Interventions to reduce harm from continued tobacco use - LIF

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Interventions to reduce harm from continued tobacco use - LIF

Interventions to reduce harm from continued tobacco use

(Review)

Stead LF, Lancaster T

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2010, Issue 9

http://www.thecochranelibrary.com

Interventions to reduce harm from continued tobacco use (Review)

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


T A B L E O F

C O N T E N T S

HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Analysis 1.1. Comparison 1 Nicotine replacement therapy to assist smoking reduction versus placebo/unassisted reduction,

Outcome 1 Reduction in cigarettes/day of >50% of baseline or cessation. . . . . . . . . . . . . . 36

Analysis 1.2. Comparison 1 Nicotine replacement therapy to assist smoking reduction versus placebo/unassisted reduction,

Outcome 2 Cessation at long-term follow-up (Subgroups by type of NRT). . . . . . . . . . . . . 37

Analysis 2.1. Comparison 2 Bupropion to assist smoking reduction versus placebo, Outcome 1 Outcomes at long term

follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Interventions to reduce harm from continued tobacco use (Review)

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

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[Intervention Review]

Interventions to reduce harm from continued tobacco use

Lindsay F Stead 1 , Tim Lancaster 1

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

Contact address: Lindsay F Stead, Department of Primary Health Care, University of Oxford, Rosemary Rue Building, Old Road

Campus, Oxford, OX3 7LF, UK. lindsay.stead@dphpc.ox.ac.uk.

Editorial group: Cochrane Tobacco Addiction Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 9, 2010.

Review content assessed as up-to-date: 23 June 2010.

Citation: Stead LF, Lancaster T. Interventions to reduce harm from continued tobacco use. Cochrane Database of Systematic Reviews

2007, Issue 3. Art. No.: CD005231. DOI: 10.1002/14651858.CD005231.pub2.

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

Background

A B S T R A C T

It may be reasonable to try to reduce the harm from continued tobacco use amongst smokers unable or unwilling to quit. Possible

approaches to reduce the exposure to toxins from smoking include reducing the amount of tobacco used, and using less toxic products.

The interventions evaluated in controlled trials have predominantly attempted to reduce the number of cigarettes smoked.

Objectives

To assess the effect of interventions intended to reduce the harm from smoking on the following: biomarkers of damage caused by

tobacco, biomarkers of tobacco exposure, number of cigarettes smoked, quitting, and long-term health status.

Search methods

We searched the Cochrane Tobacco Addiction Group Specialised Register in June 2010 using free text and MeSH terms for harm

reduction, smoking reduction and cigarette reduction.

Selection criteria

Randomized or quasi-randomized controlled trials of interventions in tobacco users to reduce amount smoked, or to reduce harm

from smoking by means other than cessation. Outcomes were change in cigarette consumption, markers of cigarette exposure and any

markers of damage or benefit to health, measured at least six months from the start of the intervention.

Data collection and analysis

We pooled trials with similar interventions and outcomes using a fixed-effect model. Other studies were summarised narratively.

Main results

Sixteen trials evaluated interventions to help those who smoke, to cut down the amount smoked and three compared different types of

cigarettes or potentially reduced-exposure products. Self-reported reduction in cigarettes per day (CPD) was validated by reduction in

carbon monoxide (CO) levels. Most trials tested nicotine replacement therapy (NRT) to assist reduction. In a pooled analysis of nine

trials, NRT significantly increased the odds of reducing CPD by 50% or more for people using nicotine gum or inhaler or a choice

of product compared to placebo (n = 3429, risk ratio [RR] 1.72; 95% confidence interval [CI] 1.41 to 2.10). Where average changes

from baseline were compared for different measures, CO and cotinine consistently showed smaller reductions than CPD. Whilst the

effect for NRT was significant, small numbers of people in either treatment or control group successfully sustained a reduction of

50% or more. Use of NRT also significantly increased the odds of quitting (RR 1.73; 95% CI 1.36 to 2.19). One trial of bupropion

Interventions to reduce harm from continued tobacco use (Review)

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

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failed to detect an effect on reduction or cessation. Four trials of different types of advice and instructions on reducing CPD did not

provide clear evidence. One study comparing cigarettes with different tar levels and one study of carbon filters showed some reduction

in exposure to some toxicants but it is unclear that the risk of harm would alter substantially. A study of an electrically heated cigarette

smoking system showed some evidence of improvement in markers of cardiovascular risk.

Authors’ conclusions

There is insufficient evidence about long-term benefit to support the use of interventions intended to help smokers reduce but not quit

smoked tobacco use. Some people who do not wish to quit can be helped to cut down the number of cigarettes smoked and reduce their

CO levels by using nicotine gum or nicotine inhaler. Because the long-term health benefit of a reduction in smoking rate is unclear,

but is likely to be small, this application of NRT is more appropriately used as a precursor to quitting.

P L A I N

L A N G U A G E S U M M A R Y

Can smokers be helped to reduce harm by smoking fewer cigarettes or using different tobacco products

People who smoke may be unwilling or unable to stop smoking completely. Cutting down the number of cigarettes smoked daily or

smoking less damaging products may reduce the harm caused by smoking. It may also be a step towards stopping smoking completely.

This approach might, however, undermine the importance of quitting which has very clear health benefits. We found 16 controlled

trials that tested ways to help people to cut down the number of cigarettes they smoked. We found three randomized controlled trials

which tested the effects of using products designed to reduce damage, such as Potentially Reduced Exposure tobacco Products (PREPs).

Eleven of the trials tested nicotine replacement therapy (NRT) as an aid to cutting down. Our combined analysis of nine of these trials

(3429 smokers) found that nicotine replacement roughly doubled the odds of reducing the number of cigarettes per day by 50% or

more. However, levels of carbon monoxide and cotinine (markers within the body of exposure to tobacco smoke) did not reduce by

the same proportion. This suggested that there may not be a direct relationship between the reduction in number of cigarettes and

the reduction in harmful effects. Although NRT helped significantly more people to cut down, few were able to sustain the reduction

over time. NRT also nearly doubled the odds of quitting completely. One trial failed to find a benefit of bupropion either for cutting

down or for quitting. Four trials tested advice or instructions for reducing the number of cigarettes smoked per day, and did not find

clear evidence of a significant effect. We did not find any trials which reported the long-term effects on health of cutting down, and it

remains uncertain how much health benefit there is from cutting down.

B A C K G R O U N D

The morbidity and mortality associated with smoking is well established.

People who stop smoking can reduce their risk of developing

smoking-related diseases (Anthonisen 2005; Doll 2004),

so the primary strategy for reducing harm must be to encourage

cessation. But despite the fact that most people who smoke say

that they want to stop, annual quit rates are less than four per

cent (West 2006; Messer 2007) and the prevalence of smoking

is only declining slowly even in countries where smoking control

policies are well developed. The current annual decline in prevalence

is estimated to be less than one per cent in the US (MMWR

2004) and UK (ONS 2003). As a secondary strategy it may be

reasonable to seek ways to reduce the harm from continued smoking

for people who are not ready to or cannot quit. This review

focuses on potential strategies for reducing harm to people who

continue to smoke. Interest in this topic has increased greatly in

the past decade. In outlining the scientific and ethical issues we

have drawn on the Institute of Medicine report (Stratton 2001),

supplements to the journals Nicotine & Tobacco Research (NTR

2002 Supplement 2) and Addiction (Addiction 2000 Supplement

1) and the Royal College of Physicians report on protecting people

who smoke by improving regulation of nicotine-containing

products (RCP 2002). People smoke or use other types of tobacco

product because they have become addicted to nicotine. Almost

all the harm is caused not by nicotine but by other toxic substances

in burning tobacco, so that any method of obtaining nicotine that

does not involve combustion will be less harmful, although not

necessarily harmless.

There are multiple possible approaches that might have potential

for harm reduction for people who do not give up tobacco or nicotine

use completely. Shiffman and colleagues have provided a cat-

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alogue of these with a conceptual structure of their characteristics

(Shiffman 2002). They cover many different intended intermediate

effects and mechanisms. They also differ in the likely ease of the

behaviour change to adopt them and related appeal to smokers,

and their expected population risk. Amongst possible approaches

for people who smoke are for them to continue to use existing

types of cigarettes but reduce exposure to the toxic substances by

reducing consumption, or to substitute or partially substitute alternative

products (Warner 2002). The Institute of Medicine report

(Stratton 2001) labelled the group of alternative products Potential

Reduced-Exposure Products (PREPS). PREPs include various

types of smokeless tobacco, modified smoked tobacco products

and ’medicinal nicotine’ products (Shiffman 2002). Public health

research has almost entirely focused on ways of reducing toxin

exposure in people who continue to use conventional cigarettes.

Most trials so far have involved the use of nicotine replacement

therapy, but other pharmacotherapies including bupropion, and

behavioural approaches, have also been considered. Research on

alternative tobacco products has largely been conducted within the

tobacco industry. Research here has attempted to modify the characteristics

of existing tobacco-containing products, or to design

new types of commercial tobacco product, to make tobacco use

less dangerous. For example, using alternative methods for curing

tobacco might reduce exposure to the carcinogenic tobacco-specific

nitrosamines (UMN TTURC 2005). Burning the tobacco

in different ways might reduce the toxins that are inhaled (UMN

TTURC 2005). Charcoal filters could reduce concentrations of

toxins (Coggins 2008). Attempts are also being made to monitor

and reduce toxin levels in conventional cigarettes (Richter 2008).

Very large, long-term trials would be required to fully evaluate the

effects of such changes (Murrelle 2010).

Evaluating possible long-term health benefit from any harm reduction

approach is difficult due to the lack of accurate biomarkers of

health risk (Stratton 2001). For interventions that aim to reduce

exposure to tobacco toxins via a reduction in amount smoked,

simply using change in number of cigarettes smoked is not an ideal

proxy outcome for health benefit. Even if a reduction can be maintained

for a long enough period, focusing only on cigarettes per

day (CPD) as an index of harm is undesirable because cigarettes

can be smoked in different ways, so a percentage reduction in

CPD may not produce an equivalent reduction in toxin exposure.

Even if fewer cigarettes are smoked, it is necessary to demonstrate

reduced exposure to the harmful components in tobacco smoke,

in order to make even tentative assessments of the probable longterm

health benefit if the reduction is sustained. It is also not clear

whether measures of CPD reduction should be assessed in relative

or absolute terms. Using for example a 50% reduction as a cutoff

measure ignores differences between the possible benefits of

reducing from, for example, 40 to 20 CPD, compared to 10 to 5

CPD. However use of an absolute measure does not distinguish

between a 40 to 30 CPD change and a 15 to 5 change. Even low

rate smoking has important health risks; people who smoke just

1 to 4 CPD have been shown to have a higher risk of death from

heart disease than nonsmokers (Bjartveit 2005). It is unclear what

biomarkers of exposure would be more suitable for demonstrating

a true reduction in harm, and a panel of indicators might be required

(Shields 2002). Reductions in exposure might not affect all

risks equally. For example a reduction in levels of a carcinogenic

substance that did reduce the risk for lung cancer might not be

an indicator that the risks for cardiovascular disease were reduced

proportionately. This is especially problematic, given that smoking

so-called low tar cigarettes is one example of a putative ’harm

reduction’ approach that does not appear to yield health benefits

because people change the way they smoke the cigarettes (Burns

2001).

The investigation and promotion of harm reduction approaches

is controversial because of uncertainty over the net impact of any

such interventions. An approach could effectively change the behaviour

of individuals who smoke so that their personal health risks

are minimized, but might have adverse effects for the population

if others’ motivation to quit is reduced (Shiffman 2004). Developments

in cigarette design such as low tar and low nicotine brands

were ostensibly harm reducing. These products may however have

encouraged those who smoked to continue their habit whilst failing

to reduce the harm significantly, thus not reducing morbidity

and mortality (Warner 2002). Some people may have failed to

reduce their harm by compensating for the reduced nicotine by

smoking more cigarettes, or inhaling more deeply (Benowitz 2001;

Burns 2001; Stratton 2001 chapter 3). The availability of ostensibly

less harmful tobacco products could even lead never-smokers

to start or ex-smokers to relapse in the belief that the risks were

acceptable. Because of this, any form of harm reduction found

to have a true health benefit for individuals needs to be tested to

determine whether it has adverse effects on smoking initiation or

quitting (Carter 2009). In addition, promotion of such products

has to be combined with clear information to the public about the

importance of quitting, or continued non-smoking. But even if

the public health impact is uncertain, ethical arguments support

the human rights of individuals who smoke to be informed about

products that could reduce their risk of harm (Kozlowski 2002).

The very clear difference between the high risks of smoking tobacco

compared to the lower risks from using smokeless tobacco

have not been clearly communicated (Kozlowski 2007). Cessation

focused public health policy has been criticised for ignoring alternative

ways to deliver nicotine (Sweanor 2007).

In clinical settings, non-cessation approaches to harm reduction

have generally focused on reducing the number of CPD. This goal

has sometimes been termed ’controlled smoking’. Proposed benefits

of controlled smoking include helping those who are unwilling

or unable to quit, and possibly enhancing future quitting by making

short-term reduction a success rather than a failure (Glasgow

1989). Objections to controlled smoking have been based on uncertainty

about whether there are health benefits; concerns that

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

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short-term decreases will not be maintained; and fears that endorsing

it will undermine quitting (Glasgow 1989). There have been

mixed results from cessation trials that looked at long-term sustainability

of reduced smoking rates (Glasgow 1978; Glasgow 1985;

Hill 1988). Analyses of longitudinal data sets from the COM-

MIT study (Hughes 1999) and the Lung Health Study (Hughes

2004) suggest that some people who smoke do reduce their intake

for long periods. A review of the feasibility of smoking reduction

(Hughes 2000; Hughes 2005) including cross-sectional studies

and prospective studies concluded that only a minority of cigarette

users report large reductions (i.e. 50% or greater). The same review

found that amongst people who had tried and failed to quit in trials,

there is an initial return to lower CPD but the effect dissipates

(Hughes 2005). The authors also added a caveat that this finding

could have been due to differential reporting of reduction outcomes.

The same authors have also conducted a review of the effect

of reduction on future cessation and disease risk (Hughes 2006).

They concluded that smoking reduction increases the probability

of future cessation. No studies suggested that reduction decreased

future cessation. Interventions to reduce smoking, in those who

currently do not want to quit may increase later quitting because

reduction increases self-efficacy, disrupts pharmacological conditioning

or reduces dependence. The review (Hughes 2006) also

concluded that there was a lack of good quality evidence on the

impact of smoking reduction and future risk of smoking-related

disease. The studies that suggest no effect of reduction on disease

might be false negatives, or tobacco consumption may need to

be reduced by much more than the 50% threshold used in most

studies in order to gain benefit. More recent studies have similarly

cautious conclusions: in a prospective study of heavy smokers who

reduced their smoking level by more than half, there was no evidence

of a reduced risk of premature death compared to continuing

heavy smokers (Tverdal 2006). In a longitudinal study that

compared biomarkers in smokers who reported reduction and in

those who maintained steady consumption, a self-reported reduction

in amount smoked resulted in at best a modest reduction in

smoke exposure (Godtfredsen 2006). A comparison between people

reducing their number of cigarettes and people consistently

smoking fewer cigarettes showed that measures of tobacco exposure

remained higher in the reducers (Hatsukami 2006).

O B J E C T I V E S

To assess the effects of interventions intended to reduce the harm

to health of continued tobacco use.

We considered the following specific questions:

• Do interventions intended to reduce harm have an effect on

biomarkers of damage caused by tobacco?

• Do interventions intended to reduce harm have an effect on

biomarkers of tobacco exposure?

• Do interventions intended to reduce harm lead to a

reduction in the number of cigarettes smoked?

• Do interventions intended to reduce harm have an effect on

quitting?

• Do interventions intended to reduce harm have an effect on

long-term health status?

In the real world, the answers to these questions may be highly context-dependent.

For example, an experimental study may find that

switching to a low-nitrosamine tobacco product reduced biomarkers

of exposure to toxins while not decreasing intentions to quit

in the study sample. In the real world a tobacco company might

promote a low-nitrosamine tobacco product as less harmful and

in so doing undermine motivation to quit. These are matters that

are not readily amenable to experimental study and have to be

addressed in other ways.

This review will not address other questions relating to perception

of risk such as:

• Do advertising and endorsements of interventions intended

to reduce harm suggest to nonsmokers that smoking is less

harmful than once thought, that there is a safe level of smoking

or that smoking is a legitimate activity?

• Do these advertisements or endorsements increase smoking

initiation?

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized controlled trials.

Types of participants

People who smoke tobacco. We expected most trials to enrol smokers

who did not currently wish to try to quit. Trials which did not

assess motivation were included if an aim was to reduce cigarette

consumption.

Types of interventions

Interventions to reduce amount smoked, or to reduce harm from

smoking by means other than cessation, including switching to

a Potential Reduced-Exposure Product (PREP), or making other

changes to cigarette characteristics. We excluded interventions

where a reduction in number of cigarettes smoked over a short

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period, or a change in type of cigarette smoked (e.g. nicotine fading),

was intended as a precursor to quitting completely.

Types of outcome measures

The preferred outcome was long-term change in health status, but

it was expected that it would be unlikely to be assessed in randomized

trials. The most appropriate proxy indicator to demonstrate a

reduction in toxin intake from tobacco use that is sufficient to lead

to a clinically useful long-term health benefit is not known (Hatsukami

2005). In the absence of a better indicator we used average

percentage change from baseline smoking rate where reported. If

percentage reduction was dichotomized, for example with a cutoff

of a 50% or greater reduction, we used this outcome. Any biochemical

indicators of reduction were included. Changes had to be

measured at least six months from baseline. Cessation of tobacco

or cigarette use at six months or more was also an outcome.

Search methods for identification of studies

We searched the Cochrane Tobacco Addiction Group Specialised

Register which includes controlled trials and other evaluations of

interventions to change tobacco use behaviour, derived from systematic

searches of MEDLINE, EMBASE, PsycINFO and the

Cochrane Central Register of Controlled Trials (CENTRAL). The

MeSH terms ’Harm reduction’ and ’Risk reduction behavior’ were

introduced in 2003, so free text searches were the main method

for identifying earlier relevant trials. Terms were ’harm reduction’,

’smoking reduction’ ’reduce* smoking’, ’tobacco harm’, ’cigarette

consumption near (reduction or reduce*)’, ’controlled smoking’,

Risk Assessment [MeSH], Harm reduction [MeSH], Risk reduction

behavior [MeSH]. The date of most recent search was June

2010.

and measures of potential harm, and any measure of change in

motivation to quit.

• The definition of ’harm reduction’, and quitting.

For outcomes measured using continuous variables, for example

carbon monoxide levels, the preferred outcome was the difference

between the average change from baseline in the intervention and

control groups. We recorded the way in which missing data were

handled, and assessed the potential for bias due to loss to follow

up.

For dichotomous outcomes, we summarized results of each study

as a risk ratio (RR). Where outcomes for individuals were missing

we planned to include these individuals and assume that they had

not stopped smoking or changed behaviour in a favourable direction.

We planned to note any exceptions to this, and to consider

the sensitivity of results to different assumptions about missing

data.

We pooled data for meta-analysis, if trials used comparable interventions,

and measured similar outcomes. We did not pool interventions

using different classes of pharmacotherapy (e.g. nicotine

replacement therapy and bupropion). We considered pooling

behavioural interventions if they were of comparable intensity in

terms of the presence or absence of face-to-face contact, and number

of contacts. We did not report pooled analyses where there was

substantial (more than 50%) heterogeneity as assessed by the I²

test (Higgins 2003). In the event of heterogeneity we considered

subgroup analyses based on the characteristics of participants, in

particular the way in which they were recruited, and their level of

motivation to reduce their harm.

We regarded trials that validated self-reported reduction of smoking

using biochemical measures as a better source of evidence than

studies using self report alone. We planned to assess the sensitivity

of meta-analysis of smoking reduction outcomes to the exclusion

of studies that either did not measure exposure or did not show a

significant reduction in exposure.

Data collection and analysis

• One author screened papers identified by the search strategy

for possible relevance. In cases of uncertainty, two authors

decided upon inclusion or exclusion. One author (LS) extracted

data from included studies, and the second (TL) checked data

extraction for accuracy.

We collected the following information for each trial:

• Country and setting of intervention

• Method of participant recruitment and main inclusion

criteria in relation to motivation to change tobacco use

• Other participant characteristics including age, sex,

previous smoking habit, quit attempt history.

• Description of intervention and control conditions

• Outcomes assessed including all measures of tobacco use

reduction and quitting, and all measures of exposure to tobacco

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

The majority of studies were trials of intervention to assist people

who smoked but were not trying to quit. There were also three

studies funded by a tobacco company comparing PREPs to conventional

cigarette use by smokers paid to participate, but not

otherwise intending to change their behaviour. We include these

separately

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1. Interventions to reduce number of cigarettes

smoked

Sixteen included studies were trials of interventions intended to

assist people who smoked and were not currently trying to quit.

The aim of these interventions was to reduce cigarette consumption

as much as possible. The main outcomes in all these studies

were reduction or cessation, and all had follow up of at least six

months. The outcomes used in this review were all assessed a minimum

of one month after the end of the treatment period, in addition

to being at least six months after the start of the intervention.

Because of the way in which cessation and reduction outcomes

were defined and reported in different studies we were not able to

use identical outcomes in all studies. The most consistently used

reduction outcome was a reduction in self-reported cigarettes per

day (CPD) of more than 50% from baseline. Most studies used

sustained reduction at multiple follow ups, validated by any level

of reduction in baseline carbon monoxide (CO). Other reduction

measures reported in some studies were average reduction in

CPD, and average reduction in carbon monoxide levels, cotinine

levels and thiocyanate levels. These reductions could be expressed

as absolute or percentage reductions and were typically calculated

using available data without imputing values for drop-outs, and

included people who were no longer smoking at assessment. Some

studies reported average reductions stratified by change in CPD.

Analyses of changes in biomarker levels amongst reducers did not

always distinguish between treatment groups.

None of these studies reported long-term health status. A small

number of studies measured and reported changes in levels of cardiovascular

risk markers including white blood cell count (WBC),

high- and low-density lipoproteins and C-reactive protein. We did

not attempt meta-analysis for these outcomes. Some reports included

an assessment of change in motivation to reduce or quit.

Type of therapy

Nicotine replacement therapy

Twelve included trials provided or offered nicotine replacement

therapy (NRT). Nine of these encouraged reduction in

all participants and included a placebo control group (Australia

NNCG-017; Batra 2005; Bolliger 2000; Etter 2004; Haustein

2003; Kralikova 2009; Rennard 2006; Wennike 2003; Hanson

2008) including one (Etter 2004) which also included a control

group receiving only minimal behavioural support. One (Joseph

2008) provided repeated counselling and encouragement to use

NRT compared to a control group that received only brief advice

on the importance of quitting.

Two other studies did not have a placebo control and reduction

was encouraged as a prelude to quitting. These were borderline for

inclusion because their focus was more clearly on cutting down as

a prelude to quitting and assessing whether reduction discouraged

cessation. Carpenter 2003 was a pilot study assessing whether assistance

with cutting down increased the impact of subsequent brief

advice to quit completely. Intervention participants were given

a choice of NRT products and a target of reducing their daily

cigarette consumption by at least 50% in four weeks, after which

they were advised to quit, and given self-help materials if desired.

The control group received brief advice to quit at the initial visit,

and those who set a quit date were offered NRT but no further support.

Carpenter 2004 had three arms; a no-intervention control,

motivational interviewing intended to increase interest in quitting;

and advice to reduce with an offer of NRT. Both intervention

arms included eligibility for free NRT if a quit date was set.

Four of the studies using nicotine replacement offered a choice of

products (Carpenter 2003; Carpenter 2004; Etter 2004; Kralikova

2009) and in one of these, participants could use a combination

of types (Etter 2004). One (Joseph 2008) the use of nicotine gum

- or, if this did not suppress withdrawal - nicotine patch. Two

studies used the inhaler alone (Bolliger 2000; Rennard 2006); two

provided 2 mg or 4 mg gum dependent on baseline dependence

(Australia NNCG-017; Wennike 2003), and two used 4 mg gum

only (Batra 2005; Haustein 2003). One of the gum studies included

additional stratification to arms supporting reduction for a

maximum of either four weeks or six months use before cessation

was encouraged (Haustein 2003).

The maximum length of time for which NRT could be used while

attempting to reduce ranged from four weeks (Haustein 2003) to

18 months (Bolliger 2000).

Bupropion

One study (Hatsukami 2004a) offered bupropion or placebo for

26 weeks to people attempting to reduce their smoking, with a

target of 50% reduction in cigarettes smoked per day. Final follow

up was six months after the end of treatment. Participants who

indicated a willingness to quit at any time remained on assigned

treatment but enrolled in a seven-week cessation programme with

weekly counselling visits followed by 19 weeks of follow up.

Other types of intervention

In a large population-based study, Inter99, participants who were

unwilling to quit were advised to reduce their smoking as much

as possible, and offered enrolment in a smoking reduction group

(Pisinger 2005). Very few enrolled in this group.

A study involving community volunteers only interested in reduction

compared two guided methods to reduce the number of

cigarettes smoked. One intervention used computerised scheduled

smoking to achieve gradual reduction to 50% of baseline in two

weeks. The comparison condition provided a treatment guide instructing

in gradual reduction by selectively eliminating cigarettes

(Riley 2002).

An intervention for members of a health maintenance organization

who were due to have outpatient surgery or a diagnostic procedure

Interventions to reduce harm from continued tobacco use (Review)

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

6


provided telephone counselling and individually tailored mailings

(Glasgow 2009).

Characteristics of participants

The methods of recruitment, and the interest in reducing versus

quitting were varied. Most studies relied on advertising to attract

community volunteers. One study proactively recruited participants

by telephoning households and identifying people who

smoked (Carpenter 2004). One study used multiple approaches

including direct mail to households (Etter 2004). One small study

was in adolescents (Hanson 2008).

All studies except Kralikova 2009 excluded people currently interested

in quitting, but the assessments and cut-off points used to establish

eligibility varied. Participants had to lack current interest in

quitting, but some studies (e.g. Batra 2005; Bolliger 2000; Joseph

2008) required past failure in a serious quit attempt. This criterion

was intended to exclude people likely to quit easily without assistance.

Despite using criteria to exclude people willing to attempt

immediate quitting, the long-term motivation to stop smoking

often appeared high. For example, Wennike 2003 reported participants

as having an average motivation to quit of 6.6 on a visual

analogue scale of 0 to10. Little information was available on the

participants in two of the studies (Australia NNCG-017; Haustein

2003).

2. Tests of PREPS

Three studies evaluated different tobacco products compared to

continued use of conventional cigarettes; light and ultralight tar

cigarettes (Mendes 2008); carbon filtered cigarettes (Sarkar 2008)

and an electrically heated cigarette smoking system (EHCSS,

Roethig 2008). These had six to twelve month follow up including

regular research clinic visits for collection of samples for biochemical

assessment of levels of markers of exposure and risk. Participants

were volunteers who were paid for participation in research

studies.

3. Excluded studies

A variety of other studies were identified as potentially relevant but

did not meet our inclusion criteria because long-term change in

smoking behaviour and associated change in biomarkers of harm

were not a target of the study. Many of these were very short-term

within-subject cross over studies of smokers switching to PREPs

developed by the tobacco industry. Another short-term excluded

study used payment for reduced levels of carbon monoxide to

encourage smoking reduction (Lamb 2005). One study estimated

the amount of compensatory smoking in people switching to lower

tar cigarette brands (Frost 1995). We classified three studies as

awaiting assessment because they may be relevant to include once

full results are published.

Risk of bias in included studies

Studies typically had around 200 participants in each intervention

or control group. The smallest had a total of 93 participants (Riley

2002), and the largest 3684 (Pisinger 2005) but this included

people not interested in reducing.

Studies typically reported sustained reduction measured by a selfreported

cigarette consumption of less than 50% of baseline, validated

by reduced levels of carbon monoxide at follow-up visits.

One study in the NRT group did not report sustained abstinence

at the two year follow up, and did not use biochemical validation

because there was no personal contact with participants (Etter

2004). Since these factors could overestimate the true reduction

we tested the sensitivity of the relevant meta-analysis to exclusion

of this trial. The population based trial (Pisinger 2005) also relied

on self-reported reduction.

All the reduction studies also reported cessation. Since there was

no expectation that participants would quit at the start of the intervention,

we have not used continuous or sustained abstinence

as the primary cessation outcome, but preferred a measure of abstinence

based on behaviour towards the end of the follow-up period

(Hughes 2003). In Joseph 2008 we used the outcome of sustained

cessation at six and twelve months.

Loss to follow up was high in some trials. Although this is a problem

in cessation trials as well, study reports indicate that it was a

larger problem in this population. Outcomes derived from continuous

variables were generally reported for continuing participants

only. If drop-outs are less likely to have changed their behaviour,

these outcomes will overestimate the change in the trial population.

In using a dichotomous outcome for reduction in cigarettes

we, like the trialists, made the assumption that drop-outs had not

reduced by more than 50%, and this is likely to underestimate

the change in the population. It does not remove the potential

to introduce bias if the true change in behaviour amongst dropouts

is confounded by treatment group. The trials of PREPS had

particularly high loss to follow up, higher in groups using the unfamiliar

products.

Two of the included studies are unpublished; one was presented at

conferences (Haustein 2003) and one was identified from internal

reports provided by Pfizer (Australia NNCG-017). Two other

unpublished studies using NRT with placebo control were identified

but could not be included; one industry-funded study did

not have long-term outcome data (Spain NNCG-008), and another

presented at conferences did not have sufficient data available

(Rennard 1994).

Effects of interventions

1. Interventions to reduce number of cigarettes

smoked

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

7


Nicotine Replacement Therapy

Smoking reduction outcomes

Pooling nine trials of nicotine replacement therapy (NRT) in

adults, there was a statistically significant effect of NRT on the

likelihood of reducing cigarette use by 50% or more from baseline.

(n = 3429, risk ratio (RR) 1.72, 95% confidence interval

(CI) 1.41 to 2.10). There was moderate heterogeneity (I² = 56%).

Two studies contributed most weight to the analysis, Etter 2004

and Kralikova 2009. Etter 2004 used self-reported reduction and

many more participants claimed to have reduced than in other

studies, although the relative effect of treatment was smaller. We

used data from the two-year follow up in the analyses but also

tested the sensitivity to use of five-year follow-up data. Kralikova

2009 was not typical because participants appear to have been

more motivated to quit than to reduce, and many did so. We did

a sensitivity analysis to assess the impact of excluding these two

studies. Since they showed relatively less effect on reduction, the

effect was to increase the point estimate whilst widening the confidence

intervals and reducing heterogeneity. The effect was still

significant (n = 2581, RR 2.60, 95% CI 1.85 to 3.66, I² = 36%).

Etter 2004 also had a non-placebo control group, not included in

the analyses above. Including this group in the control condition

would tend to increase the effect. Using the five-year data for this

study did not substantially alter the result. Joseph 2008 differed

from the other studies in combining NRT and counselling, versus

a brief advice control; there was a small and non significant effect

on reduction, but excluding this study from the meta-analysis

does not materially change the effect. In two studies the control

groups did not get a placebo and were not advised to cut down. In

the first (Carpenter 2003), cessation rates were non-significantly

different (5/32 versus 3/35, RR 1.82 95% CI 0.47 to 7.02) and

non-quitters reduced their CPD compared to controls. In the second

(Carpenter 2004), reduction and quit rates were significantly

higher in the NRT and behavioural support group than in the notreatment

control, but advice to reduce before quitting had similar

effects on reduction and cessation to the motivational interviewing

intervention designed to increase interest in quitting.

We did not pool one small pilot study amongst adolescents

(Hanson 2008). There was no evidence of a treatment effect, and

although average CPD was smaller in all three conditions at six

months, average CO and cotinine levels were non significantly

higher than baseline.

Cessation outcomes

Pooling the same nine NRT trials in adults, there was a significant

effect of the NRT in increasing quit rates by the end of follow up

(n = 3429, RR 1.73; 95% CI 1.36 to 2.19) with little evidence

of heterogeneity (I² = 27%). Including the non-placebo control

group in Etter 2004 slightly reduced the estimate (n = 3818, 1.66,

95% CI 1.33 to 2.07, I² = 34%). Using the five-year data for this

study introduces heterogeneity because point prevalence quit rates

increased more in the control group. Quit rates in the placebo

groups ranged from under two per cent, to almost 11% in the

study which was least restrictive in excluding participants who

might quit (Kralikova 2009). This trial also had the highest active

therapy quit rate (18.7% for abstinence sustained at six and twelve

month follow up); the highest quit rate in any other trial was 12%

based on point prevalence at longest follow up.

Adverse events

There were no reports of serious adverse events that might have

been attributed to nicotine overdose caused by NRT use alongside

continued smoking. In one study (Haustein 2003) nausea, or

nausea and vomiting, were more common in the active (59/193)

than placebo (17/192) group. Adverse events are summarised in

Analysis 1.3.

Other outcomes

Reported changes in CPD, CO, thiocyanate and cotinine, expressed

as percentage or absolute difference from baseline values

are summarised for the studies for which data were available in

Analysis 1.3. Studies typically showed significant reductions from

baseline in both treatment and control groups, but this was usually

based on continuing participants only and included quitters.

Differences between groups where reported were not always significant.

Because of the multiple differences in the way in which

changes were calculated and reported we did not attempt any formal

meta-analysis.

Five studies (Batra 2005; Bolliger 2000; Rennard 2006; Joseph

2008; Kralikova 2009) assessed some biomarkers of disease risk.

Changes from baseline were assessed in those available for assessment

and typically showed improvements over time but not between

groups. One study (Rennard 2006) found no differences

across treatment groups in any markers of cardiovascular risk but

also reported changes in cardiovascular risk factors from baseline

to four-month follow up in individuals who had reduced by more

than 50%, including quitters. Results were not reported by treatment

group and we cannot separate the benefit of quitting from

that of reducing; there was a significant change in HDL (highdensity

lioprotein) cholesterol.

Comparison between changes in CPD and other measures of

exposure

People who reduce their number of cigarettes may inadvertently

compensate for the reduction in nicotine by smoking the remaining

cigarettes more ’efficiently’ and therefore not reduce their intake

of toxins as much as might be suggested from CPD. Using

NRT to assist reduction may also help avoid compensation, so that

toxin levels are reduced more for a similar level of CPD reduction.

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

8


We found relatively little data about either compensation generally

amongst reducers, or differential levels of compensation for

NRT and placebo users. Bolliger 2000 reported that at 24 months

sustained reducers had an average CPD of 25% of baseline whilst

CO and cotinine levels were only about 50% of baseline. The

same study presented data on cigarette and CO reduction in the

subgroup of intervention and placebo participants who were still

using inhalers daily at various points during the treatment phase.

After 18 months the 22 active inhaler users had an average reduction

in CPD to 36% of baseline with a range of 0-100%. CO levels

were only reduced to an average of 71% of baseline with a range of

8% to 222% (i.e. range included an increase from baseline). The

eight placebo users had significantly smaller (P = 0.02) percentage

reduction in CPD than the active inhaler users (67%, range 20%

- 100%) and a non-significantly smaller percentage reduction in

CO (82%, range 50% - 177%). Batra 2005 reported the proportion

of participants with a sustained reduction in CO levels of

over 20% from baseline at 13-month follow up. The proportions

achieving this (13.6% active versus 5.6% placebo) were higher in

both conditions than the proportion reporting sustained reduction

greater than 50% in CPD, suggesting that all the reducers

had achieved at least a 20% reduction in CO.

Attitudes to future quitting

Attitudes about future quitting were assessed using a variety of

questions. Main results are summarised by study in Analysis 1.3.

Whilst in general an attempt to reduce did not appear to undermine

interest in quitting, one study reported a fall in interest in

quitting amongst unsuccessful reducers (Wennike 2003) and one

a fall in interest in successful reducers (Kralikova 2009).

Bupropion

Reduction & cessation outcomes

The single study using bupropion did not detect any long-term

effect on either reduction or cessation (Hatsukami 2004a). Participants

who became willing to make a quit attempt entered a cessation

programme; their long-term cessation rates were not significantly

different between bupropion and placebo groups, although

those in the bupropion group made their quit attempts sooner

and had better short-term quit rates. Smoking reduction in participants

who never attempted to quit, as defined by a > 50% reduction

in urine cotinine, was greater during the treatment phase

but did not differ significantly at 12-month follow up (OR 0.42,

95% CI 0.11 to 1.59). Reduction in cotinine >50%: 2% (3/153)

bupropion versus 5% (8/174) placebo, not significant (P = 0.17),

excludes participants who entered cessation arm of study.

Other interventions

In a population-based study (Pisinger 2005) participants receiving

a lifestyle consultation and motivational interviewing who had

been advised to cut down if they were unwilling or not ready to

quit were more likely to have cut their consumption by 50% or

more than untreated controls. Very few people who were offered a

smoking reduction group attended one. There was no validation

in this study, and it was not restricted to people not wanting to

quit, so the results are difficult to interpret. Successful reduction

was associated with an increased motivation to quit.

In a study comparing computerised scheduled reduction to reduction

by selective elimination of cigarettes (Riley 2002), both

groups achieved significant reductions in cigarettes and CO from

baseline but there was no difference between the groups. Point

prevalence quit rates were higher at 12-month follow up than at

the end of treatment in both groups, suggesting no deterrent effect

on quitting. At 12 months quit rates were non-significantly

higher in the computer scheduled group than the selective reduction

group.

An intervention of repeated telephone counselling and mailings

was not shown to assist reduction after 12 months in one study

(Glasgow 2009). No indicators of reduction were significantly

higher in the intervention than control group at 12 months (25%

vs 18.6% for ≥50% CPD reduction, 11% vs 7% for abstinence).

The proportions reducing CO by >50% were similar across groups

at 12 months (14.0% vs 14.1%), as were average CO levels.

2. Tests of Potentially Reduced Exposure Products

(PREPS)

We summarise the main findings of these three studies narratively.

All reported data on multiple biomarkers at multiple follow-up

points. Difficulties in interpreting the results include the large inter-individual

variation, and the loss to follow up of participants

who did not maintain use of test products. Some measures showed

marked changes from baseline (in a residential research clinic) to

end of follow up; for example CPD typically increased in both

experimental and control groups. Switching from full strength (F)

to low (L) or very low (UL) tar cigarettes (Mendes 2008) led to

significantly lower average nicotine levels in UL than F groups.

CPD increased in all groups possibly because cigarettes were provided

free. Carboxyhemaglobin (COHb) levels were similar between

F and UL groups but higher in L groups. Overall although

some exposures were reduced in these heavy smokers who switched

to lower tar alternatives the absolute differences were not large

even when statistically significant. Use of carbon-filtered low and

medium tar cigarettes led to reduced levels of gas phase biomarkers

but had no impact on particulate phase biomarkers (Sarkar

2008). Using an EHCSS did reduce exposure to tobacco smoke

constituents especially carboxyhaemoglobin. Nicotine levels were

reduced, which combined with the higher drop-out in the EHCSS

suggests that the device may not have been very acceptable to

Interventions to reduce harm from continued tobacco use (Review)

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

9


smokers (Roethig 2008). In this study markers or cardiovascular

risk factors including white blood cell counts and levels of HDL

and LDL (low-density lipoprotein) cholesterol did show significant

change in favourable directions compared to conventional

cigarette use.

D I S C U S S I O N

The studies included in the review mainly assess ways to help

people who smoke to reduce the harm caused by their smoking via

a reduction in the number of cigarettes, either by using behavioural

methods to encourage change, or by using pharmaceutical nicotine

products or other pharmacotherapy. We also found three studies

of switching tobacco products with six months or more follow up.

Results suggest that people who use nicotine replacement therapy

(NRT) are more likely to be able to reduce their cigarette consumption

than people attempting to reduce with placebo or without

NRT. All the trials included a follow-up period when NRT

was no longer provided. One trial had follow up 20 months after

the end of NRT provision. There was no evidence that using NRT

to assist reduction diverted people from attempting to quit since

cessation rates were also higher, not lower, in NRT-treated groups.

Whilst the trial evidence supports the concept of using NRT to

reduce the amount smoked, showing a significant effect and an

effect size that would be clinically important in many treatments,

the absolute benefit from this use of NRT seems to be small. NRT

increased the number of long-term sustained reducers, but against

a background of very little reduction amongst the control group.

Treatment typically increased the proportion of successful reducers

from 1 - 3% to 6 - 9%, and the benefit even for these people

is unclear. In a study amongst patients with heart disease (Joseph

2008) there was no evidence of an effect on clinical or biomarker

outcomes even amongst the subgroup achieving a 50% or greater

reduction in cigarettes smoked. Given the uncertainty about the

size of health benefit achieved from smoking reduction (Hughes

2006; Tverdal 2006), the overall public health benefit is also uncertain.

Many of the trials used in this review which were designed

as investigations of harm reduction are being used as the evidence

base to support the expansion in the licensed use of nicotine gum

and nicotine inhaler for use to support gradual cessation (’Reduce

to quit’ or ’Cut down then stop’ indications) (Wang 2008; Moore

2009). Whilst this review is not intended to address the use of

interventions for short-term reduction, the evidence summarised

here supports the use of NRT for reducing cigarette consumption

over a limited period before stopping completely.

Some of these studies allow a comparison between change in

cigarettes per day (CPD) and changes in other measure of exposure

to tobacco smoke. These studies confirm that the amount of

reduction assessed by number of cigarettes smoked is greater than

the amount of reduction in other measures of exposure to tobacco

smoke. The different ways in which the data are reported makes

it difficult to quantify differences but average percentage reductions

are consistently smaller for biomarkers of exposure including

carbon monoxide (CO) and cotinine than they are for CPD

(Batra 2005; Rennard 2006; Wennike 2003; Glasgow 2009). Another

review has estimated that the reduction in CO is typically

about a third less than the reduction in CPD (Hughes 2005). The

main study results do not directly address whether use of a specific

therapy alters the amount of compensatory smoking when number

of cigarettes is reduced. Hatsukami 2004a noted that amongst

participants who did not attempt to quit, cigarettes smoked per

day decreased by a similar amount in the bupropion and control

groups, but the mean decrease in urine cotinine was greater

in the active treatment group, suggesting that active therapy did

affect the amount of nicotine that people tried to obtain from

the reduced number of cigarettes. This was not maintained over

the follow-up period when cotinine levels increased amongst the

bupropion group. Cotinine measurements could not be compared

in the trials using nicotine replacement, because using the NRT

would increase cotinine. The same research group demonstrated

that the toxicant exposure of successful reducers remained higher

than the exposure of persistent light smokers matched by number

of cigarettes smoked (Hatsukami 2006). One small study in

adolescents cautioned that reduction should not be an end goal

of intervention in this age group, and that adolescents attempting

to reduce might have learnt to smoke more efficiently and hence

increased their exposure to toxicants (Hanson 2008).

Hughes and Carpenter (Hughes 2006) have reviewed the evidence

on whether reduced smoking decreases the health risks of smoking.

They concluded that none were adequate tests of reduced

smoking. None were specifically designed to examine reduction

and they did not adequately measure the timing and duration of

reduction or verify reduction biochemically. Most studies were

small, and effects were unclear. In an analysis of participants in

the Lung Health Study who reduced but never quit, those who

reduced to very low amounts had smaller declines in forced expiratory

volume but there was very little effect of reduction on

respiratory symptoms (Simmons 2005). More recently, studies of

a large Danish cohort have not found health effects of reduction

greater than 50% (Tverdal 2006). A large cohort study of Korean

smokers did suggest that reduction reduced the risk of lung cancer,

although the proportional risk reduction was smaller than the

reduction in number of cigarettes smoked (Song 2008). Harm reduction

that encourage individual smokers who cannot or will not

forego nicotine use to switch to nicotine delivery products other

than cigarettes appear more likely to reduce morbidity amongst

current smokers (Sweanor 2007).

One potential concern about the use of NRT whilst still smoking

is the potential for increased nicotine intake. Studies suggest that

the use of acute delivery nicotine products alongside smoking does

Interventions to reduce harm from continued tobacco use (Review)

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

10


not increase average nicotine levels, although people who smoke

whilst using the nicotine patch do not titrate their total intake

to the same degree and have increased nicotine levels (Fagerstrom

2002a). Even in studies where nicotine concentrations increased

there were no serious adverse events. In addition, nicotine via

medications does not appear to contribute substantially to any of

the health risks of smoking (Balfour 2002).

One group of studies was designed to measure changes in one

or more biomarkers of potential harm in people switching from

their usual brand of cigarette to a Potentially Reduced-Exposure

Tobacco Product (PREP). The included studies covered low tar

cigarettes, carbon-filter cigarettes, and a cigarette-like device that

heats tobacco rather than burning. Other PREPs might include

modified smoked tobacco products that might have lower concentrations

of some toxins, and smokeless oral tobacco products. A

variety of other studies were identified as potentially relevant but

did not meet our inclusion criteria because long-term change in

smoking behaviour and associated change in biomarkers of harm

were not targets. It may be argued that shorter-term studies might

also give useful data, and that if extended beyond the setting of

a clinical research centre, a three month follow up, for example,

might be adequate. However the majority of the studies we excluded

used a within-subject design comparing participants before

and after switching, and were much shorter term. An earlier

detailed review of these types of studies concluded that ’there

is no evidence to suggest that there is enough of a reduction in

tobacco toxin exposure with any of the existing PREPs to expect

a significant reduction in disease risk, nor do we know the

extent of toxin exposure reduction that is necessary to result in

reduction of disease’ (UMN TTURC 2005). Of particular note

is that studies found that some participants using some types of

PREPs had higher levels of CO than they had when smoking as

normal (e.g. Fagerstrom 2000; Fagerstrom 2002b; Rennard 2002;

Strasser 2007). Any possible reduction in exposure to a tobacco

constituent linked to long-term harm would have to be weighed

against risk from increased intake of a substance know to cause

short-term harm. There is a risk that products will be marketed

in such a way that smokers, ex-smokers and nonsmokers believe

that they do substantially reduce harmful effects (Hamilton 2004;

Shiffman 2007; Strasser 2008). However, because it is the burning

of tobacco that produces most of the toxic compounds in cigarette

smoke, there is no doubt that any type of smokeless tobacco use

is less harmful than smoking (Bates 2003) even though there remains

some carcinogen exposure (Hecht 2007) and there is debate

about exact levels of harm (Lee 2009). There are opponents to

an approach that promotes smokeless tobacco use (Tomar 2009),

and the issues surrounding the potential risks and benefits from

smokeless tobacco products continue to be debated, and future research

directions proposed (Levy 2006; Hatsukami 2007; Britton

2008; Melikian 2009; Phillips 2009).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

• Some people who smoke and do not wish to quit can be

helped to cut down the number of cigarettes smoked and their

intake of carbon monoxide by using nicotine gum or nicotine

inhaler.

• There is not enough evidence on whether Potentially

Reduced-Exposure Tobacco Products (PREPs) reduce harm.

• There is insufficient evidence of a long-term benefit of

either cigarette reduction or PREPs to give firm support to the

use of interventions intended to help people reduce or alter but

not quit tobacco use. However, attempted reduction can also

increase cessation.

• Since a high proportion of the toxins known to be harmful

are generated by the burning of tobacco, avoiding smoked

tobacco products would be more likely to reduce harm than

reducing use of smoked products

Implications for research

Studies need to identify biomarkers that are sensitive to short-term

changes in smoking behaviour and are also predictive of long-term

harm.

A C K N O W L E D G E M E N T S

Our thanks to Tobias Danielsson for providing data from unpublished

Pfizer studies and to Eva Kralikova and JF Etter for providing

additional details about their studies, and to John Hughes and

Marita Broadstock for helpful suggestions during peer review.

Interventions to reduce harm from continued tobacco use (Review)

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

11


R E F E R E N C E S

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∗ Joseph AM, Hecht SS, Murphy SE, Lando H, Carmella

SG, Gross M, et al.Smoking reduction fails to improve

clinical and biological markers of cardiac disease: a

Interventions to reduce harm from continued tobacco use (Review)

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

12


andomized controlled trial. Nicotine & Tobacco Research

2008;10:471–81.

Kralikova 2009 {published data only (unpublished sought but not

used)}

Kralikova E, Kozak J, Rasmussen T, Cort N. The clinical

benefits of NRT-supported smoking reduction. Nicotine &

Tobacco Research 2002;4(2):243.

∗ Kralikova E, Kozak JT, Rasmussen T, Gustavsson G, Le

Houezec J. Smoking cessation or reduction with nicotine

replacement therapy: a placebo-controlled double blind

trial with nicotine gum and inhaler. BMC Public Health

2009;9:433. [DOI: 10.1186/1471-2458/9/433]

Mendes 2008 {published data only}

Mendes P, Kapur S, Wang J, Feng S, Roethig H. A

randomized, controlled exposure study in adult smokers of

full flavor Marlboro cigarettes switching to Marlboro Lights

or Marlboro Ultra Lights cigarettes. Regulatory Toxicology &

Pharmacology 2008;51(3):295–305.

Pisinger 2005 {published data only}

∗ Pisinger C, Vestbo J, Borch-Johnsen K, Jorgensen T.

Smoking reduction intervention in a large population-based

study. The Inter99 study. Preventive Medicine 2005;40:

112–8.

Rennard 2006 {published and unpublished data}

Rennard SI, Glover E, Leischow S, Daughton DM, Glover

P, Muramoto M. Efficacy of nicotine inhaler in smoking

reduction. Nicotine & Tobacco Research 2002;4(3):380.

∗ Rennard SI, Glover ED, Leischow S, Daughton DM,

Glover PN, Muramoto M, et al.Efficacy of the nicotine

inhaler in smoking reduction: A double-blind, randomized

trial. Nicotine & Tobacco Research 2006;8:555–64.

Riley 2002 {published data only}

Riley W, Jerome A, Behar A, Weil J. Computer and manual

self-help behavioral strategies for smoking reduction: Initial

feasibility and one-year follow-up. Nicotine & Tobacco

Research 2002;4(Suppl 2):S183–S188.

Roethig 2008 {published data only}

∗ Roethig HJ, Feng S, Liang Q, Liu J, Rees WA, Zedler

BK. A 12-month, randomized, controlled study to evaluate

exposure and cardiovascular risk factors in adult smokers

switching from conventional cigarettes to a secondgeneration

electrically heated cigarette smoking system.

Journal of Clinical Pharmacology 2008;48(5):580–91.

Roethig HJ, Kinser RD, Lau RW, Walk RA, Wang N.

Short-term exposure evaluation of adult smokers switching

from conventional to first-generation electrically heated

cigarettes during controlled smoking. Journal of Clinical

Pharmacology 2005;45(2):133–45.

Roethig HJ, Zedler BK, Kinser RD, Feng S, Nelson BL,

Liang Q. Short-term clinical exposure evaluation of a

second-generation electrically heated cigarette smoking

system. Journal of Clinical Pharmacology 2007;47(4):

518–30.

Sarkar 2008 {published data only}

Sarkar M, Kapur S, Frost-Pineda K, Feng S, Wang J, Liang

Q, et al.Evaluation of biomarkers of exposure to selected

cigarette smoke constituents in adult smokers switched

to carbon-filtered cigarettes in short-term and long-term

clinical studies. Nicotine & Tobacco Research 2008;10(12):

1761–72.

Wennike 2003 {published data only}

Wennike P, Danielsson T, Landfeldt B, Westin A, Tonnesen

P. Smoking reduction promotes smoking cessation: results

from a double blind, randomized, placebo-controlled trial

of nicotine gum with 2-year follow-up. Addiction 2003;98

(10):1395–402.

References to studies excluded from this review

Applegate 2004 {published data only}

Applegate BW, Riley WT, Sowell A. A comparison of

computer-assisted scheduled gradual reduction vs. self help

in unmotivated smokers (POS1-028). Society for Research

on Nicotine and Tobacco 10th Annual Meeting February

18-21, Phoenix, Arizona. 2004.

Baker 2006 {published data only}

Baker A, Richmond R, Haile M, Lewin TJ, Carr VJ,

Taylor RL, et al.A randomized controlled trial of a smoking

cessation intervention among people with a psychotic

disorder. American Journal of Psychiatry 2006;163:1934–42.

Lan TH, Chiu HJ, Wu BJ, Hung TH, Hu TM. Readiness

to quit and smoking reduction outcomes. American Journal

of Psychiatry 2007;164:827–8.

Benowitz 2005 {published data only}

Benowitz NL, Jacob P, Bernert JT, Wilson M, Wang

LG, Allen F, et al.Carcinogen exposure during shortterm

switching from regular to “Light” cigarettes. Cancer

Epidemiology Biomarkers & Prevention 2005;14:1376–83.

Borland 1999 {published data only}

Borland R, Owen N, Tooley G, Treijs I, Roberts L, Hill

D. Promoting reduced smoking rates in the context of

workplace smoking bans. American Journal of Health

Promotion 1999;14:1–3.

Breland 2006 {published data only}

Breland AB, Kleykamp BA, Eissenberg T. Clinical laboratory

evaluation of potential reduced exposure products for

smokers. Nicotine & Tobacco Research 2006;8:727–38.

Caldwell 2010 {published data only}

Caldwell B, Burgess C, Crane J. Randomized crossover trial

of the acceptability of snus, nicotine gum, and Zonnic

therapy for smoking reduction in heavy smokers. Nicotine

& Tobacco Research 2010;12(2):179–83.

Cunningham 2006 {published data only}

Cunningham JA, Faulkner G, Selby P, Cordingley

J. Motivating smoking reductions by framing health

information as safer smoking tips. Addictive Behaviors 2006;

31:1465–8.

Eliasson 2001 {published data only}

Eliasson B, Hjalmarson A, Kruse E, Landfeldt B, Westin A.

Effect of smoking reduction and cessation on cardiovascular

risk factors. Nicotine & Tobacco Research 2001;3:249–55.

Interventions to reduce harm from continued tobacco use (Review)

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

13


Etter 2003 {published data only}

Etter JF, Le Houezec J, Landfeldt B. Impact of messages

on concomitant use of nicotine replacement therapy and

cigarettes: a randomized trial on the Internet. Addiction

2003;98(7):941–950.

Fagerstrom 1997 {published data only}

Fagerstrom KO, Tejding R, Westin A, Lunell E.

Aiding reduction of smoking with nicotine replacement

medications: hope for the recalcitrant smoker?. Tobacco

Control 1997;6(4):311–6.

Fagerstrom 2000 {published data only}

Fagerstrom KO, Hughes JR, Rasmussen T, Callas PW.

Randomised trial investigating effect of a novel nicotine

delivery device (Eclipse) and a nicotine oral inhaler

on smoking behaviour, nicotine and carbon monoxide

exposure, and motivation to quit. Tobacco Control 2000;9:

327–33.

Fagerstrom 2002b {published data only}

Fagerstrom KO, Hughes JR, Callas PW. Long-term effects

of the Eclipse cigarette substitute and the nicotine inhaler

in smokers not interested in quitting. Nicotine & Tobacco

Research 2002;4 Suppl 2:S141–S145.

Fatemi 2005 {published data only}

Fatemi SH, Stary JM, Hatsukami DK, Murphy SE.

A double-blind placebo-controlled cross over trial of

bupropion in smoking reduction in schizophrenia.

Schizophrenia Research 2005;76:353–6.

Feng 2006 {published data only}

Feng S, Roethig HJ, Liang Q, Kinser R, Jin Y, Scherer

G, et al.Evaluation of urinary 1-hydroxypyrene, S-

phenylmercapturic acid, trans,trans-muconic acid,

3-methyladenine, 3-ethyladenine, 8-hydroxy-2’-

deoxyguanosine and thioethers as biomarkers of exposure to

cigarette smoke. Biomarkers 2006;11(1):28–52.

Frost 1995 {published data only}

Frost C, Fullerton FM, Stephen AM, Stone R, Nicolaides-

Bouman A, Densem J, et al.The tar reduction study:

randomised trial of the effect of cigarette tar yield reduction

on compensatory smoking. Thorax 1995;50(10):1038–43.

Glasgow 1983 {published data only}

∗ Glasgow RE, Klesges R, Godding P, et al.Controlled

smoking with or without carbon monoxide feedback, as an

alternative for chronic smokers. Behavior Therapy 1983;14:

386–97.

Glasgow RE, Klesges RC, Vasey MW. Controlled smoking

for chronic smokers: an extension and replication. Addictive

Behaviors 1983;8:143–50.

Gray 2008 {published data only}

Gray JN, Breland AB, Weaver M, Eissenberg T. Potential

reduced exposure products (PREPs) for smokeless tobacco

users: clinical evaluation methodology. Nicotine & Tobacco

Research 2008;9:1441–8.

Hatsukami 2004b {published data only}

Hatsukami DK, Lemmonds C, Zhang Y, Murphy SE, Le

C, Carmella SG, et al.Evaluation of carcinogen exposure

in people who used “reduced exposure” tobacco products.

Journal of the National Cancer Institute 2004;96:844–52.

Hatsukami 2005 {published data only}

∗ Hatsukami DK, Kotlyar M, Allen S, Jensen J, Li S, Le C,

et al.Effects of cigarette reduction on cardiovascular risk

factors and subjective measures. Chest 2005;128:2528–37.

Hecht SS, Carmella SG, Le KA, Murphy SE, Li YS, Le C,

et al.Effects of reduced cigarette smoking on levels of 1-

hydroxypyrene in urine. Cancer Epidemiology, Biomarkers

and Prevention 2004;13(5):834–42.

Hecht SS, Murphy SE, Carmella SG, Zimmerman

CL, Losey L, Kramarczuk I, et al.Effects of reduced

cigarette smoking on the uptake of a tobacco-specific lung

carcinogen. Journal of the National Cancer Institute 2004;96

(2):107–15.

Kotlyar M, Jensen J, Li S, Hatsukami DK. Effect of smoking

reduction on cardiovascular biomarkers and subjective

measures. Nicotine & Tobacco Research 2004;6(4):719.

Murphy SE, Link CA, Jensen J, Le C, Puumala SS, Hecht

SS, et al.A comparison of urinary biomarkers of tobacco

and carcinogen exposure in smokers. Cancer Epidemiology

Bimarkets & Prevention 2004;13:1617–23.

Hatsukami 2007a {published data only}

Hatsukami DK, Ebbert JO, Anderson A, Lin H, Le C,

Hecht SS. Smokeless tobacco brand switching: a means

to reduce toxicant exposure?. Drug & Alcohol Dependence

2007;87(2-3):217–24.

Hatsukami 2008 {published data only}

Hatsukami DK, Ebbert JO, Edmonds A, Li C, Lin H, Le

C, et al.Smokeless tobacco reduction: preliminary study

of tobacco-free snuff versus no snuff. Nicotine & Tobacco

Research 2008;10:77–85.

Hatsukami 2010 {published data only}

Hatsukami DK, Kotlyar M, Hertsgaard LA, Zhang Y,

Carmella SG, Jensen JA, et al.Reduced nicotine content

cigarettes: effects on toxicant exposure, dependence and

cessation. Addiction 2010;105:343–55.

Hughes 2004b {published data only}

∗ Hughes JR, Hecht SS, Carmella SG, Murphy SE, Callas P.

Smoking behaviour and toxin exposure during six weeks use

of a potential reduced exposure product: Omni. Tobacco

Control 2004;13:175–9.

Hurt 2000 {published data only}

Hurt RD, Croghan GA, Wolter TD, Croghan IT, Offord

KP, Williams GM, et al.Does smoking reduction result in

reduction of biomarkers associated with harm ? A pilot

study using a nicotine inhaler. Nicotine & Tobacco Research

2000;2(4):327–36.

Jimenez-Ruiz 2002 {published data only}

Jimenez-Ruiz C, Solano S, Viteri SA, Ferrero MB, Torrecilla

M, Mezquita MH. Harm reduction - A treatment approach

for resistant smokers with tobacco-related symptoms.

Respiration 2002;69(5):452–5.

Kotlyar 2007 {published data only}

Kotlyar M, Mendoza-Baumgart MI, Li ZZ, Pentel PR,

Barnett BC, Feuer RM, et al.Nicotine pharmacokinetics

Interventions to reduce harm from continued tobacco use (Review)

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

14


and subjective effects of three potential reduced exposure

products, moist snuff and nicotine lozenge. Tobacco Control

2007;16(2):138–42.

Lamb 2005 {published data only}

Lamb RJ, Morral AR, Galbicka G, Kirby KC, Iguchi MY.

Shaping reduced smoking in smokers without cessation

plans. Experimental and Clinical Psychopharmacology 2005;

13(2):83–92.

Lichtenstein 2008 {published data only}

Lichtenstein E, Boles SM, Lee ME, Hampson SE, Glasgow

RE, Fellows J. Using radon risk to motivate smoking

reduction II: randomized evaluation of brief telephone

counseling and a targeted video. Health Education Research

2008;23(2):191–201.

Malchodi 2003 {published data only}

Malchodi CS, Oncken C, Dornelas EA, Caramanica L,

Gregonis E, Curry SL. The effects of peer counseling on

smoking cessation and reduction. Obstetrics and Gynecology

2003;101(3):504–10.

Mendoza-Baumgart 2007 {published data only}

Mendoza-Baumgart MI, Tulunay OE, Hecht SS, Zhang Y,

Murphy S, Le C, et al.Pilot study on lower nitrosamine

smokeless tobacco products compared with medicinal

nicotine. Nicotine & Tobacco Research 2007;9(12):1309–23.

PM Elec Cig {published data only}

Frost-Pineda K, Zedler BK, Liang Q, Roethig HJ.

Environmental tobacco smoke (ETS) evaluation of a thirdgeneration

electrically heated cigarette smoking system

(EHCSS). Regulatory Toxicology and Pharmacology 2008;52

(2):118–21.

Frost-Pineda K, Zedler BK, Oliveri D, Feng S, Liang Q,

Roethig HJ. Short-term clinical exposure evaluation of

a third-generation electrically heated cigarette smoking

system (EHCSS) in adult smokers. Regulatory Toxicology

and Pharmacology 2008;52(2):104–10.

Frost-Pineda K, Zedler BK, Oliveri D, Liang Q, Feng

S, Roethig HJ. 12-Week clinical exposure evaluation of

a third-generation electrically heated cigarette smoking

system (EHCSS) in adult smokers. Regulatory Toxicology

and Pharmacology 2008;52(2):111–7.

Munjal S, Koval T, Muhammad R, Jin Y, Demmel V,

Roethig HJ, et al.Heart rate variability increases with

reductions in cigarette smoke exposure after 3 days. Journal

of Cardiovascular Pharmacology & Therapeutics 2009;14(3):

192–8.

Unverdorben M, der BA, Potgieter L, Liang Q, Meyer BH,

Roethig HJ. Effects of levels of cigarette smoke exposure on

symptom-limited spiroergometry. Preventive Cardiology

2007;10(2):83–91.

Rennard 1990 {published data only}

Rennard SI, Daughton D, Fujita J, Oehlerking MB,

Dobson JR, Stahl MG, et al.Short-term smoking reduction

is associated with reduction in measures of lower respiratory

tract inflammation in heavy smokers. European Respiratory

Journal 1990;3:752–9.

Rennard 1994 {published and unpublished data}

Rennard SI, Daughton D, Buchalter S, Floreani AA, Larson

L, Millatmal T, et al.The influence of cigarette reduction

or switching to lower nicotine yield cigarettes on measures

of airway inflammation. American Review of Respiratory

Disease 1994;149:A395.

Rennard 2002 {published data only}

Rennard SI, Umino T, Millatmal T, Daughton DM,

Manouilova LS, Ullrich FA, et al.Evaluation of subclinical

respiratory tract inflammation in heavy smokers who switch

to a cigarette-like nicotine delivery device that primarily

heats tobacco. Nicotine & Tobacco Research 2002;4(4):

467–76.

Riggs 2001 {published data only}

Riggs RL, Hughes JR, Pillitteri JL. Two behavioral

treatments for smoking reduction: a pilot study. Nicotine &

Tobacco Research 2001;3(1):71–6.

Robinson 1984 {published data only}

Robinson JC, Young JC, Rickert WS. Maintain levels of

nicotine but reduce other smoke constituents: A formula

for ’less-hazardous’ cigarettes?. Preventive Medicine 1984;13

(5):437–45.

Sarkar 2010 {published data only}

Sarkar M, Liu J, Koval T, Wang J, Feng S, Serafin R, et

al.Evaluation of biomarkers of exposure in adult cigarette

smokers using Marlboro snus. Nicotine & Tobacco Research

2010;12(2):105–16.

Scherer 2006 {published data only}

Scherer G, Urban M, Engl J, Hagedorn HW, Riedel K.

Influence of smoking charcoal filter tipped cigarettes on

various biomarkers of exposure. Inhalation Toxicology 2006;

18(10):821–9.

Shiffman 2009 {published data only}

Shiffman S, Ferguson SG, Strahs KR. Quitting by gradual

smoking reduction using nicotine gum: a randomized

controlled trial. American Journal of Preventive Medicine

2009;36(2):96–104.

Spain NNCG-008 {published data only}

Pfizer Inc. Summary of Clinical Efficacy. Application for

licensing of Nicorette Inhalator/Gum for smoking reduction

leading to cessation. Company data NICORE-1013-273-

SU.

Stein 2002 {published data only}

Stein JH, Bushara M, Bushara K, McBride PE, Jorenby DE,

Fiore MC. Smoking cessation, but not smoking reduction,

reduces plasma homocysteine levels. Clinical Cardiology

2002;25(1):23–6.

Strasser 2007 {published data only}

Strasser AA, Lerman C, Sanborn PM, Pickworth WB,

Feldman EA. New lower nicotine cigarettes can produce

compensatory smoking and increased carbon monoxide

exposure. Drug & Alcohol Dependence 2007;86(2-3):

294–300.

Sun 2009 {published data only}

Sun HQ, Guo S, Chen DF, Jiang ZN, Liu Y, Di XL, et

al.Family support and employment as predictors of smoking

Interventions to reduce harm from continued tobacco use (Review)

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15


cessation success: a randomized, double-blind, placebocontrolled

trial of nicotine sublingual tablets in Chinese

smokers. American Journal of Drug & Alcohol Abuse 2009;

35:183–8.

Tonnesen 2005 {published data only}

Tønnesen P, Pisinger C, Hvidberg S, Wennike P, Bremann

L, Westin A, et al.Effects of smoking cessation and reduction

in asthmatics. Nicotine & Tobacco Research 2005;7(1):

139–48.

Windsor 1999 {published data only}

Windsor RA, Li CQ, Boyd NR, Hartmann KE. The use

of significant reduction rates to evaluate health education

methods for pregnant smokers: A new harm reduction

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26(5):648–62.

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Strasser AA, Tang KZ, Tuller MD, Cappella JN. PREP

advertisement features affect smokers’ beliefs regarding

potential harm. Tobacco Control 2008;17(Suppl. 1):I32–8.

Stratton 2001

Stratton K, Shetty P, Wallace R, Bondurant S [Editors].

Clearing the Smoke: Assessing the science base for harm

reduction. Washington, DC: Institute of Medicine, National

Academies Press, 2001.

Sweanor 2007

Sweanor D, Alcabes P, Drucker E. Tobacco harm reduction:

How rational public policy could transform a pandemic.

International Journal of Drug Policy 2007;18:70–4.

Tomar 2009

Tomar SL, Fox BJ, Severson HH. Is smokeless tobacco use

an appropriate public health strategy for reducing societal

harm from cigarette smoking?. International Journal of

Environmental Research & Public Health 2009;6:10–24.

Tverdal 2006

Tverdal A, .Bjartveit K. Health consequences of reduced

daily cigarette consumption. Tobacco Control 2006;15:

472–80.

UMN TTURC 2005

University of Minnesota Cancer Centre Transdisciplinary

Tobacco Use Research Group. Hope or Hazard? What

research tells us about “potentially reduced-exposure”

tobacco products. www.tturc.umn.edu/documents/hope_

or_hazard-3.pdf accessed 12th January 2007. University of

Minnesota, 2005.

Wang 2008

Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P,

Moore D. ’Cut down to quit’ with nicotine replacement

therapies in smoking cessation: a systematic review of

effectiveness and economic analysis. Health Technology

Assessment (Winchester, England) 2008;12(2):1–135.

Warner 2002

Warner KE. Tobacco harm reduction: promise and perils.

Nicotine & Tobacco Research 2002;4(Suppl 2):S61–S71.

West 2006

West R. Background smoking cessation rates in England.

www.smokinginengland.info/Ref/paper2.pdf (accessed 16th

May 2007) 2006.

∗ Indicates the major publication for the study

Interventions to reduce harm from continued tobacco use (Review)

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

18


C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Australia NNCG-017

Methods

Participants

Interventions

Outcomes

Notes

Country: Australia

Recruitment: community volunteers

Randomization: method not stated

436 smokers (>=15 CPD) not intending to quit

Av.age 44, av.CPD 28, CO 26

1. Nicotine gum, 2mg or 4mg according to dependence score, for 4m

2. Placebo

Reduction in CPD: sustained >50% at 12m

Abstinence: PP at 12m

Validation: Reduction by reduced CO from baseline

Unpublished study. Data from Pfizer summary

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear Unclear

Batra 2005

Methods

Participants

Interventions

Outcomes

Country: Germany & Switzerland

Recruitment: community volunteers

Randomization: method not stated

364 smokers (>=20 CPD) not intending to quit, at least 1 failed quit attempt within 2 yrs but not within

6m

41% F, av age 43, av.CPD 28

1. Nicotine gum, 4mg for up to 12m, 6-24 pieces daily

2. Placebo gum

Aim to reduce as much as possible, 50% not given as objective. Counselling on reduction provided at 9

clinic visits

Reduction in CPD: sustained >50%at 13m

Reduction in CO: Sustained >20% at 13m

% CO reduction from baseline at 13m (For 55 intervention, 39 control participants including quitters

who completed all visits)

Also % reduction in CPD, cotinine, thiocyanate.

Abstinence: PP at 13m

Validation: CO at all visits

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19


Batra 2005

(Continued)

Notes

Sustained quitters (2 intervention, 0 control) included with reducers

Attrition: 138 (75%) gum vs 111 (62%) placebo reached at 13m

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear Unclear

Bolliger 2000

Methods

Participants

Interventions

Outcomes

Notes

Country: Switzerland (2 hospital pulmonary clinics)

Recruitment: community volunteers

Randomization: computer-generated central list

400 smokers, (>15 CPD for 3+ yrs), failed at least 1 serious quit attempt in past 12m, wanting to reduce

smoking as much as possible.

52.5% F, av age 46, av.CPD 29, CO 27ppm

1. Nicotine inhalator, 6-12 cartridges over 24hrs. Encouraged to decrease after 4m but use permitted up

to 18m

2. Placebo inhalator (contained menthol only)

Counselling on smoking reduction provided at each clinic visit (1, 2, 3, 6wks , and 3, 4, 6, 12, 18, 24m)

. Smoking cessation was recommended as ultimate goal throughout study

Reduction in CPD: >50%, sustained from week 5 at 24m

Abstinence: sustained from wk 6 at 24m, PP cessation at 24m

(Paper reports outcomes after 4m and 12m, also PP rates)

Validation: Reduction validated by reduced CO from baseline (at 6wks, 3m, 4m), but amount of reduction

not specified, abstinence verified by CO


Carpenter 2003

Methods

Participants

Interventions

Outcomes

Notes

Country: USA

Recruitment: community volunteers

Randomization: method not stated

67 smokers, (>10 CPD) with an interest in quitting eventually but not in next 30 days. At least 1 previous

attempt

1. Behavioural support to reduce by > 50% in 4 wks. NRT (gum or patch or inhaler) described and

offered. At 4wks given brief advice to quit based on US guideline; weekly visits.

2. Brief advice to quit at initial visit, NRT provided only if quit date set; weekly visits

Change in CPD

(50% reduction outcome only given for intervention group)

Abstinence for 7 days at 6m

(Average reduction in CO only reported at 4 wks)

Main objective of study was to assess whether assistance to reduce enhanced quit rates compared to advice

to quit

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear Unclear

Carpenter 2004

Methods

Participants

Interventions

Outcomes

Country: USA

Recruitment: proactive calls to identify households with smokers

Randomization: method not stated

616 smokers (>=10 CPD) not interested in cessation. 71% F, av.age 40, av.CPD 22, 65% precontemplators

1. Behavioural support to reduce by either scheduled or hierarchical reduction. NRT (gum or patch)

described and offered. At 6wks given brief advice to quit based on US guideline. NRT offered at wk 6 if

quit date set, NRT no longer available otherwise. 12-17 mins at each call.

2. Motivational interviewing. ’5 Rs’ approach (Relevance/ Risks/ Rewards/ Roadblocks/ Repeated). Eligible

for free NRT if quit date set. Mailed self-help materials, counsellor call within 5 days of TQD

3. Control. No intervention, assessment calls only.

Common components: Phone contacts at 0, 3, 6, 24w

Reduction in CPD excl quitters at 24wks

PP abstinence at 24wks

Quit attempts, over 24hrs & in 6m

Notes Similar objective to Carpenter 2003

Risk of bias

Interventions to reduce harm from continued tobacco use (Review)

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

21


Carpenter 2004

(Continued)

Item Authors’ judgement Description

Allocation concealment? Unclear Unclear

Etter 2004

Methods

Participants

Interventions

Outcomes

Notes

Country: Switzerland

Recruitment: community volunteers

Randomization: computer-generated list, allocation concealment not described

923 smokers (>=20 CPD) not intending to quit in next 6m, willing to commit to reduce consumption

by half

1. Choice of nicotine patch, 4mg gum, inhaler or combination. 5 day supply of each provided initially,

more could be ordered every 2 wks for 6m

2. Same choice, placebo products

3. Control, no products

Minimal behavioural support: 20 page booklets after enrolment and after 3m survey, 2 page information

leaflet at each mailing

Reduction in CPD: >= 50% at 2y (6m & 5yr outcomes also reported in separate papers). Average reduction

in CPD also reported.

Abstinence: 4 wks at 18m.

Validation: none

Placebo group only as control in meta-analysis; this is conservative for effect of NRT on reduction, but

increases effect on abstinence.

By 5 years there was no significant difference in cessation rates or CPD due to increased cessation and

reduction in controls

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear Unclear

Glasgow 2009

Methods

Participants

Interventions

Country: USA

Recruitment: HMO members scheduled for outpatient surgery or diagnostic procedure

320 smokers (>20 CPD) not interested in quitting smoking; 73% F, av. age 55, Av. CPD

21

1. Telephone based, individualised graduated reduction to 50% of more. Cessation

encouraged following reduction. 4 phone sessions over 6 m, 4 individually tailored

newsletter, one targeted newsletter

Interventions to reduce harm from continued tobacco use (Review)

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22


Glasgow 2009

(Continued)

2. Usual care plus 3 generic health education mailings

Outcomes Reduction: >50% in CPD, >50% in CO at 12 m (and 3 m)

Abstinence: 12m PP

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Randomized using computer algorithm

Allocation concealment? Unclear Randomized after baseline telephone assessment.

Participants who did not attend

in person for baseline biochemical samples

were excluded from analyses;

Incomplete outcome data addressed?

All outcomes

Yes

71/391 without baseline samples excluded,

similar across groups. 37% intervention &

18% control lost to follow up, treated as

stable smokers

Hanson 2008

Methods

Country: USA, 14 high schools, Minneapolis St Paul

Recruitment: Adolescents smoking ≥5 CPD for at least 6 m, wanting to reduce, no quit date set

for next 2 m

Participants 103 adolescents; 58% F, av. age 17, av. CPD 11.8

Interventions

Outcomes

Notes

All participants 6 weekly visits 20-30 min incl 10-15 min CBT, medication & reduction from visit

3. At end of 6 weeks, option to set quit date with medication.

1. Nicotine Patch

2. Nicotine gum

3. Folic acid pill (placebo)

Reduction: average CPD, average CO, cotinine at 6 m

Cessation: 30-day abstinence at 6 m

(Outcomes also assessed at end of treatment and 3 m)

Not combined with adult NRT studies. Cessation not reported by group, 50% reduction only

reported at end of treatment, and not by group. No treatment effects detected at any follow up.

CPD lower than baseline in all groups at 6 m but CO and cotinine higher raising possibility that

reducing cigarettes had increased smoke exposure, but could also have been due to greater free time,

variability in smoking patterns and possibly the trajectory towards increased smoking behaviour.

5/103 reported 30 day abstinence at 6 m

Interventions to reduce harm from continued tobacco use (Review)

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

23


Hanson 2008

(Continued)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Randomized, method not stated

Allocation concealment? Unclear No details given

Hatsukami 2004a

Methods

Country: USA 12 sites

Recruitment: community volunteers

Randomization: computer-generated schedule. concealment method not described

Participants 594 smoker ( >=20 CPD) wanting to reduce amount smoked. Not quit for >3m in prev year, at least 2

failed quit attempts including 1 with NRT

Interventions

Outcomes

Notes

1. Bupropion 300 mg/day, 26 wks

2. Placebo

Common components: written materials suggesting reduction techniques, monthly brief individual counselling,

telephone contact day 2, day 12, wk 5 after target reduction date. Participants indicating a willingness

to quit at any time were enrolled in a 7 wk cessation programme with weekly counselling visits

followed by 19 wks of follow up

Reduction >50% in urine cotinine at 1yr (denominator 327 excludes 214 who entered cessation arm, and

53 with missing baseline cotinine).

Reduction >50% in CPD at 1yr

Abstinence 6m after quit date (denominator 594; 214 entered cessation phase

38% of bupropion and 34% of placebo group entered cessation phase. Median time to attempting cessation

shorter in bupropion group

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear Unclear

Haustein 2003

Methods

Participants

Country: Germany

Recruitment: community volunteers

Randomization: method not stated

385 smokers unwilling or unable to quit

Interventions to reduce harm from continued tobacco use (Review)

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

24


Haustein 2003

(Continued)

Interventions

Outcomes

Notes

1. Nicotine gum, instructed to quit within 4 wks

2. Nicotine gum, instructed to reduce gradually, recommended to quit after 6m.

3. Placebo, short reduction

4. Placebo, long reduction

Reduction >50% in CPD with CO reduction at 12m

Abstinence at 12m (28 day PP)

Validation: ?CO

Limited data available

Included a comparison of 2 schedules of NRT-assisted reduction. All participants instructed

to quit at some stage

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation?

Allocation concealment?

Incomplete outcome data addressed?

All outcomes

Yes

Yes

Yes

Joseph 2008

Methods

Participants

Country: USA, Veterans Affairs Medical Centres

Recruitment: Community volunteers & referrals and invited patients with cardiovascular

disorder

Randomized controlled trial

152 smokers (≥15 CPD) unwilling or uninterested in setting quit date in next 30 days;

88% M, av. age 58, 27 CPD, av. 6 previous quit attempts

Interventions 1. Counselling to encourage reduction by ≥50 CPD, at 1w, 2w, 1, 2, 3, 4, 6, 12, 18m,

additional visits after 4m if further interest. Encouraged to use up to 6 pieces of 4 mg

nicotine gum, or patches if need for gum greater. (88% used some form of NRT)

2. Control: single brief session emphasising importance of abstinence & encouragement

to seek cessation assistance

Outcomes

Notes

Reduction >50% in CPD at 18 m, absolute reduction in CPD

Abstinence at 18 m (PP)

Biomarkers: CO, urine cotinine, urine nicotine

Other clinical markers: WBC count, NNAL, NNK. QoL, walk test

Adverse events

5 in Control required urgent cardiac care at 6 m, vs 0 Intervention. No differences in

any clinical or QoL outcomes

Interventions to reduce harm from continued tobacco use (Review)

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25


Joseph 2008

(Continued)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated, block size 10 by site

Allocation concealment? Yes Sealed envelope opened after enrolment

Incomplete outcome data addressed?

All outcomes

Yes

64-68% followed at 18 months, no significant

differences between groups

Kralikova 2009

Methods

Participants

Interventions

Outcomes

Notes

Country: Czech Republic, 2 medical centres

Recruitment: community volunteers willing to control their smoking. Information but equal emphasis

on cessation and reduction

Randomization: method not stated, 2:1 active: placebo ratio

314 smokers (>= 15 CPD), with at least one failed quit attempt, did not have to be motivated to quit.

Excludes 11 enrolled who failed to attend baseline visit.

58% F, av. age 46, av. CPD 25

1. Choice of 4mg nicotine gum (up to 24/day) or 10mg nicotine inhaler (6-12 daily) for up to 6m with

further 3m tapering

2. Choice of placebo gum or placebo inhaler

Common components: brief behavioural cessation/reduction support at clinic visits (9 scheduled)

Sustained >50% reduction in CPD from 6-12m (excluding sustained abstainers)

Sustained abstinence from 6-12m (12m PP also reported)

CVD risk factors assessed but not reported yet

Validation: cessation - CO


Mendes 2008

Methods

Country: USA, Clinical research centre & community

Recruitment: Volunteers for a paid study of effects of different smoking devices, willing

to switch from conventional cigarettes for an extended period

Participants 257 regular smokers of 10-30 full strength cigarettes per day (15 mg tar) of whom 166

completed phase 1 of study and continued to phase 2

Interventions

Outcomes

Notes

Test of switching to low tar cigarettes: Participants continued smoking Marlboro Full

Flavour cigarettes, or switched to Marlboro Lihgts (ML) or Marlboro Ultra Lights

Biomarkers of exposure & harm; urine nicotine equivalents, cotinine, NNAL, 1-OHP,

urine mutagenicity, COHb, S-PMA, 3-PMA, Inter-Puff Interval. Longest follow up 24

weeks, measures taken daily for 8 days then 4-weekly

Funded by Philip Morris. Cigarettes provided free to participants

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Randomized, method not described

Allocation concealment? Unclear No details given

Incomplete outcome data addressed?

All outcomes

No

26% of those randomized to phase 1 study

did not enter phase 2. Higher drop-out

from low tar cigarette groups by end of

study

Pisinger 2005

Methods

Participants

Interventions

Outcomes

Country: Denmark

Recruitment: Smokers responding to a baseline questionnaire for a population-based intervention

Randomization: method not stated

3684 smokers, includes some interested in quit attempt

1. Lifestyle consultation with motivational interviewing. If unwilling or not ready to quit given free

samples of their choice of NRT.

2. Also offered smoking reduction group

3. Control

Reduction by >50% at 1 yr

Validation: none

Notes 1. and 2. combined since only 39 attended reduction group option in 2

Risk of bias

Interventions to reduce harm from continued tobacco use (Review)

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

27


Pisinger 2005

(Continued)

Item Authors’ judgement Description

Allocation concealment? Unclear Unclear

Rennard 2006

Methods

Participants

Interventions

Outcomes

Notes

Country: USA 3 sites

Recruitment: community volunteers

Randomization: method: not stated, ’double-blind’

429 smokers (>=20 CPD)

55% F, av.age 45, av.CPD 30

1. Nicotine inhalator 10mg ad lib, recommended 6-12/day, for up to 12m. Cessation recommended from

6m

2. Placebo

Common components: 9 clinic visits over 15m

Sustained reduction by >50% from 4wks to 15m

PP abstinence at 15m

CVD risk factors WBC, HDL, LDL, fibrinogen, C4RP at 4m reported for reducers + abstainers, not by

condition

Validation: CO for reduction

Some data from Pfizer internal report since only graph for reduction in published paper.

15m outcomes used. 12m gives lower effect.

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear Unclear

Riley 2002

Methods

Participants

Interventions

Country: USA

Recruitment: community volunteers

Randomization: method not stated

93 smokers (>= 15 CPD) interested in reduction, 2 failures in planned quit attempts, not quit >30 days

in past yr

44%F, av.age 45, av.CPD 27, av. 5.6 previous attempts, av.32m since last

1. Computerised scheduled gradual reduction over 2 wks to 50% goal with programme covering computer

operation, harm reduction, self-management and relapse prevention techniques.

2. Self-help treatment guide instructing in gradual reduction using selective elimination of cigarettes

Interventions to reduce harm from continued tobacco use (Review)

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28


Riley 2002

(Continued)

Outcomes

Notes

Reduction >=50% at 12m, (mean % reduction)

PP abstinence at 12m

Validation: CO


Sarkar 2008

Methods

Participants

Interventions

Outcomes

Notes

Country: USA, Clinical research centre & community

Recruitment: Volunteers for a paid study of effects of different types of cigarette, willing

to switch from their usual cigarettes for an extended period

115 regular smokers of 10-30 6 mg or 11 mg tar cigarettes daily; ~18 CPD at baseline

Two substudies of switching to carbon filtered cigarettes with 6mg or 11mg tar. Controls

continued to smoke conventional cigs with same tar levels

Biomarkers of exposure to gas phase: acrolein, 1,3-butadiene, benzene, measured by

the 24-hr urinary excretion of metabolites. Biomarkers of exposure to particulate phase:

nicotine, NNK, pyrene

Biomarkets of cardiovascular risk: LDL-cholesterol, HDL-cholesterol, and triglycerides

Longest follow up 24w, also 4, 8, 12, 16, 20 w

Funded by Philip Morris. Cigarettes provided free to participants

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Randomized, method not described

Allocation concealment? Unclear No details given

Incomplete outcome data addressed?

All outcomes

Yes

Of 115 in short term phase, 97 continued

to 2nd phase and 76 completed 24 w. More

lost in low tar test cig

Wennike 2003

Methods

Participants

Interventions

Outcomes

Country: Denmark

Recruitment: community volunteers for smoking reduction

Randomization: method not stated

411 smokers (>= 15 CPD) interested in reducing but unwilling/unable to give up

62% F, av.age 45, av.CPD 24

1. Nicotine gum, 2mg if FTND =5, 4mg if 6-10, for up to 12m

2. Placebo gum

Common components: Brief individual information on smoking reduction, effects on health, suggestions

on ways to reduce number of cigs, cessation recommended as ultimate goal

Sustained (4, 12, 24m) & PP reduction of >50% at 24m

CPD,CO, cotinine & thiocyanate average % of baseline by treatment group in continuing participants

at 24m. Also mean values by reducer categories

PP abstinence at 24m

Validation: CO


Wennike 2003

(Continued)

Notes

PP reduction gives a more conservative treatment effect.

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear Unclear

av: average

C4RP: C4-reactive protein

CPD: cigarettes per day

CO; carbon monoxide

F: female

PP: point prevalence (abstinent during a limited defined period)

ppm: parts per million

CVD: Cardiovascular Disease

FTND: Fagerstrom Test for Nicotine Dependence

HDL: high-density lipoprotein

LDL: low-density lipoprotein

m: month(s)

NRT: nicotine replacement therapy

NS: not statistically significant

TQD: target quit date

WBC: white blood cells

Characteristics of excluded studies [ordered by study ID]

Study

Applegate 2004

Baker 2006

Benowitz 2005

Borland 1999

Breland 2006

Reason for exclusion

Reported as a conference abstract. Insufficient data to include

Reduction was a secondary outcome in a trial of a cessation-focused intervention

Short term (3 wk) cross-over trial comparing conventional and ’light’ cigarettes. Outcomes were

biomarker exposures

Intervention was intended to assist smokers in coping with workplace smoking bans by learning to cope

with smoking behaviour. Smoking reduction was reported as change in CPD or any reduction. Use of

intervention was low

Short-term cross-over trial comparing Advance, Eclipse, own brand cigarettes, or no cigarettes. Outcomes

were biomarker exposures

Interventions to reduce harm from continued tobacco use (Review)

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31


(Continued)

Caldwell 2010

Cunningham 2006

Eliasson 2001

Etter 2003

Fagerstrom 1997

Fagerstrom 2000

Fagerstrom 2002b

Fatemi 2005

Feng 2006

Frost 1995

Glasgow 1983

Gray 2008

Hatsukami 2004b

Hatsukami 2005

Hatsukami 2007a

Hatsukami 2008

Short-term cross-over trial comparing snus, Zonnic and nicotine gum. Outcomes were urges to smoke,

withdrawal symptoms and the sensory quality of the products

Short-term (3m) follow up. Trial compared a questionnaire containing tips on safer smoking with a

control asking about harm reduction activities

Uncontrolled short-term study of reduction and cessation assisted by nicotine nasal spray

Outcome was effect of information about NRT and cigarette use on motivation to quit

Short-term (5wk) follow up. Test of NRT for smoking reduction. Participants tried out different types

of NRT, then chose or were assigned a product in a crossover design. No non-NRT control. No serious

adverse effects reported

Short-term (6wk) study. Compared a potentially reduced exposure product (Eclipse), nicotine inhaler

or usual cigarettes

Short-term (14 wk) follow up. Participants enrolled in a previous study (Fagerstrom 2000) self-selected

a potentially reduced exposure product (Eclipse), nicotine inhaler or usual cigarettes

Short term (8 wk) cross-over study of bupropion or placebo for smoking reduction in people with

schizophrenia

Short term (8 day) study comparing biomarkers of exposure from conventional cigarettes, low tar, or

electrically heated cigs

Study to assess compensation when smoking low tar brand.

No long-term follow up of wait list control group. Smoking reduction was maintained at 6m follow up

in both treatment groups

Laboratory study and short-term (20 day) study of toxicant exposure of different smokeless tobacco

products

Short-term (6 wk) study comparing the effect on carcinogen exposure of switching from cigarette smoking

to either the OMNI cigarette or a nicotine patch, and switching from smokeless tobacco to Swedish snus

or a nicotine patch

Short-term (12wk) study using NRT to reduce smoking with a target of 75% reduction. A wait list

control delayed reduction for 6 wks. Outcomes were change in multiple biomarkers amongst successful

reducers

Short-term (12 wk) intervention for switching smokeless tobacco brands

Short-term (12 wk) intervention for reducing smokeless tobacco use

Interventions to reduce harm from continued tobacco use (Review)

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(Continued)

Hatsukami 2010

Hughes 2004b

Hurt 2000

Jimenez-Ruiz 2002

Kotlyar 2007

Lamb 2005

Lichtenstein 2008

Malchodi 2003

Mendoza-Baumgart 2007

PM Elec Cig

Rennard 1990

Rennard 1994

Rennard 2002

Riggs 2001

Robinson 1984

Sarkar 2010

Scherer 2006

Shiffman 2009

Short-term (6 wk) parallel study comparing effects of reduced nicotine cigarettes, very low nicotine

cigarettes or nicotine lozenges on compensatory smoking behavior, biomarkers of exposure, tobacco

dependence, tobacco withdrawal and abstinence rate

Short-term (12 wk) crossover study comparing the effect on smoking behaviour and toxin exposure of

conventional cigarette smoking versus the Omni cigarette

Uncontrolled study. Nicotine inhaler used to assist smoking reduction with follow up at 24wks

Uncontrolled study. Nicotine gum used to assist smoking reduction with follow up at 18m

Short-term within-subjects crossover study comparing nicotine concentrations, craving, withdrawal and

product liking for 4 PREPs, moist snuff and medicinal nicotine

Short-tem study using financial incentives to reward reduced smoking

Outcomes were cessation and household smoking bans, not smoking reduction

Reduced smoking was a secondary outcome in a trial of a cessation intervention

Short term (5 wk) study comparing smokeless tobacco products to a nicotine lozenge for people stopping

smoking

Short-term (12 wk) study comparing biomarkers in smokers of conventional cigarettes and smokers

using an electrically heated cigarette smoking system.

Uncontrolled study. Nicotine gum used to assist smoking reduction. Outcomes were measures of lower

respiratory tract inflammation

Insufficient data available from conference abstract.

Short-term (8wk) study of respiratory tract inflammation in smokers switching to potentially reduced

exposure product (Eclipse)

Short-term (7wk) crossover pilot study of 2 reduction strategies combined with nicotine gum

Short-term (8wk) trial comparing ’light’ cigarettes to usual brand

Short-term (8 day) study comparing biomarker exposure from continuing smoking, reduction and

smokeless tobacco (ST) use, ST use alone, and complete abstinence

Short term (2 wk) cross-over study comparing conventional and charcoal filter cigarettes

Trial of nicotine gum for reduction as a precursor to cessation, amongst smokers attempting to quit

Interventions to reduce harm from continued tobacco use (Review)

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(Continued)

Spain NNCG-008

Stein 2002

Strasser 2007

Sun 2009

Tonnesen 2005

Windsor 1999

Only short-term (4m) outcomes available from Pfizer summary. There was a stratification error such that

highly dependent smokers received either nicotine 2mg gum or placebo and the low dependent smokers

received either nicotine 4mg gum or placebo. Results were consistent with other trials

Short-term (3m) study comparing homocysteine levels in continuing smokers, reducers and quitters

Laboratory study comparing carbon monoxide exposure from smoking reduced nicotine cigarettes

Trial of nicotine sublingual tablet for smoking cessation amongst people motivated to quit. Smoking

reduction was a secondary outcome

Primary analysis was based on smoking status at end of study, not by allocation to cessation, reduction

or continued smoking category. NRT was used to assist quitting or reduction and quit rates at 4m were

similar in cessation and reduction groups

Secondary analysis of 4 trials of cessation interventions for pregnant smokers. Rates of significant reduction

based on biochemical measures

CPD: cigarettes per day

NRT: nicotine replacement therapy

Interventions to reduce harm from continued tobacco use (Review)

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34


D A T A

A N D A N A L Y S E S

Comparison 1.

Nicotine replacement therapy to assist smoking reduction versus placebo/unassisted reduction

Outcome or subgroup title

No. of

studies

No. of

participants Statistical method Effect size

1 Reduction in cigarettes/day of

>50% of baseline or cessation

1.1 Choice of NRT type

versus placebo

1.2 Nicotine gum versus

placebo

1.3 Nicotine inhaler versus

placebo

1.4 Nicotine gum, or patch,

combined with counselling

2 Cessation at long-term follow-up

(Subgroups by type of NRT)

2.1 Choice of NRT type

versus placebo

2.2 Nicotine gum versus

placebo

2.3 Nicotine inhaler versus

placebo

2.4 Nicotine gum, or patch,

combined with counselling

3 Other outcomes - changes in

motivation, adverse events

4 Other outcomes - risk reduction

markers

9 3429 Risk Ratio (M-H, Fixed, 95% CI) 1.72 [1.41, 2.10]

2 848 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [1.00, 1.65]

4 1596 Risk Ratio (M-H, Fixed, 95% CI) 3.66 [2.00, 6.69]

2 829 Risk Ratio (M-H, Fixed, 95% CI) 3.39 [1.70, 6.77]

1 156 Risk Ratio (M-H, Fixed, 95% CI) 1.39 [0.83, 2.33]

9 3429 Risk Ratio (M-H, Fixed, 95% CI) 1.73 [1.36, 2.19]

2 848 Risk Ratio (M-H, Fixed, 95% CI) 1.56 [1.04, 2.33]

4 1596 Risk Ratio (M-H, Fixed, 95% CI) 1.99 [1.35, 2.93]

2 829 Risk Ratio (M-H, Fixed, 95% CI) 1.90 [1.13, 3.20]

1 156 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.42, 2.38]

Other data

No numeric data

Other data

No numeric data

Comparison 2.

Bupropion to assist smoking reduction versus placebo

Outcome or subgroup title

No. of

studies

No. of

participants Statistical method Effect size

1 Outcomes at long term

1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

follow-up

1.1 Cessation 1 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

1.2 Reduction on

1 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

cigarettes/day to >50% of

baseline or cessation

1.3 Reduction in

cigarettes/day to >50% of

baseline (excluding quitters)

1 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

Interventions to reduce harm from continued tobacco use (Review)

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

35


1.4 Reduction in

cigarettes/day to >50%

of baseline (excluding

quitters from numerator and

denominator)

1.5 Reduction in cotinine at 1

year amongst participants never

attempting to quit

1 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

1 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

Analysis 1.1. Comparison 1 Nicotine replacement therapy to assist smoking reduction versus

placebo/unassisted reduction, Outcome 1 Reduction in cigarettes/day of >50% of baseline or cessation.

Review:

Interventions to reduce harm from continued tobacco use

Comparison:

1 Nicotine replacement therapy to assist smoking reduction versus placebo/unassisted reduction

Outcome:

1 Reduction in cigarettes/day of >50% of baseline or cessation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Choice of NRT type versus placebo

Kralikova 2009 36/209 19/105 20.2 % 0.95 [ 0.58, 1.58 ]

Etter 2004 83/265 59/269 46.9 % 1.43 [ 1.07, 1.90 ]

Subtotal (95% CI) 474 374 67.1 % 1.28 [ 1.00, 1.65 ]

Total events: 119 (Treatment), 78 (Control)

Heterogeneity: Chi?? = 1.88, df = 1 (P = 0.17); I?? =47%

Test for overall effect: Z = 1.97 (P = 0.049)

2 Nicotine gum versus placebo

Australia NNCG-017 3/218 2/218 1.6 % 1.50 [ 0.25, 8.89 ]

Batra 2005 15/184 5/180 4.0 % 2.93 [ 1.09, 7.91 ]

Haustein 2003 17/193 5/192 4.0 % 3.38 [ 1.27, 8.98 ]

Wennike 2003 13/205 1/206 0.8 % 13.06 [ 1.72, 98.94 ]

Subtotal (95% CI) 800 796 10.5 % 3.66 [ 2.00, 6.69 ]

Total events: 48 (Treatment), 13 (Control)

Heterogeneity: Chi?? = 2.70, df = 3 (P = 0.44); I?? =0.0%

Test for overall effect: Z = 4.22 (P = 0.000025)

3 Nicotine inhaler versus placebo

Bolliger 2000 19/200 6/200 4.8 % 3.17 [ 1.29, 7.76 ]

Rennard 2006 15/215 4/214 3.2 % 3.73 [ 1.26, 11.06 ]

Subtotal (95% CI) 415 414 8.0 % 3.39 [ 1.70, 6.77 ]

Total events: 34 (Treatment), 10 (Control)

Heterogeneity: Chi?? = 0.05, df = 1 (P = 0.82); I?? =0.0%

0.1 0.2 0.5 1 2 5 10

Favours control

Favours intervention

(Continued ...)

Interventions to reduce harm from continued tobacco use (Review)

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

36


(... Continued)

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

Test for overall effect: Z = 3.46 (P = 0.00053)

4 Nicotine gum, or patch, combined with counselling

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Joseph 2008 25/78 18/78 14.4 % 1.39 [ 0.83, 2.33 ]

Subtotal (95% CI) 78 78 14.4 % 1.39 [ 0.83, 2.33 ]

Total events: 25 (Treatment), 18 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 1.24 (P = 0.21)

Total (95% CI) 1767 1662 100.0 % 1.72 [ 1.41, 2.10 ]

Total events: 226 (Treatment), 119 (Control)

Heterogeneity: Chi?? = 18.09, df = 8 (P = 0.02); I?? =56%

Test for overall effect: Z = 5.30 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10

Favours control

Favours intervention

Analysis 1.2. Comparison 1 Nicotine replacement therapy to assist smoking reduction versus

placebo/unassisted reduction, Outcome 2 Cessation at long-term follow-up (Subgroups by type of NRT).

Review:

Interventions to reduce harm from continued tobacco use

Comparison:

1 Nicotine replacement therapy to assist smoking reduction versus placebo/unassisted reduction

Outcome:

2 Cessation at long-term follow-up (Subgroups by type of NRT)

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Choice of NRT type versus placebo

Etter 2004 31/265 25/269 24.4 % 1.26 [ 0.76, 2.07 ]

Kralikova 2009 39/209 9/105 11.8 % 2.18 [ 1.10, 4.32 ]

Subtotal (95% CI) 474 374 36.1 % 1.56 [ 1.04, 2.33 ]

Total events: 70 (Treatment), 34 (Control)

Heterogeneity: Chi?? = 1.62, df = 1 (P = 0.20); I?? =38%

Test for overall effect: Z = 2.16 (P = 0.030)

2 Nicotine gum versus placebo

Australia NNCG-017 10/218 7/218 6.9 % 1.43 [ 0.55, 3.68 ]

Batra 2005 20/184 7/180 6.9 % 2.80 [ 1.21, 6.45 ]

Haustein 2003 23/193 15/192 14.8 % 1.53 [ 0.82, 2.83 ]

0.1 0.2 0.5 1 2 5 10

Favours control

Favours intervention

(Continued ...)

Interventions to reduce harm from continued tobacco use (Review)

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

37


(... Continued)

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Wennike 2003 19/205 7/206 6.9 % 2.73 [ 1.17, 6.35 ]

Subtotal (95% CI) 800 796 35.4 % 1.99 [ 1.35, 2.93 ]

Total events: 72 (Treatment), 36 (Control)

Heterogeneity: Chi?? = 2.35, df = 3 (P = 0.50); I?? =0.0%

Test for overall effect: Z = 3.48 (P = 0.00050)

3 Nicotine inhaler versus placebo

Bolliger 2000 21/200 17/200 16.7 % 1.24 [ 0.67, 2.27 ]

Rennard 2006 17/215 3/214 3.0 % 5.64 [ 1.68, 18.97 ]

Subtotal (95% CI) 415 414 19.6 % 1.90 [ 1.13, 3.20 ]

Total events: 38 (Treatment), 20 (Control)

Heterogeneity: Chi?? = 5.01, df = 1 (P = 0.03); I?? =80%

Test for overall effect: Z = 2.40 (P = 0.016)

4 Nicotine gum, or patch, combined with counselling

Joseph 2008 9/78 9/78 8.8 % 1.00 [ 0.42, 2.38 ]

Subtotal (95% CI) 78 78 8.8 % 1.00 [ 0.42, 2.38 ]

Total events: 9 (Treatment), 9 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.0 (P = 1.0)

Total (95% CI) 1767 1662 100.0 % 1.73 [ 1.36, 2.19 ]

Total events: 189 (Treatment), 99 (Control)

Heterogeneity: Chi?? = 11.03, df = 8 (P = 0.20); I?? =27%

Test for overall effect: Z = 4.55 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10

Favours control

Favours intervention

Analysis 1.3. Comparison 1 Nicotine replacement therapy to assist smoking reduction versus

placebo/unassisted reduction, Outcome 3 Other outcomes - changes in motivation, adverse events.

Other outcomes - changes in motivation, adverse events

Study Adverse Events Attitudes/Motivation

Batra 2005

506 AEs, 40% severe in active vs 370 AEs, 40% severe

in placebo. No serious nicotine related AE, no discontinuations

due to side effects.

Possibly nicotine related: nausea 19 vs 11 (NS).

At 13m 60% of study completers stated that participation

had increased interest in quitting, 37% no effect.

No difference between groups

Bolliger 2000

193 AEs in 114 participants in active vs 227 events in

113 in placebo. 53 serious AEs, none said to be treatment

related. Throat irritation & coughing more common in

active.

Possibly nicotine related: nausea/vomiting 9 vs 8, palpitations

1 vs 2

’With regard to changes in participants’ interest to quit,

no difference could be detected between reducers and

non-reducers or active and placebo treatment.’ No other

details

Interventions to reduce harm from continued tobacco use (Review)

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

38


Other outcomes - changes in motivation, adverse events

(Continued)

Etter 2004

Joseph 2008

Kralikova 2009

1 death from cancer, 1 from cerebral haemorrhage in

nicotine group. Neither likely to be treatment related.

No other details of AEs

’Serious cardiac events and other serious adverse events

were roughly equally distributed between treatment

groups.’ ’.. there were no reported complications of concomitant

smoking and use of NRT.’

82 AEs, 7(9%) severe, in active vs 26 AEs, 1 (4%) severe

in placebo. Mainly throat/mouth irritation & cough.

Possibly nicotine related: 6 (2 nausea, 3 vertigo, 1 palpitation)

vs 1 (vertigo)

Changes in intention to quit not reported.

Changes in intention to quit not reported.

At month 4 changes in intention to quit from baseline

were small and NS. At month 12 long-term reducers had

significantly reduced intention to quit

Rennard 2006 159 (74%) participants reported AEs in active vs 147

(69%) in placebo. 9 people with 15 serious AEs in active

vs 11 with 13 AEs in control, none assessed as medication

related.

Possibly nicotine related: nausea or vomiting 11 vs 5

At month 15 amongst non quitters, 17% active vs 18%

placebo expressed intention to quit compared to 1% vs

none at week 2. 80% overall had more interest in quitting

Wennike 2003 166 AEs in active vs 147 in placebo (NS). None of 21

serious AEs assessed to be treatment related.

Possibly nicotine related: nausea/vomiting/palpitation 6

vs 4

At month 24 67% (112/167 including successful reducers

& quitters) were more interested in quitting smoking.

Unsuccessful reducers had falls in motivation to quit and

reduce smoking (NS for placebo group quit motivation,

sig for others)

Analysis 1.4. Comparison 1 Nicotine replacement therapy to assist smoking reduction versus

placebo/unassisted reduction, Outcome 4 Other outcomes - risk reduction markers.

Other outcomes - risk reduction markers

Study CPD/CO Cotinine/Thiocyanate Other risk markers

Batra 2005

At 13m % reductions from baseline

for attenders including quitters: (n,

mean, SD)

CPD active 55, 64.0% (33.1);

placebo 39, 51.0% (33.9) (NS)

CO % reductions 55, 43.1% (39.3);

placebo 39, 27.1% (40.5) Sustained

CO reduction >20% at 13m; active

13.6% , placebo 5.6%

As for CPD/CO based on attenders

with data, including quitters

Cotinine % reduction active n=52,

31.8% (44.2), placebo 36, 25.5%

(40.0) (P=.04)

Thiocyanate active 46, 20.5% (30.5)

, placebo 33, 16.7% (22.8) (NS)

No statistically significant change

in any cardiovascular risk markers

(white blood cell count, fibrinogen ,

CRP) between baseline and month

12 in the 20 successful sustained reducers/abstainers

Bolliger 2000

% reduction in CPD and CO reported

for participants still using inhalers

at 18m. See text

Not reported Comparison between 25 (19 active 6

placebo) sustained reducers and 285

others present at 24m. Both groups

had significant favourable changes

from baseline in a range of risk

Interventions to reduce harm from continued tobacco use (Review)

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39


Other outcomes - risk reduction markers

(Continued)

markers. The difference between the

groups was statistically significant for

cholesterol/HDL ratio, hemoglobin

and pulse rate. Quality of life outcomes

increased in both, but only

general health showing a significant

between group difference. No

changes in pulmonary function

Excluding 5 who were quit did not

alter results.

Etter 2004

After 26m the mean absolute reduction

(ITT) in CPD was 9.8 for nicotine,

7.7 for placebo & control. Median

reduction 7.5 vs 5.0.

Amongst participants followed up at

60 months (excl quitters) the mean

absolute reduction in CPD ranged

from 6.3 to 7.9 (NS between groups)

.CPD as % of baseline was 74%

NRT, 80% placebo & no treatment

Not measured

Not measured

Joseph 2008

Kralikova 2009

Reductions in CPD similar in both

groups; decreasing from ~27 CPD at

baseline to ~18 CPD at 18 months,

but with considerable variation between

individuals. CO reduction in

both groups, no signigicant difference

Amongst 56 reducers the reduction

in CO was significant (25.8 ppm

to 11.5ppm, p=50% reducers at 4

months average cotinine levels fell by

less; 23% active, 29% placebo

Amongst sustained reducers

at month 15, reducers of 50%

to 75% (incl

quitters) reduced average CO by 25.

2ppm

No differences across treatment

groups in any markers. Exploratory

analyses of successful reducers at 4m

showed significant change from baseline

in HDL but no other markers

Wennike 2003

At 24m based on remaining participants

no differences between active

& placebo. CPD 54% vs 61% of

baseline, CO 63% vs 76% of base-

At 24m based on remaining participants

no differences between active

& placebo.

Cotinine 83% vs 93% baseline

Not measured

Interventions to reduce harm from continued tobacco use (Review)

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

40


Other outcomes - risk reduction markers

(Continued)

line,

Analysis 2.1.

Comparison 2 Bupropion to assist smoking reduction versus placebo, Outcome 1 Outcomes

at long term follow-up.

Review: Interventions to reduce harm from continued tobacco use

Comparison: 2 Bupropion to assist smoking reduction versus placebo

Outcome: 1 Outcomes at long term follow-up

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Cessation

Hatsukami 2004a 20/295 16/299 1.27 [ 0.67, 2.40 ]

2 Reduction on cigarettes/day to >50% of baseline or cessation

Hatsukami 2004a 28/295 28/299 1.01 [ 0.62, 1.67 ]

3 Reduction in cigarettes/day to >50% of baseline (excluding quitters)

Hatsukami 2004a 8/295 12/299 0.68 [ 0.28, 1.63 ]

4 Reduction in cigarettes/day to >50% of baseline (excluding quitters from numerator and denominator)

Hatsukami 2004a 8/275 12/285 0.69 [ 0.29, 1.66 ]

5 Reduction in cotinine at 1 year amongst participants never attempting to quit

Hatsukami 2004a 3/153 8/174 0.43 [ 0.12, 1.58 ]

0.1 0.2 0.5 1 2 5 10

Favours control

Favours intervention

W H A T ’ S

N E W

Last assessed as up-to-date: 23 June 2010.

Date Event Description

24 June 2010 New search has been performed Updated with six new studies and published data for one previously included

study. Outcome summaries changed from odds ratio to risk ratio. No substantial

change to conclusions

Interventions to reduce harm from continued tobacco use (Review)

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

41


H I S T O R Y

Protocol first published: Issue 2, 2005

Review first published: Issue 3, 2007

Date Event Description

28 October 2008 Amended Converted to new review format.

C O N T R I B U T I O N S O F A U T H O R S

The review was conceived jointly by the authors. The first author designed and ran the search strategy and screened the results &

extracted results. The second author checked data extraction. The authors jointly wrote the review.

D E C L A R A T I O N S O F

None known

I N T E R E S T

S O U R C E S O F S U P P O R T

Internal sources

• Oxford University Department of Primary Health Care, UK.

External sources

• NHS Research & Development Programme, UK.

I N D E X

T E R M S

Medical Subject Headings (MeSH)

Biological Markers [blood]; Bupropion [therapeutic use]; Carbon Monoxide [blood]; Cotinine [blood]; Nicotine [therapeutic use];

Nicotinic Agonists [therapeutic use]; Smoking [adverse effects; blood; ∗ prevention & control]; Smoking Cessation [methods]

MeSH check words

Humans

Interventions to reduce harm from continued tobacco use (Review)

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

42

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