INTRODUCTION — The distal small bowel and colon are susceptible to the deleterious effects of nonsteroidal antiinflammatory drugs (NSAIDs) [1-4]. The ileocecal region is a potential site for a variety of NSAID-induced injuries including erosions, ulcers, strictures, perforation, and the formation of diaphragms, which can lead to bowel obstruction [5-8]. NSAIDs can also lead to colitis resembling inflammatory bowel disease (IBD), exacerbate preexisting IBD, or complicate diverticular disease (ie, perforation or bleeding) [9,10]. Older adults and those on long-term NSAID therapy appear to be at highest risk [10]. There may also be an association between NSAID use and collagenous colitis. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management".)
STUDIES OF NSAID INJURY — A number of studies using different methodologies have evaluated the potential deleterious effects of nonsteroidal antiinflammatory drugs (NSAIDs) on the small bowel and colon. Considered together, they suggest that NSAID-related intestinal injury is common. However, the proportion of patients who develop clinically important NSAID-induced enteropathy remains relatively small.
The following summarizes the range of findings:
●Approximately two-thirds of NSAID users demonstrate intestinal inflammation by indirect methods of 111-Indium-labeled leukocyte scintigraphy and 111-Indium fecal excretion [11].
●In a case-control study, patients with small or large bowel perforation or bleeding were more than twice as likely to be NSAID users [12].
●An autopsy study evaluated 713 patients, 249 of whom had used NSAIDs in the six months prior to death [13]. Nonspecific small intestinal ulceration (defined as ulcers >3 mm in diameter) was much more common in those who had taken NSAIDs (8.4 versus 0.6 percent in nonusers). Three of the 21 patients with small intestinal ulcers died from perforation of an intestinal ulcer.
●A study involving double balloon enteroscopy found that 50 percent of NSAID users had small bowel mucosal breaks compared with only 5 percent in controls [14].
●At least six studies have used video capsule endoscopy to assess small bowel injury associated with NSAIDs, two of which [1,15] had a randomized design [1-4,15,16]. A common finding is the observation that small bowel mucosal abnormalities are relatively common in healthy individuals. In one study, for example, 7 percent of placebo treated patients developed such findings during the course of the study, and an additional 14 percent of healthy subjects who had been screened for the study were excluded because of baseline mucosal abnormalities [1].
COX-2 inhibitors — Studies evaluating the relative safety of COX-2 inhibitors versus nonselective NSAIDs have shown mixed results. Considered together, they suggest that COX-2 inhibitors are not fully protective against clinically important lower gastrointestinal (GI) events and may not be more protective than some nonselective NSAIDs.
●By far the largest study included 34,701 patients with osteoarthritis or rheumatoid arthritis who were older than 50 who were randomly assigned to etoricoxib (60 or 90 mg daily) or diclofenac (150 mg daily) for an average of 18 months [17]. Major lower GI clinical events (such as gross or occult rectal bleeding with hemodynamic instability without an upper GI cause) occurred in a similar proportion of patients (0.32 versus 0.38 per 1000 patient-years, respectively). On multivariable analysis, risk factors included a prior lower GI event (hazard ratio [HR] 4.06) or age ≥65 (HR 1.98).
●By contrast, an earlier post-hoc analysis of a large outcome study found a 54 percent reduction in the risk of lower GI events with rofecoxib compared with naproxen [18]. A possible explanation for the difference is that naproxen is a more potent inhibitor of platelet function than diclofenac, thus increasing the rate of lower GI events in the comparator group.
●Other studies have compared COX-2 inhibitors to combination therapy with a proton pump inhibitor plus a nonselective NSAID. One trial included 120 healthy volunteers who were randomly assigned to celecoxib, naproxen plus omeprazole, or placebo [1]. After two weeks, all patients underwent video capsule endoscopy. Significantly more mucosal breaks were observed in the naproxen-omeprazole group compared with the celecoxib group. The proportion of patients with mucosal breaks was correspondingly higher (55 versus 16 and 7 percent in the naproxen-omeprazole, celecoxib, and placebo groups, respectively). Similar conclusions were reached in a second controlled trial that compared lumiracoxib with the combination of naproxen plus omeprazole or placebo [15]. Acute small bowel injury on lumiracoxib was less frequent than with naproxen plus omeprazole and similar to placebo.
These data suggest relative protection of the COX-2 inhibitors compared with nonselective NSAIDs plus omeprazole against small bowel injury during short-term follow-up. However, the significance of mucosal breaks is unclear. As noted above, there was no difference on major lower GI events in the large randomized study described above. Furthermore, a nonrandomized cohort study found similar rates and types of small bowel injury with long-term use of COX-2 selective agents versus nonselective NSAIDs [4].
Misoprostol — Whether misoprostol decreases the risk of small bowel lesions from NSAIDs has not been well studied. A small observational study suggested a protective benefit in patients taking enteric-coated low-dose aspirin [19]. Placebo-controlled trials are needed to confirm a potential benefit.
PATHOGENESIS — In an attempt to decrease gastroduodenal side effects, the use of enteric-coated, sustained-release, or slow-release nonsteroidal antiinflammatory drugs (NSAIDs) may have shifted the damage to the distal small intestine and colon. A high local concentration of an active NSAID following ingestion or biliary excretion is necessary to increase intestinal permeability, which appears to be a prerequisite for NSAID-induced enteropathy [11,20]. The latter effect, which may be associated with increased bacterial growth, is much more likely to occur with NSAIDs that undergo enterohepatic circulation; secretion of the drug in the bile leads to repeated exposure of the intestinal mucosa to the toxic drug [21]. Studies in an animal model with two related NSAIDs found a progressive increase in epithelial permeability and intestinal ulceration only with the drug that underwent enterohepatic circulation [21].
NSAIDs may also exert their deleterious effect by localized mucosal injury. In support of this hypothesis are the observations that NSAID capsules have been found at the site of perforating ulcers, that areas of mucosal injury often have sharp demarcations, and that the distal small bowel and proximal colon are typically involved [6,22]. At the mucosal level, postulated mechanisms of injury have included inhibition of protective prostaglandins, alterations in blood flow, and increased small intestinal permeability with subsequent invasion by luminal factors [5]. The mucosal damage may lead to inflammation and ulceration, followed by reparative fibrosis and stricture formation.
Suppression of gastric acid secretion by proton pump inhibitors (PPIs) is unlikely to provide protection against NSAID-induced damage to the small intestine. In fact, in animal studies PPIs have been demonstrated to exacerbate NSAID-induced intestinal damage due to shifts in enteric microbial populations [23].
The role of the intestinal microbiota in NSAID-induced enteropathy and use of potential therapeutic agents, such as probiotics and rifaximin, are unclear [24,25].
CLINICAL MANIFESTATIONS AND DIAGNOSIS — It is likely that most nonsteroidal antiinflammatory drug (NSAID)-induced injuries are subclinical and go unrecognized. When present, symptoms and signs are nonspecific and may include iron deficiency anemia and/or frank bleeding from ulcers; anemia, hypoalbuminemia, or malabsorption from enteropathy; intermittent or complete bowel obstruction from broad-based or diaphragm-like strictures; watery or bloody diarrhea from colitis; and acute abdomen from perforation. The typical patient is one taking an NSAID for a rheumatic condition, such as osteoarthritis or rheumatoid arthritis. The duration of NSAID use to time of diagnosis is widely variable (days to years).
Virtually all classes of NSAIDs that block both COX-1 and COX-2 have been implicated. Whether the relative safety of the COX-2 selective inhibitors on gastroduodenal injury will be observed in the small and large bowel remains to be established.
Intestinal diaphragms — A lesion thought to be pathognomonic of NSAID injury is the diaphragm-like stricture (picture 1), which is likely a scarring reaction secondary to ulcerative injury. These lesions are thin, concentric, diaphragm-like septa with pinhole-sized lumen (picture 2). They are usually multiple, found mostly in the mid-intestine, but have also been described in the ileum and colon [6-8,11,26]. They are histologically characterized by submucosal fibrosis with normal overlying epithelium, apart from tip of diaphragm, which may be ulcerated. The mucosa between diaphragms is normal. As a potential cause of subacute obstruction, these strictures are difficult to diagnose since they may appear as exaggerated plica circularis under radiographic imaging (picture 3). At laparotomy, the surgeon should be alerted to this possibility, since the exterior aspect may look normal and the strictures difficult to palpate. In this regard, intraoperative enteroscopy is helpful.
Endoscopic and histologic findings — Findings on capsule endoscopy [2], balloon-assisted enteroscopy [27], and/or colonoscopy may lend support to the diagnosis of NSAID-induced injury, although there is nothing endoscopically specific about NSAID-induced erosions, ulcers (picture 4), or colitis. Histology is also nonspecific. The differential diagnosis should thus include infectious etiologies (eg, Campylobacter, Yersinia, cytomegalovirus, TB), irritable bowel disease, ischemia, radiation enteritis, vasculitides, and other drugs (eg, potassium chloride tablets) [5,6,28]. However, the right diagnosis can usually be made in conjunction with a good history and endoscopic biopsies. Furthermore, the above NSAID-induced lesions (other than strictures and diaphragms) should improve or completely resolve upon withdrawal of the drug. Endoscopic findings of cobblestoning, longitudinal ulcers, or inflammatory polyps, and histologic findings of granulomas, crypt abscesses, or crypt distortion should suggest Crohn disease instead of NSAIDs. Similarly, the presence of vasculitis on biopsy would favor a collagen vascular disorder. As mentioned above, the diaphragm-like strictures are characteristic for NSAID injury.
Assessment of intestinal permeability — Intestinal permeability can be assessed experimentally by measurement of urinary recovery of orally administered test probes such as 51Cr-EDTA [20]. Similarly, localization and quantification of intestinal inflammation can be assessed by 111-Indium-labeled leukocyte scintigraphy and 111-Indium fecal excretion, respectively [11]. Although these radionuclide tests have shed some light on the pathogenesis of NSAID-induced injury, they are of limited clinical use due to lack of availability and their expense.
MANAGEMENT — The mainstay of treatment for nonsteroidal antiinflammatory drug (NSAID)-induced injury is discontinuation of the NSAID [29]. For nonstrictured ileocecal lesions, this is usually followed by prompt improvement. If performed, a repeat colonoscopy six to eight weeks later should confirm partial or complete resolution of ulcerations and/or colitis. However, a follow-up colonoscopy is not necessary in the setting of a history and biopsy findings supportive of the diagnosis, as well as symptom resolution. Persistence or worsening of symptoms should raise suspicion for Crohn disease or other causes and investigated accordingly.
Obstructive symptoms due to strictures are unlikely to resolve without some form of intervention. Endoscopically accessible strictures or diaphragms may be amenable to through-the-scope balloon dilatation (picture 5) [30] or needle-knife electroincision (picture 6). However, the diaphragm-like strictures tend to be multiple, often requiring resection of the involved intestinal segment, and, less commonly, strictureplasty [31]. At laparotomy, the absence of serosal abnormalities or palpable areas of transition pinpointing to the enteropathy may be problematic. In such cases, an intraoperative enteroscope placed perorally or through a surgical enterostomy can be used to accurately localize and evaluate the extent of disease, and to better define the intestinal margins for resection [32,33]. Surgery is also indicated for other NSAID-induced complications such as significant bleeding or perforation, and when carcinoma cannot be reliably excluded [6].
SUMMARY AND RECOMMENDATIONS
●Nonsteroidal antiinflammatory drug (NSAID)-related intestinal injury is common. However, the proportion of patients who develop clinically important NSAID-induced enteropathy is relatively small. (See 'Studies of NSAID injury' above.)
●COX-2 inhibitors are not fully protective against clinically important lower gastrointestinal events and may not be more protective than some nonselective NSAIDs. (See 'COX-2 inhibitors' above.)
●Studies are needed to determine if misoprostol decreases the risk of small bowel lesions from NSAIDs. (See 'COX-2 inhibitors' above and 'Misoprostol' above.)
●Most NSAID-induced injuries are subclinical. When present, symptoms and signs of NSAID injury are nonspecific and may include iron deficiency anemia and/or frank bleeding from ulcers; anemia, hypoalbuminemia, or malabsorption from enteropathy; intermittent or complete bowel obstruction from broad-based or diaphragm-like strictures; watery or bloody diarrhea from colitis; and acute abdomen from perforation. (See 'Clinical manifestations and diagnosis' above.)
●Intestinal diaphragms are pathognomonic of NSAID injury. In contrast, erosions, ulcers, or colitis may be due to NSAIDs or another etiology. However, these lesions should improve or completely resolve upon withdrawal of the drug. (See 'Intestinal diaphragms' above and 'Endoscopic and histologic findings' above.)
●The mainstay of treatment for NSAID-induced injury is discontinuation of the NSAID.
For nonstrictured ileocecal lesions, discontinuation of the NSAID is usually followed by prompt improvement. If performed, a repeat colonoscopy six to eight weeks later should confirm partial or complete resolution of ulcerations and/or colitis. However, a follow-up colonoscopy is not necessary in the setting of a history and biopsy findings supportive of the diagnosis, as well as symptom resolution. Persistence or worsening of symptoms should raise suspicion for Crohn disease or other causes and investigated accordingly.
For strictures or diaphragms causing obstructive symptoms, through-the-scope balloon dilatation or needle-knife electroincision should be performed if they are endoscopically accessible. However, diaphragm-like strictures tend to be multiple, and resection and/or strictureplasty of the involved intestinal segment may be required.
Surgery is indicated for other NSAID-induced complications such as significant bleeding or perforation, and when carcinoma cannot be reliably excluded. (See 'Management' above.)
