)K102-9270/95/«0O5-O754S03.()O/(lT\» AMI-HICAN JOUkNAL ot GA.-nKOCopyrighl © 1995 by Am. Ciill. of Ciastroenicrology

Vtil, W. No. 5, 1995Printed in U.S.A.

Effect of Naproxen on Gastroesophageal Reflux and EsophagealFunction: A Randomized, Double-Blind, Placebo-Controlled

Study

J. M. Scheiman. M.D., F.A.C.G., P. M. Patel, M.D., E. K. Henson, L.P.N., and T. T. Nostrant, M.D.. F.A.CG.Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michii^an

Objectives: Gastrointestinal symptoms, particularlypyrosis, complicate nonsteroidal anti-inflammatorydrug (NSAID) use. NSAIDs cause esophageal injury, andH, blockers are often prescribed for, and successfullycontrol, NSAID-related .symptoms. To determinewhether NSAIDs can induce gastroesophageal reflux, westudied the effect of a commonly used NSAID. naproxen,on relltix parameters and esophageal function. Methods:Nine healthy volunteers (five males, four females, age2.V-34 yr) were studied. After basal measurements weretaken, (he subjects randomly received naproxen 500 mgp.o. b.Ld. or placebo for 1 wk. On day 6, the subjectsunderwent esophageal manometry with a water-per-fu.sed system and Dent sleeve. Body pressures, contrac-tion velocity, and duration of contraction were recordedin the distal 7 cm of the esophagus. The lower esophagealsphincter pressure (I.KSP) and nuniher of transient re-laxations (TLESRs) were monitored. This was followedby 24-h pH monitoring. The subjects then crossed overto the other drug after a minimum 14-day wash-outperiod. Results: No subject experienced any GI symp-toms during the study. One subject developed reflux-induced symptoms a few months after completing thestudy and was excluded from the analysis. The totalfraction of time (pH < 4) was 4.9 ± 1.0% in the basalstate, 5.5 ± 1.4% on placebo, and 5.4 ± 1.5% onnaproxen. These differences were not significant. Thenumber of reflux episodes and the e.sophageal clearancetime were not aflected by naproxen. The LESP in thebasal state was 32.1 ± 5.6 mm Hg, 32.3 ± 4.2 mm Hg onplacebo, and 29.9 ± 3.3 mm Hg on naproxen {p = NS).Tbe number of TLESRs per 30 minutes in tbe basal statewas 3.5 ± 0.9, 4.6 ± 1.2 on placebo, and 5.8 ± 1.0 onnaproxen {p = NS). Tbe speed and duration of contrac-tions were not alTected by naproxen. The excluded sub-ject had marked basal retlux (total fraction of time pH <4 = 10.7%), low LESP {8 mm Hg), and a marked in-crease in reflux on naproxen (total fraction of time pH <4 = 53%). Conclusions: Naproxen did not induce refluxin normal subjects, althougb reflux did increase in some

Received Aug. 19, 1994; accepted Jan. 25, 1995.

subjects. Naproxen had no significant effect on motilityparameters. Our data suggest that NSAIDs do not im-pair the anti-reflux barrier or induce reflux. Pyrosisexperienced during NSAID use may not arise from theesophagus or may reflect altered e.sophageal sensitivity.A single suhject with decreased LESP and asympUmiaticincreased acid exposure in the basal state had a markedincrease in reflux on naproxen. This person subse-quently developed symptomatic gastroesophageal retlux.The effect of NSAIDs on individuals with a propensity toreflux deserves further study.

INTRODUCTION

Gastrointestinal side effects frequently complicate the useof nonsterojdal anti-inflammatory drugs (NSAID) in clinicalpractice. NSAID-induced gastric and duodenal ulcers havereceived the greatest attention, but esophageal complica-tions of NSAID are also recognized. NSAIDs have beenlinked to the development of benign esophageal stricturesand esophageal ulceration (I, 2). Endoscopic investigationof chronic NSAID users has observed the presence of esoph-agitis in 20% of the users (3). In addition to the life-threatening complications, such as bleeding or perforatedulcers, NSAIDs commonly induce dyspepsia, heartburn.nausea, and vomiting. Up to 50% of subjects report thesesymptoms in short term clinical trials, and chronic users mayexperience such symptoms less frequently (4). Mucosal injurycorrelates po(.)rly with dyspeptic symptoms, and many symp-tomatic patienis have a normal upper GI endoscopy (5).

Symptomatic NSAID users are frequently prescribed H^receptor antagonists to control symptoms, despite evidence thatstandard doses of these drugs cannot prevent NSAID-inducedgastric ulcers (6). Recent clinical trials have confirmed theefficacy of cimetidine 4(K) mg h.i.d. in patients with endosco-py-negative NSAID-induced symptoms (7, 8), suggesting arelationship between acid secretion and dyspeptic symptoms.Prostaglandins are known to affect both the lower esophagealsphincter and body smooth muscle (9, 10), so we hypothesizedthat NSAIDs may induce symptoms by increasing esophageal

754

AJG- May 1995 NAPROXEN AND GASTROESOPHAGEAL REFLUX 755

VP:CL

PLACEBO NAPROXENFIG. I. Bsophageat acid exposure time for each volunteer during placebo

iind naproxen ndministration. Each data point reflects the percentage oftime esophageal pH was les.*; than 4 during each monitored period.

acid exposure, thus explaining the efficacy of acid suppressionin ameliorating symptoms.

Delailed studies of the effect of NSAIDs on the esopha-geal function and gastroesophageal reflux have not beenperformed. A prior study in humans has demonstrated thata single rectal dose of indomethacin actually increasedlower esophageal sphincter pressure (LESP), consistent withanimal data that certain prostaglandins, especially PGEj,decrease LESP (11). Histological studies have suggestedthat NSAID ingestion tnay actually reduce the severity ofesophageal inflammation in both experimental esophagitis(12) and in rheumatic patients versus control subjects (13).

Endoscopic studies confirtn that NSAID users have farless esophagitis than gastric or duodenal injury and thatlocal irritative toxicity, not esophageal reflux, is the pre-sumed predominant mechanism of esophageal injtiry. Cy-clooxygenase inhibition could potentially effect the antire-flux barrier via effects on either the LES or esophagealclearance mechanisms, so we studied normal volunteers todetermine whether a commonly prescribed NSAID,naproxen, taken for 1 wk. could induce reflux or signifi-cantly affect esophageal motility parameters.

METHODS

Nine healthy, nonsmoking volunteers (five males, fourfemales), mean age 25 yr (range 23-34). without a past

history of heartburn or intolerance to NSAIDs, were studied.None of the subjects was taking any medication, Subjectswho were pregnant, tobacco- or heavy alcohol-users andindividuals with recent use of, or allergy to, nonsteroidalanti-inflammatory drugs were excluded.

This study used a randomized, double-blind, placebo-controlled, crossover design. After a basal esophageal ma-nometry study and 24-h pH monitoring, each subject re-ceived, on separate occasions 2 wk apart, cither placebo ornaproxen 500 mg h.i.d. for 1 wk.

A symptom diary was completed by all subjects. On day6 of study medication, the subjects underwent esophagealmanometry and placement of a 24-h pH probe. The pHprobe was removed within 12 h of last dose of naproxen.After a minimum 2-wk wash-out period, the volunteerscrossed over to the other study medication. They returned onday six for repeat evaluation with esophageal manometryand placement of a 24-h pH probe.

Esophageal manometric studies and ambulatory 24-h pHmonitoring were performed using standard techniques (14.15). Contractions were recorded from an 8-!umen polyvinylcatheter with attached Dent sleeve (Arndorfer Medical Spe-cialties. Greendale. WI). The distal four openings were I cmapart at 90° angles, and the four proximal openings were at5-cm intervals. Each lumen was continuously perfused withdistilled water at a rate of 0.5 ml/minute from a low com-pliance, pneumohydraulic capillary-infusion system. Thecatheter was connected to external transducers with outputto a physiograph (Beckman 611, Sensormcdics. AnaheimCA). LESP was recorded using the Dent sleeve. Esophagealperistalsis was assessed after 10 wet swallows (5 ml of watergiven at 30-s intervals). After each swallow, the amplitude,velocity, and duration of esophageal body contractions weremeasured al 2 and 7 cm above the lower esophageal sphinc-ter. The frequency of transient lower esophageal sphincterrelaxations were also recorded over a 30-minute basal pe-riod.

The 24-h pH monitor probe (Synectics Medical Inc..Irving TX) was placed 5 cm above the manometricallydefined lower esophageal sphincter and was connected to abelt-held computer. The frequency and duration of refluxevents were measured. The results were analyzed for per-cent time pH <4 (total, supine, upright), number of refluxevents (total, supine, upright), esophageal clearance time perreflux event (total, supine, upright), and number of refluxevents greater than 5 minutes.

Statistical analysis

The effect of naproxen on the 24-h pH monitor andesophageal manometry study data were compared to theplacebo data using the Student's / test for paired data. A pvalue of <0.05 was considered significant. This researchstudy was approved by the Institutional Review Board atUniversity of Michigan Medical Center,

756 SCHEIMAN et al. AJG - Vol. 90. No. 5. 1995

TABLE 1

Results of 24'h pH Monitoring

Eaaal Placebo NaproxenValue

Total % p H < 4 4.9 2:t.ll 5.5 ± 1.4 5.4 ± 1.5 NSReflux evenis (total) 57.8 ± 2t.3 45.4 ± 11.2 36.1 ± 7.1 NSEsophageal clearance t.4 i 0.4 1.3 ± 0.2 1.5 ± 0.4 NS

(tolal) min/refluxevent

Tolal reflux events 2.4 ± 0.9 2.1 ± 1.0 2.9 ±1.2 NS>5 min

NS, not significant.

TABLE 2

Re.<iults of Esopkageal Manometric Studies

Basal Placebo Naproxen p Value

LESP (mm Hg) 32.1 ± 5.6 32.3 ± 4.2 29.9 ± 3.3 NSAmplitude (mm Hg) 77.9 ± 16.6 83.4 ± 12.6 91.1 ± 15.0 NSDuration (s) 2.82 ± 0.2 2.8 ± 0.14 2.9 ± O.I NSSpeed (cnVs) 9.32 ± 1.0 7.7 ± 1.3 8.5 ± 1.4 NSTLESR 3.50 ± 0.9 4,6 ± 1.2 5.8 ± 1.0 NS

NS. nol significant.

RESULTS

Twenty-four-hour pH monitoring

No subject developed pyrosis or any other GI symptomon naproxen. A number of months after completion of thestudy, one of the subjects developed hoarseness and sorethroat requiring evaluation. Reflux was felt to be the etiol-ogy, and the patient was successfully treated with an H2receptor antagonist. This subject was excluded from theanalysis, and her studies are described in detail separately.The eight remaining subjects had mild, asymptomatic refluxin the basal state with the total percent of time pH <4 = 4.9± 1.0% (upper limit of normal for our laboratory 4%). Thetotal percent of time (pH <4) was 5.5 ± 1.4% on placeboand 5.4 ± 1.5% on naproxen treatment {p not significant).As seen in Figure 1. the total percent time pH < 4 onnaproxen for each subject was variable. The number ofreflux events, percent of time (pH <4) in the supine orupright positions, and esophageal clearance time were notsignificantly affected by naproxen use (Table 1). The ex-cluded subject had a markedly decreased LESP (8 mm Hg)and reflux (total fraction of time pH <4 = 10.7%) in thebasal state, On naproxen, this subject developed markedasymptomatic reflux (total time pH <4 = 53%).

Esophageal motility studies

Esophageal manometry studies determined the LESP,amplitude, duration, and speed of peristaltic contractions, inaddition to the number of transient lower esophageal sphinc-ter relaxations (TLESR) over a 3n-minute monitoring pe-riod. LESP was 32.1 ± 5.6 mm Hg in the basal state, 32.3± 4.2 mm Hg on placebo, and 29.9 ± 3.3 tnm Hg {p = NS)

on naproxen. The number of TLESRs in the basal state was3.5 ± 0.9, 4.6 ± 1.2 on placebo, and 5.7 ± 1.0 on naproxen{p = NS). The speed, duration, and amplitude of contrac-tions were not significantly affected by naproxen (Table 2).There was no relationship between the LESP or number ofTLESRs and the results of 24-h pH monitoring.

DISCUSSION

Our data have demonstrated that in healthy normal indi-viduals, 1 wk of naproxen does not induce gastroesophagealreflux or significantly affect parameters of esophageal func-tion. Although prostaglandins clearly are implicated in con-trol of esophageal smooth muscle contraction, differentprostaglandin subtypes have been reported to either increaseor decrease LESP (9. 11). Animal models of reflux esoph-agitis have demonstrated that esophageal inflammation isassociated with increases in local prostaglandin production,which may contribute to further LES incompetence, aneffect blocked by indomethacin (12, 16). Our results inhumans suggest that when cyclooxygenase is inhibited, ex-isting overlapping control mechanisms (neural, hormonal)maintain esophageal function. This process may representthe esophageal equivalent to gastric adaptation to NSAIDinjury in the stomach (17).

If NSAIDs do not appear to effect esophageal motility orinduce reflux, is the reflux-like dyspepsia and pyrosis ex-perienced during NSAID therapy, which seems to respondto acid inhibition, due to increased gastroesophageal reflux?Although our acute study in healthy subjects who experi-enced no symptoms cannot directly address this question,two possibilities are suggested by our results. One subject inour study did experience a large increase in reflux onnaproxen, so there may be interindividual susceptibility tothe effects of NSAIDs. similar to the case for upper GImucosal injury. Although there was no relationship betweenLESP and esophageal acid exposure overall, the subjectwith marked increased reflux on naproxen had the lowestbasal LESP of the study group. Further study of patientswho experience pyrosis on NSAIDs and the effect ofNSAIDs on individuals with a reflux propensity are war-ranted.

Another possibility is that NSAIDs may affect esophagealsensitivity to physiological levels of retlux. because acidperfusion or balloon distention of the esophagus can identifyindividuals with normal pH monitoring who have esopha-geal symptoms (18, 19). Prospective studies using 24-h pHmonitoring and studies of esophageal sensitivity in symp-tomatic NSAID users and reflux patients are required toanswer these questions.

Reprint requests and correspondence: James M. Scheiman. M.O., Di-vision of Gastrocnterology; 3912 Taubman Centiir Box 0362. 15(H) E.Medical Cenler Drive. University uf Michigan Medical Center, Ann Arbor.Ml 48109.

AJG - May 1995 NAPROXEN AND GASTROESOPHAGEAL REFLUX 757

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