Distal ulcerative colitis refractory to rectal mesalamine : Role of transdermal nicotine versus oral mesalamine

Gastroenterology Unit, San Raffaele University Hospital, Milan, Italy Correspondence and reprints: Dr Mario Guslandi, Gastroenterology Unit, San Raffaele University Hospital, Via Olgettina 60, 20132 Milan, Italy. Telephone +39-02-26632766, fax +39-02-2152559, e-mail guslandi.mario@hsr.it Received for publication December 4, 2001. Accepted March 13, 2002 M Guslandi, R Frego, E Viale, PA Testoni. Distal ulcerative colitis refractory to rectal mesalamine: Role of transdermal nicotine versus oral mesalamine. Can J Gastroenterol 2002;16(5):293-296.

suite à la page suivante R ectal formulations of mesalamine are known to be effective in treating mild to moderate forms of active, distal ulcerative colitis (1).The medical management of patients with distal colitis refractory to mesalamine enema therapy is less straightforward.Combination therapy with oral mesalamine can be an option.Administration of a combination of mesalamine tablets and enemas reportedly induces earlier and more frequent cessation of rectal bleeding, as well as greater clinical improvement, than local therapy alone (2).Switching to rectal corticosteroids does not appear to be a reasonable alternative because hydrocortisone enemas have been found to be less effective than mesalamine enemas (3).
Transdermal nicotine should be considered as an alternative to oral steroids.Although, if administered alone, nicotine is less effective than oral prednisolone (4), the combined use of nicotine and mesalamine significantly improves the clinical outcome of left-sided ulcerative colitis (reviewed in 5,6).In particular, treatment with the combination of transdermal nicotine and oral mesalamine may be an effective alternative to treatment with oral steroids for about two-thirds of patients with mild to moderate distal ulcerative colitis (7).
The aim of the present study was to assess the efficacy of transdermal nicotine plus mesalamine enemas versus mesalamine tablets plus mesalamine enemas in patients with distal ulcerative colitis refractory to monotherapy with rectal mesalamine.

PATIENTS AND METHODS
The eligibility requirements of the study were endoscopic diagnosis of mild to moderate ulcerative colitis according to Truelove and Witt's criteria, located 5 to 50 cm above the anal verge and confirmed histologically, that had failed to respond to an initial four-week course of therapy with mesalamine 4 g rectal suspension enemas once nightly.
Treatment failure was defined as a persisting score of 7 or higher by Rachmilewitz's activity index (8), calculated on the basis of stool frequency, blood in the stools, fever, abdominal pain, erythrocyte sedimentation rate, hemoglobin level and general clinical conditions (Table 1).
Current smokers, patients with cardiovascular disorders and patients with ulcerative colitis of a severe degree were excluded from the study.Thirty consecutive patients of both sexes, aged 23 to 48 years with the above characteristics, were recruited.
The enrolled subjects, while continuing the ongoing therapy with mesalamine enemas 4 g at bedtime, were randomly allocated for four weeks to additional treatment with either oral mesalamine 800 mg tid or transdermal nicotine 15 mg patches.To minimize the possible side effects of nicotine, the patches were kept in situ for only 8 h on days 1 and RÉSULTATS : La rémission a été observée chez 12 des 15 patients traités à la nicotine comparativement à 5 patients sur 15 pour la mésalamine orale (P=0,027).CONCLUSION : L'adjonction de nicotine transdermique aux lavements de mésalamine accroît de façon significative l'efficacité du traitement par rapport à l'association de mésalamine rectale et de mésalamine orale chez les patients souffrant d'une rectocolite hémorragique distale réfractaire à la mésalamine rectale seule.
2, 12 h on days 3 and 4, and 16 h on days 5 and 6.From day 7 on, the nicotine patches were kept on the skin for 24 h.The dose of nicotine was chosen on the basis of favourable results of previous studies using the same treatment schedule (7,9).The trial was conducted in accordance with the Helsinki declaration.
Due to the lack of financial or technical support from any drug company or institution, it was not possible to carry out the study in a double-blind, double-dummy fashion using placebo patches and placebo tablets.The study was single-blind, and both the clinical evaluation and, when required, the endoscopic reassessment of patients were performed by individuals who were unaware of the prescribed therapy.
Rachmilewitz's activity index was recalculated at the end of the treatment.As in previous studies (7,9), a score of less than 6 was considered to be a sign of clinical remission.Patients who were in apparent remission underwent flexible sigmoidoscopy, with multiple biopsies, to confirm the clinical response.Patients were considered to be in endoscopic remission if exudation, spontaneous bleeding and friability were absent; the colour of the mucosa was normal; the vascular pattern was only slightly reduced; and granularity was either absent or fine.
Statistical analysis of the clinical results was carried out by χ 2 tests, with P<0.05 considered statistically significant.

RESULTS
All patients completed the prescribed treatment.The two groups were found to be comparable with respect to sex, age, previous smoking habits and clinical index at entry (Table 2).
Therapeutic success at four weeks was obtained in 12 patients in the group receiving nicotine plus rectal mesalamine and in five patients in the group treated with oral plus rectal mesalamine -a statistically significant difference (P=0.027).In all instances, clinical remission was confirmed by endoscopic and histological findings.
Mild nausea and dizziness were reported during the first week of treatment by two subjects in the group receiving nicotine (both lifetime nonsmokers), but the symptoms disappeared during the second week of treatment, and the patients were able to continue the therapy.

DISCUSSION
The pharmacological treatment of patients with distal ulcerative colitis who respond poorly to mesalamine rectal administration is not clearly defined.Combined therapy comprising both oral and rectal mesalamine has been found to be more effective than rectal mesalamine alone (2), but no studies comparing this combined therapy with other types of treatment are available.The notion that smoking exerts favourable effects on ulcerative colitis has elicited clinical studies evaluating the therapeutic properties of transdermal nicotine, which, when administered with oral mesalamine, proved to be significantly effective in the short term treatment of mild to moderate distal colitis (5,6).
Our findings indicate that, in patients with distal colitis in whom mesalamine enemas do not provide substantial clinical benefit, the addition of transdermal nicotine induces clinical and endoscopic remission to a significantly greater extent than the addition of oral mesalamine.
The success rate of combination therapy including mesalamine found in our study was rather low (only 33% of cases) compared with that reported by others (2).However, the study by Safdi et al (2) was carried out in an unselected series of patients with active, distal colitis, whereas we treated patients who were already refractory to mesalamine enemas.It is possible that doses of mesalamine higher than those used in the present study (2.4 g by mouth plus 4 g rectally) would provide better results.We used the standard oral dose that is usually given in the Gastroenterology Unit at the San Raffaele University Hospital, Milan, Italy, but the possible effect of higher amounts of oral mesalamine remains unknown.Similarly, it remains to be determined whether administering mesalamine enemas twice per day would provide a clinical benefit, but a lower degree of patient compliance would be expected.On the other hand, the good results obtained with transdermal nicotine combined with rectal mesalamine are comparable with those observed in previous studies using nicotine plus oral mesalamine (7,9).
The limited incidence of side effects in the group that received nicotine is consistent with that observed in previous studies (7,9) and is probably due to the lower dose used.Side effects are reportedly more frequent with higher doses (4,6).

CONCLUSIONS
The results of our study suggest that patients with refractory distal colitis of a mild to moderate degree can be successfully treated by adding a course of transdermal nicotine to the administration of rectal mesalamine, and that this therapeutic measure is significantly superior to the addition of 2.4 g of oral mesalamine.The other main therapeutic option is the prescription of oral corticosteroids.Our data are consistent with previous findings that transdermal nicotine at a dose of 15 mg daily combined with mesalamine can be an effective alternative to the use of corticosteroids in selected cases of distal ulcerative colitis (7).

Guslandi et al
Can J Gastroenterol Vol 16 No 5 May 2002 294