A randomized trial of nortriptyline combined with transdermal nicotine for smoking cessation

Arch Intern Med. 2004 Nov 8;164(20):2229-33. doi: 10.1001/archinte.164.20.2229.


Background: Smoking cessation rates with current therapy are suboptimal. Tricyclic antidepressants improve cessation rates. We hypothesized that addition of nortriptyline hydrochloride to transdermal nicotine would enhance cessation rates.

Methods: We conducted a randomized, double-blind, placebo-controlled trial at a Department of Veterans Affairs medical center. Subjects were aged 18 to 65 years, smoked 10 or more cigarettes per day, and did not have current major depression. Nortriptyline hydrochloride or matched placebo was started at 25 mg 14 days before quit day, titrated to 75 mg/d as tolerated, and continued for 12 weeks after quit day. Transdermal nicotine (21 mg/d) was started on quit day and continued for 8 weeks. The behavioral intervention consisted of 12 brief, individual visits. Withdrawal symptoms were measured by means of a daily diary, and smoking cessation was defined as self-reported abstinence, expired carbon monoxide level of 9 ppm or less, and a 6-month urine cotinine level less than 50 ng/mL (284 nmol/L).

Results: A total of 158 patients were randomized (79 to nortriptyline and 79 to placebo). There was no significant reduction in withdrawal symptoms. The cessation rates at 6 months were 23% (18/79) and 10% (8/79), respectively (absolute difference, 13%; 95% confidence interval, 1.3%-24.5%; P = .052). Nortriptyline caused frequent side effects, including dry mouth (38%) and sedation (20%).

Conclusions: Nortriptyline combined with transdermal nicotine resulted in an increased cessation rate with little effect on withdrawal symptoms. This combination may represent an option for smokers in whom standard therapy has failed.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Cutaneous
  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Nicotine / administration & dosage*
  • Nortriptyline / administration & dosage*
  • Probability
  • Reference Values
  • Risk Assessment
  • Smoking / adverse effects
  • Smoking Cessation / methods*
  • Statistics, Nonparametric
  • Substance Withdrawal Syndrome / diagnosis
  • Substance Withdrawal Syndrome / epidemiology*
  • Treatment Outcome


  • Nicotine
  • Nortriptyline