Annals ofthe Rheumatic Diseases 1995; 54: 277-280 277

Experience with for NSAID Ann Rheum Dis: first published as 10.1136/ard.54.4.277 on 1 April 1995. Downloaded from gastropathy in children

Madlen Gazarian, Matitiahu Berkovitch, Gideon Koren, Earl D Silverman, Ronald M Laxer

Abstract El (PGEI) analogue with gastric Objective-To determine the effect of antisecretory and cytoprotective properties.6 7 misoprostol, a synthetic prostaglandin It has been shown in adults to be effective in El analogue, on the gastrointestinal both the prophylaxis8-1 l and treatment of tract (GIT) symptoms associated with NSAID induced gastroduodenal damage, non-steroidal anti-inflammatory drug allowing continuation of therapy with NSAIDs (NSAID) administration and on the while achieving healing of ulcers.'0 12 The haemoglobin value, in children. major side effect reported has been diarrhoea, Methods-Retrospective chart review of which was dose related and often mild and self children attending the paediatric rheuma- limiting.'3 Studies of the efficacy and toxicity tology clinic at a tertiary referral hospital of misoprostol in children are few. Recently, over a three year period, who were there have been two reports suggesting that receiving NSAIDs and were prescribed misoprostol can lead to clinical improvement misoprostol for treatment of GIT in children with juvenile rheumatoid arthritis symptoms or anaemia. (JRA) who present with NSAID related Results-Twenty five children (mean age symptoms, 4 15 but the number of patients 12-0 (SD 2-8) (range 7-17) years were studied was small and no firm conclusions prescribed misoprostol (mean dose 308-4 could be drawn. We undertook a retrospective (76 5) FugIm2/day; 9-8 (2.5) ,ug/kg/day) study of the children who had been treated while NSAID therapy was continued. Of with misoprostol through the rheumatology the 22 (88%) patients with GIT com- service at The Hospital for Sick Children over plaints, 18 (82%) had complete resolution the past three years. Our aims were to evaluate of symptoms and two (9%/o) had some the effect of misoprostol on gastrointestinal improvement. Four patients (18%) had a symptoms and to determine if there were any

recurrence of symptoms after initial adverse effects. http://ard.bmj.com/ resolution while still receiving miso- prostol. Misoprostol therapy was associ- ated with a statistically significant Patients and methods increase in haemoglobin concentration We undertook a retrospective review of the (mean value before misoprostol 115 (18) charts of all children who received treatment g/l; after misoprostol 126 (15) g/l with misoprostol through the rheumatology

(p=0 02)). The only service of The Hospital for Sick Children on September 30, 2021 by guest. Protected copyright. reported was self limited diarrhoea in one between February 1990 and February 1993. child. Information was collected relating to diagnosis, Conclusion-Misoprostol appeared to be age at commencement of misoprostol therapy, effective in the treatment of GIT symp- indications for therapy, haemoglobin concen- toms in children receiving NSAIDs and to tration before treatment, dosage of misoprostol result in significant increase in the and concomitant at the start of Division of Clinical haemoglobin concentration. Further pro- therapy. If specific gastroenterological evalu- Phamacology, The spective studies are needed to evaluate the ation, such as endoscopy, had been performed Hospital for Sick role of misoprostol therapy for NSAID at any stage to assess symptoms, these results Children, Department of Pediatrics, associated GIT complaints in the were retrieved. Outcome measures included University ofToronto, paediatric population. subjective physician evaluation of gastro- Canada intestinal symptoms at follow up visits, and M Gazarian M Berkovitch (Ann Rheum Dis 1995; 54: 277-280) haemoglobin value within three months of G Koren initiation of therapy. Haemoglobin values Division of Up to 30% of adult patients taking non- before and after treatment were analysed Rheumatology steroidal anti-inflammatory drugs (NSAIDs) statistically using the two tailed Student's t E D Silverman long term experience gastrointestinal side test. R M Laxer effects, -3 but the incidence of NSAID Correspondence to: Dr Ronald M Laxer, associated gastropathy in children is not The Hospital for Sick known. However, gastrointestinal symptoms Results Children, Division of Rheumatology, 555 are commonly encountered in children with The charts of 25 children (15 females and 10 University Avenue, Room chronic arthritis treated with NSAIDs and lead males) were evaluated. The mean age at the 8253, Toronto, Ontario, Canada M5G 1X8. to discontinuation or alteration of NSAID start of misoprostol therapy was 12-0 (SD 2 8) Accepted for publication therapy, with resultant compromise of arthritis years (range 7-17). The underlying rheumato- 17 November 1994 management.4 Misoprostol is a synthetic logical conditions included systemic onset JRA 278 Gazarian, Berkovitch, Koren, Silverman, Laxer

in four, pauciarticular JRA in seven, poly- plement; the difference in haemoglobin values articular JRA in six, psoriatic arthritis in three, before and after treatment remained and spondyloarthropathy in three. There was statistically significant (p = 0-01) when data no definite rheumatological diagnosis in two from patients who were not receiving the Ann Rheum Dis: first published as 10.1136/ard.54.4.277 on 1 April 1995. Downloaded from patients. The mean dose of misoprostol supplementation were analysed separately. prescribed at the commencement of therapy The one patient in whom anaemia had been was 308 4 (76 5) pLg/m2/day (9-8 (2 5) p1g/kg/ the sole indication for misoprostol had day) (range 175-520 ig/Mm2/day (5-6-17-8 previously been treated with iron supplemen- hg/kg/day)), usually given in divided doses tation without a satisfactory response. Her twice a day. The maximum prescribed dose at haemoglobin was 87 g/l before treatment, any stage during therapy was 552 pig/m2/day increasing to 113 g/l within three months of (800 pLg/day or 18-87 jg/kg/day). The duration starting misoprostol. Iron supplementation of misoprostol therapy could not be reliably was discontinued two months later and her determined from the charts in all cases, but for haemoglobin remains satisfactory with con- those available (n = 20), the mean duration was tinued misoprostol therapy. 13-6 months (range 1-4-37-2 months). With regard to adverse effects, there was only Concomitant therapy included one NSAID in one case of diarrhoea reported; this resolved all but one child, who was receiving two. All spontaneously after two weeks while miso- children had received a minimum of one prostol therapy was continued unchanged. The month of continuous NSAID therapy before dose of misoprostol in this patient was 375 starting to take misoprostol. The NSAIDs used jig/m2/day. No other adverse effects were and mean (SD) doses (mg/kg/day) were: reported. naproxen 15-7 (2 44) (n = 11); indomethacin Only two children had upper GIT endos- 2-19 (0-61) (n=6); ibuprofen 23-26 (10.62) copy before starting misoprostol. In one the (n = 2); diclofenac 1X94 (0-66) (n = 4); indication was abdominal pain and anaemia; tolmetin sodium 24-9 (8-53) (n = 2); piroxicam endoscopy showed erosions at the gastro- 0-28 (n = 1). Other treatment consisted of oesophageal junction with oesophagitis prednisone 0-21 (0 07) mg/kg/day (n = 4); confirmed on biopsy. In the other, the pulse intravenous methylprednisolone (n = 2); indication was abdominal pain alone and gammaglobulin infusion (n = 3); sulphasala- endoscopy was normal. The symptoms zine (n = 4); methotrexate (n = 2); and improved with misoprostol and thus hydroxychloroquine (n = 1). endoscopy was not repeated in these patients. The main indication for treatment was abdominal pain, which was reported in 22 patients. Seven patients had been treated with Discussion sucralfate and one patient had been taking The present study describes our experience and antacids without adequate relief with misoprostol therapy in the largest group

of symptoms, before starting misoprostol. In of children reported to date. More than 90% http://ard.bmj.com/ addition, two patients had nausea, two had of patients presenting with abdominal pain vomiting, one had bloating and two had while receiving NSAIDs had either complete diarrhoea before starting misoprostol therapy. (82%) or partial (90/o) resolution of their Non-specific symptoms symptoms when taking misoprostol, allowing were reported in four patients. Five patients continuation ofNSAID therapy in the majority who had anaemia in addition to abdominal of cases. The study is limited by its pain were treated with oral iron. One patient retrospective and the lack of design any on September 30, 2021 by guest. Protected copyright. had no GIT symptoms but had iron deficiency controls or comparison with placebo. A recent anaemia as the sole indication for treatment trial in adults reported a placebo response rate with misoprostol. as high as 570/o;S however, the considerably Eighteen of 22 patients (82%) who greater rate of response in our patients, presented with GIT complaints had complete together with the findings that none reported resolution of symptoms, usually within three any exacerbation of their abdominal pain and months; two patients (9%) had some improve- that the majority of patients were able to ment. One patient discontinued treatment continue NSAID therapy, suggests a beneficial after only two days and another discontinued effect of misoprostol. All children were NSAIDs at the same time as starting miso- receiving NSAIDs at dosages within or below prostol. Four patients (17%) had a recurrence the accepted therapeutic ranges and some had of symptoms while receiving misoprostol after failed to derive benefit from other GIT there had been initial resolution. However, protective agents before starting to take miso- none of the patients reported an exacerbation prostol. As only two patients underwent of their initial GIT symptoms. One patient endoscopy before commencing misoprostol, experienced a recurrence of abdominal pain the attribution of the GIT symptoms to after misoprostol was stopped and this was NSAID therapy in the group overall was purely relieved when misoprostol therapy was on clinical grounds. Alternative aetiologies for recommenced. the abdominal pain experienced by these The mean haemoglobin concentration children may have included the underlying before commencement of misoprostol therapy disease process (although systemic onset JRA was 115 (18) g/l (range 73-136); after is the only subtype that is associated with treatment it was 126 (15) g/l (range 77-156) abdominal pain and none of the four patients (p = 0 02). Six patients were receiving with this disease was known to have had concomitant treatment with an iron sup- abdominal pain as a feature of their disease Experience with misoprostol therapyfor NSAID gastropathy in children 279

before the initiation of NSAID therapy), misoprostol.25 We could not assess this in the psychosocial factors, and other concomitant present study, but others have not reported any medications such as sulphasalazine, metho- change in the activity of arthritis with trexate, or gammaglobulin infusions, although misoprostol therapy.'4 Ann Rheum Dis: first published as 10.1136/ard.54.4.277 on 1 April 1995. Downloaded from the numbers receiving these medications were Diarrhoea is the most frequently reported quite small. adverse event in patients treated with Misoprostol is a synthetic PGE1 analogue. misoprostol. It is a dose related phenomenon Its mechanisms of action include inhibition of and its frequency in adults has been reported gastric secretion through a direct action on to be as low as 6% in those taking 200 ,ug or parietal cells, in addition to mucosal protection less daily and as high as 39% in those taking through increased mucus and bicarbonate 800 p.g daily.'3 Diarrhoea seems not to be a secretion; increased mucosal blood flow; and major problem in children.'4 '5 This was con- improved cellular resistance, permeability and firmed in our study, in which only one regeneration in response to irritants.'3 Recent patient (3-8%), receiving a moderate daily dose, information from studies in adults indicates experienced this symptom. In this patient it that misoprostol is effective in both the was self limited, resolving spontaneously while treatment and prophylaxis of gastroduodenal misoprostol therapy was continued. injury induced by NSAIDs.'0 16 With regard to We have demonstrated that misoprostol prophylaxis, misoprotol has been shown in relieves the gastrointestinal symptoms associ- comparative trials to be significantly better ated with NSAID use in children. In the adult than placebo and standard antiulcer treatment population, the issue of the routine use of in the prevention of NSAID induced gastric misoprostol for prophylaxis of gastroduodenal injury, but misoprostol and H2 blockers pro- pathology in patients receiving NSAIDs is vided similar protection against duodenal controversial.'0 This question has not been damage.'7 Sucralfate has been shown to be examined in the paediatric population. Our inferior to misoprostol9 and no better than retrospective study suggests that misoprostol is placebo in the prevention of gastroduodenal effective in the treatment of GIT symptoms in damage.'8 has been shown in children receiving NSAIDs and that it results volunteer studies to prevent duodenal but not in significant increase in the haemoglobin gastric damage, and so provides protection value. Future prospective studies should be similar to that of ranitidine.'9 With regard to designed to evaluate the use of misoprostol in treatment, cessation of NSAIDs is clearly the children treated with NSAIDs. If the results of best course of action whenever possible, while such studies are encouraging, the routine use various agents are useful in achieving ulcer of misoprostol with NSAID therapy should be healing. In some patients, however, it may be considered for the paediatric population. clinically preferable to continue the treatment Dr Gazarian is the recipient of the Abe Shore Ontario Juvenile with NSAIDs; in this situation, most studies Arthritis Association Fellowship for 1993. Drs Silverman and

have shown no benefit of H2 antagonists over Laxer are recipients ofAssociateships from the Arthritis Society http://ard.bmj.com/ of Canada. Dr Berkovitch is a Fellow ofthe Cooley Foundation, placebo in healing NSAID induced ulcers and USA, and Dr Koren is a Career Scientist of the Ontario damage during continued administration of Ministry of Health. NSAIDs,2022 and sucralfate has also been 1 Roth S H, Bennett R E. Nonsteroidal anti-inflammatory found not to be useful in the healing of gastric drug gastropathy. Arch Intern Med 1987; 147: 2093-100. 2 Coles L S, Fries J F, Kraines R G, Roth S H. From erosions and ulcers during continued experiment to experience: side effects of nonsteroidal treatment with NSAIDs.23 24 While there is a anti-inflammatory drugs. AmJ'Med 1983; 74: 820-8. 3 Geczy M, Peltier L, Wolbach R. Naproxen tolerability in the paucity of information regarding the manage- elderly: A summary report. J Rheumatol 1987; 14: on September 30, 2021 by guest. Protected copyright. ment of NSAID gastropathy in children, our 348-54. 4 Barron K S, Person D A, Brewer E J. The toxicity of findings are consistent with the results of two nonsteroidal antiinflammatory drugs in juvenile rheuma- recently published studies of NSAID toid arthritis.J Rheumatol 1982; 9: 149-55. 5 Furst D E. Toxicity of antirheumatic medications in gastropathy in small numbers of children children with juvenile arthritis. J Rheumatol 1992; which also suggested that misoprostol is 19(suppl 33): 11-5. 6 Dajani E Z. Perspective on the gastric antisecretory effects beneficial, at least in terms of symptomatic of misoprostol in man. 1987; 33(suppl 10): improvement." 68-77. 7 Dajani E Z. Mucosal protective activities of misoprostol in We found a statistically significant increase man: an overview. In: Bianchi Porro G, Dajani E Z, eds. in the haemoglobin concentration after miso- Gastrointestinal cytoprotection by prostaglandins. Focus on misoprostol. Verona: Cortina International, 1987; 21-31. prostol therapy, even in those patients who 8 Graham D Y, Agrawal N M, Roth S H. Prevention of were not classified as anaemic at the start of NSAID-induced gastric ulcer with misoprostol: Multi- centre, double-blind, placebo-controlled trial. Lancet therapy. Minor amounts of GIT bleeding 1988; ii: 1277-80. occur in the majority of patients receiving 9 Agrawal N M, Roth S, Graham D Y, et al. Misoprostol compared with sucralfate in the prevention of non- NSAID therapy, and the mucosal protective steroidal anti-inflammatory drug-induced gastric ulcer. A action of misoprostol may lead to healing of randomised, controlled trial. Ann Intemn Med 1991; 115: 195-200. these minor lesions, resulting in an increase in 10 Ballinger A B, Kumar P J, Scott D L. Misoprostol in the haemoglobin value. Alternatively, relief of GIT prevention of gastroduodenal damage in rheumatology. Ann Rheum Dis 1992; 51: 1089-93. symptoms by misoprostol may have resulted in 11 Scott D L, Bardhan K D, Bjarnason I, Griffin W M, Fenn improved compliance with NSAID therapy, G C, Shield M J. Misoprostol and NSAID-associated gastroduodenal damage. Br J Rheumatol 1991; 30(suppl leading to better anti-inflammatory effect and 2): 9. thus an increase in the haemoglobin value 12 Roth S, Agrawal N, Mahowald M, et al. Misoprostol heals gastroduodenal injury in patients with rheumatoid through the mechanism of improved disease arthritis receiving aspirin. Arch Intern Med 1989; 149: control. A further contribution to the latter 775-9. 13 Walt R P. Misoprostol for the treatment of peptic ulcer and mechanism may have been through the antiinflammatory-drug-induced gastroduodenal ulcer- proposed direct anti-inflammatory effect of ation. NEnglJ7Med 1992; 327: 1575-9. 280 Gazarianl, Berkovitch, Koreni, Silvermiani, Laxer

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