バレニクリン(商品名:チャンピックス)の有効性などの最新エビデンス

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2011年01月13日(Thu) 18:23

[Intervention Review]
Nicotine receptor partial agonists for smoking cessation

Kate Cahill1, Lindsay F Stead1, Tim Lancaster1

1Department of Primary Health Care, University of Oxford, Oxford, UK

Contact address: Kate Cahill, Department of Primary Health Care, University of Oxford,
Rosemary Rue Building, Old Road Campus, Oxford, OX3 7LF, UK. kate.cahill@dphpc.ox.ac.uk.

Editorial group: Cochrane Tobacco Addiction Group.
Publication status and date: New search for studies and content updated (conclusions
changed), published in Issue 12, 2010.
Review content assessed as up-to-date: 29 October 2010.

Citation: Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking
cessation. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD006103.
DOI: 10.1002/14651858.CD006103.pub4.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Abstract

Background
Nicotine receptor partial agonists may help people to stop smoking by a combination of
maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as
an agonist) and reducing smoking satisfaction (acting as an antagonist). Varenicline
was developed as a nicotine receptor partial agonist from cytisine, a drug widely used
in central and eastern Europe for smoking cessation. The first trial reports of varenicline
were released in 2006, and further trials have now been published or are currently underway.

Objectives
The primary objective of this review is to assess the efficacy and tolerability of
nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.

Search strategy
We searched the Cochrane Tobacco Addiction Group's specialised register for trials,
using the terms ('varenicline' or 'cytisine' or 'Tabex' or 'nicotine receptor partial
agonist') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE,
EMBASE, PsycINFO and CINAHL using MeSH terms and free text, and we contacted authors of
trial reports for additional information where necessary. The latest search was in September 2010.

Selection criteria
We included randomized controlled trials which compared the treatment drug with placebo.
We also included comparisons with bupropion and nicotine patches where available. We
excluded trials which did not report a minimum follow-up period of six months from start
of treatment.

Data collection and analysis
We extracted data on the type of participants, the dose and duration of treatment, the outcome
measures, the randomization procedure, concealment of allocation, and completeness of follow up.

The main outcome measured was abstinence from smoking after at least six months from the
beginning of treatment. We used the most rigorous definition of abstinence, and preferred
biochemically validated rates where they were reported. Where appropriate we performed
meta-analysis to produce a risk ratio, using the Mantel-Haenszel fixed-effect model.

Main results
We found 11 trials of varenicline compared with placebo for smoking cessation; three of
these included a bupropion experimental arm. We also found one relapse prevention trial,
comparing varenicline with placebo, and two open-label trials comparing varenicline with
nicotine replacement therapy (NRT). We also include one trial in which all the participants
were given varenicline, but received behavioural support either online or by phone calls,
or by both methods. This trial is not included in the analyses, but contributes to the data
on safety and tolerability. The included studies covered >10,300 participants, 6892 of whom
used varenicline. We identified one trial of cytisine (Tabex) for inclusion.

The pooled risk ratio (RR) (10 trials, 4443 people, excluding one trial evaluating long term
safety) for continuous abstinence at six months or longer for varenicline at standard dosage
versus placebo was 2.31 (95% confidence interval [CI] 2.01 to 2.66). Varenicline at lower or
variable doses was also shown to be effective, with an RR of 2.09 (95% CI 1.56 to 2.78;
4 trials, 1272 people). The pooled RR for varenicline versus bupropion at one year was 1.52
(95% CI 1.22 to 1.88; 3 trials, 1622 people). The RR for varenicline versus NRT for point
prevalence abstinence at 24 weeks was 1.13 (95% CI 0.94 to 1.35; 2 trials, 778 people).
The two trials which tested the use of varenicline beyond the 12-week standard regimen
found the drug to be well-tolerated during long-term use. The main adverse effect of
varenicline was nausea, which was mostly at mild to moderate levels and usually subsided
over time. Post-marketing safety data raised questions about a possible association between
varenicline and depressed mood, agitation, and suicidal behaviour or ideation. The labelling
of varenicline was amended in 2008, and the manufacturers produced a Medication Guide.
Thus far, surveillance reports and secondary analyses of trial data lend little support
to a causal relationship.

The one cytisine trial included in this review found that more participants taking cytisine
stopped smoking compared with placebo at two-year follow up, with an RR of 1.61 (95% CI 1.24 to 2.08).

Authors' conclusions
Varenicline at standard dose increased the chances of successful long-term smoking cessation
between two- and threefold compared with pharmacologically unassisted quit attempts. Lower
dose regimens also conferred benefits for cessation, while reducing the incidence of adverse
events. More participants quit successfully with varenicline than with bupropion. Two open-label
trials of varenicline versus NRT suggested a modest benefit of varenicline but confidence
intervals did not rule out equivalence. Limited evidence suggests that varenicline may have
a role to play in relapse prevention. The main adverse effect of varenicline is nausea, but
mostly at mild to moderate levels and tending to subside over time. Possible links with serious
adverse events, including depressed mood, agitation and suicidal thoughts, have been reported
but are so far not substantiated.

There is a need for further independent community-based trials of varenicline, to test its
efficacy and safety in smokers with varying co-morbidities and risk patterns. There is a need
for further trials of the efficacy of treatment extended beyond 12 weeks. Cytisine may also
increase the chances of quitting, but the evidence at present is inconclusive.

Plain language summary

Can nicotine receptor partial agonists, including varenicline and cytisine, help people to stop smoking
When people stop smoking they experience cravings to smoke and unpleasant mood changes. Nicotine
receptor partial agonists such as varenicline aim to reduce withdrawal symptoms and smoking
satisfaction. We found 11 randomized controlled trials of varenicline compared with placebo.
Three of these trials also included a direct comparison with bupropion. One other trial tested
varenicline against placebo, as maintenance therapy for those who had recently quit with varenicline.
Two further trials compared varenicline with nicotine patches. One trial gave varenicline to
all participants, but varied the delivery of behavioural support. This trial is not included
in the analyses, but contributes to the data on safety and tolerability. From these data,
varenicline at standard dose increased the chances of quitting more than two-fold compared with
placebo.
Low-dose varenicline roughly doubled the chances of quitting, and reduced the number
and severity of side effects. The number of people stopping smoking with varenicline was higher
than with bupropion. The two trials with nicotine patches did not show a clear benefit of varenicline
over the patches.
The main side effect of varenicline was nausea, but this was mostly at mild or
moderate levels and usually subsided over time. After the licensing phase, there were concerns
that varenicline may be linked with depressed mood, agitation or suicidal thinking and behaviour
in some smokers. Surveillance studies and further analyses of the trial data have not so far found
strong support for this association.
The evidence on cytisine is limited at present, and no firm conclusions can yet be drawn
about its effectiveness as an aid to quitting.

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