Nicotine for ulcerative colitis: not just an oddity.|
The inverse relationship between smoking and ulcerative colitis (UC) has been shown in a great number of clinical studies.
There is overwhelming epidemiological evidence that smoking somehow exerts protective effects against UC, whereas has a deleterious influence on Crohn's disease.
UC onset (or flare-up) after smoking cessation, and the remission of UC upon smoking resumption, have been repeatedly described. Former smokers are especially at risk - even more so than lifetime non-smokers.
The component of cigarette smoking responsible for these unusual phenomena was thought to be nicotine. The potential use of nicotine as a therapeutic agent in UC was first investigated by administering nicotine chewing gum. The results were encouraging, despite the erratic nicotine plasma levels associated with the gum.
Nicotine transdermal patches have been tried in various clinical trials carried out in Cardiff, Wales; the Mayo Clinic in Rochester, USA; and by myself at the S. Raffaele Hospital in Milan, Italy. These studies found that transdermal nicotine was significantly superior to placebo in promoting clinical (and, in one study, histological) improvement in active UC. This was true for doses of nicotine up to 25 mg daily, when combined for 4-6 weeks with conventional therapy (mostly, mesalazine).
If administered alone, nicotine appears slightly less efficacious than oral prednisolone (15 mg daily). In patients unable to receive steroids the combination of mesalazine and transdermal nicotine is clinically effective in about 60% of cases.
Maintenance treatment with transdermal nicotine alone (15 mg daily) is no better than placebo in preventing clinical flare-ups of UC in remission.
Another study examined patients who were receiving ongoing mesalazine treatment. In this incidence, the addition of a five-week course with either steroids or transdermal nicotine prevented further flare-ups of UC in remission in the one-year follow-up.
During the subsequent maintenance therapy with mesalazine alone, however, clinical flare-ups were significantly more frequent and occurred earlier, in subjects successfully treated with steroids than in those who had previously received nicotine. The reasons behind these findings are still to be determined.
The explanation for these results is probably related to the mechanism of action of nicotine in UC, which unfortunately remains elusive. A tentative list of mechanisms possibly involved includes: stimulation of colonic mucus thickening, changes in local blood flow, interference with the immune system, inhibition of inflammatory mediators, release of nitric oxide, and alterations in gut motility.
The fact is, we know that nicotine does work in UC, but we do not know why.
Transdermal nicotine can be effectively employed in selected cases of mild-to-moderate left-sided UC. I find it particularly useful when, for some reason, it is advisable to avoid oral steroids to treat the flare-up. Recent data from our unit show that, in cases of distal colitis refractory to local mesalazine, adding transdermal nicotine yields better results than combining oral and rectal mesalazine. Obviously, nicotine is contraindicated in Crohn's disease, as well as in UC patients with cardiovascular disorders or contact dermatitis.
Join the debate! Click here to post your comments about this Personal View Speech.
The potential adverse effects of nicotine administration continue to cause concern in some specialists. Nausea, lightheadedness, sleep disturbances, and contact dermatitis have been described, especially in lifetime nonsmokers. Treatment withdrawals due to poor tolerance have been reported in 6 to 13% of cases.
Results from both our clinical trials and clinical practice, suggest that the incidence of side-effects is negligible if the dose of nicotine is gradually increased during an initial run-in period of 5-7 days. In addition, the daily dose should not exceed 15 mg when treatment is at its peak.
Long-term effects of nicotine (i.e. addiction) are of no concern here, since treatment is limited to periods lasting only 4-6 weeks. Moreover, no nicotine addiction was observed in the only long-term study to date, where transdermal nicotine was continuously administered for six months.
Alternative nicotine formulations (enemas or delayed release oral capsules) have been developed to selectively deliver the substance into the colon. Several pilot reports have appeared in the medical literature, but the data are too preliminary to draw definitive conclusions.
Thus, for the time being, we must stick to nicotine patches. Administering a substance commonly seen as noxious may appear psychologically disturbing (especially in the USA). However, short-term treatment with transdermal nicotine in mild-to-moderate cases of UC is not just an oddity, but a useful therapeutic tool, which may spare the employment of oral corticosteroids.
This article originally appeared on 24 September 2001.
Thomas G.O., Rhodes J., Green J.T. Inflammatory bowel disease and smoking - a review. Am J Gastroenterol 1998; 93: 144-9.
Guslandi M. Nicotine treatment for ulcerative colitis. Br J Clin Pharmacol 1999; 48: 481-4.
Sandborn W.J. Nicotine therapy for ulcerative colitis: a review of rationale, mechanisms, pharmacology and clinical results. Am J Gastroenterol 1999; 94: 1161-71.