Discussion

It is well established that smoking causes a wide spectrum of disease, and subsequent morbidity and mortality. This precludes smoking from being a feasible therapeutic recommendation for the treatment of UC. Despite the amelioration of disease that smoking may contribute, the benefits conferred would surely not outweigh the risks inherent in this undertaking. Instead, for the greater good of the patient with UC we should indeed advise, encourage and assist those actively smoking to quit. When advising a patient with UC to quit smoking, it is important that one is open and frank about the implications this will have for the individual. Highlighting the negative impact of smoking on overall health and the benefits associated with cessation should be the focus; however, disclosure of the rebound exacerbating effect that this may have on the clinical course of their UC should not be overlooked.[5] There are many pharmacological agents available to combat flares in UC following smoking cessation that the patient should be made aware of, as this may serve to alleviate some anxiety associated with quitting.[5] The physician should be vigilant in monitoring the patient's disease activity, particularly in the first few years following smoking cessation, in order that such medicines can be used efficiently and effectively should the need arise.

However, where does this leave nicotine in the algorithm of treatment for remission induction in UC? It would appear that it is still a long way from conventional therapy for active UC. Most randomised studies of nicotine can be criticised for having small sample sizes, and therefore any conclusions made need to be viewed within the context of this limited evidence. Although the meta-analysis of five included RCTs concluded that transdermal nicotine was superior to placebo for induction of remission in active UC, it was found to be equivocal to standard therapy of oral corticosteroids or mesalazine.[20] Nikfar et al.[3] went further, to illustrate that analysing nicotine vs. oral corticosteroid alone – removing the statistical heterogeneity of the studies – nicotine was found to have inferior efficacy for induction of remission in UC. Although nicotine may not be as efficacious as oral corticosteroids, one should not overlook the possibility that nicotine therapy may still confer benefit to remission induction when used in concert with mesalazine and/or oral corticosteroids. In two of the RCTs examining transdermal nicotine vs. placebo[77,78] a number of patients remained on oral corticosteroids throughout the duration of study, and despite stratification the efficacy of nicotine in inducing clinical remission of UC was demonstrated. However, additional studies into the use of nicotine as an adjunct to conventional treatment would need to be conducted to verify this assertion. Nicotine was also shown to induce a remission that lasted longer than that achieved by oral corticosteroids.[80] Again, additional studies examining the use of nicotine and oral corticosteroid use together, compared with nicotine or oral corticosteroid use alone would strengthen this data. It is unknown if nicotine used with mesalazine or oral corticosteroids could potentially have synergistic effects; however, this remains speculative.[20]

What is severely limiting to the potential use of nicotine as treatment in UC is the high frequency of adverse events when compared to conventional therapy. Of the three RCTs examining nicotine vs. placebo in induction of remission[77,78,85] the RR of an adverse event occurring in the nicotine group was found to be 1.95 (95% CI: 1.38–2.78) and the RR of withdrawal due to an adverse event 3.44 (95% CI: 0.71–16.71).[3] The two RCTs comparing nicotine and oral corticosteroid treatments[80,82]similarly found the RR of withdrawal due to adverse events to be 2.28 (95% CI: 0.76–6.83).[3] Despite the generally benign nature of the adverse events experienced by the patients in the nicotine groups (such as nausea, light-headedness, dizziness, tremor, headache, sleep disturbance and contact dermatitis)[77–80,82,83,85] this does not bode well for the clinical significance of nicotine. Fortunately, cardiovascular risk does not appear to be adversely influenced by the use of nicotine patches or enemas, when markers of haemostasis were examined as a surrogate[86,87] Nicotine was found to significantly lower plasma fibrinogen – which may be explained in part by the nature of plasma fibrinogen being an acute phase protein – however, returned equivocal results in markers of platelet activation (platelet volume and surface expression of P selectin), endothelial damage (plasma von Willebrand factor antigen), white cell count and serum lipid levels when the use of nicotine patches vs. placebo was compared in a study of nonsmokers in remission from UC.[86] Nicotine enemas delivered no significant difference in plasma fibrinogen concentration between treatment and placebo groups in another study examining these effects in patients with active UC.[87] However, further investigation of cardiovascular risk modulation in nicotine therapy is warranted.

Additional studies of the minimum therapeutic dose of nicotine and its associated adverse events, for application as a potential medicine in UC may serve to clarify its clinical importance. Furthermore, additional research as to whether nicotine is in fact the sole moiety present in cigarette smoke responsible for the disease amelioration seen in UC is warranted. Until this and further study is undertaken, it appears that nicotine's application as a therapeutic treatment in UC is limited. Presently, it may only be an option considered in selected cases of acute UC, refractory to conventional treatment options, particularly, in circumstances where access to immunomodulatory or biological agents is limited.