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A Randomized Trial of Nicotine Enemas for Active Ulcerative Colitis

2005; Elsevier BV; Volume: 3; Issue: 11 Linguagem: Inglês

10.1016/s1542-3565(05)00849-9

1542-7714

J.R. Ingram, Gareth Thomas, John Rhodes, John T. Green, Neil Hawkes, Jill Swift, Emmanuel D. Srivastava, B K Evans, Geraint T. Williams, Robert G. Newcombe, E. Courtney, Suresh Pillai,

SARS-CoV-2 and COVID-19 Research

Background & Aims: Ulcerative colitis (UC) is largely a disease of nonsmokers in which transdermal nicotine improves the symptoms but often causes adverse events (AEs). Nicotine enemas cause fewer AEs and were used as supplemental treatment for active UC. Methods: We treated 104 patients with active UC with either 6-mg nicotine enemas or placebo enemas for 6 weeks in a randomized double-blind study. Patients continued their oral therapy, if any, for UC: 68 patients were taking mesalamine, 15 patients were taking prednisolone, and 12 patients were taking thiopurines during the study. Clinical, sigmoidoscopic, and histologic assessments were made at baseline and at the end of the study and symptoms were recorded daily on a diary card. The primary end point was induction of clinical remission and clinical improvement also was measured by the UC disease activity index. After the study, patients then used nicotine enemas daily for 4 weeks and sigmoidoscopy with a biopsy examination was repeated. AEs and salivary cotinine levels were monitored throughout the study. Results: Clinical remission was achieved in 14 of 52 (27%) patients on active treatment and 14 of 43 (33%) patients on placebo (P = .55). The UC disease activity index improved by 1.45 points in the active group and by 1.65 points for those on placebo (P = .88). Only 1 patient discontinued treatment because of an AE (abdominal pain). In the 47 patients taking mesalamine only, active treatment conferred benefit that was not statistically significant; disease remission occurred in 9 of 25 patients on active therapy and 4 of 21 patients on placebo (P = .20). Conclusions: Six-milligram nicotine enemas were well tolerated but were not found to be efficacious for active UC. Background & Aims: Ulcerative colitis (UC) is largely a disease of nonsmokers in which transdermal nicotine improves the symptoms but often causes adverse events (AEs). Nicotine enemas cause fewer AEs and were used as supplemental treatment for active UC. Methods: We treated 104 patients with active UC with either 6-mg nicotine enemas or placebo enemas for 6 weeks in a randomized double-blind study. Patients continued their oral therapy, if any, for UC: 68 patients were taking mesalamine, 15 patients were taking prednisolone, and 12 patients were taking thiopurines during the study. Clinical, sigmoidoscopic, and histologic assessments were made at baseline and at the end of the study and symptoms were recorded daily on a diary card. The primary end point was induction of clinical remission and clinical improvement also was measured by the UC disease activity index. After the study, patients then used nicotine enemas daily for 4 weeks and sigmoidoscopy with a biopsy examination was repeated. AEs and salivary cotinine levels were monitored throughout the study. Results: Clinical remission was achieved in 14 of 52 (27%) patients on active treatment and 14 of 43 (33%) patients on placebo (P = .55). The UC disease activity index improved by 1.45 points in the active group and by 1.65 points for those on placebo (P = .88). Only 1 patient discontinued treatment because of an AE (abdominal pain). In the 47 patients taking mesalamine only, active treatment conferred benefit that was not statistically significant; disease remission occurred in 9 of 25 patients on active therapy and 4 of 21 patients on placebo (P = .20). Conclusions: Six-milligram nicotine enemas were well tolerated but were not found to be efficacious for active UC. Because most patients with ulcerative colitis (UC) are nonsmokers1Harries A.D. Baird A. Rhodes J. Non smoking a feature of ulcerative colitis.BMJ. 1982; 284: 706Crossref PubMed Scopus (293) Google Scholar, 2Jick H. Walker A.M. Cigarette smoking and ulcerative colitis.N Engl J Med. 1983; 308: 261-263Crossref PubMed Scopus (157) Google Scholar, 3Boyko E.J. Koepsell T.D. Perera D.R. et al.Risk of ulcerative colitis among former and current cigarette smokers.N Engl J Med. 1987; 316: 707-710Crossref PubMed Scopus (205) Google Scholar, 4Calkins B.M. A meta-analysis of the role of smoking in inflammatory bowel disease.Dig Dis Sci. 1989; 34: 1841-1854Crossref PubMed Scopus (531) Google Scholar and smoking actually may have a beneficial effect on symptoms,5Rudra T. Motley R. Rhodes J. Does smoking improve colitis?.Scand J Gastroenterol Suppl. 1989; 170: 61-63Crossref PubMed Scopus (77) Google Scholar nicotine, a major ingredient of tobacco, may have a therapeutic role. A recent report6Wang H. Yu M. Ochani M. et al.Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation.Nature. 2003; 421: 384-388Crossref PubMed Scopus (2388) Google Scholar suggested that nicotine may exert an anti-inflammatory effect by activation of the α7 subunit of the nicotinic acetylcholine (ACh) receptor. Although transdermal nicotine is of benefit in UC,7Pullan R.D. Rhodes J. Ganesh S. et al.Transdermal nicotine for active ulcerative colitis.N Engl J Med. 1994; 330: 811-815Crossref PubMed Scopus (446) Google Scholar, 8Sandborn W.J. Tremaine W. Offord K.P. et al.Transdermal nicotine for mildly to moderately active ulcerative colitis, a randomised, double-blind, placebo-controlled trial.Ann Intern Med. 1997; 126: 364-371Crossref PubMed Scopus (247) Google Scholar frequent adverse events (AEs) limit its use.9Thomas G.A.O. Rhodes J. Mani V. et al.Transdermal nicotine as maintenance therapy for ulcerative colitis.N Engl J Med. 1995; 332: 988-992Crossref PubMed Scopus (190) Google Scholar Topical nicotine in an enema formulation is better tolerated because of fewer troublesome AEs10Green J.T. Thomas G.A.O. Rhodes J. et al.Pharmacokinetics of nicotine carbomer enemas a new treatment modality for ulcerative colitis.Clin Pharmacol Ther. 1997; 61: 340-348Crossref PubMed Scopus (29) Google Scholar, 11Green J.T. Rhodes J. Thomas G.A.O. et al.Nicotine carbomer enemas—pharmacokinetics of a revised formulation.Ital J Gastroenterol Hepatol. 1998; 30: 260-265PubMed Google Scholar, 12Green J.T. Thomas G.A.O. Rhodes J. et al.Nicotine enemas for active ulcerative colitis—a pilot study.Aliment Pharmacol Ther. 1997; 11: 859-863Crossref PubMed Scopus (69) Google Scholar, 13Sandborn W.J. Tremaine W.J. Leighton J.A. et al.Nicotine tartrate enemas for mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy a pilot study.Aliment Pharmacol Ther. 1997; 11: 663-671Crossref PubMed Scopus (75) Google Scholar, 14Ingram J.R. Routledge P. Rhodes J. et al.Nicotine enemas for treatment of ulcerative colitis a study of the pharmacokinetics and adverse events associated with 3 doses of nicotine.Aliment Pharmacol Ther. 2004; 20: 859-865Crossref PubMed Scopus (20) Google Scholar and 2 open-label pilot studies in active UC have suggested benefits; 1 study used a nicotine carbomer enema12Green J.T. Thomas G.A.O. Rhodes J. et al.Nicotine enemas for active ulcerative colitis—a pilot study.Aliment Pharmacol Ther. 1997; 11: 859-863Crossref PubMed Scopus (69) Google Scholar and the other study used a nicotine tartrate enema.13Sandborn W.J. Tremaine W.J. Leighton J.A. et al.Nicotine tartrate enemas for mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy a pilot study.Aliment Pharmacol Ther. 1997; 11: 663-671Crossref PubMed Scopus (75) Google Scholar We report here the results of a randomized, double-blind, controlled trial of nicotine carbomer enemas in patients with active UC. A nicotine carbomer enema was preferred because the release of nicotine is more prolonged and gives a lower maximum systemic concentration, which in turn reduces the likelihood of AEs.11Green J.T. Rhodes J. Thomas G.A.O. et al.Nicotine carbomer enemas—pharmacokinetics of a revised formulation.Ital J Gastroenterol Hepatol. 1998; 30: 260-265PubMed Google ScholarMethodsPatientsA total of 104 patients who fulfilled diagnostic criteria for UC15Lennard-Jones J.E. Classification of inflammatory bowel disease.Scand J Gastroenterol. 1989; 24: 2-6Crossref Scopus (1808) Google Scholar and had inflamed rectal mucosa, grade 2 or higher on sigmoidoscopy,16Dick A.P. Grayson M.J. Carpenter R.G. et al.Controlled trial of sulphasalazine in the treatment of ulcerative colitis.Gut. 1964; 5: 437-442Crossref PubMed Scopus (217) Google Scholar participated in a study on treatment with nicotine enemas or placebo for 6 weeks. Patients were not enrolled if they had other unstable medical problems, were pregnant or lactating, had used enemas in the previous week, had changed their colitis therapy with mesalamine or steroids within the past 2 weeks, had changed immunosuppressive therapy with thiopurines in the previous 3 months, or currently smoked. Both lifelong nonsmokers and ex-smokers were enrolled, provided in the latter case they had abstained for at least 6 months. The study was approved by the local research ethics committee for each center involved.Study EnemasActive enemaEach 100-mL enema (SLA Pharma, Watford, UK) contained 6 mg of nicotine (Seigfried Labs, Zofingen, Switzerland) with a carbomer (Carbopol 974P; Noveon Inc, Cleveland, OH)17Carbomer.in: The British Pharmacopoeia. Volume 1. HMSO London on behalf of The British Pharmacopoeial Commission, London2001: 301-307Google Scholar and xanthan gum (Keltrol; Kelco International, San Diego, CA), which increased the viscosity. The enema formulation was identical to that used in the pilot study by Green et al12Green J.T. Thomas G.A.O. Rhodes J. et al.Nicotine enemas for active ulcerative colitis—a pilot study.Aliment Pharmacol Ther. 1997; 11: 859-863Crossref PubMed Scopus (69) Google Scholar and its preparation and pharmacokinetics of systemic absorption have been described previously.11Green J.T. Rhodes J. Thomas G.A.O. et al.Nicotine carbomer enemas—pharmacokinetics of a revised formulation.Ital J Gastroenterol Hepatol. 1998; 30: 260-265PubMed Google Scholar Stability for at least 12 months has been shown (unpublished data). A single enema was used on retiring at night, but only half the enema was taken for the first 3 nights to allow patients to develop tolerance to nicotine.Placebo enemaA solution of 2% methylcellulose (Methocel A4C Premium; Colorcon, Dartford, UK), with similar viscosity, volume, and appearance to the active enema was used as the placebo.Concomitant MedicationDuring the trial, patients continued to take the same dose of oral colitis medications they had taken in the weeks preceding the trial. Although recognizing different intervals for changes in medication, our protocol was for pretrial doses to remain unchanged for 2 weeks for mesalazine and prednisolone, and to remain unchanged for 3 months for thiopurines.Evaluation ProceduresAt the beginning of the trial, disease severity was assessed by converting colitis symptoms to a global clinical grade, as described by Truelove and Witts.18Truelove S.C. Witts L.J. Cortisone in ulcerative colitis final report on a therapeutic trial.BMJ. 1955; 2: 1041-1048Crossref PubMed Scopus (2146) Google Scholar In addition, an inflammatory bowel disease quality-of-life questionnaire (SIBDQ),19Irvine E.J. Zhou Q. Thompson A.K. The Short Inflammatory Bowel Disease Questionnaire a quality of life instrument for community physicians managing inflammatory bowel disease. CCRPT Investigators. Canadian Crohn's Relapse Prevention Trial.Am J Gastroenterol. 1996; 91: 1571-1578PubMed Google Scholar, 20Jowett S.L. Seal C.J. Barton J.R. et al.The short inflammatory bowel disease questionnaire is reliable and responsive to clinically important change in ulcerative colitis.Am J Gastroenterol. 2001; 96: 2921-2928Crossref PubMed Google Scholar and sigmoidoscopy with rectal biopsy examination were performed. Patients then were asked to complete a daily diary, recording stool frequency and consistency, the presence of blood or mucus, episodes of abdominal pain, the degree of fecal urgency on a scale of 1 (no urgency) to 10 (incontinent of stool), and their general well being from 1 (poor) to 10 (very well). The initial assessments, including sigmoidoscopy, were repeated at the end of the 6-week trial period, or at premature withdrawal, by the same physician. Patients also recorded the occurrence of any AEs.At sigmoidoscopy, the severity of rectal inflammation was graded visually according to the system described by Dick et al.16Dick A.P. Grayson M.J. Carpenter R.G. et al.Controlled trial of sulphasalazine in the treatment of ulcerative colitis.Gut. 1964; 5: 437-442Crossref PubMed Scopus (217) Google Scholar The rectal biopsy specimens were stained with H&E and graded according to the Truelove and Richards21Truelove S.C. Richards W.C.D. Biopsy studies in ulcerative colitis.BMJ. 1956; 1: 1315-1321Crossref PubMed Scopus (286) Google Scholar system by 1 histopathologist (G.T.W.) who was unaware of treatment assignment.The primary end point of the study was induction of clinical remission, defined as a sigmoidoscopy score of 0 or 116Dick A.P. Grayson M.J. Carpenter R.G. et al.Controlled trial of sulphasalazine in the treatment of ulcerative colitis.Gut. 1964; 5: 437-442Crossref PubMed Scopus (217) Google Scholar and absence of rectal bleeding for at least 1 week. The data collected also were used to evaluate changes in the UC disease activity index (UCDAI) (Table 1).22Sutherland L.R. Martin F. Greer S. et al.5-aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.Gastroenterology. 1987; 92: 1894-1898Abstract PubMed Google ScholarTable 1UCDAIStool frequency 0 = usual number of stools for this patient 1 = 1–2 stools per day more than usual 2 = 3–4 stools per day more than usual 3 = ≥5 stools per day more than usualRectal bleeding 0 = none 1 = streaks of blood with stools 2 = obvious blood with stools 3 = blood alone passedMucosal appearance 0 = normal 1 = granular mucosa but not friable 2 = friable mucosa but no spontaneous bleeding 3 = spontaneous bleedingPhysician's rating of disease activity 0 = normal 1 = mild 2 = moderate 3 = severeMaximum score = 12Data from Sutherland et al.22Sutherland L.R. Martin F. Greer S. et al.5-aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.Gastroenterology. 1987; 92: 1894-1898Abstract PubMed Google Scholar Open table in a new tab Salivary cotinine concentrations were measured at baseline, and after 2 and 6 weeks. Most samples were obtained 12–16 hours after the nicotine enema had been administered and were stored at −20°C until analysis by gas liquid chromatography.23Feyerabend C. Russell M.A.H. A rapid gas-liquid chromatographic method for the determination of nicotine and cotinine in biological fluids.J Pharm Pharmacol. 1990; 42: 450-452Crossref PubMed Scopus (288) Google Scholar Cotinine concentrations are maximal 3 to 4 hours after administration of the enema but then decrease slowly with a half-life of 18 hours.14Ingram J.R. Routledge P. Rhodes J. et al.Nicotine enemas for treatment of ulcerative colitis a study of the pharmacokinetics and adverse events associated with 3 doses of nicotine.Aliment Pharmacol Ther. 2004; 20: 859-865Crossref PubMed Scopus (20) Google Scholar In addition, patients' blood pressure and pulse were checked at the beginning and the end of the trial and blood tests were taken for full blood count and liver and renal function.Posttrial Treatment and ObservationsPatients were offered open nicotine enema treatment for a further 4 weeks after the controlled trial, commencing with half the enema for the first 3 days. After 4 weeks they were seen by a physician and the last week's symptoms were recorded, the SIBDQ was completed, sigmoidoscopy with a mucosal biopsy examination was performed, and a salivary cotinine level was measured.Sample Size, Power Calculation, Randomization, and Statistical AnalysisThe power calculation for the study was based on detecting a 40% difference between an estimated placebo response of 20%, and a 60% response to mesalamine enemas24Marshall J.K. Irvine E.J. Rectal aminosalicylate therapy for distal ulcerative colitis a meta-analysis.Aliment Pharmacol Ther. 1995; 9: 293-300Crossref PubMed Scopus (192) Google Scholar; a total of 80 patients would have a power of 94% to detect this difference.Randomization was by sealed envelope according to a predetermined computer-generated allocation scheme, using blocks of varying lengths, and was stratified by center.Continuous outcome measures were compared between groups by analysis of covariance, the corresponding baseline value being the covariate; these analyses were confirmed by Mann–Whitney tests based on increments. Proportions of patients entering remission were compared by χ2 test, with 95% confidence intervals for the difference. Changes in sigmoidoscopic and histologic grade were expressed as better, unchanged, or worse, and were compared using a 1 degree of freedom χ2 trend component, with a 95% confidence interval for the difference in proportions that improved. Limited analyses were performed relating the main outcome measures in the active treatment group to selected baseline factors; these values were interpreted cautiously.ResultsNinety-seven of the 104 patients recruited to the study were included in the intention-to-treat analysis of efficacy because of 5 protocol violations and 2 patients being lost to follow up evaluation (Figure 1). One patient was excluded because their diagnosis subsequently was changed to Crohn's colitis, 1 patient took only 1 enema before deciding to discontinue for reasons other than a significant AE, 2 patients allocated to placebo were later found to have increased salivary cotinine levels and subsequently admitted to nicotine consumption by smoking tobacco or chewing nicotine gum, and 1 patient who was excluded had only grade 1 inflammation at initial sigmoidoscopy and therefore did not meet the inclusion criteria. At the end of the trial period, sigmoidoscopic and histologic data were available for 93 and 74 patients, respectively. Eighty-six patients received open active treatment in the posttrial phase, of whom 81 permitted sigmoidoscopy and 73 provided rectal biopsy specimens that were sufficient for grading of inflammation.Of the 97 patients analyzed, 54 had active treatment and 43 received placebo. The baseline characteristics of these patients are shown in Table 2; about half were ex-smokers and their ages ranged from 20 to 83 years. Nine of the 54 ex-smokers had smoked after onset of their disease and 8 found it improved their symptoms whereas 1 reported deterioration. The mean duration of relapse was 37 and 29 weeks in the active and placebo groups, respectively, and about a third had taken other topical treatments, enemas, or suppositories in the period from 1 to 3 weeks before trial entry (Table 2). The 2 groups were similar for all measures of initial disease activity including global clinical grade, sigmoidoscopy grade, and UCDAI.Table 2Baseline Patient CharacteristicsActive (n = 54)Placebo (n = 43)Sex, M/F29/2524/19Mean age, y (range)46 (22–83)45 (20–77)Mean weight, kg7577Maximum extent of colitis Rectal1415 Rectosigmoid1211 Left-sided2817Concomitant oral meds Mesalamine3830 Prednisolone69 Thiopurines102Smoking history (non/ex)27/2716/27Mean duration of relapse, wk3729Recent topical treatments2014Global clinical gradeaAs described by Truelove and Witts,18 a score of 0–3 based on stool frequency and consistency, blood and mucus per rectum, and the presence of any constitutional symptoms. 021 184 23427 3911Sigmoidoscopy gradebAs described by Dick et al,16 a score of 0 (normal) to 4 (fulminant disease). 22820 32623a As described by Truelove and Witts,18Truelove S.C. Witts L.J. Cortisone in ulcerative colitis final report on a therapeutic trial.BMJ. 1955; 2: 1041-1048Crossref PubMed Scopus (2146) Google Scholar a score of 0–3 based on stool frequency and consistency, blood and mucus per rectum, and the presence of any constitutional symptoms.b As described by Dick et al,16Dick A.P. Grayson M.J. Carpenter R.G. et al.Controlled trial of sulphasalazine in the treatment of ulcerative colitis.Gut. 1964; 5: 437-442Crossref PubMed Scopus (217) Google Scholar a score of 0 (normal) to 4 (fulminant disease). Open table in a new tab At the end of the 6-week placebo-controlled trial phase, 14 of 52 patients (27%) on active treatment were in remission compared with 14 of the 43 patients (33%) on placebo; this was not statistically significant (Table 3). The mean UCDAI scores improved by 1.45 and 1.65 points in the active and placebo groups, respectively. The severity of sigmoidoscopic inflammation was reduced by at least 1 point in about half of the patients in both groups. More patients showed histologic improvement on active compared with placebo treatment, but without statistical significance (P = .29) (Table 3). The SIBDQ mean score increased by 4 points for the active group and by 6.7 points for those taking placebo during the trial. In both groups most of the improvement occurred within the first 2 weeks. An analysis of the diary variables, particularly improvements in defecation urgency and the cessation of rectal bleeding, showed no significant differences between the 2 groups, including the timing of when this occurred during the trial.Table 3Results for the 6-Week Trial Period and Subsequent 4-Week Period of Open, Active TreatmentScoring system and week of assessmentActivePlaceboP valueDifference with 95% confidence intervalRemission 614/52 27%14/43 33%.55aχ2 (1 degree of freedom).−6% (−24% to +12%) 1018/46 39%18/37 49%Mean UC (SD) 07.13 (1.7) n = 537.31 (1.9) n = 45 65.65 (2.5) n = 525.60 (2.8) n = 40.73bAnalysis of covariance confirmatory Mann–Whitney tests based on increments.+.16 (−.80 to +1.13) 104.72 (2.5) n = 434.19 (2.4) n = 37Improved sigmoidoscopic grade 628/52 54%23/41 56%.78cχ2 (1 degree of freedom) trend on data classed as better, unchanged, or worse.−2% (−22% to +18%) 1017/44 39%20/36 56%Improved histology 619/37 51%10/27 37%.29cχ2 (1 degree of freedom) trend on data classed as better, unchanged, or worse.+14% (−10% to +36%) 1012/33 36%5/25 20%SIBDQ, mean (SD) 046.0 (12) n = 5444.1 (12) n = 45 249.3 (11) n = 5250.1 (12) n = 43 650.0 (14) n = 5350.8 (15) n = 43.26bAnalysis of covariance confirmatory Mann–Whitney tests based on increments.−2.7 (−7.4 to +2.0) 1053.3 (13) n = 4855.8 (12) n = 38NOTE. P values and confidence intervals are shown for the 6-week visit at the close of the placebo-controlled trial period only. Remission is defined as a sigmoidoscopic score of 0 or 1 and the absence of rectal bleeding for at least 1 week. Improvement after 10 weeks, with all patients on active nicotine for the previous 4 weeks, is relative to severity grade at 6 weeks. For UCDAI and SIBDQ means and SD are given. n = the number of patients on which the mean is calculated.a χ2 (1 degree of freedom).b Analysis of covariance confirmatory Mann–Whitney tests based on increments.c χ2 (1 degree of freedom) trend on data classed as better, unchanged, or worse. Open table in a new tab After the additional 4 weeks of open active treatment, a further 4 patients in each group entered remission. The UCDAI improved by 1.39 points in those who initially were on placebo and by .56 points in those who initially were given active treatment. More patients in the initial placebo group had improved sigmoidoscopy scores during this period: 20 of 36 patients compared with 17 of 44 in the initial active group, but this was not statistically significant.The mean salivary cotinine concentrations in those on active treatment were about 40 ng/mL (Figure 2), with a mean delay after the last enema of about 16 hours. Levels in the active group decreased from 56.3 at week 2 to 36.1 ng/mL at week 10. Levels in the placebo group during the trial period were only slightly more than 0, with means of between 1.1 and 5.0 ng/mL.Figure 2Salivary cotinine concentrations, mean, and standard error bars on entry to the study (0), and after 2 and 6 weeks in the randomized trial. At 10 weeks both groups had been on active enemas for 4 weeks. □, Active; ■, placebo.View Large Image Figure ViewerDownload (PPT)During the 6-week trial phase, 29 of 54 (54%) patients in the active group reported an AE commonly associated with nicotine, compared with 16 of 43 (37%) on placebo. Overall, 99 AEs were reported, 56 of which were from the active group (Table 4); 2 were reported as serious because they required hospital admission—1 because of temporary rectal bleeding after a rectal biopsy examination and another because of abdominal pain that settled spontaneously. This latter patient was the only patient in the trial who discontinued treatment because of an AE. Most AEs were reported during the first week of treatment in both groups. There was an excess of nausea and lightheadedness in the active group during the initial 6 weeks but in the subsequent 4 weeks of open treatment there was a tendency for patients in the placebo group, who were receiving nicotine enema treatment for the first time, to rate their AEs as more troublesome. There were no significant changes in either blood pressure or pulse associated with active treatment and no changes were observed in baseline blood parameters.Table 4AEs Experienced by Patients During Enema Treatment6-week trial period4-week open treatment periodActivePlaceboActivePlaceboNumber of AEs56432520How troublesome? Mild191264 Moderate2826146 Very95510Type of AE Nausea8233 Vomiting0110 Headache12635 Palpitations2121 Lightheadedness10210 Sleep disturbance6213 Altered dreams4404 Other1425144 Open table in a new tab An analysis was performed to assess whether any determinants of response to treatment could be established. The duration of disease relapse did not influence remission at the end of the trial, but there was a tendency for more lifelong nonsmokers to enter remission compared with ex-smokers (P = .06). A subanalysis of the efficacy data found no differences between the South Wales centers in which only 1 investigator saw all the patients, and the England centers in which several investigators assessed patients. Concomitant medications were examined and for the 47 patients taking only mesalamines, active treatment did confer benefit, but not a statistically significant one, the rate of disease remission was 9 of 25 in the active group and 4 of 21 on placebo (P = .20), and the mean improvement in UCDAI was 1.84 on active treatment and .85 on placebo (P = .15).DiscussionThere was no statistically significant difference in the primary end point of the study, induction of clinical remission, between the active and placebo groups at the end of the 6-week trial period; about one third of patients from each group were in remission. This was also the case for the secondary end points of improvements in the UCDAI and SIBDQ scores and the sigmoidoscopic and histology grades. During the subsequent 4 weeks of open active treatment there was slightly more improvement in the initial placebo group compared with the initial active group, which may reflect their exposure to topical nicotine for the first time. Reports of nausea and lightheadedness were more common in the active group, but only 1 patient discontinued treatment because of an AE (abdominal pain that subsided with conservative management). Subgroup analyses to establish any determinants of response to treatment found no effect of duration of disease relapse, patient location, or concomitant medications; more patients who had never smoked were in remission after 6 weeks, but this was not statistically significant (P = .06).The study did have sufficient power to assess the efficacy of nicotine enemas because data for the primary end point were available for 95 patients at the end of the trial; this exceeded the minimum sample size of 80 estimated from the original power calculation. By combining the absence of sigmoidoscopic mucosal friability and the symptom of rectal bleeding as the primary end point of disease remission, an attempt was made to use the most objective measures of distal UC activity. Improvement in the UCDAI score22Sutherland L.R. Martin F. Greer S. et al.5-aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.Gastroenterology. 1987; 92: 1894-1898Abstract PubMed Google Scholar is a well-recognized activity measure based on sigmoidoscopic appearance, symptoms, and the physician's own assessment. The SIBDQ19Irvine E.J. Zhou Q. Thompson A.K. The Short Inflammatory Bowel Disease Questionnaire a quality of life instrument for community physicians managing inflammatory bowel disease. CCRPT Investigators. Canadian Crohn's Relapse Prevention Trial.Am J Gastroenterol. 1996; 91: 1571-1578PubMed Google Scholar, 20Jowett S.L. Seal C.J. Barton J.R. et al.The short inflammatory bowel disease questionnaire is reliable and responsive to clinically important change in ulcerative colitis.Am J Gastroenterol. 2001; 96: 2921-2928Crossref PubMed Google Scholar provided an assessment of the effect of disease severity on functional activity.Salivary cotinines proved to be very useful. They helped to confirm that the correct allocation of treatment had been made and they provided an objective check that patients were not smoking on admission to the trial. Levels in the active group gave some indication of patient compliance with treatment and it may be that this decreased during the 10 weeks because of the reduction in mean cotinine concentrations from 56.3 to 36.1 ng/mL between weeks 2 and 10. A pharmacokinetic study measuring salivary cotinine concentrations 12