SIGNIFICANCE OF OFF-LABEL USE OF NRT

The Hammond et al. study [1] is the best estimate we have of off-label use of over-the-counter (OTC) nicotine replacement therapy (NRT) because it asked a clear question about reasons for use in a large sample. All OTC medications have some incidence of off-label use; e.g. in one survey over half of purchases of a medication for heartburn were for off-label use [2]. One-third of NRT purchased in the Hammond et al. study was for non-cessation reasons. This is certainly higher than many would have expected. However, this estimate could be inflated because smokers often forget prior quit attempts [3] or may re-classify half-hearted attempts as not quit attempts. Also, half of the non-standard use was for unknown reasons and some of these may, in fact, have been cessation-related. In fact, if one focuses only on clear responses, <10% of NRT purchases were for smoking reduction and <10% were for temporary abstinence.

Hammond et al. refer to non-cessation use as ‘nonstandard use’; other terms might be ‘off-label use’ or ‘misuse’. They appropriately do not use the terms ‘abuse’ or ‘harmful use’ or ‘addiction’ because these require demonstration that use is causing problems and impaired control over use [4].

Is off-label use harmful? Available studies suggest no significant medical harm from use of NRT itself and that use of NRT concurrent with cigarettes is not of concern [5]. The main concern has been that use of NRT for non-cessation reasons might undermine motivation to quit. Consistent with this, Hammond et al. report that the use of NRT for non-cessation reasons was associated with less intention to stop smoking. Some prior reports have found that those who chose to reduce rather than quit are less motivated to quit [6,7], but others have not [8]. In addition, this association is from a cross-sectional analysis; thus we do not know the causal flow; i.e., whether off-label use reduced motivation to quit or whether those with low motivation chose to use NRT in an off-label manner.

Prospective studies provide a more rigorous test of whether off-label use is harmful. A recent review of such studies found no evidence that NRT-associated reduction undermined future cessation in smokers and, in 16 out of 19 studies, it actually increased future cessation [9]. In fact, the use of NRT to reduce prior to quitting (‘reduce-to-stop’) has been approved as an indication in 26 countries (G. Gustavsson, personal communication). The studies on use of NRT for reduction examined smokers who currently were not interested in quitting. Whether a reduction alternative would undermine cessation in those who are ready to quit abruptly has not been tested. For this to occur, one would have to hypothesize that quitting gradually produces worse outcomes than quitting abruptly, and this is not at all clear [10].

Whether the other off-label use of NRT—to avoid withdrawal during temporary abstinence—would increase or decrease future cessation has not been tested. One could hypothesize that the ability to use OTC NRT in smoking restricted areas would undermine the effect of smoking restrictions to prompt quitting [11]. This would require that suffering withdrawal or experiencing the stigma or inconvenience of leaving home or work to smoke is essential to the beneficial effects of home/work restrictions. On the other hand, one could hypothesize that if smokers used OTC NRT during restrictions, they would experience craving and withdrawal relief from NRT [12] and this would encourage them to try to quit with NRT.

In summary, the Hammond et al. study indicates off-label use of OTC NRT does occur. The significance of such use is unclear and future longitudinal analyses from the Hammond et al. data set to test the significance of such use will be of interest. In addition, either randomized tests or prospective studies of whether use of NRT for temporary abstinence undermines or promotes future cessation are clearly needed. Finally, any harm from off-label use would need to be evaluated in the context of the substantial benefit of OTC NRT [13].