smoking cessation with cytisine

Cytisine is a plant-based alkaloid, which is a partial agonist of nicotinic acetylcholine receptors (as with varenicline), and it has been used effectively for smoking cessation since the 1960s, largely in Eastern Europe. Historically, it has been well-tolerated with no overall increase in adverse events, though gastrointestinal symptoms are more common. It is a low cost intervention, $20-30 for 25 days (as opposed to nicotine replacement therapy -- NRT -- at $112-685 for 8-10 weeks, or varenicline at $474-501 for 12 weeks), though no trials had existed comparing efficacy of cytisine with nicotine replacement therapy. Hence, this New Zealand study (see smoking cessation cytisine nejm 2014​ in dropbox, or N Engl J Med 2014;371:2353-62​), in which a 25 day therapy with cytisine is compared to 8 weeks of NRT, both with low-intensity behavioral support (basically, 3 calls of 10-15 minutes from Quitline advisors over 8 weeks). This was set up as a noninferiority trial. details:

--1310 people (57% female, 38 yo, 19 cigarettes/day averages) were randomized to cytisine vs NRT
--NRT was prescribed as patches (7, 14, or 21 mg) with gum (2 or 4 mg) or lozenges (1 or 2 mg), with strengths of each as determined by Quitline advisors
--cytisine was given as 1 tablet every 2 hours​ for days 1-3 with max of 6 tablets/d, then 1 tablet every 2.5 hours for days 4-12 with max of 5 tablets/d, then 1 tab every 3 hours for days 13-16 with max of 4/d, then 1 tab every 4-5 hours for days 17-20 with max of 3/d, then 1 tab every 6 hours for days 21-25, with max of 2/day. (i believe these were 1.5 mg tablets). Of the 100 pills given to the patient, an average of 72 were taken.

results (continuous quit rates):
--1-month abstinence rates of 40% for cytisine and 31% for NRT (relative risk 1.3, abs risk difference 9.3, p<0.001)
--2-month abstinence rates of 31% for cytisine and 22% for NRT (relative risk 1.4, abs risk difference 9, p<0.001)
--6-month abstinence rates of 22% for cytisine and 15% for NRT (relative risk 1.4, abs risk difference 6.6, p=0.002)​
--higher quit rate in women (not found in the varenicline studies)
--adverse events were more in cytisine group (288 events in 204 people) vs NRT (174 events in 134 people) -- 70% more with cytisine. Most were nonserious, mostly nausea/vomiting and sleep disorders, and 80-90% of the people experiencing adverse events said they would recommend cytisine to others interested in stopping smoking.

So, cytisine was not only not just noninferior (quite an array of negatives), but was actually superior to NRT at each time point assessed. The study was limited by no documentation of smoking cessation (only self-report). A big plus, it seems to me, is that cytisine has been around so long (since the 1960s). It would be great to have cytisine as an option which is more generally available (as in the US), and it might be more accessible to smokers given the dramatically lower cost. The above prices for varenicline etc are for New Zealand. In the US, the price is likely to be higher (eg the average wholesale price for varenicline 1mg BID is $278/month, without the pharmacy markup...). And we are now using longer courses of therapy, in the 3-6 months range, with some evidence of improved efficacy (esp with varenicline and with bupropion), with the increased attendant costs and medicalization.