What is the role of cytisinicline in smoking cessation?

Cytisinicline for Smoking Cessation

Cytisinicline (cytisine) is an effective smoking cessation aid that appears to be as effective as varenicline but with a better safety profile, making it a promising option for smoking cessation despite its current limited availability in the United States. 1, 2

Mechanism of Action and Efficacy

• Cytisinicline is a plant-based alkaloid that, like varenicline, acts as a partial agonist at α4β2 nicotinic acetylcholine receptors, which are key mediators of nicotine dependence 1
• Recent high-quality evidence from the ORCA-3 phase 3 trial demonstrates significant efficacy:
  • 12-week treatment: 30.3% abstinence rate vs 9.4% for placebo (OR 4.4) 2
  • 6-week treatment: 14.8% abstinence rate vs 6.0% for placebo (OR 2.9) 2
  • Sustained abstinence at 24 weeks was significantly higher with cytisinicline (20.5% for 12-week treatment) compared to placebo (4.2%) 2

Comparison to Other Smoking Cessation Medications

• Systematic reviews show cytisinicline is:
  • More effective than placebo (RR = 2.65) 3
  • More effective than nicotine replacement therapy (RR = 1.36) 3
  • Comparable to varenicline in efficacy (RR = 0.96, not statistically different) 3
• In a direct comparison trial, cytisinicline failed to demonstrate noninferiority to varenicline (11.7% vs 13.3% abstinence), though the difference was small 4

Safety Profile and Tolerability

• Cytisinicline demonstrates excellent tolerability with a maximum tolerated dose of 30mg, which is 10 times higher than the therapeutic dose of 3mg 5
• Most common adverse events include:
  • Nausea (reported in 19% of participants in one study) 5
  • Gastrointestinal symptoms (primarily at higher doses) 5
• Fewer adverse events were reported with cytisinicline compared to varenicline in direct comparison (997 events vs 1206 events) 4
• No treatment-related serious adverse events were observed in recent phase 3 trials 2

Dosing and Administration

• Current recommended dosing based on recent trials:
  • 3mg taken three times daily 1, 2
  • Treatment duration of either 6 or 12 weeks, with 12 weeks showing better outcomes 2
• Longer treatment duration (12 weeks vs 6 weeks) is associated with higher abstinence rates (RR = 1.29) 3

Current Status and Availability

• While cytisinicline has been used in Central and Eastern European countries for smoking cessation, it is not yet FDA-approved in the United States 6, 5
• The European Society of Cardiology noted in 2012 that cytisinicline "seems to increase the chances of quitting, but the evidence at present is not conclusive" 6
• Recent high-quality trials have since provided stronger evidence for its efficacy 1, 2

Clinical Application

• Cytisinicline represents a promising alternative to existing smoking cessation medications, particularly for patients who:
  • Experience intolerable side effects with varenicline
  • Have failed other smoking cessation methods
  • Would benefit from a medication with a favorable safety profile
• Combining cytisinicline with behavioral support is recommended, as this approach was used in clinical trials 1, 2
• The medication significantly reduces nicotine craving, which is a key mechanism for its effectiveness 2

While cytisinicline is not yet widely available in many countries including the United States, the robust evidence from recent clinical trials suggests it will likely become an important addition to smoking cessation pharmacotherapy options in the near future.