With varenicline currently unavailable, is it possible that cytisine might serve as an alternative pharmacotherapy to help patients to stop smoking? Rod Tucker takes a closer look in our Review series.

Tobacco smoking is a major cause of premature death and kills more than eight million people each year, including 1.3 million non-smokers, exposed to second-hand smoke. Much attention has focused on the relationship between smoking and lung cancer, although are many other adverse health effects associated with smoking. Estimates suggest that 90% of lung cancer deaths are due to smoking.

Fortunately, a large body of evidence supports the effectiveness of pharmacotherapies for smoking cessation and these benefits were highlighted in a 2021 systematic review. One such treatment is varenicline, which, according to the systematic review, was associated with a more than two-fold increase in the smoking cessation success rate.

However, varenicline is currently unavailable in the UK and Europe and withdrawn by the manufacturer, Pfizer in 2021, due to the presence of high levels of N-nitroso-varenicline. But are there any suitable alternatives to varenicline?

One potential treatment is cytisine. The drug has the same mode of action but despite being available for over 50 years, it is still not licensed in many countries beyond Eastern Europe. How effective is cytisine as an aid to smoking cessation, and why is it not more widely available?

Cytisine

Cytisine, or more correctly, cytisinicline, is an alkaloid that is a partial nicotinic acetylcholine receptor agonist. It is derived from the plant Cytisus laburnum, and although discovered in 1865, it was not until 1912 that its pharmacological actions were described as almost indistinguishable from that of nicotine. The drug was brought to market in 1964 under the brand name, Tabex, by the Bulgarian company, Sopharma and today, while cytisine is marketed in 18 countries, it is not authorised in the UK, European or US markets.

Much of the early research on cytisine was undertaken during the 1960s in Eastern Europe. However, due to a combination of language and Iron Curtain barriers, many clinicians in westernised countries were largely unfamiliar with the drug. But the research had not gone completely unnoticed. The development of varenicline for instance, which has an identical mode of action, was influenced by the recognition that partial nicotinic acetylcholine receptor agonists were implicated in many aspects of tobacco dependence.

Clinical efficacy of cytisine

The first systematic review of the clinical data on cytisine was undertaken in 2006. Although the authors of the review concluded that cytisine appeared to be effective, they also noted how most trials were of poor quality. Since then, several more rigorous, randomised trials have been conducted.

One trial in 2011 observed a significantly higher rate of sustained 12-month abstinence of 8.4% for cytisine compared to 2.4% with placebo (p = 0.001). Cytisine has also been studied against active comparators such as varenicline and nicotine replacement therapy. One such trial concluded that cytisine treatment for 25 days, compared with varenicline for 84 days, failed to demonstrate non-inferiority regarding smoking cessation. Another trial compared cytisine for 25 days to eight weeks of nicotine replacement therapy (NRT) and in terms of continuous abstinence, cytisine was shown to be superior to NRT after one week, two months and six months. The most recent trial found that both six and 12 weeks of treatment significantly, improved smoking cessation rates compared to placebo.

Why is cytisine not licensed more widely?

The drug is certainly cost-effective. For instance, a 2018 analysis concluded that the current provision of smoking cessation services in the Netherlands and England could benefit economically from the inclusion of cytisine. But perhaps the biggest barrier is that manufacturers have little incentive to conduct any further and regulatory required trials simply because cytisine is now a generic product.

Things may change in the near future. One US company, Achieve Life Sciences, has undertaken a number of randomised, controlled trials evaluating cytisine. Recently, for example, the company reported on how cytisine 3 mg three times a day, demonstrated a significantly significant better quit rate than placebo, among a small study of adult users of nicotine e-cigarettes or vapes.

In the absence of a marketing authorisation, cytisine will not replace varenicline, at least in the short-term. But armed with a dossier of positive data, cytisine is likely to gain FDA approval in the next year or so with UK and European regulatory expected to follow suit, finally allowing many more millions of patients access to an effective smoking cessation aid.

Rod Tucker is a clinical writer