P1.2.2 Nicotine receptor partial agonists

The addictive properties of nicotine are considered to be mediated through its action as an agonist at alpha4beta2 nAnti-Cholinergic Receptors (α4β2 nAChR), which stimulate the release of dopamine (Coe 2005). Varenicline was developed to counteract the effects of nicotine on the nAChRs, and its efficacy in smoking cessation has been assessed in a Cochrane systematic review (Cahill 2008). In five trials of varenicline compared to placebo for smoking cessation, it was found to be significantly more effective for continuous abstinence at 12 months than placebo (n = 2023, OR 3.22, 95% CI 2.43 to 4.27, NNT = 8, 95% CI 6 to 11). A 12-week course of treatment is recommended, starting 1–2 weeks before the quit date and titrating the dose as follows: days 1–3: 0.5 mg daily; days 4–7: increase to 0.5 mg twice daily; and continue with 1 mg twice daily from day 8 to the end of a 12-week treatment course. Efficacy has also been demonstrated in people with COPD in a double-blind, multinational study of 504 patients with mild to moderate COPD (Tashkin 2011a). The primary end point of carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12 was significantly higher for patients in the varenicline group (42.3%) than for those in the placebo group (8.8%) (OR, 8.40; 95% CI 5-14; p<.0001) [evidence level II]. Although adverse effects could not be pooled for analysis in the systematic review, multiple trials reported an increased incidence of minor effects, particularly nausea, which was mostly at mild to moderate levels and usually subsided over time, but also insomnia and abnormal dreams. People planning to use the drug should set a date to stop smoking and be warned that varenicline frequently causes nausea which may settle over time and taking it with food and a full glass of water may help reduce nausea.

Varenicline has no known clinically meaningful interactions with other drugs. Two trials have tested the use of varenicline beyond the 12-week standard regimen and found the drug to be well-tolerated and effective during long-term use. Three studies comparing varenicline with bupropion found it to be significantly more effective in achieving continuous abstinence at one year (n = 1,622, NNT = 14, 95% CI 9 to 32). An open-label study comparing varenicline with NRT did not find any difference in one-year cessation rates, despite higher abstinence at the end of treatment (Aubin 2008). There have been questions about the safety of varenicline in people with mental health conditions. Psychiatric comorbidity is common in those who smoke, and in a large randomised trial varenicline was found to be safe in those with stable mental illness or a past history of mental illness (Anthenelli 2013). There is also evidence that varenicline is safe and effective to assist cessation in people with schizophrenia (Pachas 2012, Williams 2012). Varenicline can be used in those who smoke with mental health problems, but these patients should be monitored during quit attempts. These patients should be advised to report unusual mood changes, depression, behaviour disturbance and suicidal thoughts, and stop using the medicine if these occur.

Cytisine, a naturally occurring substance chemically related to varenicline, has been used for smoking cessation for decades in parts of Eastern Europe. In the Cochrane meta-analysis of trials comparing cytisine with placebo, the risk ratio for cessation was 3.98 (95% CI 2.01-7.87). A non inferiority trial conducted in Australia compared standard cytisine treatment (25 days) with standard varenicline treatment (84 days). The verified 6-month continuous abstinence rates were similar (11.7% for the cytisine group vs 13.3% for the varenicline group) but the difference did not meet the noninferiority margin of 5% (Courtney 2021). Cytisine is not currently registered for use in Australia or New Zealand but importation is possible.