title: Effect of nicotine lozenges on affective smoking withdrawal symptoms: secondary analysis of a randomized, double-blind, placebo-controlled clinical trial.
abstract: BACKGROUND
  The suggested mechanism for the effects of nicotine replacement medications such as nicotine lozenges on smoking abstinence is reduction in the withdrawal symptoms of emotional distress and craving (the subjective desire to smoke).
  
  
  OBJECTIVE
  This study assessed the effect of nicotine lozenges on affective withdrawal symptoms (collectively termed emotional distress) and craving over 6 weeks of treatment and the role of emotional distress and craving in mediating the effect of the lozenges on smoking abstinence.
  
  
  METHODS
  This was a secondary analysis of data from a randomized, double-blind, placebo-controlled clinical trial of nicotine lozenges. High-dependence smokers (those who smoked their first cigarette of the day within 30 minutes of waking) were assigned to receive the 4-mg lozenge; low-dependence smokers (those who smoked their first cigarette of the day >30 minutes after waking) were assigned to receive the 2-mg lozenge. Participants were randomized to receive active or placebo lozenges within these dose and dependence strata. Smokers were to rate their withdrawal symptoms daily during the baseline week (while still smoking) and for 6 weeks after starting treatment. Study analyses included the effect of the active lozenge on affective symptoms (ie, anxiety; anger, irritability, or frustration; difficulty concentrating; restlessness; and depressed mood) during weeks 1 through 6 in high- and low-dependence smokers; the prospective associations between these symptoms and craving and subsequent abstinence; and the mediating influence of these symptoms on the lozenge's effect on abstinence. The analyses included smokers who provided symptom data for the baseline period and for at least week after the initiation of treatment.
  
  
  RESULTS
  Of 1,818 smokers enrolled in the original study, this analysis included data from 1,144. The population was predominantly white, had a mean age ranging ranging from 40.65 to 46.01 years, and included slightly more women than men. The 2-mg lozenge did not have consistently significant effects on the withdrawal symptoms of emotional distress among low-dependence smokers; however, in high-dependence smokers, the 4-mg dose was associated with significant reductions versus placebo in overall emotional distress symptoms through week 4 (P < 0.001-P = 0.025), all individual symptoms through week 3 (P < 0.001-P = 0.035), and irritability and anxiety through week 4 (P = 0.002-P = 0.049). In the low-dependence group, the 2-mg lozenge was associated with significant reductions versus placebo in craving through week 3 (P = 0.012-P = 0.033), whereas in the high-dependence group, the 4-mg lozenge was associated with significant reductions in craving in each of the first 6 weeks (P < 0.001-P = 0.028). Among high-dependence smokers, both week-1 and week-2 emotional distress scores were associated with a return to smoking by week 6 (P < 0.001); among low dependence smokers, the association applied only to week-2 symptoms (P = 0.017). Week-1 and week-2 craving was associated with a return to smoking at week 6 in both groups (P < 0.001-P = 0.001). Emotional distress modestly and inconsistently mediated the effects of the lozenges, accounting for 3% to 13% of the treatment effects, whereas craving more strongly (though incompletely) mediated the treatment effects, particularly among high-dependence smokers, in whom it accounted for 29% to 39% of the treatment effects.
  
  
  CONCLUSIONS
  In high-dependence smokers, the 4-mg nicotine lozenge significantly reduced all affective withdrawal symptoms through the first 4 weeks of treatment. Lozenge-related decreases in craving partially mediated the effect of treatment on abstinence, particularly in high-dependence smokers.
authors.affiliation: Pinney Associates, Pittsburgh, Pennsylvania 15213, USA. shiffman@pinneyassociates.com
authors.forename: Saul
authors.initials: S
authors.lastname: Shiffman
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000008:administration & dosage / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D016540:Smoking Cessation / Q000379:methods*; D013315:Stress, Psychological / Q000517:prevention & control*; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*; D013997:Time Factors; D014029:Tobacco Use Disorder / Q000188:drug therapy*
chemical_list: D018722:Nicotinic Agonists; D009538:Nicotine