The compound cytisine, an extract of acacia seeds that has been used in Eastern Europe for more than 40 years as an aid to smoking cessation, was found effective in the first placebo-controlled randomized trial of the agent that meets modern regulatory standards, according to a report in the Sept. 29 issue of the New England Journal of Medicine.
Cytisine is a partial agonist that binds with high affinity to a subtype of the nicotinic acetylcholine receptor, which is also the primary target of the smoking-cessation drug varenicline. It has been available across Eastern Europe under the brand name Tabex since 1964, said Robert West, Ph.D., of the Cancer Research U.K. Health Behavior Research Centre, department of epidemiology and public health, University College London, and his associates.
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Cytisine, which has been used to help cease smoking in Eastern Europe for more than 40 years, was finally proven effective in a modern randomized trial.
Because of its "unusual history of development," no preclinical studies, dosing studies, or large comparative trials have been reported to date. "We conducted a study to assess cytisine’s efficacy and safety in a context that could be replicated globally, with a relatively short treatment course (25 days) and minimal contact with health professionals," they noted.
Their aim was to determine whether the agent would be particularly beneficial for the millions of smokers who live in "countries in which the average household income is less than $200 per week and in which treatment of this kind is not paid for by insurance plans or national health care systems."
Unlike other pharmacotherapies for smoking cessation, cytisine is inexpensive; a full course of treatment costs the equivalent of $15 in Poland and $6 in Russia. This "may make it an attractive treatment option for smokers in low-income and middle-income countries," the researchers noted.
They performed a single-center, double-blind trial in which 740 subjects were randomly assigned to either active drug or placebo in equal numbers. "Behavioral support and the number of follow-up sessions were kept to a minimum to simulate, as much as possible, what might happen in a routine clinical situation" in low-income regions.
This included a baseline clinic visit where the drug was dispensed, telephone calls from staff on the target quit day (day 5) and 1 week later, a clinic visit 1 month after the target quit date, further follow-up calls, and a clinic visit for those who remained abstinent at 6 and 12 months following the conclusion of treatment.
The study participants were adults who smoked 10 or more cigarettes per day and were willing to try to stop smoking permanently. At baseline, all reported heavy smoking and showed high concentrations of carbon monoxide in exhaled breath, and all scored high on the Fagerström Test for Nicotine Dependence. Approximately half the study subjects were manual laborers, and more than 80% said they had tried to quit smoking previously.
The primary efficacy outcome was 12 months of sustained smoking abstinence after the end of treatment. This rate was 8.4% with cytisine, significantly better than the 2.4% rate with placebo.
"The net improvement in the abstinence rate with cytisine was 6 percentage points. The relative rate of abstinence in the cytisine group as compared with that in the placebo group was 3.4," Dr. West and his colleagues said (N. Engl. J. Med. 2011;365:1193-200).
This 3.4 relative difference in smoking cessation between cytisine and placebo "was higher than previous studies have shown for varenicline (2.3) and nicotine-replacement therapy (1.6). However, the absolute difference in the rate of abstinence between participants receiving cytisine and those receiving placebo in this trial (6 percentage points) was lower than that shown for varenicline and similar to that shown for nicotine-replacement therapy," they noted.
The rates of drug discontinuation or dose reduction were similar between subjects taking the active drug and those taking placebo. There were no serious adverse effects attributed to cytisine. The incidence of minor gastrointestinal adverse effects, chiefly stomach ache, dyspepsia, and nausea, was higher with cytisine than with placebo.
Using more intensive behavioral support along with cytisine may improve absolute quit rates. "Also, the treatment period was only 4 weeks, as compared with 8 weeks for nicotine-replacement therapy and 12 weeks for varenicline, and it is possible that efficacy could be improved by a longer regimen," the investigators added.
This study was supported by University College London, the U.K. National Prevention Research Initiative, Cancer Research U.K., and the U.K. National Institute for Health Research. Cytisine and matching placebo were provided at no cost by the manufacturer, Sopharma AD. Dr. West and his associates reported ties to Pfizer, McNeil, Celtic, Johnson & Johnson, and GlaxoSmithKline, and Dr. West holds a patent pending on a nicotine delivery device.