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

Abstract and Introduction

Background and objectives: Discontinuation of benzodiazepines can be associated with the emergence of a withdrawal syndrome which compromises successful termination of treatment. The objective of the present study was to evaluate whether a six week administration of captodiamine during benzodiazepine discontinuation could prevent emergence of a benzodiazepine withdrawal syndrome and thus facilitate discontinuation of these drugs.
Subjects and methods: A controlled, randomised, double-blind trial of captodiamine versus placebo was conducted in 81 subjects presenting mild to moderate anxiety and treated for at least 6 months with a stable dose of benzodiazepine. Each subject was gradually weaned from benzodiazepines over a 14 day period using a tapering dose schedule and received captodiamine (150mg/d) or placebo for 45 days from the beginning of the weaning period.
Outcome measures: The primary outcome criterion was the extent of withdrawal symptoms assessed using the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire. Secondary outcome criteria were; self-evaluation of tension, anxiety, drowsiness and slowing of physical and mental performance using visual analogue scales; quality of sleep using the Spiegel questionnaire; anxiety using the Hamilton Anxiety Rating Scale; and cognitive function using a driving stimulation test.
Results: Analysis of the primary study criterion revealed a statistically significant difference ( p < 0.0001) in the emergence of withdrawal symptoms between the two groups in favour of captodiamine at two, six and eight weeks following initiation of therapy. These results were supported by significant beneficial effects of captodiamine on the majority of secondary outcome measures. The switch to captodiamine was associated with an improvement in vigilance, which may be an advantage for the overall safety of the anxiolytic treatment, for example with regard to road safety. Discontinuation of captodiamine was not associated with the emergence of rebound anxiety.
Conclusion: Captodiamine represents an interesting strategy for achieving benzodiazepine substitution with a low risk of dependence or impairment of cognitive function. Further clinical studies addressing the anxiolytic activity and safety of captodiamine in such subjects are merited.

Anxiety disorders are one of the most frequent psychi atric disorders encountered in the general population.[1] For the past 40 years, benzodiazepines drugs have been the reference treatment for anxiety disorders, due to their potent anxiolytic effects, their rapid onset of action and their good overall tolerability. However, the use of these drugs is not without limitations. Firstly, their anxiolytic activity is associated with pronounced sedative effects, characterised by decreased vigilance, impaired psychomotor performance, drowsiness and memory impairment.[2,3,4,5] This brings an increased risk of falls,[6,7] accidents in the workplace and driving accidents.[8,9,10,11,12]

Secondly, long-term use of benzodiazepines can lead to the development of benzodiazepine dependence[13,14,15,16,17,18,19] due to adaptive changes in the neurochemical pathways on which these drugs act in the brain.[20] Benzodiazepine dependence can be revealed by the emergence of a transient withdrawal syndrome, characterised by agita tion, anxiety and sleep disturbances, when attempts are made to discontinue benzodiazepines. These symptoms are distressing for the patient and frequently lead to a return to benzodiazepine use.

In light of these drawbacks, current medical practice, often enshrined in official prescribing recommendations, tends to limit use of benzodiazepines in the treatment of anxiety disorders, by restricting prescription to short-term regimens (six months), by proposing alternative first-line treatment for active subjects, such as certain antidepressants, or by the use of non-pharmacological treatments. In addition, patients who have received benzodiazepines for many years may no longer gain any benefit from these drugs and would profit from stopping treatment. Benzodiazepine use in the commun ity often goes beyond the strict medical management of generalised anxiety disorder and the extent of inappro priate use of benzodiazepines in France is estimated as high.[21] From a public health standpoint, this high prevalence of benzodiazepine use compounds the risks associated with the sedative effects of these drugs. For example, a recent European literature review[22] con cluded that around 8% of road accidents involved a driver who had taken benzodiazepines. For this reason, the French Health Ministry has identified reduction of unjustified benzodiazepine use in the community as a key health objective for 2004.

The chances of successful interruption of long-term benzodiazepine use are nonetheless compromised by the risk of emergence of a withdrawal syndrome. This has led to attempts to identify switching regimes that atten uate this risk. These include gradual tapering of the dose of benzodiazepines,[23,24,25] psychotherapeutic strategies[26,27,28] and use of other drugs to cover the discontinuation period. Drugs that have been assessed as adjunctive therapy to cover benzodiazepine discontinuation include propranolol,[29] antidepressants such as imipramine, trazodone or dothiepin,[30,31,32] anticonvulsants such as carbamazepine or valproate,[33] antihistamines such as hydroxyzine,[34] clonidine[35] and buspirone.[36] However, for most of these drugs, a clear demonstration of utility has not been made. Furthermore, several of these drugs have their own side effects that can be detrimental to optimal functioning in active subjects, such as the sedative effects of certain antihistamines and anti depressants.

Captodiamine is a derivative of diphenhydramine developed in Denmark in the 1950's that has demonstrated tranquillising properties in animals[37] and man.[38] Unlike diphenhydramine, captodiamine is devoid of specific histamine receptor antagonist properties and its mechanism of action remains unclear. Captodiamine was subsequently developed for the treatment of anxiety disorders and marketed as an anxiolytic (Covatine). The clinical profile of captodiamine differs from that of benzodiazepines in several aspects, notably by its relatively low degree of sedative properties.[38] We have recently performed a randomised, double-blind, cross-over study comparing captodiamine and lorazepam on vigilance levels in healthy volunteers using measures of reaction times, subjective measures of sedation and

an assessment of driving performance.[39] This study demonstrated significant deleterious effects of lorazepam on subjective and objective measures of vigilance, whereas captodiamine, used at the standard anxiolytic dose of 150mg/day, presented none of these effects. The low sedative potential of captodiamine may make it an interesting alternative for benzodiazepines.

The present study was thus intended to assess the value of substitution of a benzodiazepine by capto diamine. The objective of the study was to evaluate whether a six week treatment with captodiamine during benzodiazepine discontinuation could prevent emerg ence of a benzodiazepine withdrawal syndrome and thus facilitate discontinuation of these drugs. A controlled, randomised, double-blind, placebo-controlled design was chosen and implemented in subjects who had been treated for at least six months previously with a stable dose of benzodiazepines for the treatment of anxiety disorders.