Nonsteroidal Anti-Inflammatory Drug–AssociatedDyspepsia: Basic Mechanisms and Future Research

John Jones, MA, MRCP, Johan Raud, MD, PhD

Dyspepsia, whether or not related to nonsteroidalanti-inflammatory drugs (NSAIDs), is a poorlydefined clinical entity that lacks a scientific basis.

Clinical studies have been hampered by inadequatesymptom definition, inexact treatment goals, and lack ofobjective measures of response so that we have little un-derstanding of what underlies this important complaint.However, because pain is an important component ofdyspepsia, it should be considered no less suitable forresearch than any other type of visceral pain. There arenumerous animal studies of colonic and urogenital painbut little information regarding gastric pain. If we assumethat pain begins with a peripheral noxious stimulus, wecan target research at this initial receptor interaction.Clinical studies on acid suppression, luminal distension,and NSAID toxicity suggest that these are importantstimuli of dyspeptic pain.

NOCICEPTORSEvidence supports the existence of three classes of recep-tor relevant to visceral sensation. High threshold recep-tors are modality specific for pain by responding to nox-ious but not mild or moderate stimuli. In contrast, inten-sity-encoding receptors respond, above a low threshold,to a range of stimuli so that sensations from the innocu-ous to the painful can be encoded. Finally, silent nocicep-tors fail to respond to any stimulus under normal circum-stances but can be recruited by an inflammatory responseto transmit pain.1 Specific evidence for the role of thesereceptors in dyspepsia is lacking, but animal studies sup-port their existence in visceral pain. Single nerve record-ings from spinal afferents arising in the opossum esoph-agus revealed high threshold and intensity-encoding re-ceptor activity.2,3 Silent nociceptors have been betterstudied in the bladder, where mucosal inflammation bymustard oil appears to recruit previously silent recep-tors.4

The stomach has been less well studied, but experi-ments over the last 40 years using electrical, mechanical,and chemical stimulation with recording from spinal andvagal afferents have suggested the existence of three layersof gastric nerve endings (reviewed in Leek5). Those end-ing in the muscle and serosa were responsive to disten-

sion and distortion of the gastric lumen, whereas those inthe gastric mucosa were predominantly chemically sensi-tive. Acid was the main stimulus used, but the fibers alsoresponded to alkaline, hypotonic, and hypertonic solu-tions. There was evidence of both vagal and spinal affer-ent responses.

ACID AND NOCICEPTION

The effect of acid on nerves has been studied in a numberof different systems. Injection of acidic solutions of pH5.2 to 6.1 into human skin causes pain.6,7 At the mucosallevel, a pH of 4 to 5 causes calcitonin gene–related peptideand substance P release consistent with activation ofsmall unmyelinated fibers.8 –10 Finally, at the cellularlevel, low pH can activate dorsal root ganglion cells inculture manifested by changes in voltage clamp potentialsand/or influx of calcium ions.11,12

This action of acid is not the result of caustic damage ofthe nerve endings, because activation can be prevented byinhibition of voltage-gated calcium channels either phar-macologically or by use of a calcium-free medium.8 Theeffect is likely to be mediated by a direct proton-receptorinteraction; this is supported by the discovery of a num-ber of acid-sensing ion channels in nervous tissue bycDNA cloning.13

PROSTAGLANDINS AND INFLAMMATION

Prostaglandins (PG) are well-established potentiators ofnociception in both somatic and visceral tissues. In therat, inhibition of PG formation attenuates the behavioralpain response to peritoneal acid exposure but not to du-odenal distention.14 This may be particularly importantin acutely inflamed tissue where a number of other me-diators such as bradykinin, adenosine triphosphate, sub-stance P, and histamine are released together with PG.

HELICOBACTER PYLORI

There are large patient studies that both do15 and donot16,17 support Helicobacter pylori eradication as a treat-ment for nonulcer dyspepsia. H. pylori is known to in-duce mucosal PG synthesis18,19 and may enhance dyspep-sia.20,21 Eradication therapy restores PG levels22 and inthis way may resolve symptoms. On the other hand, fail-ure of benefit may occur either because H. pylori is irrel-evant or because it has a permanent irreversible effect onmucosal sensitivity, possibly through inflammatory dam-age followed by abnormal regeneration of mucosalnerves.

From the Division of Gastroenterology, Queen’s Medical Centre, Uni-versity Hospital, Nottingham, United Kingdom (JJ); and AstraZeneca,Research & Development, Sodertalje, Huddinge, Sweden (JR).

Requests for reprints should be addressed to John Jones, MA, MRCP,Division of Gastroenterology, Queen’s Medical Centre, University Hos-pital, Nottingham NG7 2UH, United Kingdom

14S © 2001 by Excerpta Medica, Inc. 0002-9343/01/$20.00All rights reserved. PII S0002-9343(00)00630-6

CLINICAL INVESTIGATION OF DYSPEPSIA

In dyspepsia, luminal distension is the easiest pain stim-ulus to study. Consequently, a number of studies, includ-ing those minimizing response bias, have shown morepain or lowered pain thresholds in dyspeptic patients.23,24

The evolution of noninvasive techniques for monitoringcentral nervous system activation, such as cortical evokedpotentials, positron emission tomography, and func-tional magnetic resonance imaging, have revealed valu-able information on central pathways of nociception,particularly in response to electrical and distension stim-ulation of the esophagus.25 Distension pain appears to beat least partially vagally mediated, because patients withcervical cord lesions have similar responses. As in the caseof the colon, specific areas of the brain appear to respondto noxious as opposed to nonpainful stimuli, and there issome evidence that acid- and distension-initiated painmay activate different areas of the brain.26

NSAID DYSPEPSIA

NSAID dyspepsia is even less well studied, but becauseacid suppression is often effective,27,28 proton-mediated

nociception may be important. NSAIDs appear to delaygastric emptying, perhaps by interfering with PG-en-hanced motility, but there is no relation to symptoms.29 Itis more likely that NSAID dyspepsia is independent ofcyclooxygenase (COX) inhibition because PGs tend topotentiate pain, and an NSAID with limited COX-inhib-iting activity, sodium salicylate, causes significant gastro-intestinal upset. Other NSAIDs, particularly aspirin, dohave an immediate effect on mucosal integrity. Theycause a rapid decrease in mucosal potential differenceand mucosal pH coincident with a net loss of acid fromthe stomach lumen, consistent with acid back diffu-sion.30,31 It is possible that this acidification of the mu-cosa in response to NSAIDs activates mucosal nocicep-tors, possibly in concert with PGs if the COX inhibitionby the NSAID is incomplete (Figure 1).

FUTURE RESEARCH

Human StudiesLittle has been achieved through exhaustive attempts toclassify dyspepsia by symptoms alone. Most studies onNSAID dyspepsia have been in chronic NSAID users and

Figure 1. Proposed mechanism of nonsteroidal anti-inflammatory drug (NSAID) dyspepsia. NSAIDs disrupt the gastric mucosalbarrier leading to acid back diffusion, opening of proton-sensing ion channels, and activation of mucosal nerves facilitated byprostaglandins (PGs).

A Symposium: NSAID-Associated Dyspepsia/Jones and Raud

January 8, 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 (1A) 15S

may have underestimated the problem by excludingthose with early intolerance. Suffice it to say symptomsexist, but we have almost no information on the relationbetween NSAID dyspepsia and underlying organic dis-ease. As a consequence, we tend to adopt a conservativeapproach to its management that may deny patients aneffective analgesic.

These important questions could be answered by pro-spective endoscopy-based studies on new NSAID users.In those without preexisting symptoms, prevalence andtiming of symptom onset could be recorded. By en-doscoping these symptomatic patients with case controls,it should be possible to determine the relation to under-lying peptic ulcer. Moreover, by using planned intervalendoscopy to compare ulcer incidence in dyspepticNSAID users with nondyspeptic users, it should be pos-sible to determine whether dyspepsia is a risk factor forNSAID complications.

Another fundamental question is whether dyspepsia isCOX dependent. To study these mechanisms, there is aneed for alternatives to luminal distension, which is un-likely to be an important physiological stimulus inNSAID dyspepsia. Ideally, one should use NSAID chal-lenges; however, because they may not provide a consis-tent response, it may be better to use more-establishedneural irritants. Such a model would be of use in theinitial evaluation of novel drugs against dyspepsia.

Animal ModelsAs mentioned above, there are very few animal studies ofgastric nociceptive behavior. A common approach in an-imal (usually rat) studies of visceral pain is to distend thecolon and measure contractions of abdominal musclesusing electromyogram (EMG) technology.32 A similarapproach has been reported for gastric nociception where(presumed) pain was induced by distending the stom-ach.33 Interestingly, the authors found that gastric disten-sion caused raising of the head and stretching of the bodyrather than abdominal contractions. Consequently, EMGwas recorded from neck muscles, and subsequent exper-iments showed that the muscle contractions in responseto gastric distension were sensitive to morphine analge-sia. Although gastric distension in combination withEMG appears useful for studies of gastric pain, it mustalso be pointed out that the different experimental pro-cedures involved are time consuming and the equipmentrather expensive. A considerably simpler approach hasbeen described by Lichtenberger et al,34 who used rats tostudy (presumed) gastric pain induced by peppers. In thisstudy, the classic tail-flick test of radiant heat was used asan indicator of the spice-induced gastric pain, the justifi-cation being that visceral pain in humans is often associ-ated with cutaneous hyperalgesia on the trunk or extrem-ities. The experiments showed that gastric challenge withpeppers indeed shortened the tail-flick latency in appar-

ent correlation to changes in mucosal integrity. However,it is difficult to rule out the possibility that the effects wererelated to systemic uptake of pepper, and control experi-ments with parenteral pepper challenge as well as treat-ment with analgesics would have been of interest from amodel-validation point of view. With regard to validationof gastric pain models in animals, a potentially importantpharmacological validation tool (in addition to analge-sics) would be treatment with proton pump inhibitors(PPIs). Another mode of validation would be to use stim-uli (natural or artificial) that are known to cause gastricpain in humans.

The two studies above indicate that it is indeed possibleto study gastric pain using animal models. Additional ap-proaches to assess the nociceptive behavior could includemeasurements of withdrawal thresholds to mechanicalstimulation of specific skin areas displaying, for example,referred hyperalgesia, motor activity in general (e.g., lo-comotion using telemetry, video-based systems), sponta-neous vocalization, autonomic functions (e.g., heart rateusing telemetry), and food and water intake. Most ofthese techniques should be possible to automate (orsemiautomate) for the purpose of pharmacologicalscreening. Regardless of the test system used, a very inter-esting question is, Does NSAID challenge at all cause de-tectable behavioral nociceptive responses in rodents?

Potential Drug TargetsThere is obviously a wide variety of interesting basic sci-entific questions to address within the area of gastric no-ciception, including the identification of molecularmechanisms that are suitable as targets for new drugseffective against gastric pain. Among the first steps insuch an effort could be evaluation of some of the numer-ous molecular mechanisms putatively involved in so-matic pain (see Millan35 for review). This approach couldinvolve studies of gastric expression of a target receptor/enzyme, changes in pain behavior in transgenic versuswild-type animals, levels and effects of endogenous li-gands and products, and effects of agonists and antago-nists.

Among the different potential targets for future “gas-tric analgesics” are the acid-sensing ion channels (ASICs)ASIC1, ASIC2a (MDEG1), ASIC2b (MDEG2), andASIC3 (DRASIC).13 These are members of the amiloride-sensitive Na1 channel/degenerin family of ion channelsand are expressed in the central and peripheral nervoussystem, where they are suggested to play a role in paincaused by tissue acidosis. Which of the ASICs are respon-sible for acid-induced currents in sensory neurons is notclear, although DRASIC is one interesting candidate be-cause it is present only in peripheral sensory neurons andnot in the brain. Whether ASICs are involved in gastricnociceptive transmission remains to be investigated. An-other interesting group of putative targets is the family of

A Symposium: NSAID-Associated Dyspepsia/Jones and Raud

16S January 8, 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 (1A)

neurokinin (NK) receptors, in particular the NK1 recep-tor. Although NK1 antagonists have failed in differentclinical trials of somatic pain, there are several lines ofevidence indicating that NK receptors may be relativelymore important in visceral rather than somatic pain. Forexample, most visceral afferents seem to express peptideneurotransmitters, and transgenic animals lacking theNK1 receptor develop inflammatory hyperalgesia in so-matic but not visceral tissues.36 A third obvious targetgroup is the prostanoid receptor family. PGs, in particu-lar PGE2 and PGI2, are well known for their ability tosensitize nociceptors to cause inflammatory allodyniaand hyperalgesia.37 The fact that NSAID-induced ulcersare often “silent”38,39 supports the existence of similarmechanisms in the stomach. The effects of PGs are medi-ated by means of G-protein– coupled prostanoid recep-tors that are discriminated according to differential rankorders of agonist potency for the different PGs (e.g.,PGE2/EP-receptor, PGI2/IP-receptor).37 The PGE recep-tors have been divided into four subtypes (EP1, EP2, EP3with splice variants, EP4). An interesting question iswhether PG-induced gastric pain and mucosal protectionare mediated by means of different receptors. There issome evidence to support such a possibility37,40,41; how-ever, better pharmacological tools and further researchwould be required to fully validate this hypothesis. Otherreceptors suggested to be involved in somatic pain in-clude serotonin, vanilloid, opioid, glutamate, purine, andbradykinin receptors,35 all of which would deserve atten-tion from a gastric pain perspective.

CONCLUSIONS

Very little has been done so far to determine the preva-lence of NSAID dyspepsia, its relation to peptic ulcer-ation, and the nociceptive mechanisms that may be in-volved. The tools are now available to study which noci-ceptor interactions are important, but this will requirethe development of new animal models of dyspepsia be-fore further therapeutic advances in patients are possible.

REFERENCES1. Cervero F, Janig W. Visceral nociceptors: a new world

order? Trends Neurosci. 1992;15:374–378.2. Sengupta JN, Kauver D, Goyal RK. Characteristics of vagal

esophageal tension-sensitive afferent fibers in the opos-sum. J Neurophysiol. 1989;61:1001–1010.

3. Sengupta JN, Saha JK, Goyal RK. Stimulus–response func-tion studies of esophageal mechanosensitive nociceptorsin sympathetic afferents of opossum. J Neurophysiol. 1990;64:796–812.

4. Habler H-J, Janig W, Koltzenburg M. Activation of unmy-elinated afferent fibres by mechanical stimuli and inflamma-tion of the urinary bladder in the cat. J Physiol. 1990;425:545–562.

5. Leek BF. Abdominal and pelvic visceral receptors. Br MedBull. 1977;33:163–168.

6. Steen KH, Reeh PW. Sustained graded pain and hyperal-

gesia from harmless experimental tissue acidosis in humanskin. Neurosci Lett. 1993;154:113–116.

7. Steen KH, Issberner U, Reeh PW. Pain due to experimentalacidosis in human skin: evidence for non-adapting noci-ceptor excitation. Neurosci Lett. 1995;199:29–32.

8. Geppetti P, Tramontana M, Patacchini R, Del Bianco E,Santicioli P, Maggi CA. Neurochemical evidence for theactivation of the “efferent” function of capsaicin-sensitivenerves by lowering of the pH in the guinea-pig urinarybladder. Neurosci Lett. 1990;114:101–106.

9. Geppetti P, Del Bianco E, Patacchini R, Santicioli P, MaggiCA, Tramontana M. Low pH-induced release of calcitoningene-related peptide from capsaicin-sensitive sensorynerves: mechanism of action and biological response. Neu-roscience. 1991;41:295–301.

10. Bevan S, Geppetti P. Protons: small stimulants of capsa-icin-sensitive sensory nerves. Trends Neurosci. 1994;17:509–512.

11. Baumann TK, Burchiel KJ, Ingram SL, Martenson ME. Re-sponses of adult human dorsal root ganglion neurons inculture to capsaicin and low pH. Pain. 1996;65:31–38.

12. Garcia-Hirschfeld J, Lopez-Briones LG, Belmonte C,Valldeolmillos M. Intracellular free calcium responses toprotons and capsaicin in cultured trigeminal neurons. Neu-roscience. 1995;67:235–243.

13. Waldmann R, Champigny G, Lingueglia E, De Weille JR,Heurteaux C, Lazdunski M. H1-gated cation channels. AnnN Y Acad Sci. 1999;868:67–76.

14. Deleo JA, Colburn RW, Coombs DW, Ellis MA. The differ-entiation of NSAIDs and prostaglandin action using a me-chanical visceral pain model in the rat. Pharmacol BiochemBehav. 1989;33:253–255.

15. McColl K, Murray L, El-Omar E, et al. Symptomatic benefitfrom eradicating Helicobacter pylori infection in patientswith nonulcer dyspepsia. N Engl J Med. 1998;339:1869–1874.

16. Blum AL, Talley NJ, O’Morain C, et al. Lack of effect oftreating Helicobacter pylori infection in patients with non-ulcer dyspepsia. N Engl J Med. 1998;339:1875–1881.

17. Talley NJ, Janssens J, Lauritsen K, Racz I, Bolling-Sternevald E. Eradication of Helicobacter pylori in func-tional dyspepsia: randomised double blind placebo con-trolled trial with 12 months’ follow up. BMJ. 1999;318:833–837.

18. Rommano M, Ricci V, Memoli A, et al. Helicobacter pyloriup-regulates cyclooxygenase-2 mRNA expression andprostaglandin E2 synthesis in MKN 28 gastric mucosal cellsin vitro. J Biol Chem. 1998;273:28560–28563.

19. Jackson LM, Wu K, Mahida YR, Jenkins D, Donnelly MT,Hawkey CJ. Cox-1 expression inhuman gastric mucosainfected with Helicobacter pylori: constitutive or induced[abstract]? Gastroenterology. 1998;114:A160.

20. Hudson N, Balsitis M, Filipwicz F, Hawkey CJ. Effect ofHelicobacter pylori colonisation on gastric mucosal eico-sanoid synthesis in patients taking non-steroidal anti-in-flammatory drugs. Gut. 1993;34:748–751.

21. Goggin PM, Collins DA, Jazrawi RP, et al. Prevalence ofHelicobacter pylori infection and its effect on symptomsand non-steroidal anti-inflammatory drug induced gastro-intestinal damage in patients with rheumatoid arthritis. Gut.1993;34:1677–1680.

22. Oderda G, D’Alessandro M, Mariani P, et al. ProstaglandinE2 in gastric mucosa of children with Helicobacter pylorigastritis: relation to thickness of mucus gel layer. J ClinPathol. 1993;46:836–839.

A Symposium: NSAID-Associated Dyspepsia/Jones and Raud

January 8, 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 (1A) 17S

23. Salet GA, Samsom M, Roelofs JM, van Berge HenegouwenGP, Smout AJ, Akkermans LM. Responses to gastric dis-tension in functional dyspepsia. Gut. 1998;42:823–829.

24. Mertz H, Fullerton S, Naliboff B, Mayer EA. Symptoms andvisceral perception in severe functional and organic dys-pepsia. Gut. 1998;42:814–822.

25. Aziz Q, Thompson DG. Brain–gut axis in health and dis-ease. Gastroenterology. 1998;114:559–578.

26. Kern MK, Birn RM, Jaradeh S, et al. Identification andcharacterization of cerebral cortical response to esopha-geal mucosal acid exposure and distention. Gastroenterol-ogy. 1998;115:1353–1362.

27. Van Groenendael JHLM, Markusse HM, Dijkmans BAC,Breedveld FC. The effect of rantidine on NSAID relateddyspeptic symptoms with and without peptic ulcer diseaseof patients with rheumatoid arthritis and osteoarthritis. ClinRheumatol. 1996;15:450–456.

28. Bijlsma JWJ. Treatment of endoscopy-normal NSAID-in-duced upper gastrointestinal symptoms with cimetidine: aninternational multicentre collaborative study. Aliment Phar-macol Ther. 1988;2S:75–83.

29. Kulkarni SG, Parikh SS, Shankhpal PD, et al. Gastric emp-tying of solids in long-term NSAID users: correlation withendoscopic findings and Helicobacter pylori status. Am JGastroenterol. 1999;94:382–386.

30. Kivilaakso E, Silen W. Pathogenesis of experimental gas-tric-mucosal injury. N Engl J Med. 1979;301:364–369.

31. Chvasta TE, Cooke AR. The effect of several ulcerogenicdrugs on the canine gastric mucosal barrier. J Lab ClinMed. 1972;79:302–315.

32. Coutinho SV, Gebhart GF. A role for spinal nitric oxide in

mediating visceral hyperalgesia in the rat. Gastroenterol-ogy. 1999;116:1399–1408.

33. Rouzade ML, Fioramonti J, Bueno L. A model for evaluationof gastric sensitivity in awake rats. Neurogastroenterol Mo-til. 1998;10:157–163.

34. Lichtenberger LM, Romero JJ, Carryl OR, Illich PA, WaltersET. Effect of pepper and bismuth subsalicylate on gastricpain and surface hydrophobicity in the rat. Aliment Phar-macol Ther. 1198;12:483–490.

35. Millan MJ. The induction of pain: an integrative review. ProgNeurobiol. 1999;57:1–164.

36. Cervero F, Laird JM. Visceral pain. Lancet. 1999;353:2145–2148.

37. Bley KR, Hunter JC, Eglen RM, Smith JA. The role of IPprostanoid receptors in inflammatory pain. TIPS. 1998;19:141–147.

38. Festen HP. Diagnosis of gastrointestinal lesions duringtreatment with non-steroidal anti-inflammatory drugs. Ali-ment Pharmacol Ther. 1988;2(suppl 1):113–119.

39. Agrawal NM. Anti-inflammatories and gastroduodenaldamage: therapeutic options. Eur J Rheumatol Inflamm.1993;13:17–24.

40. Morimoto K, Sugimoto Y, Katsuyama M, et al. Cellularlocalization of mRNAs for prostaglandin E receptor sub-types in mouse gastrointestinal tract. Am J Physiol. 1997;272:G681–G687.

41. Takeuchi K, Ukawa H, Furukawa O, et al. Prostaglandin Ereceptor subtypes involved in stimulation of gastroduode-nal bicarbonate secretion in rats and mice. J Physiol Phar-macol. 1999;50:155–167.

A Symposium: NSAID-Associated Dyspepsia/Jones and Raud

18S January 8, 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 (1A)