Colitis Induced by Nonsteroidal Anti-inflammatory Drugs

Colitis Induced by Nonsteroidal Anti-inflammatory DrugsReport of Four Cases and Review of the Literature

Gary R. Gibson, MD; Eric B. Whitacre, MD; Carlos A. Ricotti, MD

In four patients, ulcerative disease of the colon developedwhile they were taking nonsteroidal anti-inflammatorydrugs (NSAIDs). Clinical presentation and laboratory andcolonoscopic findings were similar to those of inflammatorybowel disease. Review of the literature disclosed 74 addi-tional cases of NSAID-induced colitis in adults. This is a rarebut serious, sometimes fatal, complication of NSAID ther-apy. The elderly and those taking long-term NSAID therapyappear to be at highest risk. The pathogenesis is thought tobe related to inhibition of intestinal prostaglandin synthesis.Whether some NSAIDs are more likely to induce colitis thanothers is not known. Since NSAIDs are so widely prescribedand some are available without a prescription, heightenedawareness by physicians and the lay public will be impor-tant in reducing injury from this disease, both by preventionand earlier recognition.

(Arch Intern Med. 1992;152:625-632)

Nonsteroidal anti-inflammatory drugs (NSAIDs) havegained wide popularity in recent years. This is due

in part to a favorable safety profile when compared withthose of steroids or narcotic analgesics, particularly in thesetting of long-term therapy.

Ulcerogenic effects of NSAIDs on the upper gas¬trointestinal tract are well known. However, little hasbeen written in the US prescribing information or stan¬dard reference literature about effects of NSAIDs on thedistal small bowel and colon. In the 1991 Physicians' DeskReference, for example, many NSAIDs have no mention ofcoUtis as an adverse drug effect.

We treated four cases of colitis induced by NSAIDs.These patients all presented within 1 year in a single in¬ternal medicine practice; if representative of the geriatricpopulation, these cases indicate that coUtis due toNSAIDs is neither rare nor benign. We also reviewed theliterature concerning NSAID-induced colitis in adults.Most of the reported cases and two excellent reviews have

come from Europe. Increased awareness of the problemin the United States is needed.

REPORT OF CASESCase 1.—An 82-year-old woman was admitted to the hospital

with weakness and anemia. Three months earlier, diclofenacsodium (Voltaren, Ciba-Geigy Corp, Summit, NJ), 75 mg twicea day, had been prescribed for left hip pain due to osteoarthri-tis. The hemoglobin at that time was 135 g/L (normal, 120 to150 g/L). The left hip pain improved dramatically, but the patientdeveloped weakness and diarrhea and lost 5.5 kg.

On admission, her abdomen was nontender. The hemoglobinlevel was 86 g/L; white blood cell count, 12.9 x 107L; serum ironlevel, 2 p.mol/L (normal, 11 to 29 pmol/L); iron-binding capacity,51 p,mol/L (normal, 45 to 82 pmol/L); creatinine level, 110 pmol/L(normal, 50 to 110 ujmol/L); albumin level, 32 g/L (normal, 40 to60 g/L); total protein level, 68 g/L (normal, 60 to 80 g/L); andWestergren erythrocyte sedimentation rate (ESR), markedly el¬evated at 140 mm/h (normal, 0 to 30 mm/h). The aspartate ami-notransferase level was 16 U/L (normal, 0 to 35 VfL), and thealanine aminotransferase level was 11 U/L. The stool was posi¬tive for occult blood.

The patient received a transfusion of 2 U of packed red bloodcells, and the hemoglobin level rose to 117 g/L. Colonoscopy re¬vealed multiple patchy areas of erosion and superficial ulcérationin the ascending colon and proximal transverse colon. Gas-troduodenoscopy showed a duodenal ulcer without signs of ac¬tive or recent bleeding. Diagnoses of NSAID-induced colitis andpeptic ulcer disease were made. Diclofenac treatment was discon¬tinued, and sucralfate was given. One month after discharge, shefelt well except for the return of some arthritis pain. The hemo¬globin level was 114 g/L, and the ESR had fallen to 51 mm/h.

Case 2. —A 75-year-old woman was admitted to the hospitalwith night sweats, weakness, and anemia. She had a long his¬tory of osteoarthritis and had been taking NSAIDs for the past3 years. These included diflunisal (Dolobid, Merck & Co Inc,West Point, Pa) and piroxicam (Feldene, Pfizer Inc, New York,NY) at different times in the past and naproxen (Naprosyn,Syntex Laboratories Inc, Palo Alto, Calif), 375 mg twice a day, forthe month before admission. She had lost 8.2 kg in the preced¬ing 6 months.

On examination, the patient was morbidly obese. The abdo¬men was tender in both lower quadrants, but without guarding.Tests on admission showed a hemoglobin level of 92 g/L; whiteblood cell count, 9.5xl09/L; ESR, 143 mm/h; albumin level,31 g/L; total protein level, 73 g/L; creatinine level, 100 pmol/L;and alanine aminotransferase level, 20 U/L.

Colonoscopy revealed erosions and a cecal ulcer as well as

sigmoid diverticulosis with spasm. The mucosal erosions were

Accepted for publication July 31, 1991.From the Departments of Medicine (Drs Gibson and Ricotti)

and Surgery (Dr Whitacre), Trumbull Memorial Hospital, War-ren, Ohio.

Reprint requests to 1651 E Market St, Warren, OH 44483 (DrGibson).

Downloaded From: http://archinte.jamanetwork.com/ by a University of Massachusetts User on 08/28/2013

thought to be due to NSAIDs; no biopsy specimens were taken.On the 5th hospital day, the patient developed increasedabdominal pain and signs of peritonitis. At surgery, an acuteperforation of the cecum and a chronic sigmoid diverticular ab¬scess were found. She underwent right hemicolectomy and sig¬moid resection with end colostomy and Hartmann's pouch. Sherecovered and was discharged after 40 days in the hospital. Eightweeks after discharge, she was doing well. The hemoglobin levelhad risen to 120 g/L, and the ESR had faUen to 61 mm/h. She hastaken no further NSAIDs.

Case 3.—A 71-year-old man was admitted to the hospital withfever, night sweats, and a 9-kg weight loss. He had rheumatoidarthritis, hypertension, and a 25-year history of diabetes melli-tus. His medications were enteric-coated aspirin (Easprin, Parke-Davis, Morris Plains, NJ), 975 mg four times a day; hydroxy-chloroquine, 200 mg/d; atenolol, 25 mg/d; intermediate-actinghuman insulin (Humulin N, Eli Lilly & Co, Indianapolis, Ind),36 U subcutaneously each morning; methotrexate, 5 mg 1 weekalternating with 2.5 mg the next; and folie acid, 1 mg daily. Hehad been taking the enteric-coated aspirin for more than 5 years.There had been no flare in his arthritis symptoms and no nau¬

sea, abdominal pain, or change in the stools.Results of abdominal examination were normal. Laboratory

studies disclosed the following values: hemoglobin, 116 g/L (nor¬mal, 136 to 172 g/L); white blood cells, 8.4xl09/L, with 0.07eosinophils; ESR, 97 mm/h; iron, 4 umol/L (normal, 14 to32 pmol/L); iron-binding capacity, 41 |i.mol/L; glucose, 3.7 mmol/L(normal, 3.9 to 6.1 mmol/L); creatinine, 90 p,mol/L; albumin, 33 g/L;total protein, 66 g/L; and salicylate, 5 mg/dL (normal, 2 to29 mg/dL). Serum complement levels were normal, with a C3 levelof 1.1 g/L (normal, 0.7 to 1.6 g/L) and a C4 level of 0.17 g/L (nor¬mal, 0.15 to 0.45 g/L). The patient developed daily fevers, with thetemperature reaching as high as 38.5°C Two sets of blood cultureswere negative. Stools were positive for occult blood.

Colonoscopy revealed three circumferential ulcers in theascending colon, with marked erythema and edema of the sur¬

rounding mucosa. Biopsy specimens showed a mixed neutro-philic and mononuclear cell infiltrate without cellular atypia.Enteric-coated aspirin treatment was discontinued, and he was

discharged after 9 days in the hospital.The patient took no further aspirin or NSAIDS. Three months

after stopping the enteric-coated aspirin, the hemoglobin levelhad risen to 127 g/L and the ESR had fallen to 33 mm/h. The fe¬ver and night sweats had resolved and had not recurred in 1 yearof follow-up. He had no flare of arthritis symptoms, and hisweight had stabilized at 72.7 kg. He continued to take meth¬otrexate, folie acid, a multivitamin, atenolol, and prednisone,5 mg every other day.

Case 4.—An 87-year-old woman was given diclofenac so¬

dium, 50 mg twice a day, for arthritis pain involving the hips.The arthralgias improved, but she developed abdominal painand sores in her mouth 8 weeks after starting treatment. Exam¬ination disclosed a small aphthous ulcer on the inside of thelower lip and external hemorrhoids with traces of occult bloodin the stool. There was no abdominal tenderness. Misoprostol,100 p.g four times a day, was prescribed, and diclofenactreatment was continued.

The patient developed diarrhea consisting of four bowelmovements per day with small amounts of red blood in the stool.She lost 2.3 kg. The stomatitis persisted, and she developednight sweats. On reexamination, her abdomen was moderatelytender in the left lower quadrant. The hemoglobin level was113 g/L; white blood cell count, 10.8xl07L; ESR, 79 mm/h;albumin level, 37 g/L; and total protein level, 76 g/L. Tests forantinuclear antibody and rheumatoid factor were negative.

Colonoscopy revealed segmental colitis of the sigmoid colon,with patchy erythematous and friable areas with increased mu¬cus. A diagnosis of NSAID-induced colitis was suspected, anddiclofenac treatment was discontinued. During the next2 months, the patient's condition steadily improved, with reso¬lution of the night sweats, abdominal pain, and diarrhea. Fourmonths after diclofenac treatment was stopped, the hemoglobin

level had risen to 140 g/L, and the ESR had fallen to 27 mm/h.She was taking acetaminophen as needed for her osteoarthritis.

COMMENTClinical Features

These patients shared several common clinical features:they were all elderly, they had been taking NSAIDs reg¬ularly for 2 months to 5 years before symptoms and signsof colitis developed, and they all had abdominal com¬plaints or blood in the stool. Three of the four had nightsweats, and the average weight loss was more than 6 kg.None had any history of inflammatory bowel disease.They all had anemia, a markedly elevated ESR, and a se¬rum albumin-globuUn ratio less than or equal to 1. In eachcase, the presentation and findings were similar to thoseof inflammatory bowel disease. All four patients re¬

sponded well to withdrawal of the NSAID, although one

required emergency surgery for cecal perforation.De novo coUtis associated with NSAID usage has been

reported many times in the Uterature1"21 (Table 1). Reviewof the Uterature revealed four distinct types of NSAID-induced colitis: de novo colitis,123 reactivation of quies¬cent inflammatory bowel disease,5-15,17-24"31 hypersensitiv-ity reactions,17'25-26-31 and proctitis from suppositories.17-24These will be reviewed in order.

De Novo Colitis.—Forty cases of new-onset colitis inpatients taking NSAIDs are presented in Table 1, includ¬ing the four from the present series. The average age was63 years, and the median was 67 years. Women outnum¬bered men 24 to 16 (not statistically significant). The du¬ration of exposure until diagnosis ranged from 2 days to12 years, with a median of 3 months. Roughly two thirdsof these patients had been taking NSAIDs for longer than1 month before presenting with colitis.

Most of the various NSAIDs are represented. The rel¬atively large number of cases due to mefenamic acid, di¬clofenac, and indomethacin should be noted, although itmay only be proportional to their use among the NSAIDs.

Treatment included cessation of NSAID therapy and,when necessary, surgery. Two of the 40 patients died, in¬cluding one who underwent rechallenge. A total of38 additional cases of NSAID-induced coUtis were cited byseveral of the investigators5,6,12'1319 mentioned in Table 1,including eight confirmed fatalities. All 12 patients whounderwent rechallenge had relapses.

Laboratory features of NSAID-induced colitis are diffi¬cult to characterize because of the varying presentationsof data in the reports. Most patients had diarrhea withoccult or obvious blood.2,5"10,14,15,18,19 Most patients inwhom laboratory studies were reported had anemia,5"8,14,18and many had leukocytosis5"8,10,15-19 and elevation in theESR 5,6,i3,i5,i8 Some had wejght loss5"7-15 and some had fe¬ver.15,19 As in two of our four patients, very low serum ironlevels were reported in two,6,8 and a low albumin level was

reported in one.6 Eosinophilia was noted in one of our

patients and in one described by Rampton and Tapping.9In several cases, the complete blood cell counts and ESRwere reported as normal7-14,16,18; thus, the anemia and el¬evated ESR seen in all four of the patients in the presentstudy do not appear to be uniformly present in NSAID-induced colitis.

Six of the patients had perforation of colonie diverticulain association with documented colitis,4,11,12 including onefrom the present series. The question of whether personswith diverticular disease are at increased risk of compli-


Table 1. —De Novo Colitis Induced by NSAIDs*

SourcePatient

Age, y/Sex Indication Drug

Durationof

Administration Findings Treatment OutcomeDebenham1

Bravo andLowman2

Baas et al3

Coutrot et al4

Schwartz5t

Hall et al6*

Phillips et al7

Rampton andTapping9

Williams andGlazer10

Day11

Stewartet al12§

32/F

70/M

61/F

82/F

74/F

60/M

Incisional pain Oxyphenbutazone

Arthritis Phenylbutazone

Osteoarthritis Naproxen

Vertebral Indomethacincompression

Rheumatoidarthritis

Rheumatoidarthritis

67/F Arthritis

Indomethacin

Naproxen

Naproxen,fenbufen

43/M Psoriatic Mefenamic acidarthropathy

69/M Ureteral stones Mefenamic acid

39/M

71/F

63/M

62/M

Edwards et al8 49/F

Rheumatoidarthritis

Osteoarthritis

Ischémie footulcer

Osteoarthritis

Mefenamic acid

Mefenamic acid

Mefenamic acid

Mefenamic acid

69/M

51/F

Musculoskeletal Mefenamic acidpain

Musculoskeletal Mefenamic acidpain

70/M Arthritis

79/F

38/M

Arthritis

Painful toe

Mefenamic acid

Indomethacin,slow release

Indomethacin,slow release

Indomethacin

5 d Perforated cecal Surgeryulcer

9 y 2 large sigmoid Surgeryulcers withrectal bleeding

2 d Proctitis D/C

4 d 2 perforated Surgerysigmoiddiverticula,multipleulcérations

18 d Sigmoid Surgeryperforationand mucosalulcérations

4-6 wk Right colonie Surgerydiverticulawith Gl tractbleeding

7 mo Perforated Surgerysigmoiddiverticulitis

3 y Aphthous D/Culcération indescendingcolon

8 mo Proctitis, loss D/Cof vascularpattern insigmoid colon

4 mo Proctitis D/C

3 mo Proctocolitis, D/Ccecal ulcération

3 mo Proctitis D/C

6 mo Erythema of D/Crectal mucosa,diarrhea

6 mo Acute and Steroidschronicinflammatorychange inrectal mucosa

10 wk Granular Steroidshemorrhagicrectal mucosa

6 mo Friable rectal D/Cand coloniemucosa

2 wk Meal and right Surgerycolonieulcérations withperforation

2 wk Sigmoid Surgeryperforation

4 d Sigmoid Surgeryperforation,small- andlarge-bowelperforation

Recovered

Relapse withrechallenge(preoperative)

Relapse withrechallenge

Recovered

Recovered


Good clinicalresponse


Relapse anddeath withrechallenge






Died

Recovered

Recovered after4 laparotomies

(Continued on p 628.)


Table 1. —De Novo Colitis Induced by NSAIDs* (cont)

SourcePatient

Age, y/Sex Indication Drug

Durationof

Administration Findings Treatment Outcome

Doman and 90/F Degenerative joint MeclofenamateGoldberg13|| disease sodium

Ravi et al" 77/F Osteoarthritis Flufenamic acid

73/F Osteoarthritis

67/F Superficialthrombophlebitis

69/F Osteoarthritis

Ritschard and 44/F Low-back painFill ippini15

Uribe et al16

Guller17

Tanner andRaghunath11

53/F Back pain

43/M Ankylosingspondylitis

59/M Myalgias

Mefenamic acid

Naproxen

Ibuprofen

Phenylbutazone

Naproxen, aspirin

Diclofenac

Mefenamic acidsuppositories

53/F Cervical disk pain Mefenamic acid

68/F Osteoarthritis Mefenamic acid

78/F Degenerative joint Piroxicamdisease

Badettiet al19t

Perreardet al20

Giardielloet al21

Present study

45/M Arthralgias

42/F Arthralgias

53/F Low-back pain

60/M Gout

77/M Arthralgias

82/F Osteoarthritis

75/F Osteoarthritis

71/M Rheumatoidarthritis

87/F Osteoarthritis

Piroxicam

Piprofen

Diclofenac

Indomethacin

Ibuprofen,indomethacin

Diclofenac

Naproxen,diflunisol,piroxicam

Enteric-coatedaspirin

Diclofenac

2 mo

6 mo

3 mo

2d

5d

2d

1 mo

12 y

1 wk

8 mo

4 mo

6 mo

2 mo

5d

3 wk

6 wk

2 mo

3 mo

1 mo

5y

10 wk

D/CSegmentalascending colitis

Bleedingrectosigmoidmucosa withlymphocyticinfiltration

Actively inflamedrectal mucosa

Acutely inflamed Steroidsrectosigmoidmucosa

Inflamed bleedingrectal mucosa

D/C

D/C

D/C

Proctocolitis

Transverse colonieulcération

Diffuse colitis

Nonspecificproctocolitis

Pancolitis

Steroids

D/C

Steroids

Sulfasalazine

Sulfasalazine,steroids

SteroidsInflamedrectosigmoidmucosa

Focal inflammation D/Cof sigmoidmucosa

Severe D/Cinflammationand focalulcération rectalmucosa

Proctocolitis with D/Crectal bleeding

Cecal ulcérations D/Cwith bleeding

Diffuse colitis Sulfasalazinesteroids

Diffuse colitis Steroids

Multiple D/Csuperficialcoloniemucosalulcérations

Cecal ulcération, Surgerywith perforation,sigmoiddiverticularabscess

Mucosal D/Culcération,colon

Segmental D/C(sigmoid)colitis









Recovered


Recovered


Recovered






Recovered



*NSAID indicates nonsteroidal anti-inflammatory drug; D/C, NSAID discontinued; and Gl, gastrointestinal.tFour other cases of lower Gl tract bleeding reported to the Upjohn Co, Kalamazzo, Mich (ibuprofen, indomethacin).tFour other cases of colitis reported to Warner-Lambert Co, Ltd, Eastleigh, England.§Nineteen other cases of lower Gl tract ulcération or perforation, with eight fatalities, reported to the UK Committee on Safety of

Medicines.||Nine other cases of colitis reported to Parke-Davis, Morris Plains, NJ.llSix other cases of colonie mucosal lesions with NSAIDs in a thesis written in 1988 (Nice, France).


cations by taking NSAIDs was studied by Langman andcoworkers.22 They reported on 268 patients with colonieor small-bowel perforation or hemorrhage; patients withperforation or hemorrhage were more than twice as likelyto have taken NSAIDs than were age-matched controlswith uncomplicated lower-bowel disease. They sug¬gested, "The association between complicated lowerbowel disease and intake of NSAIDs may be causal." Ina similar retrospective study, de Boer and coworkers23found that 18 (39%) of 46 patients with diverticulitisrequiring laparotomy were users of NSAIDs. With the useof a control group, they estimated that the relative risk ofan NSAID-related laparotomy was 4.3. Of note, they alsoidentified two patients who appeared to have coUtisdirectly caused by the NSAIDs.

The series of reports on mefenamic acid are intriguing.Hall and coworkers6 described two patients with colitisdue to mefenamic acid in the October 1983 issue of theBritish Medical Journal. In the following issue, four sepa¬rate letters reporting an additional seven cases of colitisdue to mefenamic acid were pubUshed.7"10 Either this was

coincidence, or the heightened suspicion provoked by thefirst article resulted in more frequent identification ofNSAID-induced colitis among elderly Britons with bloodydiarrhea; the latter explanation seems more likely.

Reactivation of Quiescent Inflammatory BowelDisease.—Nineteen cases of relapse in ulcerative colitis orCrohn's disease in association with NSAID inges¬tion5,15,17,24"31 are presented in Table 2. Every one of the eightpatients who were rechallenged had a relapse, strength¬ening the conclusion that NSAIDs precipitated the reac¬tivation.5,17,25,26,29-30 The average age was 42 years, signifi¬cantly less than that of the patients with de novo colitis(P<.01 by two-tailed t test). The median latency betweenexposure to the NSAID and the appearance of coUtissymptoms was less than 1 week among the patients withinflammatory bowel disease who had relapses. Nine dif¬ferent NSAIDs are represented, and the findings rangedfrom mild sigmoid edema with friability to pancolitis.Treatment included steroids in half of the patients, withuniformly good outcome.

Rampton et al32 reported on analgesic ingestion andother factors preceding relapse in ulcerative colitis. Sixteen(76%) of 21 patients who suffered relapses took acet¬aminophen or NSAIDs in the month before relapse,whereas only 24 (39%) of 62 who were in remission hadingested these agents in the previous month. The authorstheorized that colonie mucosal prostaglandin deficiencyinduces relapse in some patients with ulcerative colitis.One problem with this theory is that acetaminophen isonly a weak inhibitor of cyclo-oxygenase outside the cen¬tral nervous system; this has led some to speculate that thepathogenesis of reactivation of inflammatory bowel dis¬ease by NSAIDs differs from that of de novo colitis fromNSAIDs.28,33

Hypersensitivity Reactions. — Several cases of coUtis inpatients with salicylate hypersensitivity have been de¬scribed.17,25,26,31 These were patients with a history of atopywho developed abrupt symptoms within hours of rechal¬lenge. Findings included proctitis and bleeding, andtreatment consisted of cessation of saUcylate therapy.Most of these patients had a previous diagnosis of ulcer¬ative colitis and were taking sulfasalazine17-26,29 whensymptoms began. Pearson and coworkers26 subjected one

patient to separate provocation testing with sulfapyridine

and salicylate; he had a relapse within hours of rechal¬lenge by saUcylate but had a negative reaction to sulfapy-ridine provocation. One of five patients described byGuller17 developed proctitis after taking aspirin; he had no

history of inflammatory bowel disease.Proctitis From Suppositories. —Cases of proctitis in

patients treated with indomethacin34 and mefenamic acidsuppositories17 have been reported. Relapse with rechal¬lenge was seen in one case.34

FrequencyHow frequent is NSAID-induced coUtis? If the forego¬

ing cases represented the only instances of the disease, itwould be extremely rare. However, these cases probablyrepresent only the "tip of the iceberg." In 1981, Schwartz5reported two cases and mentioned that The Upjohn Cohad told him of an additional four cases of lower gas¬trointestinal tract bleeding associated with NSAID usage.In 1985, Stewart et al12 described one case and cited 19 ad¬ditional cases of lower gastrointestinal tract ulcération or

perforation, with eight fataUties, reported to the Com¬mittee on Safety of Medicines of the United Kingdom. In1986, Doman and Goldberg13 reported one case ofmeclofenamate-induced coUtis and mentioned nine otherunpubUshed cases that had been reported to Parke-Davis.In 1989, Badetti et al19 reported one case of NSAID-induced colitis and cited six other cases from a thesis Ba¬detti had written 1 year earlier. It appears that only afraction of recognized cases of NSAID-induced colitishave been published.

More significant is the possibiUty that only a fraction ofthe cases have been recognized. Lower gastrointestinaltract bleeding of obscure origin is a well-recognized clinicalentity. Among elderly patients, the bleeding is sometimesassumed to come from diverticula or ischémie bowel, al¬though no specific site can be identified. Tanner and Ra-ghunath18 estimated that 10% of newly diagnosed coUtismay be related to NSAID administration and that subjectstaking NSAIDs were five times as likely as the general pop¬ulation to develop colonie inflammation.

Although Tables 1 and 2 include only cases of coUtis, ul¬cération of the üeum has also been reported in patients takingNSAIDs.35 This is in agreement with experimental studies inhumans36 and animals37 that show a substantial effect ofNSAIDs on the ileum. Necrotizing enterocoütis and intesti¬nal perforation have also been seen in infants given indo¬methacin for closure of patent ductus arteriosus.38

PathogenesisThe mechanism of NSAID-induced colitis may relate to

inhibition of intestinal prostaglandin synthesis. TheNSAIDs inhibit cyclo-oxygenase, thereby reducing pros¬taglandin production. In the gut, prostaglandins havecytoprotective actions.39 In animal studies, NSAIDs haveshown a cytotoxic effect on the distal small bowel;concomitant administration of a variety of prostaglandinshas prevented these lesions.39 These cytoprotective prop¬erties for the gut are seen in varying degree for all pros¬taglandins, vasodilating (prostaglandin E2) as well as vas-

oconstricting (prostaglandin F2o) types.Transepithelial potential difference, a measure of mem¬

brane integrity, was studied in the rat and rabbit colon byPhillips and Hoult.40 Indomethacin and other NSAIDs re¬duced the potential difference and reduced prostaglandinE2 release from cells of the lamina propria when applied


Table 2.—Reactivation of Inflammatory Bowel Disease (IBD) With NSAIDs*

PreviousSource Age, y/Sex IBD Indication Drug

Durationof

Administration Findings Treatment Outcome

Schwartz5

Rampton andS laden24

Pearson et al26

Rutherfordet al27

Walt et al26Ritschard and

Fillippini15Culler17

Chakrabortyétal29

Kaufmann andTaubin30

Shanahan andTargan31

49/M Crohn's

34/M UC

36/F UC

33/F UC

54/F UC

Schwartz et al25 35/M UC

55/M UC

35/M UC

26/M UC21/F Crohn's

37/F UC

55/M UC

60/M UC

25/F UC

57/M UC

44/M UC

?/? UC

Arthritis/back pain

Ankylosingspondylitis

Arthralgias

Carpal tunnel

Osteoarthritis

Ulcerativecolitis

Ulcerativecolitis

Musculo¬skeletalpain

ArthritisBack pain

Diarrhea

Arthralgias

Ulcerativecolitis

Ulcerativecolitis

58/M Crohn's Bursitis

46/M Crohn's Bursitis

Osteoarthritis

Low-backstrain

Ulcerativecolitis

Ibuprofen

Indomethacin

Benorilate

Flurbiprofen

Ibuprofen

Sulfasalazine,aspirin

Aspirin

IbuprofenDiclofenac

Sulfasalazine

Diclofenac,naproxen

Sulfasalazine

Sulfasalazine

6 wk

1 wk

4 wk

1 wk

8 wk

Sulfasalazine Hours

Hours

1 wk

1 d2wk

"Days""Days"

5d

1 d

"Shortly"Phenyl¬butazone,indomethacin

Phenyl- 1 dbutazone,indomethacin

Piroxicam 3 d

Naproxen 1 wk

Azodisalicylate 1-2 d

Diffuse mucosal Steroidscolonieulcérations

Sigmoid edema, D/Chyperemia,friability



Sigmoid edema, D/Cspontaneousbleeding

Sigmoiditis, Steroidswith hyperemiaand focalhemorrhages

Severeproctocolitiswithspontaneousbleeding

Severeproctitis withrectal bleeding

Colitislleocolitis

Left hemicolitis

Rectosigmoidulcérations

Severeproctocolitis

Severeproctocolitis

Sigmoid ulcersurrounded bypseudopolyps

Chronicinflammationof L colonand sigmoid

Pancolitis

Pancolitis

Abdominalcrampingand bloodydiarrhea

D/C

Steroids

Steroids

Steroids

D/C

Steroids

Steroids

Steroids

D/C









?

?







Sulfasalazine Good clinicalresponse

Slow clinicalSteroids

D/Cresponse


*NSAID indicates nonsteroidal anti-inflammatory drug; UC, ulcerative colitis; and D/C, NSAID discontinued.

serosally but not mucosally in epithelial-intact prepara¬tions.40 This would support the theory that cytotoxiceffects of NSAIDs in the distal small bowel and colon fol¬low systemic absorption.

Banerjee and Peters37 studied the effects of NSAIDs on

rat intestine and found that the maximal effect of indo¬methacin was on the midileum. There was enhancedmucosal permeability, increased tissue myeloperoxidase

levels, and reduced weight gain, analogous to inflamma¬tory bowel disease in the human. Their studies alsoshowed that the lesions could be reversed with pred-nisolone and, to a lesser extent, with sulfasalazine.

Using radiolabeled indium 111 leukocytes, Bjarnasonand coworkers36 studied NSAID-induced intestinal in¬flammation in humans by fecal indium 111 excretion andscintigraphy. Two thirds of 70 patients with rheumatoid


arthritis receiving long-term NSAID therapy had in¬creased fecal indium 111 excretion, and 46% had abnor¬mal late indium scintiscans involving the right lowerquadrant, presumably the ileum. There was a significantinverse correlation between fecal indium 111 excretionand hemoglobin levels in patients treated with NSAIDs.Eighteen of these patients underwent a radiologie exam¬ination of the small bowel, and three were found to haveasymptomatic ileal disease with ulcération and strictures.Among nine patients with rheumatoid arthritis who werenot taking NSAIDs, the fecal indium 111 excretion andabdominal scintigrams were normal. These studies werealso normal in a control group of eight patients with irri¬table bowel syndrome. Scintigraphic abnormalities in thepatients taking NSAIDs persisted for up to 16 months af¬ter discontinuing the drug. The authors concluded thatlong-term administration of NSAIDs is associated withsubcUnical intestinal inflammation in many patients,although only an occasional patient taking NSAIDs willshow radiographie evidence of small-intestine disease.

Prostaglandin E2, thromboxane, and other prostaglan¬dins are synthesized by human colonie tissue. The phys¬iologic role of endogenous prostaglandins in maintainingmucosal integrity is under study. In their review, Sembleand Wu41 speculated that NSAIDs, in addition to decreas¬ing prostaglandin production by inhibiting the enzymecyclo-oxygenase, may also divert arachidonic acid towardthe lipoxygenase pathway. This would lead to formationof leukotrienes and free radicals, which may cause in¬flammation and tissue injury in the lower gut.

These studies, combined with the clinical experience ofthe response of inflammatory bowel disease to NSAIDs,suggest that, at least in the intestine, prostaglandins actnot as proinflammatory agents but rather primarily as cy¬toprotective agents and that inhibition of prostaglandinproduction may act to initiate or aggravate intestinal in¬flammation. This was the same conclusion reached byStenson and MacDermott42 in their recent review of theimmunologie features of inflammatory bowel disease.This is in contrast to arthritis, where prostaglandins seemto act as proinflammatory agents and NSAIDs reduce in¬flammation.

Diagnosis and Treatment

Diagnosis of NSAID-induced colitis requires awarenessthat the problem exists. Monitoring of symptoms, weight,and tests for fecal occult blood may help detect the diseaseat an earlier stage. Complete blood cell counts and ESRshould be determined if NSAID-induced colitis is sus¬

pected. Colonoscopy can confirm or exclude the diagno¬sis, although isolated ileitis may still escape detection.

Treatment of NSAID-induced colitis requires only dis¬continuation of the offending agent in most cases. Somepatients will require more aggressive intervention, in¬cluding steroids or surgery. Reexposure to NSAIDsshould be avoided, given the observed risk of relapse.

Medical therapy used to combat effects of NSAIDs onthe upper gastrointestinal tract, including histamine2 an¬

tagonists, sucralfate, and misoprostol, may not be effec¬tive in preventing or treating NSAID-induced colitis. Thehistamine2 antagonists exert their effects by competitive,reversible inhibition of histamine on the histamine2 recep¬tors on the gastric cells, thus reducing gastric acid secre¬tion. Sucralfate acts locally, forming an ulcer-adherentcomplex with proteinaceous exúdate at the ulcer site in up-

per gastrointestinal tract disease. Misoprostol, a syntheticprostaglandin Ei analogue, reduces gastric acid secretionand stimulates gastric mucus secretion as well as duodenalbicarbonate secretion. These effects appear to be local andnot systemic.43 The effects of histamine2-antagonists, su¬

cralfate, and misoprostol on colonie prostaglandin metab¬olism have not, to our knowledge, been reported.

ConclusionIn three exceUent reviews, Aabakken and Osnes,33

Guller,17 and O'Brien and Bagby44 all concluded thatNSAID-induced colitis was a significant clinical problem.On the basis of our clinical experience and investigation,we agree with these conclusions. We recommend the fol¬lowing to help reduce the risk of NSAID-induced colitis:(1) critical assessment of the need for NSAIDs, particu¬larly for minor or self-limited ailments; (2) limitation onthe course of NSAID therapy when possible; (3) particu¬lar attention to effects of NSAIDs on elderly patients; asin the case of sedatives and antihypertensives, the lowesteffective dosage should be sought; (4) consideration ofNSAID-induced colitis in the differential diagnosis of ab¬dominal pain, diarrhea, hematochezia, unexplained ane¬mia, and weight loss and in patients presenting with anysigns or symptoms of inflammatory bowel disease; (5) in¬forming patients of possible adverse effects of NSAIDs onthe colon; and (6) special caution in prescribing NSAIDsfor patients with a history of inflammatory bowel diseaseand diverticular disease.

We wish to thank Diane Richardson for assistance in obtaining thereferences cited and Rolf Nissen, MD, for translation of the articleswritten in German.

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Colitis Induced by Nonsteroidal Anti-inflammatory Drugs