Tobacco: preventing uptake, promoting quitting and treating dependence

Evidence that triggered the exceptional review

Cochrane review on nicotine receptor partial agonists – a total of 8 studies were included that assessed the efficacy of cytisine for smoking cessation in adults. Four studies comparing cytisine to placebo which showed that cytisine helped people to quit smoking, with a moderate-certainty of evidence (risk ratio [RR] 1.30, 95% confidence interval [CI] 1.15 to 1.47). A further 2 studies randomised people to receive either cytisine or varenicline, these showed that more people in the varenicline arm quit smoking (RR 0.83, 95% CI 0.66 to 1.05). This showed a moderate-certainty of evidence, limited by the fact that the confidence intervals incorporated the potential for benefit from either cytisine or varenicline. One study compared cytisine to NRT and found that more people in the cytisine arm successfully quit than in the NRT arm (RR 1.43, 95% CI 1.13 to 1.80). The final study compared 40 days and 84 days of cytisine, and found that more people successfully quit on the longer treatment, the standard duration of treatment is 25 days. None of these studies were set in a UK population. There was no evidence of a difference between cytisine and placebo in the number of reported serious adverse events.

Cochrane component NMA – this assessed pharmacological and e‑cigarette interventions for smoking cessation in adults. The studies described in the nicotine receptor partial agonists review described above were included in this analysis. In total 322 studies were included covering nicotine e‑cigarettes, cytisine, varenicline, NRT, bupropion, nortriptyline and non-nicotine e‑cigarettes. The authors concluded that the most effective interventions were nicotine e‐cigarettes, varenicline and cytisine (all with high-certainty). The hierarchy of results of the NMA when comparing smoking cessation rates at 6 months or longer, in comparison to placebo were:

There was no clear difference in the number of people reporting serious adverse events (SAEs) for nicotine e‑cigarettes, varenicline, cytisine or NRT when compared to no pharmacotherapy/e‑cigarettes or placebo, this was classed as low-certainty evidence. Bupropion may slightly increase rates of SAEs.

Details on potential costs of cytisine

A National Institute for Health and Care Research (NIHR) funded economic analysis from 2014 (ScHARR) reported that cytisine was estimated to be more cost-effective than varenicline. The outputs from the economic model estimated more mean life-years and quality of life-adjusted years, and lower mean lifetime costs, for cytisine than varenicline treatment.

The costs of cytisine to the NHS is not currently listed in the BNF but reports suggest that a course may be available for £115 (25 days). This appears to compare favourably with varenicline, which cost £230 for a full course when it was available in the UK, and bupropion having an estimated price for a standard 7 week course of £134.

Results of update of search

We searched for studies investigating cytisine that were published since the searches conducted for the Cochrane review in April 2022. We found 6 RCTs and 4 systematic reviews, 2 of these being the Cochrane reviews already identified. These are reported in detail in appendix A. There was also 1 cost-utility analysis and 1 publication was a report of the methods used to develop a Spanish guideline on smoking cessation. The studies we found agree with the results of the Cochrane reviews.

There were 2 studies comparing cytisine and varenicline. The first of these was an RCT located in Russia which included 400 participants and concluded that cytisine had equivalent efficacy to varenicline at 6 months. The participants had HIV and showed behaviour of high drinking and smoking, which questions the external validity of this study. The second study recruited 377 participants in Croatia and Slovenia, from the general population, and reported results at 24 weeks, which would limit this study's inclusion in the guideline evidence review and the Cochrane review, both of which stipulated a minimum follow-up of 6 months. The results showed the cytisine group to have a lower cessation rate and a lower rate of adverse events.

Two studies randomised participants to receive cytisine or placebo. A study from the US randomised 810 adults and reported 'abstinence rates' were higher in cytisine groups than placebo at 24 weeks. The second study was set in Thailand (n=132) and all participants received counselling in addition to cytisine or placebo. The results stated that the 'abstinence rates' at week 48 were higher in cytisine than placebo groups.

One Italian RCT recruited 869 participants from a lung cancer screening programme, they were described as heavy tobacco users. Cytisine and counselling or counselling alone were provided. At 12 months the 'quit rate' was higher for the cytisine group than counselling alone group.

One study, set in Iran, randomised 47 hospitalised patients to receive cytisine or nicotine gum. Showing favourable results for cytisine, but was limited by the low number of participants.

The 2 systematic reviews were both published after the Cochrane review and included a higher number of trials on cytisine than the Cochrane reviews. The results of both confirmed that cytisine had a positive impact on smoking cessation when compared to placebo. When compared to varenicline the results favoured varenicline but were not significant with the confidence intervals crossing the line of no effect.

Results of ongoing trials searches

The results of the searches of the clinical trial registries identified 3 studies. One of these is set in New Zealand (n=800) and compares cytisine and nicotine containing e‑cigarettes, with a follow-up period of 6 months. This is due for completion in 2024. A US based study comparing cytisine to placebo in 792 adults is expected to publish in 2024. A Canadian RCT recruited 48 participants, comparing cytisine to placebo, and is due for completion in 2024. The two larger studies will be monitored and have been added to the NICE event tracker.