Colin Feyerabend

Transdermal Nicotine for Active Ulcerative Colitis

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.

A RAPID GAS-LIQUID CHROMATOGRAPHIC METHOD FOR THE DETERMINATION OF COTININE AND NICOTINE IN BIOLOGICAL FLUIDS

Abstract— A rapid method is described for the simultaneous measurement of nicotine and cotinine in biological fluids using capillary column gas‐liquid chromatography. Using 100 μL sample volume the lower limit of detection for both nicotine and cotinine was 100 pg mL−1, allowing the method to be used for the measurement of these compounds in both smokers and non‐smokers. The extraction time is 3 min per sample, and by using multi‐pipetting and vortexing systems 250 samples can be extracted per day. The average coefficient of variation over the nicotine range 10 to 100 ng mL−1 was 3.9% and for cotinine over the range 1.0 to 1000 ng mL−1 was 2.2%. Saliva cotinine concentrations were quantitatively related to passive exposure to parental smoking in a population study of 1118 non‐smoking schoolchildren.

Passive smoking and risk of coronary heart disease and stroke: prospective study with cotinine measurement

Abstract Objective To examine the associations between a biomarker of overall passive exposure to tobacco smoke (serum cotinine concentration) and risk of coronary heart disease and stroke. Design Prospective population based study in general practice (the British regional heart study). Participants 4729 men in 18 towns who provided baseline blood samples (for cotinine assay) and a detailed smoking history in 1978-80. Main outcome measure Major coronary heart disease and stroke events (fatal and non-fatal) during 20 years of follow up. Results 2105 men who said they did not smoke and who had cotinine concentrations < 14.1 ng/ml were divided into four equal sized groups on the basis of cotinine concentrations. Relative hazards (95% confidence intervals) for coronary heart disease in the second (0.8-1.4 ng/ml), third (1.5-2.7 ng/ml), and fourth (2.8-14.0 ng/ml) quarters of cotinine concentration compared with the first (≥ 0.7 ng/ml) were 1.45 (1.01 to 2.08), 1.49 (1.03 to 2.14), and 1.57 (1.08 to 2.28), respectively, after adjustment for established risk factors for coronary heart disease. Hazard ratios (for cotinine 0.8-14.0 ν ≥ 0.7 ng/ml) were particularly increased during the first (3.73, 1.32 to 10.58) and second five year follow up periods (1.95, 1.09 to 3.48) compared with later periods. There was no consistent association between cotinine concentration and risk of stroke. Conclusion Studies based on reports of smoking in a partner alone seem to underestimate the risks of exposure to passive smoking. Further prospective studies relating biomarkers of passive smoking to risk of coronary heart disease are needed.

Randomised controlled trial of nasal nicotine spray in smoking cessation

Studies with nicotine chewing gum and nicotine skin patches indicate that nicotine replacement can help people to give up smoking. The rapidity with which nicotine is absorbed when given as a nasal spray suggests that it might be effective for those for whom the other means of replacement are too slow. The efficacy and safety of a nasal nicotine spray as an adjunct to group treatment for stopping smoking were assessed in a randomised, double-blind, placebo-controlled trial in which 227 cigarette smokers attending the Maudsley Hospital Smokers Clinic received 4 weeks of supportive group treatment plus active nicotine (0.5 mg per shot) or placebo nasal spray. The main end-point was biochemically validated complete abstinence from smoking from the third week of group treatment until the 12-month follow-up. Side-effects were assessed by self-reports and, where necessary, by physical examination. Of subjects assigned to active treatment 26% (n = 30) were validated abstinent throughout the year, compared with 10% (n = 11) of those assigned to placebo (relative abstinence rate 2.6, 95% CI 1.5-4.5, p less than 0.001). The advantage of the active spray was greatest in the heaviest smokers. Plasma nicotine concentrations from the spray were typically between one-half and three-quarters of baseline smoking levels. Tobacco-withdrawal symptoms, craving for cigarettes, and weight gain in abstinent subjects were reduced by the active spray. Minor irritant side-effects were frequent in both active and placebo sprays, but only 2 subjects had the spray discontinued as a result. No serious adverse effects were encountered. Nasal nicotine spray combined with supportive group treatment is an effective aid to smoking cessation.

Elimination of cotinine from body fluids: implications for noninvasive measurement of tobacco smoke exposure.

Cotinine elimination from plasma, saliva, and urine was studied over 11 days in five subjects (three nonsmokers and two occasional smokers). Half-lives for cotinine averaged 16-19 hours in the different body fluids (range 10 to 27 hours between subjects). There was no tendency for the half-life in saliva to be longer than in plasma or urine. We conclude that choice of body fluid for cotinine assay in smoking studies should depend on practical rather than pharmacokinetic considerations.

Dose effects and predictors of outcome in a randomized trial of transdermal nicotine patches in general practice.

The transdermal nicotine patch has proved an effective aid to smoking cessation. The ease of securing good compliance gives it a potential advantage over nicotine gum as an adjunct to brief advice and support in primary care settings where the major public health impact is obtained. In a preliminary report of half the sample of a randomized placebo controlled trial, we showed the patch to be effective in a general practice setting. We report here the definitive results of the full sample, including dose effects, predictors of outcome and other issues of theoretical and practical interest. A total of 1200 heavy smokers (> or = 15 per day), attending 30 general practices in 15 English counties received brief GP advice, a booklet and 16 hours per day patch treatment for 18 weeks. Dose increase and abrupt vs. gradual reduction of patch dosage were also randomized and follow-ups conducted at 1, 3, 6, 12, 26 and 52 weeks. Outcome was measured by self-reported complete abstinence from week 3 to 52 with biochemical validation at all follow-up points. Nicotine patch treatment doubled the rate of continuous abstinence up to 1 year (nicotine 9.6%, placebo 4.8%, p < 0.01); it most likely worked by reducing withdrawal symptoms. It enhanced cessation during the first week and reduced relapse during the second week. The dose increase after week 1 produced no sustained increase in cessation. Gradual reduction was no better at preventing relapse than abrupt withdrawal of patches after week 12. Whether relapse would have increased by ending treatment at some point between weeks 3 and 12 was not tested. Although pre-treatment dependence on cigarettes was prognostic of failure, the patches were equally helpful to both highly and less dependent smokers. Patches were particularly helpful to smokers with pre-treatment subclinical dysthymic symptoms. All but one of the 96 subjects eventually achieving long-term abstinence in the study quit during the first week of cessation.

Determinants and effects of attentional bias in smokers.

Much research has shown that individuals exhibit an attentional bias to stimuli related to their current concerns or pathologies. Using the emotional Stroop task, we investigated attentional bias in smokers. Ninety-six smokers either abstained from smoking for 24 hr or smoked normally before color-naming smoking-related and neutral words. Both a blocked format (smoking and neutral words presented in separate blocks) and an unblocked format (smoking and neutral words presented in a mixed random sequence) were used. In the blocked format, abstinence caused an attentional bias to smoking-related stimuli, and the degree of attentional bias predicted the latency to the first cigarette of the morning. However, different results were obtained from the unblocked version of the task. We conclude that the emotional Stroop task is a useful tool to measure attentional bias in smokers and could be used in cessation studies.

Transdermal Nicotine as Maintenance Therapy for Ulcerative Colitis

BACKGROUND Ulcerative colitis is largely a disease of nonsmokers. Having found previously that treatment with transdermal nicotine patches and mesalamine (5-aminosalicylic acid) has a beneficial effect on active colitis, we examined the value of transdermal nicotine for the maintenance of remission. METHODS We treated 80 patients with ulcerative colitis in remission with either transdermal nicotine or placebo patches for six months in a randomized, double-blind study. Incremental doses of nicotine were given for the first three weeks to achieve a maintenance dose; most patients tolerated 15 mg for 16 hours daily. All patients were taking mesalamine preparations as maintenance treatment at entry into the study; this treatment was stopped once the maintenance dose of nicotine was achieved. Clinical, sigmoidoscopic, and histologic assessments were made at the beginning and the end of the study, or at relapse. Side effects and serum nicotine and cotinine concentrations were monitored throughout the study. RESULTS There was no significant difference in the number of relapses between the groups. Twenty-two patients in the nicotine group were prematurely withdrawn from the study, 14 because of relapse and 8 for other reasons, including side effects and protocol violations. In the placebo group, 20 patients were withdrawn prematurely, 17 because of relapse and 3 for other reasons. Among patients using 15-mg nicotine patches, serum nicotine and cotinine concentrations were lower than expected and may reflect poor compliance. Side effects were reported by 35 patients--21 in the nicotine group and 14 in the placebo group--the most common of which were nausea, lightheadedness, and itching. CONCLUSIONS Transdermal nicotine alone was no better than placebo in the maintenance of remission of ulcerative colitis, and premature withdrawal due to side effects was more common in the nicotine group.

Targeting heavy smokers in general practice: randomised controlled trial of transdermal nicotine patches.

OBJECTIVES--(a) To evaluate the efficacy of transdermal nicotine patches as an aid to stopping smoking when used as an adjunct to brief advice and support in a general practice setting; (b) to see whether an increase in nicotine patch dosage enhances the rate of initial cessation. DESIGN--Randomised double blind placebo controlled parallel group study with one year of follow up. SETTING--30 general practices in 15 English counties. SUBJECTS--600 dependent heavy smokers (> or = 15 cigarettes daily) who were well motivated to give up. INTERVENTIONS--Brief general practitioner advice, booklet, and 16 hours per day patch treatment for 18 weeks with brief support and follow up at one, three, six, 12, 26, and 52 weeks. MAIN OUTCOME MEASURES--Self reported complete abstinence for up to one year with biochemical validation at all follow up points. RESULTS--Nicotine patches reduced the severity of craving and adverse mood changes in the first weeks of withdrawal and doubled the rate of initial cessation at week 3 (nicotine group 36% of patients (144/400), placebo group 16.5% of patients (33/200)) and of continuous abstinence throughout one year (nicotine group 9.3% (37), placebo group 5.0% (10)). A dose increase at week 1 among patients experiencing difficulty in quitting increased the proportion who achieved abstinence at week 3. There were no adverse systemic effects attributable to nicotine, but the incidence of moderate or severe local irritation or itching at the patch site was 16.4% (63 patients), compared with 3.8% (seven) with placebo. CONCLUSION--Transdermal nicotine patches used as an adjunct to brief advice and support in a general practice setting are an effective aid to long term cessation of smoking in highly dependent smokers.

Discriminative stimulus properties of nicotine: Further evidence for mediation at a cholinergic receptor

Rats were trained to discriminate nicotine (0.4 mg/kg SC) from saline in a standard two-bar operant conditioning procedure with food reinforcement. The response to nicotine was dose-related and at the ED50 of 0.14 mg/kg, plasma nicotine concentrations were similar to those reported previously for cigarette smokers who inhale. The nicotine analogues anabasine and cytisine increased nicotine-appropriate responding in a dose-related manner. Animals predominantly responded on the saline-associated lever when administered drugs from a range of pharmacological classes, even at doses that were sufficiently large to reduce the overall numbers of responses. The results confirm that the nicotine discriminative stimulus is highly specific. Previous work has shown anabasine and cytisine to be active at nicotinic-cholinergic binding sites in rat brain. The finding that there is some correlation between the behavioural effects of these compounds and their actions at the nicotine binding site may indicate that the nicotine cue is mediated throuth a cholinergic receptor.