Symptoms of nicotine toxicity in subjects achieving high cotinine levels during nicotine replacement therapy.
BACKGROUND
Nicotine replacement therapy (NRT) aids smoking reduction and cessation. Although NRT is effective and safe, some smokers may achieve high nicotine levels. The purpose of this study was to determine the incidence and severity of nicotine-related adverse events in subjects with levels of cotinine, a metabolite of nicotine, that increased by >50% compared with baseline smoking in controlled clinical trials of NRT.


METHODS
Data from participants in randomized, double-blind, controlled trials of various formulations of NRT (Nicorette®), including patch, gum, oral inhaler, sublingual tablet, nasal spray, mouth spray, and combinations, were extracted from a clinical database. Eligible studies were performed between 1989 and 2010. In addition to baseline, at least 1 subsequent plasma or salivary cotinine concentration was measured, and adverse events were recorded simultaneously. Of 28 eligible studies, 24 were smoking cessation studies and 4 were smoking reduction studies.


RESULTS
Cotinine levels that increased by >50% above baseline were recorded during treatment in 746 of 7,120 subjects (10.5%). Nausea was reported in 16 subjects (0.2% of the total, upper 99% confidence limit [CL] 0.4%), vomiting in 2 subjects (0.0%, upper 99% CL 0.1%), palpitations in 5 subjects (0.1%, upper 99% CL 0.2%), dizziness in 11 subjects (0.2%; upper 99% CL 0.3%), and headache in 35 subjects (0.5%, upper 99% CL 0.7%).


CONCLUSIONS
Typical symptoms indicating nicotine overdose together with high cotinine levels were rare during treatment with NRT. These findings support the safety of NRT for smoking cessation or reduction.
Department of Preventive Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; serton@ous-hf.no.
Serena
S
Tonstad
R&D, McNeil AB, Helsingborg, Sweden;
Gunnar
G
Gustavsson
Global Clinical Research, McNeil AB, Helsingborg, Sweden;
Elisabeth
E
Kruse
Global Medical Development, Johnson and Johnson Ltd, Maidenhead, UK;
James M
JM
Walmsley
Global Biostatistics, McNeil AB, Helsingborg, Sweden.
Åke
Å
Westin
D000279:Administration, Cutaneous; D000280:Administration, Inhalation; D003367:Cotinine / Q000097:blood*; D004311:Double-Blind Method; D006801:Humans; D009538:Nicotine / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012907:Smoking / Q000188:drug therapy*; D016540:Smoking Cessation / Q000379:methods*; D061485:Tobacco Use Cessation Devices; D014029:Tobacco Use Disorder / Q000188:drug therapy*
D009538:Nicotine; D003367:Cotinine