A nonprescription agent used outside the United States, the naturally occurring plant-based alkaloid cytisinicline (historically known as cytisine) is used by patients 6 times daily for smoking cessation in a recommended 25-day regimen. In this placebo-controlled clinical trial, a “novel pharmacokinetically based dosing regimen” of cytisinicline is tested for use 3 times daily in 6- or 12-week regimens. With behavioral support to all participants during up to 15 visits, both durations of treatment “demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options,” the investigators conclude.
In the ORCA-2 trial, a 3-group, double-blind, placebo-controlled, randomized design was used for 810 adults who smoked cigarettes daily and wanted to quit. Participants at 17 U.S. sites were randomized to cytisinicline treatment for 6 or 12 weeks or to placebo, with all patients receiving behavioral support and follow-up to 24 weeks.
Using a main outcome measure of biochemically verified continuous smoking abstinence for the last 4 weeks of treatment, the study found, “Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred.”
Editorial: “It is … a very positive development that another new and effective drug may be added to the limited list that clinicians and individuals who smoke can choose from to help end their deadly addiction to cigarettes,” editorialists write. “The US government is considering whether to implement decisive regulations to reduce the appeal and addiction to smoked tobacco products, by abolishing menthol as a characterizing flavor and requiring a 95% reduction in nicotine content in smoked tobacco products. Meanwhile, the government of New Zealand is already moving forward with its comprehensive plan to become a smokefree country by 2025. The Smokefree Environments and Regulated Products (Smoked Tobacco) Amendment Act was signed into law in December 2022 and includes provisions to (1) ban the sale of tobacco to those born after 2008, (2) reduce the number of tobacco retailers by at least 90%, (3) reduce the permissible nicotine content in cigarettes by more than 90%, and (4) increase smoking cessation services, including continued adult access to approved electronic cigarettes. We hope that this decisive action by New Zealand might inspire countries like the US to tackle addiction to cigarettes with the vigor and speed that its effects on public health deserve. Until that happens, we hope that cytisinicline can help more people who smoke in the US to quit.”