Systematic review of the relationship between the 3-hydroxycotinine/cotinine ratio and cigarette dependence

Rationale Individual differences in the rate of nicotine metabolism (RNM) could be related to dependence and success in stopping smoking. A range of studies have examined RNM measured by the ratio of trans-3'-hydroxycotinine and cotinine in body fluids (the ratio). A systematic review of this literature is needed to draw conclusions and identify gaps in evidence. Objective The aim of this study is to review evidence on the association of the ratio to cigarette dependence and its role in individual tailoring of smoking cessation pharmacotherapy. Results We reviewed 27 studies of the ratio related to its reliability, validity, and relationship to dependence. The ratio is a reasonably accurate proxy for RNM. There is little evidence that the ratio is related to questionnaire measures of dependence, though the existing data are limited and the ratio has been linked to smoking at night and to some aspects of smoking topography. The ratio is also only weakly associated with cigarette consumption. Its relationship to the severity of withdrawal symptoms seems also weak at best, but limited data exist. One study suggests the ratio predicts outcome of unaided quitting. Importantly, the ratio seems to predict responses both to NRT and bupropion, and thus could guide pharmacotherapy. Conclusions The evidence that the ratio is related to smoking behaviours and to cigarette dependence is limited, but the ratio seems to influence treatment response to two stop smoking medications. Further studies of the relationship between the ratio and cigarette dependence and trials of ratio-guided pharmacotherapy are needed.