n engl j med 371;25 nejm.org december 18, 2014 2429

e d i t o r i a l s

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Cytisine — A Tobacco Treatment Hiding in Plain SightNancy A. Rigotti, M.D.

A randomized, controlled trial published in this issue of the Journal brings renewed attention to cytisine, a potentially useful pharmacotherapy for smoking cessation that has been hiding in plain sight.1 A naturally occurring plant alka-loid, cytisine has been sold in Eastern Europe as an inexpensive smoking-cessation aid for 50 years but is unavailable elsewhere.2

Two events brought it to broader attention in 2006. First, Etter’s review2 of overlooked, older studies suggested a potential efficacy of cytisine for smoking cessation, although a firm conclu-sion could not be drawn because previous trials did not meet contemporary standards. Second, varenicline, a drug with a similar mechanism of action, was licensed as a new smoking-cessation aid. Cytisine, like varenicline, is a partial ago-nist that binds selectively to the α4β2 nicotinic acetylcholine receptor subtype that appears to mediate nicotine dependence.2

Subsequently, two randomized trials and two meta-analyses incorporating them provided bet-ter evidence of cytisine’s efficacy as compared with placebo.3-6 The study reported here is note-worthy for its direct comparison of cytisine with an established, first-line smoking-cessation phar-macotherapy. In this randomized, noninferiority trial, cytisine was not just similar to nicotine-replacement therapy but actually superior to it for continuous tobacco abstinence at 1 month, the trial’s primary outcome measure. This is only an end-of-treatment intermediate outcome, but cytisine remained superior to nicotine-replace-ment therapy at a 6-month follow-up in one of two typical measures of long-term efficacy.

Conducted as a pragmatic clinical trial,7 the study recruited smokers seeking treatment in a real-world setting. New Zealand’s national telephone quitline provided minimal behavioral

support and had few exclusion criteria. The ad-vantage of this design is that an intervention found to be truly effective is likely to work in many settings.7 In contrast with the tightly con-trolled conditions used in standard efficacy (or explanatory) trials to maximize internal validity, in this study, participants were aware of the study treatment and there was no biochemical verification of their self-reported tobacco absti-nence at follow-up.

Although cytisine was associated with a higher rate of adverse events than nicotine-replacement therapy, only 5% of patients discontinued cyti-sine because of side effects. The most common symptoms, nausea and vomiting and sleep dis-orders, had previously been observed and mirror patients’ experience with varenicline.6 The psy-chiatric side effects reported in postmarketing surveillance of varenicline were not observed,6 but the study was too small to detect rare events. These symptoms did not emerge during decades of use of cytisine in Eastern Europe,3 but the extent of monitoring for these effects is unclear.

Several features of the trial may have biased the results against nicotine-replacement therapy. More than 20% of participants had used nico-tine-replacement therapy in their most recent attempt to stop smoking and were already non-responders to nicotine-replacement therapy. Both groups received vouchers to subsidize the pur-chase of nicotine-replacement therapy, and 4% of the participants in the cytisine group used these vouchers along with their assigned drug. Nicotine-replacement therapy is more effective when users combine the skin patch with an orally absorbed treatment such as gum or loz-enges.8 Nicotine-replacement therapy might have produced a better outcome if different means of

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

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delivery had been combined, but combination therapy was not part of the protocol for the trial.

Overall, the study shows that cytisine is at least equivalent to nicotine-replacement therapy, since both were used in real-world practice. Fur-ther trials will be needed to determine whether cytisine is truly superior to nicotine-replacement therapy and how it compares with other first-line pharmacotherapies that help smokers achieve long-term tobacco cessation. Studies could also explore whether the efficacy of cytisine could be improved with alternative dosing regimens.

A more urgent issue with regard to cytisine concerns public health. Cytisine is an inexpen-sive drug that has been used for decades and for which there are now current data showing its safety and effectiveness. There are millions of smokers worldwide who might benefit from it.9,10 The compelling rationale for bringing cyti-sine to market is not that its efficacy is superior to that of current pharmacotherapies but that current pharmacotherapies are unavailable to so many smokers — especially those in low-income and middle-income countries — because of their cost.11 Stakeholders in high-income countries seeking to contain health care costs would also benefit from a lower-cost pharmacotherapeutic option.

The challenge is to protect public health while retaining cytisine’s affordability for con-sumers. Unfortunately, in the United States and Western Europe there is now no direct pathway through the regulatory and pharmaceutical mar-ket structure for a potentially useful drug with cytisine’s unconventional history. The solution will require creative collaboration among a range of stakeholders. These include regulators, pharmaceutical companies, government agencies that fund research, and both public and private organizations whose mission is to improve

global public health. A first step might be to convene these stakeholders and challenge them to identify a way forward.

The need is urgent. Tobacco use is now the leading preventable cause of death worldwide. Smoking cessation benefits virtually every smok-er, and the use of pharmacotherapy improves the likelihood of success for those who attempt to quit.8 We can save lives by making effective treatments available to all smokers.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

From the Department of Medicine, Division of General Internal Medicine, and the Tobacco Research and Treatment Center, Massachusetts General Hospital and Harvard Medical School, Boston.

1. Walker N, Howe C, Glover M, et al. Cytisine versus nicotine for smoking cessation. N Engl J Med 2014;371:2353-62.2. Etter JF. Cytisine for smoking cessation: a literature review and a meta-analysis. Arch Intern Med 2006;166:1553-9.3. Hajek P, McRobbie H, Myers K. Efficacy of cytisine in help-ing smokers quit: systematic review and meta-analysis. Thorax 2013;68:1037-42.4. West R, Zatonski W, Cedzynska M, et al. Placebo-controlled trial of cytisine for smoking cessation. N Engl J Med 2011;365: 1193-200.5. Vinnikov D, Brimkulov N, Burjebaeva A. A double-blind, randomised, placebo-controlled trial of cytisine for smoking cessation in medium-dependent workers. J Smoking Cessation 2008;3:57-62.6. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2012;4:CD006103.7. Thorpe KE, Zwarenstein M, Oxman AD, et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol 2009;62:464-75.8. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 2013;5:CD009329.9. Prochaska JJ, Das S, Benowitz NL. Cytisine, the world’s old-est smoking cessation aid. BMJ 2013;347:f5198.10. Aveyard P, West R. Cytisine and the failure to market and regulate for human health. Thorax 2013;68:989.11. Piné-Abata H, McNeill A, Murray R, Bitton A, Rigotti N, Raw M. A survey of tobacco dependence treatment services in 121 countries. Addiction 2013;108:1476-84.DOI: 10.1056/NEJMe1412313Copyright © 2014 Massachusetts Medical Society.

Out of Africa — Caring for Patients with EbolaEric J. Rubin, M.D., Ph.D., and Lindsey R. Baden, M.D.

Although the Ebola virus was recognized in 1976,1 until now Ebola virus disease (EVD) had been confined to remote areas in Africa, occur-ring in discrete outbreaks. Even with the thou-sands of cases in the current outbreak, most

cases occur in areas where tragically few resources are available to care for affected patients — in Guinea, Liberia, and Sierra Leone. However, a small number of patients have been transferred to hospitals with modern technology. In addition,

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