EDITORIAL

Preventing nonsteroidal anti-inflammatory drug–inducedsmall-bowel injury: the saga continues

Nonsteroidal anti-inflammatory drugs (NSAIDs) are ex-tensively prescribed for relief of pain and inflammation as-sociated with arthritis, but their benefits are often offsetby the morbidity and mortality related to their GI adverseeffects. It has been estimated that 50% of all peptic ulcer–related bleeding could be attributed to NSAID use,1 and40% of serious GI events originate distally, below the liga-ment of Treitz.2 NSAIDs exert their anti-inflammatory andanalgesic action through inhibition of prostaglandin synthe-sis. The rate-limiting step in the synthesis of prostaglandinsinvolves the cyclooxygenase (COX) enzymes. The COX-1isomer of cyclooxygenase is constitutively expressed inthe gut and is believed to play a pivotal role in protectingthe GI mucosa. The COX-2 isomer, by contrast, is oftenupregulated in various inflammatory states and is the ther-apeutic target for selective and nonselective anti-inflamma-tory drugs.

NSAIDS AND SMALL-BOWEL INJURY

NSAIDs can cause a spectrum of disease in the smallbowel, which may range from asymptomatic and occult GIbleeding that causes iron deficiency anemia to unexplainedhypoalbuminemia that results from increased intestinal per-meability, with protein loss. Symptomatic disease can occuras a result of NSAID-induced webs, strictures, and dia-phragms that lead to small-bowel obstruction, along withovert GI bleeding and small-bowel perforation.3

The mechanism of small-bowel injury caused by NSAIDsremains to be fully elucidated. A study by Bjarnason et al3

suggested that the inciting event is the disruption of mito-chondrial energy metabolism in the intestinal epithelialcells caused by NSAID-induced uncoupling of oxidativephosphorylation with adenosine triphosphate (ATP) deple-tion. The depletion of mitochondrial ATP in the enterocytesleads to increased intestinal permeability. The intestinal bar-rier function is further weakened by the NSAID-inducedprostaglandin depletion. Luminal contents, such as bileacids, overwhelm the weakened intestinal mucosal defensemechanisms and leads to intestinal inflammation andulceration.

Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy

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doi:10.1016/j.gie.2008.10.014

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ASSESSING SMALL-BOWEL INJURY BY USINGWIRELESS CAPSULE ENDOSCOPY

Before the advent of capsule endoscopy, the small bowelremained largely inaccessible to direct observation. Allisonet al4 reported NSAID-induced small-intestinal lesionsthrough postmortem examination of the stomach, duode-num, and small intestine. The prevalence of nonspecificsmall-intestinal ulcerations was 8.4% in the 249 patientswho had used NSAIDS during the 6 months before their de-mise versus 0.6% in the 464 patients who had not used

NSAIDs (P ! .001); 3 patients died from NSAID-inducedsmall-intestinal perforation. Because the NSAID group in-cluded patients who had used NSAIDs either intermittentlyor daily, the results underestimated the true incidence ofNSAID-induced small-bowel injury. Other studies reportedon the prevalence of NSAID-induced enteropathy by measur-ing surrogate markers of inflammation, such as fecal calpro-tectin and indium In 111 labeled leukocytes. Althoughsensitive, these tests are complex, not widely used, and non-specific to the precise nature of small-bowel inflammation.Graham et al5 used capsule endoscopy to assess the extentof small-bowel mucosal injury among 41 patients who werechronic NSAID users (O3 months’ duration) and foundthat 71% of them had evidence of small-bowel injury com-pared with 10% of controls (P ! .001). Capsule endoscopyalso proved to be useful for comparing the small-bowel toxic-ity of COX-2 selective inhibitors and nonselective anti-inflam-matory drugs administered concurrently with a proton pumpinhibitor.6 In healthy subjects who had lesion-free baselinecapsule endoscopy, acute (2 weeks) administration of cele-coxib caused fewer mucosal breaks compared with naproxenplus omeprazole. Results of this study suggest that

The clinical relevance and predictive value ofendoscopically detected mucosal lesions inthe small intestine and their correlation to de-veloping signs and symptoms of nonsteroidalanti-inflammatory drug enteropathy remainto be fully established.

Volume 69, No. 7 : 2009 GASTROINTESTINAL ENDOSCOPY 1347

Editorial Tadiparthi & Agrawal

concurrent administration of proton pump inhibitors was anineffective strategy in protecting the small bowel from NSAID-induced injury, possibly because NSAID enteropathy is notacid mediated. The COX-2 selective inhibitors showed prom-ise in reducing upper-GI and lower-GI toxicity, but increasingconcerns about their cardiovascular adverse effects led to a re-duction in their usage. In addition, capsule endoscopy studiesindicate that the extent of small-bowel injury caused by COX-2selective agents does not differ significantly from NSAIDswhen used over a long period (O3 months).7

IS MISOPROSTOL THE ANSWER?

Misoprostol is a synthetic prostaglandin E1 analog that hasbeen shown to be effective in preventing gastroduodenal ulcer-ationwhenadministeredconcurrentlywithNSAIDsand is supe-rior to ranitidine and sucralfate in preventing NSAID-induced gastric ulceration.8 Misoprostol acts in multiple ways:it enhances mucosal defenses by replacing the NSAID-sup-pressed endogenous prostaglandins, increases mucosal bloodflow, stimulates bicarbonate production, inhibits gastric-acid se-cretion, and helps protect microvascular integrity, which pre-serves the ability of mucosa to reepithelialize damagedtissue.9 Silverstein et al,10 in a randomized, double-blind, pla-cebo-controlled trial that involved 8843 NSAID users showedthat concurrent administration of misoprostol led to a 40% re-duction in the incidence of serious upper-GI complications.The potential role of misoprostol in preventing NSAID enterop-athy has been indirectly assessed in the past by Morris et al,11

who reported that, in patients with iron deficiency anemia sec-ondary to enteroscopically proven NSAID-induced small-bowelinjury, mean hemoglobin levels improved significantly when mi-soprostol was coadministered with NSAIDs compared with thegroup that did not receive misoprostol (P! .004).

In the present study, Fujimori et al12 for the first timeuse capsule endoscopy to directly assess the impact ofconcurrent misoprostol administration in preventingNSAID-induced small-bowel injury. This is a single-center, sin-gle-blind, prospective trial in which 34 healthy volunteerswere randomized to either the NSAID-control group or theNSAID prostaglandin (PG) group. Patients in both groups re-ceived diclofenac 25 mg 3 times a day along with omeprazole20 mg once a day. The NSAID-PG group received 200 mg mi-soprostol 3 times a day in addition to the diclofenac and ome-prazole treatment. Fifteen eligible subjects in each groupunderwent capsule endoscopy before and 14 days after treat-ment. Mucosal breaks were described as lesions with sloughsurrounded by erythema and these lesions were systemati-cally quantified in both groups. A statistically significant in-crease in the mean (� SD) number of mucosal breaks wasnoted in the NSAID-control group after treatment from 0.1� 0.3 up to 2.9 � 6.3 (P Z .012); however, the NSAID-PGgroup had no significant change in the mean number ofmucosal breaks before and after treatment (P Z .42). The

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percentage of subjects with at least 1 mucosal break in-creased from 6.7% to 53.3% in the NSAID–control group 2weeks after treatment, whereas no change in incidence wasseen among the NSAID-PG group, which remained at13.3%. The results of this pilot study are very encouraging,but, as cautioned by Fujimori et al,12 certain study limitationspreclude drawing firm conclusions. This was a small, open-la-bel trial that may have led to biased results; in addition, thesubjects enrolled were young healthy volunteers who tookNSAIDs for a short period. It remains to be seen whether re-sults from this study can be extrapolated to an older popula-tion with multiple comorbidities and dependent on NSAIDsfor daily relief of pain. NSAIDs tend to cause toxicity in a dose-dependant manner, and one must note that the dose of diclo-fenac used in this study was lower than the dose typicallyused by patients for relief of pain from arthritis, which tendsto be closer to 100 to 150 mg per day. Furthermore, the clin-ical relevance and predictive value of endoscopically de-tected mucosal lesions in the small intestine and theircorrelation to developing signs and symptoms of NSAID en-teropathy remains to be fully established. The tolerability ofmisoprostol must also be given due consideration. Misopros-tol stimulates smooth-muscle contraction in the GI tract andcan lead to abdominal cramping and diarrhea. In the currentstudy, 3 patients in the NSAID-PG arm had mild diarrhea. Mi-soprostol must be used with caution in premenopausalwomen, because it can induce uterine smooth-musclecontraction.

It is interesting to note that Fujimori et al12 used omepra-zole in the NSAID-control group as well as in the NSAID-PGgroup. A major stumbling block to cotherapy is patient com-pliance and the cost of drug therapy. Because misoprostolhas proven efficacy in preventing upper-GI injury fromNSAIDs and the results from the present study indicate itspossible role as an agent to prevent small-bowel injury,Arthrotec (Pfizer Inc, New York, NY), a drug that combinesdiclofenac with misoprostol (available as 50 mg and 75 mgdiclofenac combined with 200 mg misoprostol), may bea better alternative for future studies on this subject.

In conclusion, NSAIDs can cause significant small-bowelinjury, and effective strategies for protection against NSAID-induced small-bowel injury are currently lacking. The effi-cacy of misoprostol in protecting the small bowel fromNSAIDs will need to be validated by long-term randomizedstudies among chronic NSAID users.

DISCLOSURE

All authors disclosed no financial relationships rele-vant to this publication.

Rashmi Tadiparthi, MDNaurang M. Agrawal, MD

Division of Gastroenterology/HepatologyKansas University Medical Center

Kansas City, Kansas, USA

www.giejournal.org

Tadiparthi & Agrawal Editorial

Abbreviations: ATP, adenosine triphosphate; COX, cyclooxygenase enzyme;

NSAID, nonsteroidal anti-inflammatory drug; PG, prostaglandin.

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