The time to first cigarette is a distinct nicotine dependence phenotype associated with the uptake of nicotine and tobacco smoke. The “high” dependent phenotype is associated with significantly higher cotinine levels than the low dependent phenotype per cigarette smoked. The TTFC is biochemically validated and can be considered a risk factor for smoking-related diseases. The current study shows that an early TTFC is significantly associated with an increased risk of head and neck cancer. The association was consistent for most cancer sites. The highest risk was found for pharyngeal cancer, which has the highest smoking-related risk of these sites (19
Cotinine has a 24 hour half-life and has little value as a biomarker of smoke uptake in case-control studies. The dose of smoke uptake in epidemiologic studies has traditionally been measured by proxy measures such as the frequency and duration of cigarette smoking. However, the effect of inter-individual variability in nicotine dependence on cancer risk has not been determined. One study of 55 smoking lung cancer cases and 49 smoking controls did find a significant trend in the risk associated with the FTND score, although this association reflects to a certain extent just the association with smoking frequency, which is the single biggest contributor to the FTND index (20
). The current analysis shows that the time to first cigarette after waking is a strong and independent predictor of head and neck cancer risk in a large study of ever smokers. A 1.6 pack-year adjusted risk was associated with smoking within 30 minutes after waking. The risk may be even higher among subjects who smoked within the first 15 minutes.
Limitations in this study include those that are known to be common in case-control studies including bias, measurement error and confounding. Cases and controls were hospitalized patients whose lifestyles might be different than the general population. Responses on smoking and alcohol consumption are subject to recall biases. While it is not possible to completely validate lifetime lifestyle habits, repeat interviews on a random sample of subjects showed high internal consistency for smoking and alcohol consumption. Little is known about smoking behaviors such as time to first cigarette over the course of a lifetime. This behavior was assessed by a single question, and it is possible that this particular smoking behavior may change over time or change in relation to smoking habits. Subjects may have switched from high yield cigarettes to low yield cigarettes which could potentially affect symptoms of nicotine dependence and smoking behaviors. However, the associations were similar for current and former smokers, indicating that recall bias was unlikely to have affected the findings. The association might have been confounded by smoking, although the study did carefully control for smoking dose in a number of different ways and the results were fairly consistent. The large sample size suggests the findings are generalizeable to the larger population of white smokers. However, there were few blacks or other minorities in this study and the results may not be applicable to these groups. Finally, the association might have been confounded by other factors. Human papilloma virus causes oropharyngeal carcinoma. It is unlikely that this was a major confounder for the cases with oropharyngeal cancer in the current study. The incidence of this cancer has increased dramatically since 2000, which was after the data collection period of our study.
A shorter time between waking and the first cigarette is associated with higher blood cotinine levels. Early morning smokers might have a greater craving for nicotine. The temporal effect is dose-dependent, where prolonging smoking abstinence after waking is associated with lower cotinine levels. If the TTFC-cotinine association is due to cravings, it likely reflects greater cravings throughout the day since intensive smoking of just the first cigarette only would not appreciable raise cotinine levels. We did not collect information on nicotine cravings throughout the day as this is not possible in case-control studies, especially for subjects who have quit smoking. There is little data on the relationship between TTFC and the urge to smoke or cravings. In a clinical smoking cessation trial of 207 smokers treated with buproprion, craving and withdrawal symptoms were lessened after smoking the first cigarette of the day. The TTFC was not correlated with a 10-item questionnaire that assessed the urge to smoke (21
The cancer risk associated with time to first cigarette might reflect differences in smoking topography associated with nicotine cravings. There is also little data on this topic. The time to first cigarette after waking was unrelated to puffing intensity in a British study (22
). Variation in the time to first cigarette could be due to genetic differences in nicotine dependence, non-genetic behavioral and socioeconomic factors, or both genetic and non-genetic factors interacting together.
To validate the current findings, prospective cohort studies with nicotine metabolite determinations are needed. Such studies would need to show the relationship between TTFC and cotinine, and determine the incidence rate of cancer according to TTFC groups. In conclusion, the significance of these findings is that TTFC may be a behavioral phenotype that identifies smokers who are at high risk of head and neck cancer. The risk of head and neck cancer was substantially elevated even among ever smokers. This underscores the need to recognize nicotine dependence rather than smoking habits as the major risk factor in smoking research since it the physiological dependence to nicotine that affects the dose of exposure. The study indicates that smokers who smoke soon after waking may require special efforts to make aware their increased risk and need for smoking cessation therapies.