Cytisine for Smoking Cessation

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humans with nicotine than with cytisine, and both situations are quite rare. Studies of the toxicity of cytisine in humans were conducted by Sopharma, the company that produces Tabex, but these reports (in Bulgarian) (cited on: http://www.tabex .net) were not published in scientific journals and were not sent to the author when requested. COMMENT Research conducted during the past 40 years suggests that cytisine is effective for smoking cessation. Thus, an apparently effective smoking cessation drug that has been used for decades in Germany and Eastern European countries remained unnoticed inothercountries.Mostofthearticles reviewed herein were never cited in the English-language literature. Despite the existence of 3 placebocontrolledtrials,recentreviewsofthe efficacy of smoking cessation drugs omitted cytisine 2,14,15 and little researchoncytisinehasbeenconducted in recent years. This omission is probably explained because studies of the efficacy of cytisine were not published in English and because the available evidence is based on studies that do not conform to current standards in conducting and reporting drug trials. In particular, only 1 recent study 16 used biochemical verification of smoking status, and most studies did not indicate which criterion was used to define smoking abstinence. Only 1 of the 3 placebocontrolled studies clearly indicated that randomization took place, and only 2 were double blind. Most studies were short term, and the number of participants present at follow-up was not always reported. This research probably also remained unnoticed because all studies except 2 16,28 were conducted in Eastern European countries before democratization. However, the only randomized, double-blind, placebocontrolled study 28 was conducted in West Germany, and it showed statistically significant effects of cytisine. Research conducted in the West during the same period (1960s and 1970s) was also often of poor quality, because current methodological standards were not widely adopted at that time, even in the West. 42 Probably because of their poor quality, several studies reported unrealistically high quit rates (60%-70%) and should be interpreted with caution. However, quit rates and ORs in the 3 placebocontrolled trials are well in the range of short-term outcomes in studies of other smoking cessation drugs (nicotine replacement therapy and bupropion). 2 These 3 studies seem, therefore, to be credible, if considering in addition that cytisine binds strongly with nicotinic receptors and that varenicline is effective for smoking cessation. Few adverse effects of cytisine were reported in the studies reviewed herein, which does not mean that cytisine is innocuous. Cytisine causes poisoning, and toxicity tests of cytisine in humans were conducted and results published as internal industry reports in Bulgarian; however, despite repeated attempts, I was unable to obtain these reports. Thus, it is apparently not known whether cytisine has any effect on organ damage or whether it is carcinogenic, teratogenic, or genotoxic in humans. Apart from the relatively short-term adverse effects reported in smoking cessation trials, it is unknown whether the recommended dose of Tabex and cytisine films (9 mg/d) carries any risk and what would be the consequences if children swallowed these tablets. 3 There is some discrepancy between the adverse effects reported in published studies and the list of adverse effects in the manufacturer’s leaflet. In particular, more weight gain using cytisine than using placebo was reported in 1 study, 25 and vertigo was mentioned in some studies but not in the manufacturer’s leaflet. On the other hand, increases in blood pressure and heart rate are listed in the manufacturer’s list of adverse effects, but were not consistently reported in published studies. One limitation of this review is that it was conducted by only 1 person. A duplication of the data search and extraction processes by a second person would have been preferable, but the search process was, nevertheless, extensive and comprehensive. The available data suggest that cytisine may be effective for smoking cessation. This result is all the more interesting considering that no behavioral support was provided to participants in any of the 3 placebo-controlled trials. It is necessary to conduct state-of-the-art clinical trials to confirm these results. However, given the uncertainties about the toxicity of cytisine, it may not be ethical to conduct phase 3 clinical trials before more is known about the toxicity and tolerability of cytisine in humans, at the dosage recommended by the manufacturer. An apparently effective treatment for the first avoidable cause of death in developed countries remained largely unnoticed, despite research published during the past 40 years. How many other effective drugs are there for which efficacy remained unnoticed because existing trials were not published in English in Western countries? Accepted for Publication: April 21, 2006. Correspondence: Jean-François Etter, PhD, MPH, Institute of Social and Preventive Medicine, University of Geneva, 1, rue Michel-Servet, CH-1211 Geneva 4, Switzerland (jean-francois.etter@imsp.unige.ch). Financial Disclosure: None reported. REFERENCES 1. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United States, 2000. JAMA. 2004;291:1238-1245. 2. Lancaster T, Stead L, Silagy C, Sowden A. Effectiveness of interventions to help people stop smoking: findings from the Cochrane Library. BMJ. 2000;321:355-358. 3. Seeger R. Cytisine as an aid for smoking cessation [in German]. 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suit of 42 nicotinic receptor partial agonists for smoking cessation: carbon analogs of (-)-cytisine. Bioorg Med Chem Lett. 2005;15:2974-2979. 9. Papke RL, Heinemann SF. Partial agonist properties of cytisine on neuronal nicotinic receptors containing the 2 subunit. Mol Pharmacol. 1994; 45:142-149. 10. Imming P, Klaperski P, Stubbs MT, Seitz G, Gundisch D. Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands. Eur J Med Chem. 2001;36:375-388. 11. Glass LE. Alkaloids that have a pharmacology like nicotine. http://legacy.library.uscf.edu. Accessed November 24, 2005. 12. Vagg R, Chapman S. Nicotine analogues: a review of tobacco industry research interests. Addiction. 2005;100:701-712. 13. Tilotta MC. 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Med Sci Law. 1970;10: 260-266. 38. Barlow RB, McLeod LJ. Some studies on cytisine and its methylated derivatives. Br J Pharmacol. 1969;35:161-174. 39. Clarke ML, Clarke EG, King T. Fatal laburnum poisoning in a dog. Vet Rec. 1971;88:199-200. 40. Moriya F, Hashimoto Y. A fatal poisoning caused by methomyl and nicotine. Forensic Sci Int. 2005; 149:167-170. 41. Lavoie FW, Harris TM. Fatal nicotine ingestion. J Emerg Med. 1991;9:133-136. 42. Gehan EA, Schneiderman MA. Historical and methodological developments in clinical trials at the National Cancer Institute. Stat Med. 1990;9: 871-880. (REPRINTED) ARCH INTERN MED/ VOL 166, AUG 14/28, 2006 WWW.ARCHINTERNMED.COM 1559 Downloaded from www.archinternmed.com at Health Sci Lib - State Univ of NY at Stony Brook, on September 22, 2006 ©2006 American Medical Association. All rights reserved.
Page 1 and 2: REVIEW ARTICLE Cytisine for Smoking
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Cytisine for Smoking Cessation

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