Do Placebo Response Rates from Cessation Trials Inform on Strength of Addictions?

Article (PDF Available)inInternational Journal of Environmental Research and Public Health 9(1):192-211 · December 2012with41 Reads
DOI: 10.3390/ijerph9010192 · Source: PubMed
Abstract
There is an implied assumption that addictions to different substances vary in strength from weak (easier to stop) to strong (harder to stop), though explicit definitions are lacking. Our hypothesis is that the strength of addictions can be measured by cessation rates found with placebo or no treatment controls, and that a weaker addiction would have a higher cessation rate than a stronger addiction. We report an overview of systematic reviews and meta-analyses of cessation trials, using randomised or quasi-randomised trials and reporting objectively-measured abstinence. The outcome for comparison was quit rates-typically the percentage of participants abstinent according to an objective test of abstinence at six months or longer. Twenty-eight cessation reviews (139,000 participants) were found. Most data came from reviews of smoking cessation in over 127,000 participants, and other reviews each covered a few thousand participants. Few reviews used data from studies shorter than three months, and almost all determined abstinence using objective measures. Cessation rates with placebo in randomised trials using objective measures of abstinence and typically over six months duration were 8% for nicotine, 18% for alcohol, 47% for cocaine, and 44% for opioids. Evidence from placebo cessation rates indicates that nicotine is more difficult to give up than alcohol, cocaine, and opioids. Tobacco is also a severe addiction, with a number of major deleterious health effects in a large number of people.
Int. J. Environ. Res. Public Health 2012, 9, 192-211; doi:10.3390/ijerph9010192
International Journal of
Environmental Research and
Public Health
ISSN 1660-4601
www.mdpi.com/journal/ijerph
Article
Do Placebo Response Rates from Cessation Trials Inform on
Strength of Addictions?
Robert A. Moore
1
and Henri-Jean Aubin
2,
*
1
Nuffield Division of Anaesthetics, University of Oxford, The Churchill, Oxford OX1 2JD, UK;
E-Mail: Andrew.moore@pru.ox.ac.uk
2
Hôpital Universitaire Paul Brousse, Université Paris-Sud, INSERM U699, 12 Avenue PV Couturier,
BP 200, Villejuif Cedex 94804, France
* Author to whom correspondence should be addressed; E-Mail: henri-jean.aubin@pbr.aphp.fr;
Tel.: +33-145-59-39-51; Fax: +33-145-59-38-63.
Received: 2 December 2011; in revised form: 6 January 2012 / Accepted: 6 January 2012 /
Published: 11 January 2012
Abstract: There is an implied assumption that addictions to different substances vary in
strength from weak (easier to stop) to strong (harder to stop), though explicit definitions
are lacking. Our hypothesis is that the strength of addictions can be measured by cessation
rates found with placebo or no treatment controls, and that a weaker addiction would have
a higher cessation rate than a stronger addiction. We report an overview of systematic
reviews and meta-analyses of cessation trials, using randomised or quasi-randomised trials
and reporting objectively-measured abstinence. The outcome for comparison was quit
ratestypically the percentage of participants abstinent according to an objective test of
abstinence at six months or longer. Twenty-eight cessation reviews (139,000 participants)
were found. Most data came from reviews of smoking cessation in over 127,000 participants,
and other reviews each covered a few thousand participants. Few reviews used data from
studies shorter than three months, and almost all determined abstinence using objective
measures. Cessation rates with placebo in randomised trials using objective measures of
abstinence and typically over six months duration were 8% for nicotine, 18% for alcohol,
47% for cocaine, and 44% for opioids. Evidence from placebo cessation rates indicates that
nicotine is more difficult to give up than alcohol, cocaine, and opioids. Tobacco is also a
severe addiction, with a number of major deleterious health effects in a large number
of people.
OPEN ACCESS
Int. J. Environ. Res. Public Health 2012, 9 193
Keywords: tobacco; alcohol; opiates; cocaine; cannabis; addiction
1. Introduction
A recent review considering the definition of addiction highlighted five essential elements, which
mainly addressed issues of the individuals and their behaviour and interaction with addictive
stimuli [1]. Addictive interactions also involve the addictive stimulus itself, and the interactions are
often described as strong or severe, without clear explanation of what strong or severe means. Here we
hypothesis that it may be possible to assess the strength of an addiction in terms of how hard it is to
break, and the severity of an addiction in terms of adverse physical, psychological and social effects,
the duration of the addiction, and the number of people affected. It should be emphasised that a
dictionary definition of hypothesis isa supposition or proposed explanation made on the basis of
limited evidence as a starting point for further investigation”; that is exactly the case here, where there
is no significant prior evidence, merely an assumption that this might be reasonable.
There is an implied assumption that addictions to different substances vary in strength from weak
(easier to stop) to strong (harder to stop), though explicit definitions are lacking. Using the data of the
National Epidemiologic Survey on Alcohol and Related Condition, Lopez-Quintero et al. have shown
that the probability of a transition from first use to dependence was greater with nicotine followed by
alcohol, cocaine, and cannabis [1], and that after the onset of dependence, remission appeared usually
first for cocaine, followed by cannabis, alcohol, and finally nicotine [2]. Another way to explore the
strength of addictions is to measure cessation rates found with placebo or no treatment controls; a
weaker addiction would have a higher cessation rate than a stronger addiction.
Comparing different forms of addiction in order to categorise the strength of addiction is not easy
for reasons concerning participants, setting, and details of study design:
1. Motivation to quit and the anticipated benefit are predictors of substance cessation [3], and
treatment intensity affects outcome, as shown in smoking cessation meta-analysis [4]. These
can be linked and differ markedly between addictions. Alcohol dependent subjects entering
treatment with current social and psychological distress that improves dramatically in days or
weeks of inpatient treatment are quite different from smokers with no apparent immediate
benefit trying to quit alone and at home.
2. Individual circumstances differ. An example might be individuals recruited in primary care for
a short intervention for smoking cessation, compared to those in hospital with a recent
diagnosis of smoking-related disease [5]. Recent smoking cessation trials have shown quit rates
to be better after admission for coronary heart disease [6,7].
3. Types and intensity of intervention may be an influence, divided mainly between psychosocial
interventions (cognitive behavioural, support psychotherapy) and drugs of various sorts.
4. Cessation can be defined in a number of ways. Best is to have some objective test, like breath
carbon monoxide or urine cotinine for nicotine, benzoylecgonine or opioid metabolites for
illicit drugs, and biochemical tests for alcohol. Self-reported abstinence is likely to be less
reliable, unless confirmed by a significant other.
Int. J. Environ. Res. Public Health 2012, 9 194
5. Duration of observation is likely to be an issue. Many smokers have given up for a day; few
give up for a month, and only a small percentage for a year or more. Comparing studies of
different duration may be problematical.
6. Issues around size. Many studies in addiction are quite small, with a few tens of participants. We
know that small studies are problematic, and that the random play of chance can have a major
influence on results [8] such that results with fewer than 200 actual events may mislead [9].
The best source of information will be from published systematic reviews and meta-analyses of
randomised trials of interventions to improve quit rates with information after defined periods (six months,
12 months, longest), and in which placebo or no-treatment controls are a common comparator.
2. Methods
Systematic reviews and meta-analyses were sought of interventions to increase quit rates. Two
main searching strategies were employed:
1. Searching of Cochrane Library for Cochrane reviews, using key words tobacco, nicotine,
alcohol, drinking, cocaine, heroin, opioids, and by examining lists of reviews from the
appropriate review groups.
2. Searching PubMed, using similar key words in title or abstract, in humans, and in English.
Related article links were also used.
Only systematic reviews or meta-analyses were used. Where several examined the same subject, the
most recent and largest was chosen. Analyses of predominantly short-term outcomes were excluded
because these may not provide a reliable measure of longer-term abstinence. In general, articles with
cessation rates after at least six months were chosen; some included a few studies with shorter duration
(three months, for example), but the proportion of short duration studies was small. Those using
randomised or quasi-randomised trials were preferred; in some conditions where there was limited
evidence from randomised trials, some controlled trials that were not convincingly randomised had
been included in the reviews, but the amount of information from this source was a small minority of
the total available. These few reviews were included to provide information where otherwise none
would have been available; this was mostly in interventions for cocaine abuse, where the number of
subjects for any review was small. For example, non-randomised studies contributed fewer than 1% of
patients in reviews of smoking cessation.
The outcome for cessation trials was quit ratestypically the percentage of participants abstinent
according to an objective test of abstinence at six months or longer. Results from each review are
presented as absolute quit rates with treatment and placebo, together with a relative benefit or risk, and
number needed to treat (NNT). We abstracted cessation rates for individual trials included in the
reviews, and calculated overall cessation rates for intervention and placebo. For completeness, and to
demonstrate that studies measuring placebo responses were sensitive in that interventions caused
change in response, we also calculated relative risk with 95% confidence interval (CI) using the fixed
effects models [10]; statistical significance was assumed when the 95% CI did not include one.
Numbers needed to treat (NNT) compared with placebo with 95% confidence interval were calculated
from pooled data [11] only with a statistically significant results.
Int. J. Environ. Res. Public Health 2012, 9 195
3. Results
Table 1 contains details of and references to 12 systematic reviews for tobacco cessation studies,
three for alcohol, seven for cocaine, and five for opioids. Another meta-analysis of psychosocial
interventions reported results for polysubstance use, cocaine, opioids, and cannabis [12]. In total,
the 28 reviews reported on almost 139,000 participants.
3.1. Nicotine
Information was available from 12 systematic reviews [13-24], 11 of which were Cochrane
reviews, covering drug interventions and interventions including behavioural counselling, group
therapy, and exercise programmes, as well as nurse or doctor interventions. Data were available on
over 127,000 participants with cessation rates at six months or longer, with the bulk from reviews of
nicotine replacement therapy (NRT), physical intervention, self-help, nursing interventions and
bupropion. Most reviews used only properly randomised trials (one used controlled trials), used
objective means to assess abstinence, and used either placebo or, in the case of behavioural
interventions, used an appropriate control like a minimal intervention or brief advice.
Table 2 shows the main results in terms of percentage of abstinent participants with intervention
and placebo or control. There was a consistent response for placebo, of between 3% and 14%, with an
overall average cessation rate of 8.4% in 57,867 participants on placebo. There appeared to be a lower
cessation rate of 6.7% in 30,837 participants with placebo or minimal interventions in behavioural
interventions, compared with 10.3% in 27,640 participants for placebo in drug interventions. This may
reflect differences in populations studied or differences in methods, like blinding differences. Most
interventions were effective to some extent, with NNTs varying between 7 (95% CI 6 to 10) for
varenicline to 65 (45 to 110) for self-help.
The very large numbers of participants in nicotine replacement therapy (NRT) studies [22] allowed
investigation of a number of variables that might affect the results obtained with placebo. The first
was size.
Figure 1 demonstrates a consistent cessation rate with placebo below 20%, and predominantly
below 10% with group sizes of 300 participants and above. It also shows very variable cessation rates
of a few percent to almost 50% where group size was 100 or below. Figure 2 shows the cessation rates
with placebo or control in nicotine, alcohol, cocaine and opiates.
Table 3 examines other possible influences. Neither type of NRT product (gum, patch, inhaler,
lozenge, or spray) nor duration of follow up beyond six months made any difference to placebo
cessation rates. Participants from smoking clinics, and those with a high level of support in a group
setting achieved somewhat higher rates of cessation, though below 20%. Twelve month studies were
less effective (NNT 21; 95% CI 18 to 25) than sixth month studies (NNT 9.4; 7.9 to 12).
This very large body of data, from many different interventions conducted in a variety of settings,
shows that with placebo or no treatment after six months or longer the overall quit rate for smoking
cessation is low, at about 10%. The information allows the conclusion that small studies can give
highly variable and misleading results, especially where the group size is below 200 participants.
Int. J. Environ. Res. Public Health 2012, 9 196
Table 1. Details of included reviews.
1. Tobacco smoking cessation reviews
Reference Interventions Study characteristics Duration Outcome
Abstinence with
Comments
Intervention
Placebo
Cahill and Ussher
2007 [13]
Rimonabant
(cannabinoid
receptor antagonists)
and placebo for
tobacco cessation
RCTs in adult smokers
Lost to follow up
regarded as continuing
smokers
Prolonged abstinence
defined biochemically at
each study visit
At least
6 months
Smoking status at
minimum of
1 year
Prolonged abstinence
R 20 mg week 50:
87/528 (16.4%)
Prolonged abstinence
R 5 mg week 50:
63/518 (11%)
Prolonged
abstinence week
50: 57/521 (11%)
RR 1.5
(1.1 to 2.1)
for 20 mg
Gourlay et al.
2004 [14]
Clonidine and
placebo for tobacco
cessation
RCTs in adult smokers
Control (placebo)
usually involved some
form of behavioural
therapy.
4.5 months to
1 year
Smoking status
by a variety of
methods,
including self
report
Smoking cessation at
longest time: 98/393
(25%)
Smoking cessation
at longest time:
55/383 (14.4%)
RR 1.6
(1.2 to 2.2)
Hughes et al.
2007 [16]
Antidepressants and
placebo for smoking
cessation
RCTs in adult smokers
Control (placbeo)
sometimes used
behavioural therapy or
similar interventions
At least
6 months
from start of
intervention
Abstinence from
smoking,
assessed at
follow up by
various means
Nortriptyline
Smoking cessation at
6 months or longer:
100/480 (20.8%)
Bupropion
Smoking cessation at
6 months or longer:
1,056/5,557 (19%)
Placebo
Smoking cessation
at 6 months or
longer: 49/495
(9.9%)
Bupropion
Smoking cessation
at 6 months or
longer: 417/4383
(9.5%)
RR 2.0
(1.5 to 2.8)
RR 1.8
(1.6 to 1.9)
(data here for
clinical
setting, 6 and
12 months
follow up,
type of
patient)
Int. J. Environ. Res. Public Health 2012, 9 197
Table 1. Cont.
Reference Interventions Study characteristics Duration Outcome
Abstinence with
Comments
Intervention Placebo
Cahill et al.
2007 [15]
Nicotine receptor
partial agonists and
placebo for smoking
cessation
RCTs in adult smokers
Lost to follow up
regarded as continuing
smokers
Control (placebo)
usually involved some
form of behavioural
therapy.
Minimum
follow up of
at least 6
months
Abstinence from
smoking,
assessed at
follow up by
various means
Varenecline 2 mg
Smoking cessation at
6 months or longer:
232/1,082 (21.4%)
Placebo
Smoking cessation
at 6 months or
longer: 75/941
(8.0%)
RR 2.7
(2.1 to 3.5)
Stead et al.
2008 [22]
Nicotine
replacement therapy
and placebo for
smoking cessation
RCTs in adult smokers
Lost to follow up
regarded as continuing
smokers
Control (placebo)
usually involved some
form of behavioural
therapy.
Minimum
follow up of
at least
6 months
Abstinence from
smoking,
assessed at
follow up by
various means
All NRT/doses
Smoking cessation at
6 months or longer:
3,822/22,711 (16.8%)
All NRT/doses
Smoking cessation
at 6 months or
longer:
2,115/20,307
(10.4%)
RR 1.6
(1.5 to 1.7)
Placebo
results
virtually
identical for
all modes of
delivery of
NRT
Lancaster and
Stead 2005 [17]
Individual
behavioural
counseling
Not all were properly
randomised trials (but
these were a minority of
the trials included, most
of which were properly
randomised), and with
versus no treatment,
brief advice or self-help
materials as the control
Minimum
follow up of
at least
6 months
Abstinence from
smoking,
assessed at
follow up by
various means
Behavioural therapy
Smoking cessation at
6 months or longer:
291/2,513 (11.6%)
Control
Smoking cessation
at 6 months or
longer: 195/2,515
(7.8%)
RR 1.5
(1.3 to 1.8)
Int. J. Environ. Res. Public Health 2012, 9 198
Table 1. Cont.
Reference Interventions Study characteristics Duration Outcome
Abstinence with
Comments
Intervention Placebo
Ussher 2005 [23] Supervised or
unsupervised
exercise
programmes
RCTs in smokers
wishing to quit or recent
quitters
Minimum
6 months
Abstinence from
smoking
Exercise
Smoking cessation at
6 months or longer:
113/635 (18%)
Control
Smoking cessation
at 6 months or
longer: 83/610
(14%)
RR 1.2
(0.9 to 1.5)
Stead and
Lancaster
2005 [21]
Group therapy
versus individual
self help
RCTs Minimum
6 months
Abstinence from
smoking by
measurement
Group
Smoking cessation at
6 months or longer:
249/2,388 (10%)
Control
Smoking cessation
at 6 months or
longer: 116/2,007
(5.8)
RR 1.9
(1.5 to 2.3)
Rice and Stead
2008 [19]
Nursing intervention RCTs Minimum
6 months
Abstinence from
smoking by
measurement
Nursing
Smoking cessation at
6 months or longer:
1,154/8,383 (14%)
Control
Smoking cessation
at 6 months or
longer: 761/6,822
(11%)
Stead et al.
2008 [20]
Physician
intervention
RCTs Minimum
6 months
Abstinence from
smoking by
measurement
PhysicianSmoking
cessation at 6 months
or longer:
1,029/12,584 (8.2%)
ControlSmoking
cessation at
6 months or longer:
470/9,676 (4.9%)
Int. J. Environ. Res. Public Health 2012, 9 199
Table 1. Cont.
2. Alcohol cessation reviews
Reference Interventions Study characteristics Duration Outcome
Abstinence with
Comments
Intervention
Placebo
Srisurapanont and
Jarusuraisin
2005 [25]
Opioid antagonists
or placebo
RCTs only
Participants with
alcohol dependence
established by any
criteria
Various
durations, up
to 3 months,
more than
3 months,
longer than
12 months
Number not
returned to any
drinking, or
heavy drinking
Short term:
Heavy drinking or
relapse 300/415
(72%)
Any drinking 220/517
(43%)
Medium term:
Heavy drinking or
relapse 56/107 (52%)
Any drinking 9/40
(23%)
Short term:
Heavy drinking or
relapse 234/407
(57%)
Any drinking
172/497 (35%)
Medium term:
Heavy drinking or
relapse 37/101
(37%)
Any drinking 6/40
(15%)
Results
converted to
quit rates
Very low
quit rates in
small study
longer than
1 year
Srisurapanont and
Jarusuraisin
2004 [25]
Acamprosate or
placebo
RCTs only
Standard definition of
alcoholism
Usually with some form
of psychosocial
intervention
Duration 2 to
24 months
Abstinence rate 417/1,775 (24%) 231/1,549 (14.9%) 1.6
(1.4 to 1.9)
Bouza et al.
2004 [26]
Naltrexone or
placebo
RCTs only
Standard definition of
alcoholism
Usually with some form
of psychosocial
intervention
Duration 2 to
24 months
Abstinence rate 190/544 (35%) 160/533 (30%) 1.2
(0.98 to 1.4)
Int. J. Environ. Res. Public Health 2012, 9 200
Table 1. Cont.
3. Cocaine cessation reviews
Reference Interventions Study characteristics Duration Outcome
Abstinence with
Comments
Intervention
Placebo
Minozzi et al.
2008 [27]
Anticonvulsants and
placebo
Randomised trials and
controlled trials
Cocaine dependent
patients (DSM
classification)
Adults
Mean
duration
11 weeks
(range 1–24
weeks)
Non-use of
cocaine (self
report or
measurement)
126/270 (47%) 102/198 (52%) RR 1.1
(0.9 to 1.3)
Lima Reisser et al.
2002 [28]
Carbamazepine and
placebo
Randomised trials
Cocaine dependent
patients (DSM
classification)
Adults
1–6 months Maintained in the
programmedid
not drop out
60/152 (39.5%) 51/161 (31.7%)
Silva de Lima et al.
2003 [29]
Antidepressants and
placebo
results for
desipramine
Randomised trials and
controlled trials
Cocaine dependent
patients (DSM
classification)
Adults
1–6 months Non-use of
cocaine
(measurement)
59/136 (43.3%) 65/130 (50%)
Soares et al.
2003 [30]
Dopamine agonists
and placebo
results for
amantadine
Randomised trials
Cocaine dependent
patients (DSM
classification)
Adults
2–16 weeks+,
but mainly
12–16 weeks
Non-use of
cocaine
(measurement)
34/88 (38.6%) 34/127 (26.8%)
Amato et al.
2007 [31]
Antipsychotics and
placebo
Randomised trials and
controlled trials
Cocaine dependent
patients (DSM
classification)
Adults
6–24 weeks Maintained in the
programmedid
not drop out
62/106 (58%) 46/102 (45%)
Int. J. Environ. Res. Public Health 2012, 9 201
Table 1. Cont.
Reference Interventions Study characteristics Duration Outcome
Abstinence with
Comments
Intervention Placebo
Knapp et al.
2007 [32]
Cognitive
behavioural therapy
versus counseling
Randomised trials
Cocaine dependent
patients (DSM
classification)
Adults
4–6 months Maintained in the
programmedid
not drop out
157/289 (54%) 130/281 (46%)
Castells et al.
2007 [33]
Mandizol,
dexamphetamine,
methylphenidate,
modafinil,
buproprion and
placebo
Randomised trials
Cocaine dependent
patients (DSM
classification)Adults
1–6 months Maintained in the
programmedid
not drop out
177/344 (51%) 158/296 (53%)
4. Opioids cessation reviews
Reference Interventions Study characteristics Duration Outcome
Abstinence with
Comments
Intervention Placebo
Amato et al.
2004 [34]
Psychosocial and
pharmacological
treatments versus
pharmacological
treatments
RCTs Mostly of
6 months or
more
Number opioid
free at end of
treatment
Psych + Pharm
Opioid free at about
6 months: 37/89
(42%)
Pharm only
Opioid free at
about 6 months:
24/95 (25%)
Farré et al.
2002 [35]
Methadone,
buprenorphine,
placebo
RCT
Methadone maintenance
at least 12 weeks
Various measures of
retention or illicit drug
use
Studies 1340
weeks, mostly
6 months or
more
Freedom from
illicit drug use
Methadone:
481/1,004 (52%)
Buprenorphine:
164/275 (40%)
Placebo:
65/131 (50%)
Int. J. Environ. Res. Public Health 2012, 9 202
Table 1. Cont.
Reference Interventions Study characteristics Duration Outcome
Abstinence with
Comments
Intervention Placebo
Mattick et al.
2003 [36]
Methadone
maintenance versus
tapering
RCTs Various
times, largely
of the order of
6 months
Retained in
treatment
Drug free urine
Methadone
maintenance:
Retained 173/254
(68%)
DFU: 103/195 (53%)
Tapered
Retained: 63/251
(25%)
DFU: 49/214
(23%)
Mattick et al.
2008 [37]
Buprenorphine or
placebo
RCTs Shortest
4 week,
others
2 months or
longer
Retained in
treatment opioid
free
Buprenorphine
Opioid free: 495/742
(67%)
Placebo
Opioid free:
202/476 (42%)
Gowing et al.
2006 [38]
buprenorphine,
clonidine, other
active, but not
placebo
RCTs or quasi
randomised trials
Mostly short
term
Number
completing
programme,
presumably drug
free, but that is
not explicitly
stated
Buprenorphine
317/506 (63%)
Clonidine
155/378 (41%)
Int. J. Environ. Res. Public Health 2012, 9 203
Table 2. Results of smoking cessation reviews, ordered by number of participants. The
order is by numbers of participants in the reviews. Intervention is as described in each
review, and details of the reviews is in Table 1.
Intervention
(trial six months or
longer)
Numbers of
patients
Percent abstinent with Relative
benefit
(95% CI)
NNT
(95% CI)
Active Placebo
Nicotine
replacements
therapy
43,108 17 10 1.6 (1.5 to 1.7) 16 (14 to 17)
Physician
intervention
22,260 8 5 1.8 (1.6 to 2.0) 30 (25 to 37)
Self help 19,504 7 5 1.3 (1.2 to 1.5) 65 (45 to 110)
Nursing intervention 15,205 14 11 1.4 (1.3 to 1.5) 38 (27 to 64)
Bupropion 9,940 19 10 2.0 (1.8 to 2.2) 11 (9 to 12)
Counselling 5,028 12 8 1.5 (1.3 to 1.8) 26 (18 to 46)
Group therapy
(versus self help)
4,395 10 6 1.9 (1.5 to 2.3) 22 (16 to 33)
Varenecline 2,023 21 8 2.7 (2.1 to 3.4) 7 (6 to 10)
Cut down to quit
with NRT
1,833 7 3 2.0 (1.3 to 3.0) 30 (19 to 74)
Exercise 1,245 18 14 1.2 (0.9 to 1.5) 24 (12 to 640)
Rimonabant 1,049 17 11 1.5 (1.1 to 2.1) 18 (10 to 72)
Notriptyline 975 21 10 2.1 (1.5 to 2.9) 9 (6 to 16)
Clonidine 776 25 14 1.7 (1.3 to 2.4) 9 (6 to 20)
Figure 1. Cessation (quit) rates with placebo in NRT studies according to number in
placebo group (size of symbol proportional to number in placebo group, inset scale) (data
from Stead et al., 2008 [22]).
Int. J. Environ. Res. Public Health 2012, 9 204
Figure 2. Cessation rates with placebo across different addictions (number of participants).
Table 3. Influence of variables in NRT trials on cessation rates with placebo. Intervention
is as described in each review, and details of the reviews is in Table 1.
Variable
Numbers
of patients
Percent abstinent with
Relative benefit
(95% CI)
NNT
(95% CI)
NRT
Placebo
All trials six months or longer 43,108 17 10 1.6 (1.5 to 1.7) 16 (14 to 17)
Duration of follow up
Six months 4,480 20 9 1.9 (1.6 to 2.2) 9.4 (7.9 to 12)
Twelve months 24,520 15 10 1.5 (1.4 to 1.6) 21 (18 to 25)
Trial setting
Community volunteers 18,823 20 14 1.5 (1.4 to 1.7) 17 (14 to 20)
Smoking clinic 1,283 30 19 1.6 (1.3 to 1.9) 9 (7 to 17)
Primary care 11,427 11 7 1.5 (1.3 to 1.7) 25 (20 to 34)
Hospital recruitment 3,236 14 10 1.3 (1.04 to 1.6) 25 (16 to 62)
Level and type of support
Low level of support 12,348 13 8 1.6 (1.4 to 1.7) 20 (16 to 25)
High level support for individual 16,907 15 10 1.5 (1.4 to 1.6) 21 (17 to 26)
High level support for group 7,140 27 18 1.6 (1.4 to 1.7) 11 (9 to 14)
Type of NRT
Gum 19,120 18 11 1.4 (1.3 to 1.5) 15 (13 to 17)
Patch 18,175 16 10 1.7 (1.5 to 1.8) 17 (15 to 20)
Inhaler 986 17 9 1.9 (1.3 to 2.6) 13 (8 to 28)
Lozenge or tablet 3,109 16 8 2.0 (1.6 to 2.5) 12 (10 to 17)
Nasal spray 887 24 12 2.0 (1.5 to 2.7) 8 (6 to 14)
3.2. Alcohol
Information was available from two systematic reviews [25,26] with data on over 4,600 participants
(predominantly acamprosate and naltrexone [26]) were used, with cessation rates between three and 12
or 24 months; one review of opioid antagonists had 208 participants in longer-term studies [25]. Both
used only properly randomised trials, used various means to assess abstinence, and used placebo,
usually with some form of psychosocial intervention.
Int. J. Environ. Res. Public Health 2012, 9 205
Table 4 shows the main results in terms percentage of abstinent participants with intervention and
placebo. The quit rate with placebo in the two larger reviews was 15% and 30%, with an overall
average cessation rate of 18% in 2,082 participants on placebo. Only acamprosate had sufficient
information to demonstrate effectiveness, with an NNT of 12 (95% CI 9 to 17).
Table 4. Results of alcohol cessation reviews, ordered by number of participants. The
order is by numbers of participants in the reviews. Intervention is as described in each
review, and details of the reviews is in Table 1.
Intervention
Number of
patients
Percent abstinent with
Relative benefit
(95% CI)
NNT
(95% CI)
Active Placebo
Acamprosate 3,324 23 15 1.6 (1.4 to 1.8) 12 (9 to 17)
Naltrexone 1,077 35 30 1.2 (1.0 to 1.4) not calculated
Opioid antagonists 208 52 37 1.4 (1.0 to 2.0) 6 (3 to 43)
3.3. Cocaine
Information was available from seven systematic reviews [27-33], six of which were Cochrane
reviews. Six reviews examined drug therapies, and one cognitive behavioural therapy.
There was data on over 2,600 participants with cessation rates ranging between one and six months,
though most comparisons were relatively small in size. All used only properly randomised trials in
participants with defined cocaine addiction, used a mixture of non-use of cocaine by measurement or
retention in a programme to assess abstinence, and used placebo or counselling. Studies using
validated non-use by measurement or maintenance in programme appeared not to differ in cessation
rates with placebo.
Table 5. Results of cocaine cessation reviews, ordered by number of participants. The
order is by numbers of participants in the reviews. Intervention is as described in each
review, and details of the reviews is in Table 1.
Intervention
Number
of patients
Percent abstinent with
Relative benefit
(95% CI)
NNT
(95% CI)
Active Placebo
CNS stimulants 640 51 53 1.0 (0.8 to 1.1) not calculated
Cognitive
behavioural therapy
570 54 46 1.2 (1.0 to 1.4) not calculated
Anticonvulsants 468 47 52 0.9 (0.8 to 1.1) not calculated
Carbamazepine 313 39 32 1.3 (0.9 to 1.7) not calculated
Desipramine 266 43 50 0.9 (0.7 to 1.1) not calculated
Amantadine 215 39 27 1.4 (1.0 to 2.1) not calculated
Antipsychotics 208 58 45 1.3 (1.0 to 1.7) not calculated
Table 5 shows the main results in terms percentage of abstinent participants with intervention and
placebo, and the relative benefit. The quit rate with placebo varied between 27% and 53%, with an
overall average cessation rate of 47% in 1,134 participants on placebo (not double counting
carbamazepine results with those of anticonvulsants). A review of psychosocial interventions had a
Int. J. Environ. Res. Public Health 2012, 9 206
placebo quit rate of 21% in a small number of small trials [12]. No intervention was significantly
better than placebo.
3.4. Opioids
Information was available from five systematic reviews [34-38], four of which were Cochrane
reviews. Three reviews included data of six months or longer, and two [37,38] of one to six months.
There were a variety of interventions, including psychosocial and pharmacological, mainly methadone
or buprenorphine. The reviews mainly used only properly randomised trials in participants with
defined opioid addiction, used a mixture of non-use of opioid by measurement or retention in a
programme to assess abstinence, and used placebo, or, in one review, maintenance methadone versus
tapered withdrawal. There was information on over 2,300 participants with cessation rates over
various times.
Table 6 shows the main results in terms percentage of abstinent participants with intervention and
placebo. For methadone, results are taken from a review [35] reporting true placebo and not
contaminated with tapering methadone dose. For psychosocial plus pharmacological interventions, the
placebo response included pharmacological interventions and may not be a true placebo, and some of
the buprenorphine trials used clonidine as a control. The quit rate with placebo varied between 25%
and 50%, with an overall average cessation rate of 43% in 590 participants on true placebo in
methadone and buprenorphine trials. A review of psychosocial interventions had a placebo quit rate of
24% in a small number of small trials [12]. Only buprenorphine showed any efficacy in a sensible
number of patients, with an NNT of 4.6 (95% CI 3.6 to 6.6).
Table 6. Results of opioid cessation reviews, ordered by number of participants. The order
is by numbers of participants in the reviews. Intervention is as described in each review,
and details of the reviews is in Table 1.
Intervention
Number of
patients
Percent abstinent with
Relative benefit
(95% CI)
NNT
(95% CI)
Active Placebo
Methadone 1,135 48 50 1.0 (0.8 to 1.7) not calculated
Buprenorphine
884
63
41
1.7 (1.5 to 2.0)
4.6 (3.6 to 6.6)
Psychosocial plus
pharmacological
184 42 25 1.7 (1.1 to 2.6) 6.1 (3.4 to 35)
3.5. Cannabis
The abstinence rate in a single review [12] of mostly short term psychotherapeutic interventions for
cannabis dependence was 15% in a small number of small trials.
4. Discussion
Cessation rates with true placebo in randomised trials using objective measures of abstinence and
typically over six months duration were 8% for nicotine, 18% for alcohol, 47% for cocaine, and 43%
for opioids. This overview of systematic reviews sought evidence of different quit rates with placebo
Int. J. Environ. Res. Public Health 2012, 9 207
in addictions to different substances, and apparently found it. Before accepting such a result at face
value, it is necessary to explore how robust it is.
By concentrating on data from systematic reviews and meta-analyses of randomised trials reporting
abstinence at six months or longer it relied on studies least open to bias. Most information came from
reviews of smoking cessation in over 127,000 participants, though reviews for treatments of other
addictions covered a few thousand participants. Most of the reviews included had a preponderance of
longer-term studies, with determination of abstinence using objective measures. As much as possible,
therefore, comparisons were of like for like.
The example of nicotine replacement therapy, with over 43,000 participants in trials of six months
or longer, showed that vagaries of trial design made little difference to placebo response rates, though
trials lasting 12 months were less effective than those lasting only six months. Together, these
approaches support the contention that between-addiction comparisons of quit rates with placebo
are justified.
Unresolved issues include how missing data are treated in clinical trials; missing data should
probably be counted as failure, but this may not be uniformly applied, and is not generally discussed.
Trials with cocaine addicts had shorter durations than with other substances. As the abstinence rate
tends to decrease with time, this bias is of concern.
The use of a no-treatment control rather than actual placebo might be important in both non-drug
and drug interventions. Placebo has been shown to produce genuine effects through psychological
mechanism (involving expectations, conditioning learning, memory, motivation somatic focus, reward,
anxiety reduction, and meaning), as well as changes of metabolic activity in different brain regions in
cocaine abusers [39]. Context effects could also be a source of variation in placebo response
rates [40,41]. However, placebo response rates tend to be consistent in particular randomised trial
models, using the same outcomes, over the same period of time [42], differing only when the outcome
differs [43-45]. In the case of addiction, the same outcome was being sought over the same time.
We have shown a high variability of success rates in smoking cessation trials where the group size
is below 200 subjects. Trials with fewer than 200 participants were over-represented in opiate and
cocaine studies.
Finally, studies included in the systematic reviews were sensitive in that interventions caused
change in response, with statistically significant relative benefit. This should give comfort that placebo
response measured were meaningful. Few interventions were shown to be highly effective, and low
NNTs were rare, except for buprenorphine treatment for opioid addiction, where one opioid replaces
another (Table 5).
The conclusion, then, is that in the circumstances chosen, placebo quit rates are a useful proxy
marker for the strength of different addictions. The results point to tobacco being by far the strongest,
as has already suggested the findings from epidemiological data [1,2].
Tobacco addiction is far more widespread than other addictions. Many smokers are not alcohol or
drug addicts, though most alcohol or drug addicts are also smokers. One can hypothesize on individual
vulnerability to addictive behaviours, this vulnerability being highest in alcohol and drug addicts. One
other approach could be to look at differential outcomes in tobacco and other substance cessation
in subjects having a dual addiction. In this respect, it has been shown that alcohol outcome was far
better than tobacco outcome in alcoholic smokers undergoing an alcohol and tobacco concurrent
Int. J. Environ. Res. Public Health 2012, 9 208
intervention [46]. Everyday practice shows that many alcoholics consider that quitting tobacco to be
far more difficult to quit than alcohol. Likewise, polydrug abusers often consider that tobacco would
be the last substance they would be able to quit.
It is also the case that, of all abused substances, nicotine is the one where the risk of developing a
dependence syndrome is the highest after first exposure [1,47,48]. Even this leaves us problems, as the
authors themselves use conflicting language [47]: “Over 80% of those who had used tobacco six or
more times met dependence criteria…It appears that tobacco readily produces dependence (perhaps
more so than most other substances), yet it does not progress to severe levels of dependence as readily
as cocaine, heroin and most other drugs. Though it easily causes compulsive use, tolerance, and
withdrawal, tobacco may be less likely to get “out of control” and progress to severe dependence than
most other drugs”.
Perhaps the biggest difficult is that, with addiction, there are several dimensions. These include the
swiftness with which an addiction takes hold, the severity or otherwise of deleterious effects, the time
course of their development, whether they are balanced by any possible beneficial effects, how many
are affected, and how easy it is for an addiction to be broken. In all of these dimensions, tobacco
addiction rates high. It is a strong addiction, being of rapid onset and hard to break, as evidenced by
the large amount of good quality evidence of low placebo response rates in cessation trials, and of
major public health concern because of its negative effects on health in a large number of people.
Acknowledgments
This work was funded by Pfizer.
Conflict of Interest
This work had its genesis in discussions between RAM and Pfizer personnel about how addictions
might be differentiated. That resulted in a piece of commissioned work relating to the use of placebo.
The authors were free to publish the results of any research if they chose, free of any constraints by
Pfizer, which had no role in design, planning, or execution of the study, or in writing the manuscript.
RAM is funded by NIHR Biomedical Research Centre Programme, and has received research funding
from Pfizer. HJA has received sponsorship to attend scientific meetings, speaker honorariums and
consultancy fees from Pfizer, McNeil, GlaxoSmithKline, Pierre-Fabre Santé, Sanofi-Aventis, and
Merck-Lipha.
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    • "However the response to sham acupuncture in our study is remarkable, in that it was higher than the response that has been reported to no treatment. An overview of 12 systematic reviews, including 11 Cochrane reviews, found that the response to no or minimal interventions was low, below 20%, and after 6 months the smoking cessation rate for placebo was 3% − 14%, with an overall average cessation rate of 8.4% in 57,867 participants on placebo [39]. Our treatment with TCM included interventions like pharmacopuncture which are a new evolution of typical TCM practices. "
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