Ability of a new oral nicotine substitute to reduce smoking urge in moderate smokers

Addictive Behaviors 31 (2006) 537 – 543

Short communication

Ability of a new oral nicotine substitute to reduce smoking urge in moderate smokers A. Demazie`res a,T, R. Luthringer a, E. Coppel b, C. Gilles a, C. Fleury a, J. C. Roegel a, A. Delarue b, C. Laur b, G. Lagrue c a

FORENAP bResearch Institute for Neuroscience, Pharmacology and PsychiatryQ, 27 rue du 4eme RSM, 68250 Rouffach, France b Institut de Recherche Pierre Fabre, De´partement Innovation De´veloppement, 3 rue Ariane, 31527 Ramonville Cedex, France c Hoˆpital Albert Chenevier, Service de Tabacologie, 40 rue de Mesly, 94000 Cre´teil, France

Abstract The aim of this study was to assess the effectiveness of a new nicotine lozenge ( NicopassR 1.5mg) in reducing smoking urge after an overnight abstinence. Twenty-four moderate smokers participated in a randomized, doubleblind, placebo-controlled, 2-period crossover trial. The results showed that 1.5 mg-nicotine lozenge is superior to placebo in reducing smoking urge ( p = 0.0001). In addition, nicotine lozenge, but not placebo, significantly improved vigilance and psychomotor performances ( p b 0.05) and displayed a cardiac chronotropic effect. Thus, the 1.5-mg nicotine lozenge appears as an effective aid to alleviate acute tobacco withdrawal symptoms in moderate smokers. D 2005 Elsevier Ltd. All rights reserved. Keywords: Nicotine replacement therapy; Smoking urge; Withdrawal symptom; Lozenge

1. Introduction Nicotine replacement therapies (NRT) are widely approved as a pharmacological help for smoking cessation (Fiore, Smith, Jorenby, & Baker, 1994; Henningfield, 1995; Li Wan Po, 1993; Silagy, Mant, Fowler, & Lancaster, 1998; Tang, Law, & Wald, 1994). In 1984, nicotine gum was the first NRT to be approved by the FDA. However, nicotine gum is rejected by many smokers due to fillings, dyspepsia, bridgework, unpleasant taste or for esthetic reasons. To avoid these drawbacks, new convenient oral T Corresponding author. Tel.: +33 3 89 78 74 43; fax: +33 3 89 78 51 24. E-mail address: [email protected] (A. Demazie`res). 0306-4603/$ - see front matter D 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.addbeh.2005.05.017

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nicotine formulations were developed, including sublingual tablets and lozenges. Institut de Recherche Pierre Fabre has developed a lozenge to be sucked, containing 1.5mg of nicotine and presenting with pharmacokinetic profile similar to 2-mg nicotine gums, which should offer an alternative to other NRT in low to moderate smokers. The present study was designed to determine whether this 1.5-mg nicotine lozenge is effective to reduce smoking urge and other withdrawal symptoms that are frequently observed during smoking abstinence.

2. Materials and methods This randomized, double-blind, placebo-controlled, crossover study carried out at FORENAP Pharma facilities (France) was approved by an independent ethics committee. 2.1. Participants Twenty-four subjects (10 women and 14 men, mean age = 29.3 +/ 8.2 years) participated in two assessment periods of 2 days each (from the evening of Day-1 to the morning of Day 2), with an interval of at least 12 days, after having given their free written consent. All were moderate smokers (mean daily cigarettes consumption = 17.5 +/ 2.9; mean smoking duration = 12.8 +/ 8.3 years), with a mean global score at the Fagerstro¨m test of 5.5 +/ 0.7 (Heartherton, Kozlowski, Frecker, & Fagerstrom, 1991). Twenty subjects smoked their first cigarette between 6 and 30 min and four subjects between 31–60 min of waking up in the morning. All expressed a high motivation to quit, assessed by a score z 7 (mean 15.2 +/ 2.5) at the Demaria, Grimaldi and Lagrue test (Lagrue, Demaria, & Grimaldi, 1991). All were free of any abnormal clinical or laboratory findings; none had a past use of psychoactive drugs, NRT or any other treatment for smoking cessation (e.g. bupropion) in the past 3 months. Women were required to provide proof of non-pregnancy through a b HCG serum test and to use proper contraceptive techniques to avoid pregnancy for the study duration. 2.2. Interventions The 1.5-mg nicotine lozenges, NicopassR, and the placebo lozenges were identical in appearance and had the same mint flavor. During each study period, the first lozenge was given at least 30 min after breakfast (between 7:30 am and 9:00 am) and also 30 min after the subject expressed his/her first need of smoking. The following lozenges were available on request, after evaluation of smoking urge, with an interval of at least 30 min between two intakes. The subjects were given instructions on how to take the lozenges properly before each intake. Throughout each study period, the subjects stayed in a controlled smoke-free Clinical Unit and were strictly not allowed smoking. Local tolerability was followed all along the study. 2.3. Measurements Baseline values were measured just before dosing, i.e. at least 30 min after the subject expressed the need to smoke, considering that the withdrawal effects are maximal at this moment. Exact times of assessments are indicated in Table 1.

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Table 1 Measurement schedule Times relative to the first lozenge intake QSU Smoking urge VAS Bond and Lader VAS CFFT and MCRT* Heart rate

Times relative to the additional lozenge intakes

Baseline + 15 min + 30 min + 60 min + 90 min Before

+ 30 min

x x x x x

x

x x

x x x x x

x x

x x x x x

x x

x

* training session at screening. QSU: Questionnaire for Smoking Urge; VAS: Visual Analog Scale; CFFT: Critical Flicker Fusion Threshold; MCRT: Multiple Choice Reaction Task.

The main outcome measure of efficacy was defined as changes of the smoking urge after the first intake of nicotine lozenge compared to placebo. Reported urge to smoke was assessed by the 1-item VAS for smoking urge (score 0 = absolutely no urge to smoke to 100 = strongest urge to smoke) and by the abbreviated version of the questionnaire for smoking urge (total score = mean of the 10 items of the QSU-Brief) (Cox, Tiffany, & Christen, 2001). Subjective feelings such as alertness, calmness and satisfaction were assessed by the 16-item Bond and Lader VAS (Bond & Lader, 1974). Vigilance and motor performances were assessed by the validated computerized Leeds tests: the Critical Flicker Fusion Test -CFFT-(Smith & Misiak, 1976) and the Multiple Choice Reaction Test -MCRT (Hindmarch, 1980). In the latter, three parameters are calculated: the recognition reaction time (RRT), the motor reaction time (MRT), and the total reaction time (TRT = RRT + MRT). Prior to formal testing, subjects were trained to the tests to avoid a confounding learning effect during the study evaluations. 2.4. Holter ECG Cardiac changes were assessed using a Holter ECG device (GeTeMed/Rozinnk CD200) on Day 1 from 7:30 a.m. to 4:00 p.m.. Mean RR interval (interval between the R wave peaks of adjacent normal QRS complexes in s) and standard deviation of differences between adjacent normal RR intervals (SD RR) were calculated over 6-min periods (software package Cardioday GeTeMedk) and mean heart rate was derived [HR (bpm) = 60 / mean RR interval (s)]. 2.5. Statistical analyses Changes from baseline for each treatment and at each time after lozenge intake were tested using a paired t-test. For the main criterion (smoking urge) and cardiac parameters, treatments were compared by an analysis of variance (ANOVA) for a crossover design with sequence (order of administration), treatment, period and time effects. In addition, comparability of baseline values between periods was assessed using a similar ANOVA test. Alpha was established at 0.05, 2-tailed.

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3. Results Results are expressed by their mean +/ standard error. A sequence effect (order of administration) was never observed, that validates the comparison of treatments according to the crossover design. One subject was excluded from the analyses because of Holter ECG device failure during the first study period, which precluded Holter ECG data analyses. No other protocol deviations were observed. Consequently, 23 subjects were included in the pharmacodynamic analyses. 3.1. Smoking urge Smoking urges measured at baselines by the QSU or the smoking urge VAS were comparable between periods. Smoking urges significantly decreased at all time points compared to baseline following the intake of the first nicotine lozenge or its matched placebo (QSU and VAS: p b 0.0001). However, this improving effect was more important after nicotine lozenge than after placebo intake ( p = 0.0001) (Fig. 1a, b). The maximum effect was observed at + 30 min with the nicotine lozenge when at + 60 min with the placebo. 3.2. Cardiac parameters Baselines were comparable between periods for the 3 cardiovascular parameters (RR interval, SD RR, and heart rate). However, placebo and nicotine lozenge differently affect these parameters ( p = 0.0001) (Fig. 2a, b, c). A significant increase of RR interval and a significant decrease of HR were observed for at least 90 min after the first placebo intake ( p b 0.001) (Fig. 2a and c). On the contrary, these parameters were not significantly modified after nicotine lozenge intake except a slight but significant decrease of mean RR interval measured 30 min post-administration ( 0.025 +/ 0.011, p = 0.0338) (Fig. 2a and c). SD RR tended to increase after placebo intake while this parameter tended to decrease after nicotine lozenge intake (Fig. 2b). 3.3. Vigilance and motor reactions (CFFT and MCRT) Significant differences from baseline were decreased in RRT and TRT after nicotine lozenge intake at both time-points with a peak observed at time + 30 min (RRT: 23.74 +/ 8.17, p = 0.0082; TRT: 29.30 +/ 10.37, p = 0.0098). 3.4. Bond and Lader VAS Two subjective parameters were found to be improved after intake of the nicotine lozenge: alertness (+ 30 min: 3.24 +/ 1.36, p = 0.0266) and relaxation (+ 90 min: 8.87 +/ 3.35, p = 0.0147). Positive changes from baseline were also found after intake of the placebo lozenge: well-being (+30 min: 4.85 +/ 2.04, p = 0.0266; + 90 min: 4.64 +/ 1.95, p = 0.0263) and relaxation (+30 min: 10.96 +/ 3.57, p = 0.0056; + 90 min: 7.85 +/ 3.77, p = 0.0491).

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a

541

0

changes from baseline (mean +/- SE)

-5

#

-10

#

-15 -20

#

#

#

#

60

90

-25

#

-30

#

-35 -40 0

30

time after first lozenge intake (min)

changes from baseline (mean +/- SE)

b

0 -5 -10

#

-15

#

-20 -25

#

#

-30 -35

#

-40 -45 -50 0

#

#

30

60

# 90

time after first lozenge intake (min)

Fig. 1. a Effects of nicotine lozenge and placebo on the global score of the QSU. Values are the means with standard errors, expressed as changes from baseline. There was a significant decrease in the feeling of smoking urge at all time-points after the first intake of nicotine lozenge and placebo (#p b 0.0001), but this effect was globally significantly more important after nicotine lozenge compared to placebo (ANOVA, p = 0.0001). Square=Nicotine lozenge; Circle=placebo. b Effects of nicotine lozenge and placebo on the mean score of the craving VAS. Values are the means with standard errors, expressed as changes from baseline. There was a significant decrease in craving at all time-points after the first intake of both nicotine lozenge and placebo (#p b 0.0001), but this effect was globally significantly more important after nicotine lozenge compared to placebo (ANOVA, p = 0.0001). Square=Nicotine lozenge; Circle=placebo.

3.5. Safety The nicotine lozenge was well tolerated. In particular, none of the unwanted local effects usually reported with gum, sublingual tablets and lozenges, such as mouth irritations occurred during this study.

4. Discussion The present findings show that NicopassR, a nicotine lozenge dosed at 1.5 mg of nicotine, rapidly alleviates smoking urge after only one intake in moderate smokers. Indeed, while both nicotine lozenge and placebo significantly reduced smoking urge, this effect was significantly more important with

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changes from baseline (mean +/- SE)

a 0,1 0,08 0,06 0,04 0,02 0 -0,02 -0,04 -0,06 -0,08 -0,1

***

***

60

90

***

*

*

0

30

time after first lozenge intake (min)

changes from baseline (mean +/- SE)

b

0,03

* 0,02

*

0,01 0

*

-0,01 -0,02 0

30

60

90

time after first lozenge intake (min) changes from baseline (mean +/- SE)

c 4 3 2 1 0 -1 -2 -3 -4 -5 -6

*

0

***

30

***

***

60

90

time after first lozenge intake (min)

Fig. 2. a Effects of nicotine lozenge and placebo on the mean RR intervals. Values are the means with standard errors, expressed as changes from baseline. Globally, the effects of nicotine lozenge significantly differ from those of placebo (ANOVA, p = 0.0001). Stars represent a significant difference from baseline (*p b 0.05, **p b 0.01,***p b 0.001). Square=Nicotine lozenge; Circle=placebo. b Effects of nicotine lozenge and placebo on SD RR. Values are the means with standard errors, expressed as changes from baseline. Globally, the effects of nicotine lozenge significantly differ from those of placebo (ANOVA, p = 0.0001). Stars represent a significant difference from baseline (*p b 0.05). Square =Nicotine lozenge; Circle=placebo. c Effects of nicotine lozenge and placebo on the mean heart rates. Values are the means with standard errors, expressed as changes from baseline. Globally, the effects of nicotine lozenge significantly differ from those of placebo (ANOVA, p = 0.0001). Stars represent a significant difference from baseline (*p b 0.05, **p b 0.01,***p b 0.001). Square= Nicotine lozenge; Circle=placebo.

nicotine lozenge than with placebo. The superiority of nicotine lozenge over placebo to relief from smoking urge was obtained using the 1-item VAS and the multi-item questionnaire QSU, with a similar kinetic of the reducing smoking urge effects on both tests. This consistency between the two tests gives robustness to the present data. As classically reported during smoking abstinence (Hughes, Higgins, & Bickel, 1994), heart rate significantly decreased and RR intervals increased in the placebo condition

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while nicotine lozenge tended to affect these parameters in an opposite direction. Thus, the nicotine lozenge counterbalanced withdrawal-induced heart rate slowing, but also overshoot it at least transiently (Fig. 2a, b, c), suggesting a proper chronotropic effect of the drug. Noteworthy, the effects of nicotine lozenge on smoking urge and heart rate, which peaked 30 min post administration seem related to the pharmacokinetic profile of the drug since maximal plasma concentrations of nicotine were obtained 50 min after the administration of a nicotine lozenge according to previous data (data on file, Institut de Recherche Pierre Fabre). The results related to the effects of the nicotine lozenge on psychomotor activity and mood are less obvious. It can only be concluded from this study that a single administration of the nicotine lozenge did not impair the psycho-affective status of the subjects. The nicotine lozenge was globally well tolerated. In particular, none of the unwanted effects classically observed with oral nicotine treatment occurred during the study. In conclusion, NicopassR 1.5 mg appears as an effective aid to rapidly alleviate acute tobacco withdrawal symptoms (smoking urge and decreased heart rate) in moderate smokers.

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