sign in sign up
<<
Home , Flufenamic acid, Ibuprofen

Postgrad Med J: first published as 10.1136/pgmj.62.730.773 on 1 August 1986. Downloaded from Postgraduate Medical Journal (1986) 62, 773-776

Colitis caused by non-steroidal anti-inflammatory drugs

S. Ravi', A.C. Keat2 and E.C.B. Keat1 'Cuckfield Hospital, Cuckfield, West Sussex, and2Westminster Hospital, Horseferry Road, London SWIP2AP, UK.

Summary: Four cases of acute proctocolitis associated with non-steroidal anti-inflammatory drug therapy are presented. The drugs implicated were flufenamic , , and . After resolution of symptoms and signs of proctocolitis three of the four patients were subsequently rechallenged with the implicated drug: in each there was a rapid relapse.

Introduction Ulcerative colitis is a disease of unknown aetiology Case reports with characteristic clinical features and a protracted course. A similar clinical picture, but running a shorter Case I and usually benign course, is occasionally seen follow- ing the administration of certain drugs. This was first A 77 year old woman was referred with intermittent noticed following the administration of , bleeding per rectum for 6 months, associated for the often with pseudomembrane formation. Later, this last 2 months with bloody diarrhoea up to eight times was shown to be associated with infection by toxigenic daily. Previously, she had had troublesome symptoms Clostridium difficile. Until 1978, most cases were from of her back and knees for which copyright. associated with treatment with but since she had been prescribed 200 mg thrice that time nearly all antibiotics have been implicated. daily. Her general health had remained good but she Other drugs capable of causing proctocolitis, though appeared pale and her haemoglobin was reduced to by different mechanisms, include phenindione (Keat & 8 g/dl. Apart from osteoarthritis at the knees there Tanser, 1966), penicillamine (Hickling & Fulbi, 1979), were no abnormal physical signs. Sigmoidoscopy gold salts (Fami et al., 1980), methyl dopa (Graham et revealed an inflamed, bleeding mucosa in the rectum al., 1981), cimetidine (Collins, 1982) and methotrexate and sigmoid colon and rectal biopsy showed heavy (Atherton et al., 1984). Inflammatory bowel disease mucosal infiltration with lymphocytes and plasma http://pmj.bmj.com/ resembling Crohn's disease, though nearly always cells. Stool cultures were negative for bacterial and with rectal sparing, has also been associated with oral fungal pathogens and parasites and a enema contraceptives (Tedesco et al., 1982). showed loss of haustration in the descending and In contrast to non-specific diarrhoea, which is a sigmoid colon. Flufenamic acid was discontinued and well-known side effect of anti-rheumatic , after 2 weeks her bowels had returned to normal with a ulcerative proctocolitis has been associated with inges- dramatic improvement in the sigmoidoscopic tion ofsalicylate (Pearson et al., 1983) and mefenamic appearances. She was subsequently re-challenged with acid (Hall et al., 1983; Phillips et al., 1983; Edwards et 200 mg of flufenamic acid daily; she discontinued the on September 24, 2021 by guest. Protected al., 1983; Rampton & Tapping, 1983; Williams & tablets after 48 hours because of recurrence of diarr- Glazier, 1983) usually after prolonged exposure to the hoea. drug. We report four cases of proctocolitis in which three further non-steroidal anti-inflammatory drugs Case 2 (NSAIDs) are implicated. In three out of four cases colitis recurred on rechallenge. None of the patients A 73 year old woman complained of diarrhoea for 3 had suffered from colitis previously. Possible mechan- months with six to seven bowel actions daily isms of induction of colitis are briefly discussed. associated with tenesmus and the passage ofblood and mucus. Previously, she had complained of painful knees and 9 days before the onset ofdiarrhoea, she had been prescribed mefenamic acid 500mg t.d.s. She Correspondence: A.C. Keat, M.D., M.R.C.P. appeared well with mild osteoarthritis ofthe knees but Accepted: 20 January 1986 no other abnormal physical signs. Sigmoidoscopy ©) The Fellowship of Postgraduate Medicine, 1986 Postgrad Med J: first published as 10.1136/pgmj.62.730.773 on 1 August 1986. Downloaded from 774 CLINICAL REPORTS

revealed actively inflamed rectal mucosa with contact apart from mild tenderness in the abdomen there were bleeding and blood-stained mucus. Stool cultures were no abnormal physical signs in the alimentary system. negative. Mefenamic acid was discontinued and a Sigmoidoscopy showed an inflamed bleeding rectal barium enema arranged. Her symptoms rapidly sub- mucosa. Stool cultures were negative for pathogens sided, however, and she cancelled the examination. and a barium enema revealed only scattered diver- Repeat sigmoidoscopy, two weeks later, showed the ticula. Five days after stopping ibuprofen her symp- mucosa to have returned almost to normal with only toms had abated and repeat sigmoidoscopy after a mild injection and no contact bleeding. She was further 5 days showed clearing of the . subsequently re-challenged with mefenamic acid Thereafter, she remained well and when reviewed 3 250 mg/day; she developed loose motions again and weeks after discharge, had no gastrointestinal symp- discontinued medication after 72 hours. Following toms. She did not agree to re-challenge. this she remained well and, when reviewed several months later, had had no further bowel symptoms. Discussion Case 3 Four different NSAIDs, prescribed for osteoarthritis A 67 year old woman was admitted to hospital with or are implicated in the development of abdominal and severe watery diarrhoea at hourly proctocolitis in these patients. None of the patients intervals containing blood and mucus. She had de- had previously suffered from colitis, all rapidly veloped superficial of her right calf became symptom-free on cessation of treatment and, two and a half weeks previously for which she had in three patients, symptoms ofcolitis rapidly returned been prescribed a 6 day course of flucloxacillin. The on re-challenge with the drug. A diagnosis of proc- leg remained painful and, 8 days after discontinuing tocolitis was made by the presence of diarrhoea the , she was prescribed naproxen 250mg varying from four to twelve or more times daily, twice daily. After 2 days she developed diarrhoea, inflamed mucosa on sigmoidoscopy and negative stool which became increasingly frequent with blood stain- cultures. Biopsy ofthe rectal mucosa in Case 1 showed anorexia and loss and neces- infiltration with and cells. ing, prostration, weight heavy lymphocytes plasma copyright. sitated admission to hospital. At that time she was thin In all four cases resolution was complete by 10 days and dehydrated but not anaemic and the abdomen was with the formation of normal or constipated stools diffusely tender but not distended. Sigmoidoscopy and disappearance of blood and mucus. A barium showed acutely inflamed mucosa in the rectum and enema was performed on three of the four patients; in sigmoid colon. The stools contained leucocytes and two, changes were compatible with distal idiopathic red cells but cultures were negative for fungal and ulcerative colitis, showing lack of haustration and/or bacterial pathogens, including C. difficile, cysts, ova shallow ulceration of the mucosa, and in the third and parasites. A barium enema examination showed diverticular disease only was demonstrated. It is of lack of haustration of the descending and sigmoid interest that a flare-up of diverticular disease and http://pmj.bmj.com/ colon with a fine granular appearance of the mucosal perforation has been recorded in association with lining. Naproxen was stopped and she was treated NSAIDs (Coutrot et al., 1978; Schwartz, 1981) though with prednisdone enemas daily for 7 days, during in our case the predominant disease was proctocolitis. which time her stools returned to normal. She was The time interval from starting the drug to the onset of discharged 3 days later requiring no treatment. On re- diarrhoea varied from 2 days to 4 months but the three challenge with naproxen 125 mg/day, 3 weeks later, patients who were re-challenged relapsed within 72 she developed looseness ofthe bowels after 3 days and hours. On all remained well and free of follow-up on September 24, 2021 by guest. Protected symptoms similar to the onset of her previous illness. bowel symptoms. The patient, therefore, discontinued naproxen. Vane in 1971 first proposed that the action of NSAIDs involved the inhibition of Case 4 synthesis and the four drugs implicated in these cases are all potent inhibitors ofprostaglandin synthesis. As A 69 year old woman was admitted to hospital with a mucosal are known to be increased in history offrequent bloody diarrhoea and tenesmus for active ulcerative colitis (Sharon et al., 1978) and may 2 days together with malaise and feeling unwell. She play some part in the inflammatory response in this had suffered from osteoarthritis of the hips for many condition, drugs ofthis kind might be expected to have years for which she had taken one tablet twice a beneficial effect on the mucosa. Indeed, sul- daily until a week before admission. At that time, her phasalazine and its cleavage product 5-aminosalicylic general practitioner had changed her prescription to acid both inhibit prostaglandin synthesis in the rectal ibuprofen 400mg twice daily. She developed diarr- mucosa, at high concentrations, although they are less hoea 5 days later. Her general health was good and potent inhibitors than indomethacin or Postgrad Med J: first published as 10.1136/pgmj.62.730.773 on 1 August 1986. Downloaded from CLINICAL REPORTS 775

(Hawkey & Truelove, 1983). tent with the speed of onset ofdiarrhoea following re- However, Levy & Gaspar (1975) reported proctitis challenge in our cases. occurring after the use ofindomethacin suppositories, It is now recognized that, in addition to their the severity of which appeared to be related to the involvement in tissue-damaging inflammatory reac- dose. In individuals known to have ulcerative colitis tions, prostaglandins exert a protective effect on the attempts to lower prostaglandin levels in the gut with a gastric mucosa when exposed to necrotizing agents short course of oral flurbiprofen, compared with such as absolute and to NSAIDs such as conventional treatment, showed that the patients aspirin. This property has been termed cytoprotection given flurbiprofen fared significantly worse (Rampton by Robert (1979). Mucosal inflammation could result & Sladen, 1981). Others have shown that local treat- therefore from reduced synthesis of cytoprotective ment with indomethacin retention enemas failed to prostaglandins. Alternatively, this may be due to produce improvement in distal proctocolitis (Gilat et enhancement of intestinal permeability by the al., 1979). Furthermore, ibuprofen has been reported NSAIDs thus allowing antigenic material within to be associated with an acute relapse of ulcerative the lumen increased access to the immune system colitis after only six tablets (Walt et al., 1984). (Bjarnason et al., 1984). Rampton & Sladen (1980) reported four patients with Although these four cases are uncommon, NSAIDs inactive ulcerative proctocolitis in whom the adminis- may cause serious inflammatory bowel disease. tration of NSAIDs appeared to precipitate relapse Mucosal damage may result from impairment oflocal and proposed that this might be due to inhibition of prostaglandin synthesis and disturbance of the synthesis of prostaglandins which may be playing a equilibrium between the cyclo- and lipoxygenase path- protective role in the mucosa. Relapse of quiescent ways of metabolism. The develop- ulcerative colitis appears to occur fairly quickly after ment of more specific inhibitors of inflammatory NSAIDs but in those without underlying colitis, the factors and drugs which enhance cytoprotection will time interval is more variable. This would be consis- be of great value to the clinician.

References copyright. ATHERTON, L.D., LEIB, E.S. & KAYE, M.D. (1984). Toxic HICKLING, P. & FULLER, J. (1979). Penicillamine causing megacolon associated with methotrexate therapy. Gas- acute colitis. British Medical Journal, 2, 367. troenterology, 86, 1583. KEAT, E.C.B. & TANSER, A.R. (1966). Phenindione induced BJARNASON, I., WILLIAMS, P., SO, A., ZANELLI, G.D., LEVI, haemorrhagic colitis. British Medical Journal, 1, 588. A.J., GUMPEL, J.M., PETERS, T.J. & ANSELL, A. (1984). LEVY, N. & GASPAR, L. (1975). Rectal bleeding and in- Intestinal permeability and inflammation in rheumatoid domethacin suppositories. Lancet, i, 577. : effects ofnon-steroidal anti-inflammatory drugs. PEARSON, D.J., STONES, N.H. & BENTLEY, S.J. (1983). Proctocolitis induced by salicylate and associated with Lancet, ii, 1171. http://pmj.bmj.com/ COLLINS, J. (1982). Cimetidine induced ulcerative colitis. and recurrent nasal polyps. British Medical Jour- Medical Journal ofAustralia, 1, 307. nal, 287, 1675. COUTROT, S., ROLAND, D., BARBIER, J., VAN DER MARCQ, PHILLIPS, M.S., FEHILLY, B., STEWART, S. & DRONFIELD, P., ALCALAY, M. & MATUCHANSKY, C. (1978). Acute M.W. (1983). Enteritis and colitis associated with mefen- perforation of colonic diverticula associated with short- amic acid. British Medical Journal, 287, 1626. term Indomethacin. Lancet, R, 1055. RAMPTON, D.S. & SLADEN, G.E. (1980). Relapse of EDWARDS, A.L., HEAGERTY, A.M. & BING, R.F. (1983). ulcerative proctocolitis during treatment with anti-inflam- Enteritis and colitis associated with metenamic acid (letter) matory drugs. Postgraduate Medical Journal, 57, 297. British Medical Journal, 287, 1626. RAMPTON, D.S. & SLADEN, G.E. (1981). Prostaglandin on September 24, 2021 by guest. Protected FAM, A.G., PATON, T.W., SHAMESS, C.J. & LEWIS, A.J. synthesis inhibitors in ulcerative colitis: flurbiprofen com- (1980). Fulminant colitis complicating gold therapy. Jour- pared with conventional treatment. Prostaglandins, 21, nal of Rheumatology, 7, 479. 417. GILAT, T., RATAN, J., ROSEN, P. & PELED, Y. (1979). RAMPTON, D.S. & TAPPING, P.J. (1983). British Medical Prostaglandins and ulcerative colitis. Gastroenterology, 76, Journal, Enteritis and colitis associated with metenamic 1033. acid (letter) 287, 1626. GRAHAM, C.F., GALLAHER, K. & JONES, J.K. (1981). Acute ROBERT, A. (1979). Cytoprotection by prostaglandins. Gas- colitis with methyl dopa. New England Journal of troenterology, 77, 761. Medicine, 304, 1044. SHARON, P., LIGUMSKY, M., RACHMILEWITZ, D. & ZOR, V. HALL, R.I., PETTY, A.H., COBDEN, I. & LENDRUM, R. (1983). (1978). Role ofprostaglandins in ulcerative colitis: enhan- Enteritis and colitis associated with mefenamic acid. ced production during active disease and inhibition by British Medical Journal, 287, 1182. sulphasalazine. Gastroenterology, 75, 638. HAWKEY, C.J. & TRUELOVE, S.C. (1983). Inhibition of SCHWARTZ, H.A. (1981). Lower gastrointestinal side effects prostaglandin synthesis in human rectal mucosa. Gut, 24, of non-steroidal anti-inflammatory drugs. Journal of 213. Rheumatology, 8, 952. Postgrad Med J: first published as 10.1136/pgmj.62.730.773 on 1 August 1986. Downloaded from 776 CLINICAL REPORTS

TEDESCO, F.S., VOLPICELLI, N.H. & MOORE, F.S. (1982). WALT, R.P., HAWKEY, C.J. & LANGMAN, M.J.S. (1984). - and -associated colitis, a disorder Colitis associated with non-steroidal anti-inflammatory with clinical and endoscopic features mimicking colitis. agents. British Medical Journal, 288, 238. Gastrointestinal Endoscopy, 28, 247. WILLIAMS, R. & GLAZIER, G. (1983). British Medical VANE, J.R. (1971). Inhibition of prostaglandin synthesis as a Journal, Enteritis and colitis associated with metenamic mechanism of action for aspirin-like drugs. Nature, 231, acid (letter) 287, 1626. 232. copyright. http://pmj.bmj.com/ on September 24, 2021 by guest. Protected