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Amphetamine withdrawal: II. A placebocontrolled, randomised, double-blind study
of amineptine treatment
Manit Srisurapanont, Ngamwong Jarusuraisin, Jaroon Jittiwutikan
Objective: The aim of this study was to examine the benefits of amineptine, a
dopamine agonist antidepressant, in treating amphetamine withdrawal.
Method: Inpatients with amphetamine withdrawal were recruited to participate in this
placebo-controlled, randomised, double-blind, parallel group, 2-week comparison of
amineptine and placebo treatments. The treatment effects were evaluated by means
of the self-administered Amphetamine Withdrawal Questionnaire (AWQ) and the
interviewer-administered Clinical Global Impression (CGI) scale. An intention-to-treat
analysis was applied to evaluate the therapeutic effects at the end of week 1 and
week 2.
Results: Twenty-two patients took part in each treatment group. The week-1 and
week-2 intention-to-treat analyses showed that the mean AWQ reversed vegetative
scores (combined scores of decreased energy, increased appetite and craving for
sleep items) of the amineptine group were significantly lower than those of the
placebo group. The general condition of the amineptine group assessed by CGI also
significantly improved at the end of week 2. Although the discontinuation rate due to
dissatisfaction with treatment of amineptine group (1/21) was much lower than that
of placebo group (6/22), those rates were not significantly different (p = 0.09).
Conclusions: Amineptine is specifically effective for treating a major component of
amphetamine withdrawal: a reversed vegetative syndrome. Although more than
2 weeks of amineptine treatment may contribute further benefits, both risks and benefits should be taken into account in doing so.
Key words: amineptine, amphetamines, antidepressant, substance withdrawal.
Australian and New Zealand Journal of Psychiatry 1999; 33:94–98
Amphetamine abuse causes severe medical,
psychological, legal and financial difficulties.
Although amphetamine withdrawal is usually mild,
Manit Srisurapanont, Assistant Professor (Correspondence)
Department of Psychiatry, Chiang Mai University, PO Box 102,
Amphur Muang, Chiang Mai 50202, Thailand. Email:
<[email protected]>
Ngamwong Jarusuraisin, Staff Psychiatrist; Jaroon Jittiwutikan,
Director
Northern Drug Dependence Treatment Centre, Chiang Mai,
Thailand
Received 5 December 1997; revised 17 July 1998; accepted 7 October
1998.
many patients may have severe withdrawal symptoms and need some intensive treatments, including
hospitalisation [1,2]. Both temporary inability to
function and withdrawal symptoms that occur during
abstinence in part enhance the repetitive use of
amphetamines. Despite effective treatment for
amphetamine withdrawal being helpful to encourage
users to stop taking amphetamines, no current medication is specifically effective for treating this withdrawal [3]. At present, only supportive and
psychosocial treatments can be administered to help
amphetamine users pass the withdrawal state.
Due to the similarity of amphetamine and cocaine
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M. SRISURAPANONT, N. JARUSURAISIN, J. JITTIWUTIKAN
withdrawal syndromes, as well as the lack of amphetamine-withdrawal treatment studies, clinicians
usually use treatments appropriate for cocaine withdrawal to relieve symptoms of amphetamine withdrawal. However, this practice should be used with
caution. Although amphetamines and cocaine act primarily by stimulating catecholamine release [4], differential effects on monoamine systems have been
reported [5]. In addition, amphetamines have longer
half-lives and more potent sympathomimetic effects
[6,7].
Dopaminergic hypoactivity appears to play an
important role in causing amphetamine withdrawal.
It occurs rapidly and persistently for several days
after the cessation of amphetamine use [8,9]. In addition, high doses of amphetamine may damage the
dopaminergic elements in the reward system, which
results to prolonged anhedonia [10,11].
Giving a medication that can increase the dopaminergic activity should be of benefit in treating amphetamine withdrawal. According to the mechanism of
action, amineptine, a dopamine agonist antidepressant available in Europe, should ameliorate
amphetamine-withdrawal symptoms. Several studies
have shown that both amphetamines and amineptine
can increase dopamine release and block dopamine
reuptake [12–15]. In addition, the results of an
animal study have also shown that the locomotor
activity, stereotyped behaviour and hypothermia
induced by amineptine are similar to but not as
marked as those produced by amphetamines [16].
Since amineptine may be able to relieve the symptoms of amphetamine withdrawal, we proposed to
examine the therapeutic effects of amineptine in
patients with amphetamine withdrawal.
Method
Patients with amphetamine withdrawal who were
hospitalised at the Northern Drug Dependence
Treatment Centre were recruited to participate in this
placebo-controlled, randomised, double-blind, parallel group, 2-week comparison of amineptine and
placebo treatments. The inclusion criteria were:
(i) aged between 15 and 65 years; (ii) fulfilling the
DSM-IV diagnostic criteria for amphetamine withdrawal [7]; (iii) a score of 10 or more on the
Amphetamine Withdrawal Questionnaire (AWQ)
[17], (iv) positive urine test for amphetamine; and
(v) giving a written consent. The patients were
excluded if they had more than 5 days of amphetamine abstinence, positive urine tests for opiates, psy-
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chotic symptoms or serious physical illness. Pregnant
and nursing women were also excluded.
To ensure blinding of the patients and raters, either
100 mg amineptine or placebo was enclosed within
an unmarked, identical capsule. Blocked randomisation by using tossing-a-coin technique was applied
throughout the study. After 24–120 h of amphetamine
abstinence, the investigators assessed the severity of
amphetamine withdrawal at baseline and randomly
assigned either amineptine or placebo to the patients.
The medication was administered as two capsules
after breakfast and one capsule after lunch. However,
those fixed doses of trial medications could be
lowered if the intolerable adverse effects occurred.
Lithium, antipsychotics and other antidepressants
were not given during the study. However, low-dose
lorazepam might be occasionally used in patients with
moderate to severe anxiety or insomnia. Supportive
treatment, for example, vitamin and special nutrition,
could be given if necessary. In addition, every patient
was given a set of psychosocial treatments, including
therapeutic milieu, group and individual therapy and
psycho-education.
The therapeutic effects of amineptine and placebo
were evaluated by means of the self-administered
AWQ and the interviewer-administered Clinical
Global Impression (CGI) scale [18]. Both measures
were completed at baseline (after 24–120 h of
amphetamine abstinence or day 0), at the end of
week 1 and at the end of week 2.
Initial analysis of the data involved determining the
two-tailed, significant differences (p < 0.05) between
groups with regard to sex, age, duration of amphetamine use and duration of amphetamine abstinence.
Since AWQ can be divided into three subscales [17],
the differential treatment effects between groups
were assessed by comparing the means of AWQ
hyperarousal score (combined scores of drugcraving, agitation and vivid or unpleasant dreams
items), AWQ reversed vegetative score (combined
scores of decreased energy, increased appetite and
craving for sleep items), AWQ anxiety score (combined scores of loss of interest or pleasure, anxiety
and slowing of movement items), AWQ total score
and CGI score. In addition, the difference of discontinuation rates due to dissatisfaction with treatment
or adverse effects was also assessed.
An intention-to-treat analysis was applied for
assessing the therapeutic effects at the end of week 1
and week 2. All patients assessed at least once at the
end of week 1 were included in the last observation
carried forward (LOCF) method of the 2-week inten-
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AMINEPTINE FOR AMPHETAMINE WITHDRAWAL
tion-to-treat analysis. The two-tailed, significant differences (p < 0.05) of nominal data (male/female),
ordinal data (AWQ subscale score, AWQ total score
and CGI score) and numerical data (age, months of
use and hours of abstinence) were assessed by using
Fisher’s exact test, Wilcoxon Rank Sum W-test and
Student’s t-test, respectively.
Results
A total of 41 male and three female patients participated in this trial. All patients were amphetamine
smokers or oral users. Twenty-two patients took part
in each treatment group. For all 44 patients, the
means of age, amphetamine-use duration and
amphetamine-abstinence period were
19.6
(SD = 5.5) years, 23.5 (SD = 11.9) months and 52.7
(SD = 22.8) hours, respectively. The demographic
and baseline characteristics of amineptine- and
placebo-treated groups were not significantly different with regard to sex, age, amphetamine-use duration, amphetamine-abstinence period, the AWQ
score and the CGI score (Table 1). A small number of
patients (four amineptine-treated patients and three
placebo-treated patients) were also given lorazepam
in the dose range of 0.5–1.5 mg day–1 for 5–14 days.
Since all patients tolerated the trial medications
well, the standard dose (as described) was administered to all of them. All of those taking amineptine
were therefore treated at the dose of 300 mg per day.
Of 44 patients included at the study entry, 43 and
35 patients completed 1 week and 2 weeks of treatment, respectively. During the first week, one
amineptine-treated patient requested an early discharge and dropped out of the study. This patient’s
data were not included in any subsequent analysis.
During the second week, one placebo patient with
much improvement, one amineptine patient with no
improvement and six placebo patients with no
improvement discontinued the treatments. Although
the discontinuation rate due to dissatisfaction with
treatment of amineptine group (1/21) was much
lower than that of placebo group (6/22), those rates
were not significantly different (p = 0.09).
The 1-week and 2-week intention-to-treat analyses
showed that the mean AWQ reversed vegetative
scores of the amineptine group were significantly
lower than those of placebo group (see Table 2). The
general condition of the amineptine group assessed
by CGI also significantly improved at the end of
week 2. No significant differences were found on any
comparisons of AWQ hyperarousal score, AWQ
anxiety score and AWQ total score, as well as CGI
score at the end of week 1.
Discussion
The significantly lower AWQ reversed vegetative
scores of amineptine group can be seen at the end of
week 1 and week 2. The results suggest that aminep-
Table 1. Demographic and baseline characteristics of amineptine- and placebo-treated groups
Demographic and
baseline characteristics
Amineptine
group
Placebo
group
Significant
difference*
Male/female ratio
Mean age ± SD (years)
Mean duration of amphetamine
use ± SD (months)
Mean duration of amphetamine
abstinence ± SD (hours)
AWQ score (mean ± SD)
Hyperarousal
Reversed vegetative
Anxiety
Total
CGI score (mean ± SD)
21/1
18.2 ± 1.5
20/2
21.1 ± 7.4
NS
t = 1.83; p = 0.07
21.3 ± 11.3
25.6 ± 12.3
t = 1.21; p = 0.23
54.3 ± 26.2
51.1 ± 19.2
t = 0.47; p = 0.64
2.7 ± 2.0
7.6 ± 2.0
4.5 ± 2.3
16.6 ± 5.2
3.6 ± 0.7
3.0 ± 2.4
7.8 ± 1.7
4.1 ± 2.0
17.0 ± 4.1
3.3 ± 0.8
Z = 0.19; p = 0.85
Z = 0.08; p = 0.93
Z = 0.55; p = 0.58
Z = 0.52; p = 0.60
Z = 0.70; p = 0.28
AWQ, Amphetamine Withdrawal Questionnaire; CGI, Clinical Global Impression Scale.
*The two-tailed significant differences (p < 0.05) of nominal data (male/female ratio), ordinal data (AWQ score and CGI
score) and numerical data (age, months of use and hours of abstinence) were assessed by using Fisher’s exact test,
Wilcoxon Rank Sum W-test and Student’s t-test, respectively.
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M. SRISURAPANONT, N. JARUSURAISIN, J. JITTIWUTIKAN
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Table 2. The scores of measures used to compare the therapeutic effects of amineptine and placebo
Measures
AWQ score (mean ± SD)
At the end of week 1
Hyperarousal
Reversed vegetative
Anxiety
Total
At the end of week 2
Hyperarousal
Reversed vegetative
Anxiety
Total
CGI score (mean ± SD)
At the end of week 1
At the end of week 2
Amineptine
group (n = 21)
Placebo
group (n = 22)
Significant
difference*
1.7 ± 1.7
4.2 ± 2.1
2.8 ± 2.0
9.7 ± 5.1
1.9 ± 2.0
5.5 ± 1.7
2.2 ± 2.2
10.5 ± 5.4
1.6 ± 2.4
4.0 ± 1.9
2.0 ± 1.9
8.1 ± 5.6
1.7 ± 1.8
5.3 ± 1.4
1.7 ± 2.3
9.5 ± 4.9
Z=
Z=
Z=
Z=
2.1 ± 0.5
1.6 ± 0.7
2.3 ± 0.7
2.1 ± 0.7
Z = 1.45; p = 0.15
Z = 2.20; p = 0.03
Z = 0.15; p = 0.88
Z = 2.08; p = 0.04
Z = 1.28; p = 0.20
Z = 0.23; p = 0.82
0.90; p = 0.37
2.68; p = 0.01
0.76; p = 0.45
1.07; p = 0.28
a
AWQ, Amphetamine Withdrawal Questionnaire; CGI, Clinical Global Impression Scale.
*The two-tailed, significant differences (p < 0.05) were assessed by using Wilcoxon Rank Sum W-test.
tine is an effective treatment for the reversed vegetative symptoms of amphetamine withdrawal, including decreased energy, increased appetite, craving for
sleep. The significant improvement seen at the end of
week 1 also indicates the rapid relief of those symptoms. However, amineptine has no benefits on the
other two components of amphetamine withdrawal.
As the baseline scores of AWQ reversed vegetative
subscale in both groups were moderately higher than
those of the other two subscales, the reversed vegetative symptoms of amphetamine withdrawal should
be considered as a major component of amphetamine
withdrawal. Therefore, the therapeutic effect of
amineptine on reversed vegetative symptoms found
in this study is in part beneficial for patients with
amphetamine withdrawal.
While the CGI score revealed significant improvement of amineptine patients’ general condition, the
AWQ total score showed no trend in that benefit. The
concordance of CGI score and AWQ reversed vegetative score, but not AWQ total score, infers that a
health professional tends to pay more attention to
reversed vegetative symptoms than others. This may
be due to the fact that reversed vegetative symptoms
are more easily elicited since they are objective
signs, but most other withdrawal symptoms are subjective symptoms.
The benefit of amineptine on the reversed vegetative component, but not on the other two components, may reflect a variety of pathophysiological
processes occurring during amphetamine abstinence.
As amineptine selectively increases dopamine activity, the reversed vegetative symptoms may closely
relate to the dopamine dysfunction. Whether the
medications that can restore other neurotransmitter
dysfunction, especially noradrenaline dysfunction,
will be beneficial on other components of amphetamine withdrawal syndrome should be further studied.
Similar to the drug treatment of amphetamine withdrawal, very few studies of cocaine-withdrawal pharmacotherapy have been conducted. Although many
investigators have reported the benefits of using
desipramine, amantadine and bromocriptine for
cocaine craving [19–21], their therapeutic effects
have not been established [22]. On one hand, those
medications should be investigated for treating
amphetamine withdrawal. On the other hand, the
results of the present study may encourage attempts
to investigate the benefits of amineptine in treating
cocaine withdrawal.
Probably due to the amphetamine-like effects but
in a lesser extent, a few patients with amineptine
abuse have been reported [23,24]. However, its
prevalence seems to be very low in comparison to the
very large number of patients who have been treated
with this medication. In several countries, amineptine is still widely used after several years of prescription. The duration of this study was limited to
only 2 weeks in order to reduce the risk of amineptine abuse. Since amphetamine withdrawal can last
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AMINEPTINE FOR AMPHETAMINE WITHDRAWAL
for several weeks, longer than 2 weeks of amineptine
treatment may contribute further benefits. However,
both risks and benefits should be taken into account
in doing so. In this study, we gradually stopped
amineptine within 1 week after the end of study and
did not find any amineptine abusers.
A limitation of this study is the small sample size.
AType II error is possible in viewing the non-signif icant differences found in this study, especially the
discontinuation rate, the CGI score at the end of
week 1.
In conclusion, amineptine is specifically effective
for treating a major component of amphetamine
withdrawal: a reversed vegetative syndrome.
Although longer than 2 weeks of amineptine treatment may contribute further benefits, both risks and
benefits should be taken into account in doing so.
9.
10.
11.
12.
13.
14.
15.
Acknowledgements
We wish to thank Ms Montira Viriya for her coordination and Associate Professor Keith Godfrey for
his language assistance.
16.
17.
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