Original Article
Transdermal Nicotine for Active Ulcerative Colitis
N Engl J Med 1994; 330:811-815March 24, 1994
- Abstract
Background
Ulcerative colitis is largely a disease of nonsmokers. Because anecdotal reports suggest that smoking and nicotine may improve the symptoms of the disease, we examined the effect of nicotine as a supplemental treatment for ulcerative colitis.
Methods
We treated 72 patients with active ulcerative colitis with either transdermal nicotine patches or placebo patches for six weeks in a randomized, double-blind study. Incremental doses of nicotine were given; most patients tolerated doses of 15 to 25 mg per 24 hours. All the patients had been taking mesalamine, and 12 were receiving low doses of glucocorticoids; these medications were continued without change during the study. Clinical, sigmoidoscopic, and histologic assessments were made at base line and at the end of the study; symptoms were recorded daily on a diary card, and the clinician made a global assessment. Side effects and plasma nicotine and cotinine concentrations were monitored throughout the study.
Results
Seventeen of the 35 patients in the nicotine group had complete remissions, as compared with 9 of the 37 patients in the placebo group (P = 0.03). The patients in the nicotine group had greater improvement in the global clinical grade of colitis (P<0.001) and the histologic grade (P = 0.03), lower stool frequency (a difference of 1.6 stools daily; P = 0.008), less abdominal pain (P = 0.05), and less fecal urgency (P = 0.009). More patients in the nicotine group had side effects (23, vs. 11 in the placebo group; P = 0.002), the most common of which were nausea, lightheadedness, headache, and sleep disturbance. Withdrawals due to ineffective therapy were more common in the placebo group (3 vs. 8, P = 0.12).
Conclusions
The addition of transdermal nicotine to conventional maintenance therapy improves symptoms in patients with ulcerative colitis.
Media in This Article
Table 1
Grading Systems for the Assessment of Patients with Ulcerative Colitis.Table 2
Clinical Characteristics of 72 Patients with Ulcerative Colitis.Article Activity
- Article
Most patients with ulcerative colitis are nonsmokers, and patients with a history of smoking usually acquire their disease within a few years after they have stopped smoking1-4. Among patients who continue to smoke, symptoms may improve, suggesting that smoking may have a beneficial effect5,6. Given the possibility that nicotine is the ingredient of tobacco smoke responsible for improvement, we treated 16 patients with active ulcerative colitis in an uncontrolled fashion with transdermal nicotine patches, and symptoms improved in 127. We report here the results of a randomized, double-blind, controlled trial of transdermal nicotine in patients with active ulcerative colitis.
Methods
Patients
Seventy-seven patients with known left-sided ulcerative colitis who had relapsed, as confirmed by rigid sigmoidoscopic examination, were invited to participate in the study of treatment with transdermal nicotine or placebo for six weeks. Patients were not enrolled if they had enteric infection or other medical problems (particularly of the cardiovascular system), were pregnant or lactating, had changed their maintenance anticolitis therapy during the previous four weeks, or currently smoked. Both former smokers and lifelong nonsmokers were enrolled; the two groups were not stratified separately in the randomization.
The study was approved by the appropriate review committees at each of the three study hospitals, and all the patients gave informed written consent.
Nicotine Patches
We used two sizes of transdermal nicotine patch that released 5 or 15 mg of nicotine over a period of 16 hours (the average smoker absorbs about 1 mg of nicotine per cigarette smoked)8,9. The patients applied the patches before going to bed to limit side effects and wore them for 24 hours.
Since the therapeutic trial involved the administration of nicotine to patients who had never smoked, we studied the tolerance and pharmacokinetics of transdermal nicotine in 12 normal subjects (7 men and 5 women) who were lifelong nonsmokers. The nicotine doses were increased in a stepwise manner over a period of five days to minimize side effects. On days 1 and 2 single 5-mg patches were worn, on days 3 and 4 two 5-mg patches, and on days 5 and 6 single 15-mg patches. Three of these subjects were intolerant of nicotine, but in the remaining nine the mean (±SD) plasma nicotine concentrations eight hours after the application of the patches on days 2, 4, and 6 were 3.4 ±1.0, 7.3 ±2.1, and 13.3 ±5.6 ng per milliliter, respectively.
Nicotine Dose in the Therapeutic Trial
The incremental dose regimen used in the preliminary studies was repeated in the patients with ulcerative colitis, most of whom tolerated a dose of 15 mg. If no clinical benefit was evident after two weeks the dose was increased to 25 mg daily. The patients who were unable to tolerate 15-mg patches were given a lower-dose patch. The mean (±SD) dose in the nicotine group was 17 ±6 mg. The placebo patches were identical to the nicotine patches in appearance and were increased in size in a similar manner. The mean patch “dose” for patients in the placebo group was 19 ±5 mg. Changes in treatment were monitored by one physician at each hospital; none of the three physicians were aware of the patients' treatment assignments.
Study Design
All the patients had relapsed despite treatment with their usual medication. During the trial the patients continued to take the same doses of anticolitis drugs (oral formulations of mesalamine and glucocorticoids) that they had taken during the previous four weeks. Those who were taking glucocorticoids were randomized separately. The effect of transdermal nicotine on the course of the patients' disease was evaluated by analyzing changes in clinical, sigmoidoscopic, and histologic indexes during the six-week study period.
Evaluation Procedures
The severity of disease was assessed clinically at the start of the trial and after two, four, and six weeks; at each center one physician saw every patient and made a global clinical assessment using the grading system described by Truelove and Witts (Table 1Table 1
Grading Systems for the Assessment of Patients with Ulcerative Colitis.)10. The patients were asked to complete a daily diary recording stool frequency and consistency, the presence of blood or mucus, and episodes of abdominal pain. Pain, fecal urgency, and the degree of general well-being were also noted. Fecal urgency was scored daily by the patient on a scale from 1 (no urgency) to 10 (incontinent of stool), and general well-being on a scale from 1 (poor) to 10 (very well). Each day the patients also recorded the occurrence of nine common side effects and any others.At the beginning of the study all the patients underwent sigmoidoscopy and rectal biopsy. When the proximal extent of disease could not be seen, colonoscopy or barium enema was performed. Sigmoidoscopy and biopsy were repeated by the same physician at the end of the study or at the time of a premature withdrawal. The extent of inflammation of the rectal mucosa was graded visually,11 and biopsy specimens stained with hematoxylin and eosin were graded histologically according to a system described by Truelove and Richards (Table 1)12. Biopsies were performed at the start and end of the trial in all but one patient, and the specimens were examined without knowledge of treatment assignment.
Plasma nicotine and cotinine concentrations were measured at base line and after two, four, and six weeks. Most of the blood samples were obtained 12 hours after the nicotine patch had been applied, and they were stored at -20 °C until analysis13. Nicotine and cotinine concentrations are maximal about eight hours after application of the patch. To determine whether any patient had resumed smoking, breath carbon monoxide was measured with a Bedfont MicroSmokerlyzer at each clinic visit.
Side Effects and Mood
The side effects of treatment were recorded at each visit and graded as absent, mild, moderate, severe, or severe enough to cause withdrawal from the study; they were scored from 0 (none) to 4 (severe) for analysis. Mood was assessed by questionnaire before, during, and at the end of the trial and 6 to 12 weeks later to identify any change after nicotine withdrawal.
Statistical Analysis
The base-line characteristics of the patients in the two study groups were compared by the chi-square test, Mann-Whitney test, Fisher's test, or unpaired t-test as appropriate. All P values are two-tailed. The changes in clinical, sigmoidoscopic, and histologic scores in the two groups were compared by analysis of covariance of the results for all patients who remained in the study for more than three days; the corresponding base-line value was the covariate. The effect of active treatment was assessed by the corresponding adjusted mean difference. Changes in the proportion of patients reporting mucus were compared by the Mantel-Haenszel method14.
Results
Base-Line Data
Seventy-seven patients entered the trial, but five in the nicotine group withdrew within three days and are not included in the analysis. One of the five had colitis of the entire colon, another did not use any patches, and three had severe side effects. Of the remaining 72 patients, 15 (5 in the nicotine group and 10 in the placebo group) withdrew before the end of the trial. The reasons for the premature withdrawals were side effects (two patients in the nicotine group and one in the placebo group), a change of mind (none and one, respectively), worsening symptoms (two and three), and ineffective treatment (one and five); all these patients had end-of-treatment assessment measures. Analyses of the 72 patients were based on the principle of intention to treat. Of the 72, 35 received nicotine and 37 placebo. The base-line characteristics of the two groups were similar (Table 2Table 2
Clinical Characteristics of 72 Patients with Ulcerative Colitis.), as were their symptomatic and sigmoidoscopic findings (Table 3Table 3
Results of Clinical, Sigmoidoscopic, and Histologic Assessments at Base Line and at the End of the Trial.). The initial general well-being and histologic scores were both significantly higher in the nicotine group than in the placebo group (Table 3).Outcome
The global clinical score, other clinical scores, and sigmoidoscopic and histologic scores improved in both groups, but the improvements were greater and more consistent in the nicotine group (Table 3). Comparisons of the improvement in the two groups by analysis of covariance, taking into account differences in disease activity at base line, revealed greater improvement in the nicotine group in global clinical grade, stool frequency, abdominal pain, fecal urgency, and histologic score (Table 3).
Seventeen of the 35 patients in the nicotine group had complete symptomatic relief and a global clinical grade of 0, as compared with 9 of the 37 patients in the placebo group (P = 0.03). The proportion of patients reporting no stool mucus at the end of the trial was 57 percent (20 patients) in the nicotine group and 22 percent (8 patients) in the placebo group (P = 0.002). The mean changes in each treatment group and the differences between groups are shown in Table 3.
Influence of Smoking History, Age, and Sex
The smoking history of the patients in the two groups was similar (Table 2). There was no difference in the severity of ulcerative colitis at base line between the former smokers and the lifelong nonsmokers. There was also no significant relation between age, sex, or smoking history and the response to nicotine, although the small numbers of patients in the subgroups limited the power of these analyses.
Nicotine Dose and Side Effects
Twenty-three patients in the nicotine group and 11 patients in the placebo group had side effects during the study (P = 0.002). Three patients, two in the nicotine group and one in the placebo group, withdrew because of side effects. Six patients in the nicotine group, five of whom were lifelong nonsmokers, had side effects within the first few days that improved when the dose was reduced to 5 or 10 mg daily. Most of the other patients in the nicotine group had some side effects in the first few days, which subsequently subsided. During the first four weeks of the study 20, 15, 12, and 6 patients, respectively, in the nicotine group had side effects, as compared with 10, 7, 6, and 4 patients in the placebo group. The side effects in the nicotine group were more severe; of the 20 patients with side effects in the first week, 12 had moderate or severe effects and 8 mild effects. The side effects in the placebo group included headache, nausea, and dizziness and were mild, with one exception that led to premature withdrawal. The most common side effects in the nicotine group, in order of frequency, were nausea, lightheadedness, headache, sleep disturbance or vivid dreams, dizziness, skin irritation, sweating, vomiting, and tremor. The occurrence of side effects in the nicotine group was related to the patients' smoking history; they occurred in 10 of the 11 lifelong nonsmokers as compared with 13 of the 24 former smokers (P = 0.04). There were no significant correlations between side effects in the first two weeks and plasma nicotine or cotinine concentrations.
Plasma Nicotine and Cotinine Concentrations
Plasma nicotine and cotinine concentrations reflect the dose of nicotine given. By the fourth week, when the doses of nicotine had become acceptable, 2 patients were using 5 mg per 24 hours, 1 was using 7.5 mg, 3 were using 10 mg, 19 were using 15 mg, and 10 were using 25 mg; the respective mean plasma nicotine concentrations in these five groups were 1.2, 1.0, 8.7, 8.3, and 12.1 ng per milliliter. The mean value in the patients using 15-mg patches (8.3 ng per milliliter) was lower than the mean value of 13.3 ng per milliliter in the pilot study, which was similar to the values reported by others15. Altogether, the patients using 15 or 25 mg of nicotine daily had plasma nicotine and cotinine concentrations that were approximately 35 percent of the average for smokers16.
The plasma nicotine and cotinine concentrations before the trial and after two, four, and six weeks of treatment reflected the patients' treatment assignments (Table 4Table 4
Plasma Nicotine and Cotinine Concentrations in Patients with Ulcerative Colitis Given Transdermal Nicotine or Placebo for Six Weeks.). There was considerable variation between patients in the nicotine group, but the concentrations in individual patients were more consistent. Four patients in the nicotine group had low plasma nicotine concentrations at the end of the trial, suggesting poor compliance; subsequent inquiry revealed that they had not worn patches in the last few days of the trial. The plasma nicotine and cotinine concentrations in the placebo group were uniformly low in all but two patients, who had plasma cotinine concentrations of 48 and 76 ng per milliliter throughout the trial, including the base-line measurements. The cutoff point for distinguishing smokers from nonsmokers is 14 ng per milliliter17. On average, in steady state, each increase of 11 ng per milliliter in the plasma cotinine concentration reflects a nicotine intake of 1 mg (about one cigarette) in 24 hours18.Mood Changes
During the trial most former smokers in the nicotine group felt well, but the lifelong nonsmokers tolerated treatment with more difficulty. After the trial none reported a craving for smoking, and none reported any smoking during the subsequent 12 weeks.
Discussion
We found that the condition of patients with active ulcerative colitis improved when they were treated for six weeks with transdermal nicotine. This positive outcome may be a step toward clarifying the relation between smoking status and colitis.
Although the patients in both the nicotine group and the placebo group improved, the improvement in clinical and histologic grades was greater in the nicotine group. These results are based on the study of a substantial number of patients. Most were able to tolerate nicotine given in stepwise increments, although many had side effects; three patients withdrew within three days of beginning treatment because of intolerable side effects, two withdrew later, and the dose was reduced in another six. The greater frequency of side effects in the nicotine group may have suggested that they were receiving nicotine and may have influenced the subjective assessments of colitis. However, many patients had no side effects, and the physicians responsible for the clinical assessments remained unaware of the group assignments.
Our results suggest that nicotine may be a suitable treatment in patients able to tolerate the drug, and they provide information on the proportion of patients who are able to tolerate transdermal nicotine. There may be a subgroup of patients with colitis who are more likely to respond to nicotine therapy, but our data do not provide a definitive answer because of the small size of the subgroups classified according to age, sex, smoking history, and duration of relapse. In some epidemiologic studies the relation between smoking and colitis has been stronger in men than in women4,19-21.
Our results are consistent with epidemiologic findings that ulcerative colitis is a disease of nonsmokers and those who have recently stopped smoking3,4. In previous uncontrolled studies, nicotine patches,7 nicotine chewing gum, and smoking appeared to improve symptoms,5,22,23 and a survey of 30 intermittent smokers with colitis revealed that half of them thought their colitis improved when they smoked24. Nicotine is probably the active agent and may act through an effect on inflammatory mediators25 or by changing adherent surface mucus in the colon26-31. Whether nicotine will become an established treatment for patients with ulcerative colitis awaits further investigation. We have shown that it is tolerated by most patients and has a beneficial clinical effect. Better understanding of its mode of action could open the way to the development of alternative therapeutic approaches more acceptable than nicotine itself. Although addiction is a major problem associated with smoking, our patients did not have recognizable withdrawal symptoms after six weeks of treatment with nicotine, although many had absorbed doses equivalent to 35 percent of those absorbed by smokers. Addiction may depend on the sharp increases in plasma nicotine concentrations that follow smoking, which are unlike the steady release from transdermal patches32-34.
Currently available treatment for ulcerative colitis is far from satisfactory; there are only two major drugs, glucocorticoids and mesalamine, either of which may be poorly tolerated or ineffective in regular use. Alternative safe and effective treatments would be useful. Nicotine or agents that have similar effects on colonic mucosa may emerge as useful therapeutic agents for colitis.
Supported in part by Kabi Pharmacia, which provided the transdermal nicotine patches.
We are indebted to Miss Bel Adamson, pharmacist, University Hospital of Wales, for trial randomization and prescriptions.
Source Information
From the Department of Gastroenterology, University Hospital of Wales, Cardiff, United Kingdom (R.D.P., J.R., G.A.O.T.); Leigh Infirmary, Leigh, Greater Manchester, United Kingdom (S.G., V.M.); Princess of Wales Hospital, Bridgend, Mid Glamorgan, United Kingdom (J.S.M.); the Departments of Pathology (G.T.W.) and Medical Computing and Statistics (R.G.N.), University of Wales College of Medicine, Cardiff, United Kingdom; the Health Behaviour Unit, Institute of Psychiatry and Maudsley Hospital, London (M.A.H.R.); the Nicotine Laboratory, Poisons Unit, New Cross Hospital, London (C.F.); and Kabi Pharmacia Therapeutics, Helsingborg, Sweden (U.S.).
Address reprint requests to Dr. Rhodes at the Dept. of Gastroenterology, Ward A7, University Hospital of Wales, Heath Park, Cardiff, United Kingdom.
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