Amphetamine Withdrawal: II. A Placebo-Controlled,Randomised,Double-Blind Study of Amineptine Treatment

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, psychotic 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 drug-craving, 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 intention-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 amineptine 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, 20, 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, 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 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-significant 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.