Transdermal Nicotine for Mildly to Moderately Active Ulcerative Colitis

Ulcerative colitis is primarily a disease of nonsmokers [1-4]. Nonsmokers who have ulcerative colitis and begin smoking may go into remission [5]. These observations led to uncontrolled trials of nicotine administered through chewing gum [6] or a transdermal patch [7]. A controlled trial of 15 to 25 mg of transdermal nicotine for active ulcerative colitis reported that 49% of patients responded to nicotine, whereas only 24% responded to placebo [8]. A subsequent controlled trial of 15 mg of transdermal nicotine used to maintain remission of ulcerative colitis reported that 45% of patients receiving nicotine had remission compared with 50% of patients receiving placebo [9]. Finally, a controlled trial [10] showed a clinical response in 32% of patients with active ulcerative colitis who received 15 to 25 mg of transdermal nicotine and in 58% of patients who received oral prednisolone. These studies suggest that transdermal nicotine may be efficacious for active ulcerative colitis, but confirmatory placebo-controlled trials are needed. We conducted a 4-week placebo-controlled trial in which transdermal nicotine, 11 to 22 mg/d, was used to treat active ulcerative colitis. Methods Study Design Our study was a randomized, double-blind, placebo-controlled trial that used the highest tolerated dosage of transdermal nicotine ( 22 mg/d) in nonsmoking patients with mildly to moderately active ulcerative colitis. To ensure that the nicotine and placebo groups were similar, patients were assigned to 1 of 16 strata on the basis of concomitant medical treatment (mesalamine, sulfasalazine, and olsalazine; oral corticosteroids; both; or neither), smoking history (persons who formerly smoked or persons who never smoked), and extent of disease (extensive or left-sided only). Eligible patients were sent to the Nicotine Research Center of the Mayo Clinic in Rochester, Minnesota, for randomization and dispensing of study medication. In each stratum, patients were randomly assigned to treatment by a computer-generated randomization sequence that was developed from SAS software (SAS Institute, Cary, North Carolina) [11]. Nicotine and placebo transdermal patches, labeled only by an identifying letter, were placed in clear plastic bags without any treatment-identifying information and were dispensed by Elan Pharmaceutical Research Corp. To the staff of the Nicotine Research Center along with a key for breaking the randomization code. The staff of the Center then dispensed study medication to the patients. The staff was not involved in patient care or assessment of disease activity, and treatment allocation was concealed from the medical personnel involved in patient care or assessment of disease activity and from the patients. Patients From April 1993 to September 1995, 66 adult patients with mildly to moderately active ulcerative colitis were referred by colleagues at the Mayo Clinic for study enrollment. Active ulcerative colitis was diagnosed by the usual symptomatic, radiographic, and endoscopic criteria [12]. The Institutional Review Board of the Mayo Clinic approved the study, and all patients gave written informed consent. Patients were classified as having never smoked or as having formerly smoked. Patients who had used products that contained nicotine within 3 months of study entry were excluded. To confirm patients' self-reported abstinence from nicotine products at study entry, CO concentrations in expired air [13] and serum nicotine and plasma cotinine concentrations were measured [14, 15]. During the trial, therapy with oral 5-aminosalicylate compounds (sulfasalazine, olsalazine, and mesalamine), oral corticosteroids ( 20 mg/d), topical corticosteroids, and topical mesalamine was continued at prestudy doses if the doses had not been changed during the 2 weeks preceding study entry. Patients who were receiving corticosteroids at a dosage greater than 20 mg/d and patients who were taking cyclosporine, 6-mercaptopurine, azathioprine, or methotrexate were excluded. At the initial visit, the extent of colonic mucosal involvement was determined by using flexible sigmoidoscopy. Left-sided disease was defined as a demarcation between inflamed colonic mucosa and normal colonic mucosa (both shown by endoscopy) that was located less than 60 cm from the anal verge; in extensive disease, the demarcation extended more than 60 cm from the anal verge. Assessment of Disease Activity Each day, patients recorded the number of stools, any rectal bleeding, and any other symptoms coinciding with therapy that might represent adverse reactions. Patients were evaluated at study entry and after 4 weeks according to a previously described 13-point disease activity index that measured stool frequency, rectal bleeding, endoscopic findings, and the physician global assessment [16]. Clinical remission was defined as a disease activity index score of 0, and clinical improvement was defined as a decrease in the disease activity index of at least 3 points (or a decrease of 2 points if the baseline disease activity index was 3). Colonic mucosal biopsy specimens were obtained at study entry and after 4 weeks, and histologic disease activity was assessed according to a previously described 5-point histologic disease activity index [17]. Endoscopic biopsy specimens were obtained from the site in the rectosigmoid colon that appeared to have the most severe inflammation. One pathologist blindly determined the histologic disease activity index scores in random order at one sitting. Histologic remission was defined as a histologic disease activity index score of 0, and histologic improvement was defined as a decrease in the histologic disease activity index of at least 1 point. Transdermal Nicotine Patch Transdermal nicotine and placebo patches (Elan Pharmaceutical Research Corp., Athlone, Ireland) were used in our study. The transdermal nicotine patches were dispensed in two sizes and doses: small (11 mg) and large (22 mg). Placebo patches identical in appearance to the nicotine patches were also dispensed in two sizes. Patients were instructed to use the small patches for 7 days and then change to the large patches for 21 days. Patients who wore the larger patch and then developed intolerable side effects that lasted 3 consecutive days were instructed to resume using the smaller patch. Patients who wore the smaller patch and then developed intolerable side effects that lasted 3 consecutive days were instructed to discontinue patch therapy. The patients were instructed to apply fresh patches to the skin of the upper torso every 24 hours. Compliance was determined by review of patient diaries and by counting the number of used and unused transdermal patches at the week 4 visit. Adverse Reactions to Nicotine Intolerable adverse reactions (such as severe contact dermatitis, lightheadedness, dizziness, nausea, or vomiting) that occurred before week 4 were reported to the study coordinator; therapy was then changed as described in the preceding paragraph. At the week 4 visit, patients were specifically asked about the following adverse reactions: skin erythema or irritation or contact dermatitis, nausea or vomiting, headaches, sleep disturbance or violent or sexual dreams, diaphoresis or sweating, lightheadedness or dizziness, and shakiness or tremor. Tachycardia and hypertension were also noted. Concentrations of Serum Nicotine, Plasma Cotinine, and Expired Air Carbon Monoxide Serum nicotine and plasma cotinine concentrations were determined in venous blood by using standard assays [14, 15]. At study entry, blood samples were collected to confirm abstinence from products that contain nicotine. At the week 4 visit, blood samples were collected at the peak time (the time of maximum concentration, which occurs approximately 8 hours after the transdermal patch is placed on the skin), and at the trough time (the time just before application of the next transdermal patch). Blood samples were processed immediately after venipuncture, and serum and plasma were stored at 20C until assays were done. Concentrations of CO in expired air were measured at study entry and at the week 4 visit by using a Vitalograph EC 50 monitor (Vitalograph, Inc., Lenexa, Kansas) [13]. The results of this assay confirmed the patients' self-reported abstinence from smoking (a concentration of 8 parts per million indicates recent smoking). Statistical Analysis The baseline characteristics of the treatment groups were compared by using the rank-sum test for continuous variables and the Fisher exact test for categorical variables. We also used the Fisher exact test to compare the percentage of patients in each group who had overall clinical improvement and remission. The Cochran-Mantel-Haenszel general association statistic was used to test for a difference between treatment groups on overall clinical improvement after simultaneous adjustment for the three stratification factors. For each treatment group, the changes from baseline to week 4 in the 13-point clinical disease activity index, the components of the clinical disease activity index (stool frequency, rectal bleeding, sigmoidoscopic findings, and physician global assessment), and the histologic disease activity index were compared to a score of 0 by using the one-sample signed-rank test. The changes in these scores in the nicotine group were compared with the changes in the placebo group by using the two-sample rank-sum test. When data at the week 4 visit were missing, the last-value-carried-forward technique was used. In all cases, two-tailed tests were used; P values less than 0.05 were considered statistically significant. Results Randomization Sixty-six patients were randomly assigned to treatment, but 2 patients dropped out of the study before receiving any study medication: One decided not to participate in the study, and 1 was severely ill and required hospitalization immediately after randomization (in retrospect, this patient's ulcera