The objectives of this study were to assess extrinsic stain reduction from baseline while quitting smoking using either Nicorette® Freshmint Gum (nicotine polacrilex) or Nicorette® Microtab (nicotine beta-cyclodextrin); a neutral sublingual tablet with no whitening properties compared to the gum. The primary efficacy parameter was the mean change in the modified extrinsic tooth stain score (all sites) between baseline and 6 weeks as this was consistent with the duration of other whitening studies. A secondary outcome measures was the change in tooth shade, measured by the Vita Shade Guide, between baseline and Weeks 2, 6 and 12.
The duration of the current trial in smokers was 12 weeks, with observations at weeks 2, 6 and 12.
Thus, the study was an evaluator-blinded, randomized, 12-week parallel group controlled trial which compared the stain reduction efficacy of a nicotine replacement gum against the reference product a nicotine replacement sub-lingual tablet in healthy smokers motivated to quit smoking and with visible staining of teeth. It was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines [14
]. The Irish Medicines Board and the Clinical Research Ethics Committee of The Cork Teaching Hospitals, approved the study, trial participants provided informed consent.
Stain was measured using the MacPherson Modification of the Lobene Stain Index [9
] which scores eight sites per tooth, four facial and four lingual or palatal. The stain score per tooth site was determined by multiplying the score for stain intensity (scores 0-3) by that for stain area (scores 0-3). The test teeth were the eight incisors; if one of the eight incisors was not present or scorable, a canine was substituted. The stain score per subject was determined by averaging scores across tooth sites for that subject.
The intrinsic tooth shade was visually graded using a traditional Vita® Lumin Shade guide as a reference standard (VITA Zahnfabrik, H.Rauter GmbH & Co. KG, D-79713 Bad Säckingen, Germany). The shade assessments were made under standardized lighting conditions: assessments were all conducted in the same windowless room using color-corrected lighting in the range of 5000 degrees Kelvin, with the subject seated in a special upright examining chair with the arch tooth position parallel to the floor. A blue bib was placed over the subject's clothing, and all lipstick was removed before scoring. Color shade values for the upper right central incisor and upper left lateral incisor were determined by selecting one Vita® Lumin Shade sample that most closely matched each tooth. For analysis, each of the 16 shade tabs was assigned a number from 1 (dark) to 16 (light) according to the Munsell colour ranking system [15
] as follows:
An increase in difference from baseline after treatment suggests an improvement in tooth shade. Subject scores were computed for each visit by averaging individual scores across teeth. Change from baseline was computed for each subject using these averages.
Inclusion criteria were a minimum of 20 natural teeth present with at least 10 of the 12 anterior teeth present and scorable, and a total extrinsic facial tooth stain score
28 according to Lobene stain index. Teeth that were grossly carious, fully crowned, or extensively restored on the facial or lingual surfaces were not included in the tooth count.
The trial was carried out at the Oral Health Services Research Centre in University College Cork over a 5 month period between July and November. The flow of subjects into and through the trial is illustrated in the CONSORT flow chart [16
] in Figure
. Of the 546 adults assessed for eligibility, 200 smokers were randomized at baseline to receive either the nicotine replacement gum or the nicotine replacement tablet to help them quit smoking. Reasons for non-enrollment are outlined in Figure
. Subjects were classified according to the Fagerström Test for Nicotine Dependence (FTND) [17
]. The randomization schedule was produced by the sponsor using an SAS Based Randomization Generator. The randomization was stratified according to 8 combinations of nicotine dependence level (defined as Low
5 and High
6) and baseline facial stain level (defined as sum of the facial scores equal to 28-49, 50-74, 75-99, or
100). Participants were allocated to groups at the study site by the local clinical trial coordinator, according to the randomisation schedule. The examiner was blind to the group allocation and participants were asked not to break the examiner blinding. High-nicotine dependent smokers (FTND
6,) received nicotine 4 mg gum or were instructed to use a 4 mg dosage of the tablet (2 tablets); low-nicotine dependent smokers (FTND
5) received nicotine 2 mg gum or were instructed to use a 2 mg dosage of the tablet (one tablet). The trial comprised of five visits: Baseline (entry visit), week one, week 2, week 6 and week 12 (study end). A trained and calibrated examiner rated tooth stain and shade at baseline and weeks 2, 6 and 12. Intra-examiner reliability was checked by repeat examination of 11 subjects with dental staining prior to study examinations. At all visits after baseline, smoking status and use of study treatment (gum or tablets) was checked. All subjects were instructed to use the chewing-gum or sublingual tablet for 12 weeks and to quit smoking the day after enrolment. Subjects were advised to use the trial medication (gum or tablet) frequently in accordance with product labelling to minimize symptoms of tobacco deprivation. The maximum recommended dosage per day was 15 x 4 mg pieces of gum or 40 x 2 mg tablets for the high-nicotine dependent group, and 15 x 2 mg pieces of gum or 20 x 2 mg tablets for the low-nicotine dependent group. Smoking status was assessed by self-reported abstinence and biochemically verified by measuring the level of CO in exhaled air, using a Bedfont monitor [18
Figure 1 Flow of subjects through tooth stain removal study. The flow of subjects through the study is shown according to the CONSORT Statement. 
Oral care was standardized throughout the trial. At baseline, subjects were given a soft-bristled toothbrush and regular fluoride toothpaste and instructed to brush their teeth no more than twice a day. Use of any other oral hygiene or tooth-whitening product was prohibited during the trial. There were no dietary or drink restrictions. All observed or volunteered Adverse Events, the severity (mild, moderate, or severe) of each event, and the investigator’s opinion of the relationship to the trial medication were recorded.