Journal of Substance Abuse Treatment 24 (2003) 251 – 255
Regular article
Twenty-four week maintenance treatment of cigarette smoking with
nicotine gum, clonidine and naltrexone
Jamshid Ahmadi, M.D. *, Hamid Ashkani, M.D., Mojtaba Ahmadi, M.D., Nahid Ahmadi, M.S.
Shiraz University of Medical Sciences, Abiverdi Street, Shiraz, Fars Province, Iran
Received 8 November 2002; received in revised form 19 February 2003; accepted 20 February 2003
Abstract
This research study investigated the effect of nicotine gum, clonidine, and naltrexone, in the maintenance treatment of cigarette smoking.
In a double blind study, 171 nicotine-dependent male subjects who met DSM-IV criteria for nicotine dependence and smoking 10 cigarettes
or more per day, were allocated randomly to three equal groups of 57. Subjects received nicotine gum, clonidine, or naltrexone over a
24-week treatment period. The nicotine gum dose was 2 mg every 1 to 2 h for the first 6 weeks, 2 mg every 2 to 4 h for the next 3 weeks, and
2 mg every 4 to 8 h for the remaining 15 weeks. The clonidine dose was 0.4 mg and the naltrexone dose was 50 mg per day. Continuous
abstinence rates were recorded weekly for 24 weeks from the quit date.
The abstinence rates by treatment groups were 36.8% for the nicotine gum group, 19.3% for the clonidine group, and 5.3% for the
naltrexone group,and all between groups differences were significant. These results support the efficacy and safety of nicotine gum and
clonidine for smoking relapse prevention among Iranian nicotine-dependent patients, but call in question the utility of naltrexone treatment
for smoking relapse prevention. D 2003 Elsevier Inc. All rights reserved.
Keywords: Cigarette smoking; Relapse prevention; Nicotine gum; Clonidine; Naltrexone
1. Introduction
Nicotine dependency is regarded as a psychiatric disorder
(Diagnostic and Statistical Manual of Disorders, 4th edition
[DSM-IV]; American Psychiatric Association, 1994; World
Health Organization, 1993). Although cigarette smoking is
the greatest source of preventable morbidity and mortality,
however, most clinicians dealing with individuals using
alcohol and abusing substances do not diagnose or treat
this disorder (Hurt, Eberman, & Slade, 1993).
The main reasons clinicians do not treat nicotine dependence is that the majority have had little, if any, training in
dealing with nicotine dependence (Bobo & Gilchrist, 1983)
and that such dependency is largely socially accepted.
Lifetime prevalence rates of tobacco/ nicotine dependence have been reported as 20% to 40% of the total
community population in the United States of America
(Anthony, Warner, & Kessler, 1994; Breslau, Kilbey, &
* Corresponding author. P.O. Box 71345-1416, Department of
Psychiatry, Hafez Hospital, Shiraz, Iran. Tel.: +98-711-6281511; fax:
+98-711-6287295.
E-mail address: [email protected] (J. Ahmadi).
0740-5472/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S0740-5472(03)00027-8
Andreski, 1991). In a survey in Iran, 26% of men and 3.6%
of the women reported being current cigarette smokers
(Ahmadi et al., 2001).
Accordingly, it is essential to promote quitting smoking;
however, cessation of tobacco smoking is not easy and as
Garvey, Bliss, Hitchcock, & Rosner (1992) reported,
without treatment most quit attempts (97%) were unsuccessful. Pharmacotherapy and behavior therapy could
enhance success rate (Fiore et al., 2000). Although treatment of nicotine dependence is difficult, nicotine replacement therapy with nicotine gum or nicotine patch is fairly
effective (Silagy et al., 2000).
The public health impact of treatment of cigarette
smoking, i.e., the number of cigarette smokers converted
to non-smoking, depends on the effectiveness of treatments in actual use (Shiffman et al., 1997). Use of
nicotine replacement therapy is highly influenced by its
regulatory status, which may impose limitations on access
(Shiffman & Gitchell, 2000). Pharmacotherapy has been
shown to help cigarette smokers stop smoking (Blondal
et al., 1999; Shiffman et al., 2002). Drugs that do not
contain nicotine have special interest for researchers.
Naltrexone has been reported to be effective for treatment
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J. Ahmadi et al. / Journal of Substance Abuse Treatment 24 (2003) 251–255
of alcohol dependents (O’Malley, Croop, Wroblewski,
Labriola, & Volpicelli, 1995; Volpicelli, Alterman, Hayashida, & O’Brien, 1992). Some researchers have theorized that there could be an interaction between
endogenous opiates and the reinforcement of smoking
behavior mediated by nicotine. Cigarette smoking enhances the levels of plasma h-endorphin by 30– 200%;
this enhancement was correlated with plasma level of
nicotine (Pomerleau, Fertig, Seyler, & Jaffe, 1983).
The results of various studies involving the use of opioid
antagonists in cigarette smokers have been mixed. Some
investigators have shown that opioid antagonists such as
naltrexone reduce cigarette smoking (Gorelick, Rose, &
Jarvik, 1989; Karras & Kane, 1980). However, other investigators have reported that opioid antagonists have no effects
on cigarette smoking (Nemeth-Coslett & Griffiths, 1986;
Sutherland, Stapleton, Russell, & Feyerabend, 1995; Wong
et al., 1999).
Due to the modest success the current approaches have
achieved, further research is needed, especially research
directed to specific cultures. Therefore, the goal of this
study was to evaluate the efficacy and the safety of
nicotine replacement therapy compared to clonidine and
naltrexone as well among a sample of Iranian smokers
seeking treatment.
pants were also excluded if they had substance dependence other than tobacco/nicotine.
2.2. Procedures
After physical examination and biochemical tests, subjects
were allocated randomly to one of three treatment groups:
nicotine gum (2 mg pieces), oral naltrexone (50 mg), and
oral clonidine (0.4 mg). Induction onto nicotine gum was
done by administering nicotine gum (2 mg every 1 to 2 h for
the first 6 weeks, 2 mg every 2 to 4 h for the next 3 weeks, and
2 mg every 4 to 8 h for the remaining 15 weeks).
Subjects were visited by an outreach worker once a week
and were asked to discuss their general health and adjustment, and their smoking within the past week. Induction
into clonidine group was done by administering 0.2 and
then 0.4 mg over the first 2 study days and then continuing
with 0.4 mg daily. The naltrexone group was started on
50 mg naltrexone and then continued with 50 mg daily. All
groups were eligible to continue at their assigned dose for
up to 24 weeks. Abstinence rates were based on self-report
and test verification.
2.3. Statistical analysis
Analysis of data was done on SPSS for Windows. Chisquare analyses were used to test for differences in 24-week
2. Materials and methods
2.1. Subjects
The present study was a prospective, double blind,
randomized trial carried out in an outpatient treatment center
in the capital city of Shiraz with a population of 1.5 million.
One hundred seventy-one (171) male cigarette smokers (3
groups with 57 patients in each group) seeking treatment
were screened for participation in the year of 2002. Men
were selected for the study because not only is the rate of
nicotine dependence thought to be negligible in women, but
also women usually do not refer for treatment. In addition it
should be noted that in Iran, women are socially downgraded if they smoke cigarettes.
Patients were stratified into treatment groups by levels
of physical dependence and number of cigarettes per
day. Research staff consisted of addiction psychiatrist,
general practitioner, and psychologist. At screening,
patients were examined by a physician to establish
eligibility and to discuss the informed consent. Patients
had to meet DSM-IV criteria for nicotine dependence
(American Psychiatric Association, 1994). Daily use of
10 cigarettes or more for at least one year was also a
requirement. The patients were eligible for inclusion if
they were between 17 and 64 years old, and had good
health. The patients were excluded if they were using
any medications that were a contraindication for the use
of nicotine gum, naltrexone, or clonidine. The partici-
Table 1
Sample characteristics
Characteristics
Age group (year)
< 20
20 – 24
25 – 29
30 – 34
35 – 39
40 – 44
45 – 49
z 50
Total
Marital status
Single
Married
Total
Educational status
Illiterate
Primary school
High school
Higher education
Total
Occupational status
Laborer
Government-employee
Private sector job
Unemployed
Other
Total
Number
%
8
6
21
25
38
45
12
16
171
4.7
3.5
12.3
14.6
22.2
26.3
7.0
9.4
100
18
153
171
10.5
89.5
100
3
53
76
39
171
1.8
31
44.4
22.8
100
36
68
32
20
15
171
21
39.8
18.7
11.7
8.8
100
J. Ahmadi et al. / Journal of Substance Abuse Treatment 24 (2003) 251–255
Table 2
Frequency distribution of completers by group
Completers
Non-completers
Total
Group
n
%
n
%
N
%
Nicotine gum
Clonidine
Naltrexone
Total
21
11
3
35
36.8
19.3
5.3
20.5
36
46
54
136
63.2
80.7
94.7
79.5
57
57
57
171
100
100
100
100
m2 = 17.53, DF = 2, Significance (2-tailed) = 0.000.
Nicotine gum vs. clonidine, m2 = 4.34, DF = 1, Significance (2-tailed) = 0.04.
Nicotine gum vs. Naltrexone, m2 = 17.10, DF = 1, Significance
(2-tailed) = 0.000.
Clonidine vs. Naltrexone, m2 = 5.21, DF = 1, Significance (2-tailed) = 0.02.
abstinence rates among the three groups, and two-sided ttests were used to test for differences in means. A p-value of
less than .05 was considered significant.
3. Results
253
ns). The majority (63.1%) were between 30 and 44
years of age. The mean number of cigarettes per day
was 19.93 for the total group and there were no
significant differences among groups on mean number
of cigarette smoking per day ( F = 0.04, DF = 2, p =
ns). One hundred fifty-four (90.1%) had no history of
abstinence and only 17 (9.9%) gave history of abstinence before study entry. As Table 1 shows, only 10.5%
of the subjects were single and the others (89.5%)
were married.
3.2. Effects of nicotine gum, clonidine and naltrexone
on smoking
As Table 2 shows, overall 35 (20.5%) subjects were
abstinent throughout the 24-week study. Abstinence rates
at 24 weeks were 21 (36.8%) for the nicotine gum
group, 11 (19.3%) for the clonidine group and 3
(5.3%) for the naltrexone group (m2 = 17.53, DF = 2,
p = .000). The Kaplan-Meier survival analysis is shown
in Fig. 1.
3.1. Demographic variables
3.3. Safety
One hundred seventy-one (171) nicotine-dependent
male patients were allocated randomly to receive nicotine
gum (57), clonidine (57), and naltrexone (57). The mean
age of the total group (171) was 37.68 years (SD = 10.07,
range 17 – 64).
There were no significant differences among the
three groups on mean age ( F = 0.006, DF = 2, p =
Although subjects did not report any severe side effects,
some of them complained of minor adverse effects during
the study as discussed below.
Nicotine gum: Forty-two percent of nicotine gum
users reported experiencing at least one adverse event.
The most common reported adverse events were:
Fig. 1. Kaplan-Meier survival analysis of relapses.
254
J. Ahmadi et al. / Journal of Substance Abuse Treatment 24 (2003) 251–255
headache, nausea, mouth and throat irritation, bad taste, and
anxiety, respectively.
Clonidine: Approximately 31.6% of clonidine users
reported drowsiness, hypotension, or lethargy.
Naltrexone: A majority (84.2%) of naltrexone users
complained of at least one side effect. The most common
side effects reported by the patients were headache, gastrointestinal upset, or sleep disturbances.
4. Discussion
The present study examined the efficacy of nicotine gum,
clonidine, and naltrexone in a sample of Iranian cigarette
smokers. Our study did not show any strong evidence that
naltrexone can considerably reduce cigarette smoking. Our
findings (5.3% success rate for naltrexone) are consistent
with previous studies, which showed no effect of naltrexone
on smoking consumption (Palmer & Berens, 1983; Sutherland et al., 1995).
The current study demonstrated that clonidine was more
effective than naltrexone (19.3% for clonidine vs. 5.3% for
naltrexone, p = .02) in the treatment of nicotine dependence.
Finally, the study showed that nicotine gum could be used
safely and was more effective than clonidine or naltrexone
(36.8% for nicotine gum, 19.3% for clonidine, 5.3% for
naltrexone). Our findings are consistent with previous studies
on nicotine replacement therapy, with nicotine gum (Shiffman et al., 2002) or nicotine patch (Fiore, Smith, Jorenby, &
Baker, 1994; Hurt, Lauger, Offord, Kottke, & Dale, 1990).
Our study had several positive points which strengthened
our findings: (1) it was a 24-week study; (2) the subjects
were allocated randomly; (3) it was prospective; and (4) it
was the initial study with three large groups in Iran.
5. Conclusions
The results support safety and efficacy of both nicotine
replacement therapy (nicotine gum) and clonidine, but not
naltrexone, for quitting smoking for Iranian nicotinedependent individuals.
Acknowledgments
We are very grateful to Professor Jude Ohaeri and
Professor Robert Newman for their constructive comments.
Thanks to Drs. Mohammadsadegh Mohagheghzadeh and
Taghi Hidari for their assistance.
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