"and can occurin any
`above 15 to 20 aspirin tablets per week at an aspirin dose
`location in the stomach."°1" After many repeated doses
`of 325 mg.”
`of aspirin, multiple erosions appear, mostly in the an-
`Data on long-term mucosaleffects of NSAID consump-
`trum,1.9 but potentially in any gastric location. Endo-
`tion come mostly from endoscopic studies of patients with
`scopic gastric mucosal injury peaks withinthefirst 3 days
`rheumatoid arthritis or osteoarthritis." McCar-
`and then tends to decrease despite continued aspirin ad-
`thy,by combining data from all available point preva-
`ministration,°!%."* despite the fact that mucosal PG
`lence studies, estimated a GU point prevalence of 13%
`and a DU point prevalence of 11% for patients with
`content remains low.®!™ This phenomenon has been re-
`ferred to as gastric adaptation.'"' Increased epithelial cell
`arthritis taking long-term NSAID therapy. Enteric-coated
`regeneration and mitoses have been observed to occur in
`aspirin appears to be associated with fewer GUs than
`response to aspirin-induced injury.">"""
`plain aspirin.” However, incidences of DUs after use of
`"References 77-79, 62, 85, 87, 80, 101-114.
`either aspirin preparation are similar.™
`Effects of NSAIDs on Prostaglandins —Cryer & Feldman
`
`1448 Arch Intern Med—Vol 152, June 1992
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`Prospective, point-prevalence trials are limited by the
`fact that they look at the mucosa at only one pointin time,
`after variable lengths of NSAID use.
`It
`is not certain
`whetherthe observedulcer is truly a direct consequence
`of the NSAID or whether it was present before NSAID
`therapy began. To assess the risk of ulcer formation
`directly attributable to NSAIDs, a lesion-free mucosa
`needs to be observed at a zero time point, and the
`incidence of ulcers arising while the patient is taking
`NSAIDs as compared with placebo treatmentis then re-
`corded. Caruso and Bianchi-Porro™™ observed new gastric
`lesions in 31% of patients after 3 months of NSAIDs. The
`incidence of ulcers among these “lesions” was not re-
`ported, and there was no placebo-treated group for com-
`parison. An alternative means to study the evolution of
`mucosal damage in long-term NSAIDusersis to use data
`from placebo-controlled trials of protective agents coad-
`ministered with NSAIDs. To date, there have been four
`large (ie, >100 subjects each)trials in which either a his-
`tamine, (H;) blocker, a synthetic PG, or placebo was
`coadministered with one of various NSAIDsto patients
`with arthritis who were without mucosal abnormalities at
`initial endoscopy.” Again, there was no group of pa-
`tients with arthritis who received placebo without
`NSAIDs. Nevertheless, it appears that, at least after 2
`months of NSAID therapy, a new GU may develop ina
`little greater than 10% of NSAID users, and a DU will de-
`velop in somewhereless than 10%. It is likely that gastric
`and duodenal ulceration with NSAID usage beyond 2 to
`3 monthswill continue to occur, since NSAID-related ul-
`cer complications, such as bleeding or perforation, occur
`frequently in long-term NSAIDusers. '3!.1
`RISK FACTORS FOR NSAID-INDUCED ULCERS
`Dose
`
`As the prescribed dose of an NSAID increases, the per-
`centageof patients presenting with upper gastrointestinal
`bleeding or hospitalized for ulcers increases.!”! Griffin
`et al! recently reported that the relative risk of ulceration
`in older subjects who have consumed NSAIDsfor less
`than 30 days is almost twice the risk for longer periods of
`consumption.'*! The authorsstated that the estimated risk
`for developmentof an ulcer amongan elderly individual
`whohas recently begun a high dose of an NSAID is 10
`times that of a nonuser.'! Prospective data directly eval-
`uating dose-response or duration-response relationships
`between long-term NSAID use and ulcer developmentare
`lacking.
`
`Ulcer History
`A history of idiopathic ulcer disease may increase the
`risk of ulceration during NSAID therapy. After 2 months
`of NSAID consumption, six of 11 patients with a history
`of peptic ulcers developed recurrent ulceration, compared
`with only 11 of 115 patients with no ulcer history."%* More
`studiesofthis risk factor are required before previousul-
`cer disease can be accepted as a definite risk factor,
`
`Age
`Ageis one factor that has been consistently associated
`with an increased risk for NSAID-related ulcer complica-
`tions. 7415.16.31 The risk of perforated ulcers may be high
`in elderly NSAID users, especially elderly women,™and
`mortality from ulcer complications is also markedly ele-
`vated in the aged.” Onelikely explanation for this asso-
`Arch Intern Med—Vol 152, June 1992
`
`ciation of greater age and risk of NSAID ulcerationsis that
`NSAID use increases with advancing age, especially in
`those over 60 years old.*5 However, there may be other
`factors that predispose the elderly to damage by NSAIDs.
`For example, our group and a group from Japan recently
`showedthat bothgastric'3 and duodenal mucosal PG
`concentrations decline with aging in humans. Thus, older
`patients, at baseline, may have an already compromised
`potential for mucosal protection, perhaps placing this
`groupat highrisk for the development of NSAID-induced
`ulcers.
`
`Smoking
`It is not known whethercigarette smoking influences
`the potential for NSAID-inducedulceration. Theability of
`the gastroduodenal mucosa to protect itself against injury
`maybe decreased in smokers, since smokingis associated
`with reduced mucosal PG concentrations in humans."
`Use of NSAIDs by smokers should further reduce their
`already low mucosal PG concentrations.
`PREVENTION OF NSAID-INDUCED ULCERS
`
`Initial attempts to lower gastroduodenal toxic effects
`seen with aspirin were directed toward developmentof
`alternative formulations. Newer NSAIDs, enteric-coated
`preparations, suppositories, and prodrugs disappoint-
`ingly continue to be associated with significantulceration.
`None has demonstrated conclusive superiority to the
`others for decreased gastroduodenaltoxic effects. Conse-
`quently, a major researchinterest has arisen to investigate
`other drugs that, when coadministered with NSAIDs, will
`either protect against or prevent mucosalinjury.
`Evaluation ofthe efficacy of a coadministered agent to
`prevent mucosal damage is strongly influenced by the
`type of scale used to measure injury. Mucosal protection
`may or may not be observed, depending on which pattern
`of injury has been most heavily weighted in the scoring
`system. In a study of prevention of naproxen-induced
`acute gastroduodenal
`injury, cimetidine was demon-
`strated to be superior to placebo whena scale primarily
`reflective of mucosal hemorrhage was used, but cimeti-
`dine wasnotdifferent from placebo whena scale in which
`erosions were incorporated into the scoring system was
`used.Results of cotreatmenttrials are more reliably ap-
`plied to clinical practice when erosionsandulcers are used
`as end points to define response to therapy. Here again,
`findings of the short-term trials may not be relevant to
`long-term administration and, thus, the weight of our
`conclusions should be based on results of trials of ex-
`tended cotherapy in the long-term NSAID user.
`
`H,-Receptor Antagonists
`It has become common practice to prescribe H,-
`antagonists, such as cimetidine (Tagamet), ranitidine
`(Zantac),
`famotidine (Pepcid), and nizatidine (Axid),
`along with NSAIDsfor ulcer prophylaxis, even though
`supporting evidence from clinical trials is sparse. None-
`theless, coadministration of an antisecretory agent does,
`for the following reasons, have some theoretical merit: (1)
`after mucosal
`integrity has been interrupted by an
`NSAID, further cellular damage can occur through the
`back diffusion of acid; (2) during NSAID therapy,acid se-
`cretion may increase,™'” possibly because of decreased
`mucosal PG content; and (3) in animals, NSAID mucosal
`damagein the presenceof acid is greater than when mu-
`Effects of NSAIDs on Prostaglandins—Cryer & Feldman
`1149
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`cosa is exposed to a higher pH."* Onthe other hand, the
`fact that H,-antagonists have no knowneffects on gastric
`mucosal PGs theoretically argues against their possible
`benefit in a PG-deficient mucosa."°!
`Coadministration of H,-antagonists and aspirin, dosed
`for 7 days or less, to normal volunteers produced less
`gastric and duodenal mucosal injury than did adminis-
`tration of placebo." Thus,
`in the short term, H,-
`antagonists are effective for prophylaxis against gastric
`and duodenal NSAID-induced injury. During longer pe-
`riods of NSAID administration, H,-antagonists, such as
`ranitidine (150 mg twice daily), are effective for NSAID-
`induced ulcer prevention in the duodenum but not the
`stomach. #1
`There is limited information on ulcer prevention after
`an NSAID-induced ulcer has been healed by an H,-
`antagonist, assuming that coadministration of an H,-
`antagonist and the NSAID is continued.*"!* Available
`data suggest that recurrence rates during cotherapy are
`low.In these maintenance studies, however, repeated
`endoscopy was only performed for symptomatic recur-
`rences. Since a considerable number of patients taking
`NSAIDs have asymptomatic ulcerations, !1%829.138.1 it is
`likely the recurrence rates have been underestimated.
`Given that full-dose H,-antagonist
`therapy does not
`effectively preventinitial NSAID-induced GUs, the abil-
`ity o