Recently three randomized, placebo-controlled trials have tested whether adding NRT to varenicline increases quit rates. The rationale for adding NRT to varencline typically involves hypothesizing a) varenicline does not bind to all nicotine receptors leaving some to be influenced by adding NRT, b) some smokers who do not respond fully to varenicline will be helped by NRT, or c) NRT is better at relieving initial withdrawal than varenicline. An alternate hypothesis is that adding NRT would have no effect because any effects would be blocked by varenicline.
The first study of 117 UK smokers examined adding active nicotine vs placebo patches beginning on the quit date (Hajek et al, BMC Medicine 11:140, 2013) and found a small but not statistically significant positive trend for unverified point prevalence at 12 weeks (36% vs 29%). The second study of 341 Spanish smokers examined adding patch beginning on the quit date also found a small, non-significant positive effect (33% vs 28%) at 6 months. A post-hoc subgroup analysis found the active patch more effective in those who smoked > 29 cigarettes/day (OR = 1.5 vs 1.0). The third study of 435 South African smokers examined patch begun 2 weeks prior to the quit date (Koegelenberg et al, JAMA 312:155-161, 2014) and found its addition doubled quit rates at 6 months (44% vs 28%). None of the three studies found a clinically significant increase in adverse events with nicotine vs placebo patches. Why this third study found more robust effects is unclear. Of course, one possibility is that it’s the starting of the patch prior to the quit date. Otherwise, my comparison of the studies does not suggest it’s due to differences in sample or methods or compliance. In addition, the last, more positive study failed to find reductions in craving whereas the less positive studies did find this.
So is this sufficient to declare combo therapy more effective? It’s only three studies, but I bet if one did a meta-analysis it would be positive. In addition, given nicotine replacement therapies have almost no significant side-effects, maybe the only downside to combo is their cost. So for me, this rationale is sufficient to offer combo varenicline and NRT as an option to those who fail varenicline alone.
Finally, the above studies probably used the nicotine patch rather than short acting NRT to insure a significant dose of nicotine. However, most combined treatments for smoking cessation include a short-acting NRT to provide relief of sudden onset craving and withdrawal; thus, I would probably offer either using patch, or using a short-acting NRT as needed.