Cytisine — A Tobacco Treatment Hiding in Plain Sight Nancy A. Rigotti, M.D. N Engl J Med 2014; 371:2429-2430December 18, 2014

1. n engl j med 371;25 nejm.org december 18, 2014 2429
edi t or i a l s
The new engl and jour nal of medicine
Cytisine — A Tobacco Treatment Hiding in Plain Sight
Nancy 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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2. The new engl and jour nal of medicine
n engl j med 371;25 nejm.org december 18, 20142430
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.
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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:
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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
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6. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial
agonists for smoking cessation. Cochrane Database Syst Rev
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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/NEJMe1412313
Copyright © 2014 Massachusetts Medical Society.
Out of Africa — Caring for Patients with Ebola
Eric 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,
The New England Journal of Medicine
Downloaded from nejm.org on March 4, 2015. For personal use only. No other uses without permission.
Copyright © 2014 Massachusetts Medical Society. All rights reserved.