The Role of Captodiamine in the Withdrawal From Long-Term Benzodiazepine Treatment

C. Mercier-Guyon; J. P. Chabannes; P. Saviuc


Curr Med Res Opin. 2004;20(9) 

In This Article

Discussion and Conclusions

This study demonstrated that captodiamine treatment was associated with lower severity of withdrawal symp toms compared to placebo in 81 subjects discontinuing a treatment with benzodiazepines that had lasted at least six months.

Following benzodiazepine discontinuation, the subjects in the placebo group presented more marked withdrawal symptoms on the Tyrer BWSQ score. None theless, the symptoms observed were less pronounced than those seen in previous studies,[24,34] although it should be pointed that they were receiving lower doses of benzodiazepines. In the placebo group, benzodi azepine discontinuation led to a rise in anxiety scores on the HARS. Although scores nearly doubled, they did not reach the threshold required for a diagnosis of clinical generalised anxiety disorder. This suggests that at the time of the study, the initial anxiety disorder for which they had been prescribed benzodiazepines had resolved. It should be noted, however, that the inclusion criteria simply required benzodiazepine use without specifying that the subjects originally presented a formal diagnosis of generalised anxiety disorder. It cannot therefore be ruled out that the original prescription of benzodiazepines was inappropriate. In the captodiamine treatment group, mean BWSQ scores were significantly lower, and no increase in HARS anxiety scores was observed. In fact, at the end of the 45 day treatment period, HARS scores were lower than they were at baseline. This probably reflects the intrinsic anxiolytic activity of captodiamine against symptoms of benzodi azepine withdrawal anxiety. The latter was also captured in our study by the subjective visual analogue scale assessments. Patient satisfaction rating scores were consistently in favour of captodiamine throughout the study period.

Importantly, once captodiamine treatment was stopped after 45 days, there was no re-emergence of anxiety or evidence for withdrawal symptoms. This suggests that a previous benzodiazepine dependence was not simply transferred to captodiamine. However, the absence of recent mechanistic or clinical data differ entiating captodiamine from benzodiazepines prevents us from being able to state unequivocally that the former drug provides a mechanistically different anxio lytic effect. At the end of the two week captodiamine washout period, scores on the BWSQ had actually improved compared to Day 45.

A limitation of the study is that we have little information available on real benzodiazepine use during the discontinuation and follow-up phases, which is the most relevant measure of successful benzodiazepine discontinuation. Moreover, the study provides no information on whether subjects remained abstinent from benzodiazepines after the end of the study once captodiamine treatment had ceased. Urine tests were performed at predefined study visits at days 14, 21, 45 and 60, and these were all negative. However, given that all the benzodiazepines used in the study would have been eliminated within three days, this gives little indication on use between scheduled study visits. A further limitation is that all the benzodiazepines used by the study sample had short elimination half-lives, and the extent to which our findings can be generalised to frequently used benzodiazepines with longer half-lives such as diazepam is unknown. Nonetheless, it has been suggested that the short half-life benzodiazepines may pose the greatest risk of dependence.[18,19] Similarly, the pertinence of our findings for subjects with more severe benzodiazepine dependence is unknown.

We also monitored psychomotor performance over the course of the study using visual reaction time and a driving simulation test. Between the beginning of the study and Day 45, all parameters evaluated improved. This is consistent with the disappearance of the sedative effects of the benzodiazepine. However, there was no difference in psychomotor performance between the captodiamine-treated subjects and the placebo group, suggesting that this drug does not itself possess overt sedative effects. In this respect, captodiamine possesses a clinically relevant advantage compared to several other drugs that have been proposed as adjunctive therapy for benzodiazepine discontinuation such as imipramine, dothiepin and hydroxyzine, all of which interfere with psychomotor performance.[43]

The results of the present study, taken together with a previous study demonstrating that compared to lorazepam, captodiamine has minimal effects on vigilance and does not impair performance on an on-road driving challenge, suggest that captodiamine may be a safe alternative to benzodiazepines in certain types of anxious patients. In the wider public health context, such strategies may respond to the need to decrease inappropriate benzodiazepine use in the general population.

In conclusion, captodiamine represents an interesting option for accompanying benzodiazepine substitution among subjects being treated for mild to moderate anxiety and in whom it is desirable to avoid any risk of dependence or cognitive impairment. Further clinical studies addressing the anxiolytic activity and safety in such subjects are merited.

Covatine is a registered tradename of Laboratoires Bailly-Creat, Paris, France.