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

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

Disclosures

Curr Med Res Opin. 2004;20(9) 

In This Article

Subjects and Methods

This study was a randomised, double-blind, placebo-controlled trial performed in 81 long-term benzo diazepine users recruited in fourteen study centres in France. Participating centres were all general practices.

The study included subjects aged 25 to 55 years who had been prescribed certain benzodiazepines for the treatment of an anxiety disorder for at least six months at the time of inclusion. The benzodiazepines admitted were lorazepam, bromazepam, alprazolam, oxazepam or clobazam, which represent the most commonly prescribed anxiolytic benzodiazepines in France. The dose of these drugs was required to be that recom mended in the official prescribing information, and to have been stable over the six-month period. Subjects using other anxiolytic or hypnotic benzodiazepines were not included in the study. Subjects with a history of alcohol dependence in the five years prior to inclusion were excluded, as were those consuming excessive quantities of alcohol as defined in the CAGE questionnaire. Proven consumption (either openly declared or detected by urine testing) of illicit psychotropic drugs (opiates, cocaine, cannabis, amphet amines) or of any other sedatives also constituted grounds for exclusion. Additionally, subjects with severe, unstable or uncontrolled hepatic, renal or cardiac insufficiency, with glaucoma or prostate hypertrophy or with any psychiatric disease other than generalised anxiety disorders were also considered as exclusion criteria. Female subjects who were pregnant or breast-feeding were also excluded. Since alertness was assessed with a driving simulation test, included subjects were required to be in possession of a valid driving license for at least five years.

The study lasted ten weeks, including six weeks experimental treatment, divided into four phases (Figure 1).

Study design. The hatched segments indicate treatment with captodiamine and the stippled segments treatment with placebo. Subjects were randomised to captodiamine or placebo at D0. BDZ: benzodiazepines.

The first run-in period started with the screening visit (D-15) when entry criteria were verified and informed consent was obtained. During the run-in period, no modification of drug treatment was made. At the end of this period (D0), subjects were randomised either to placebo or captodiamine and treatment initiated for the following six weeks. Captodiamine was given as three 50mg tablets per day. During the following two weeks (weaning phase), each subject was individually weaned from benzodiazepine treatment. Each subject was instructed to reduce benzodiazepines consumption to zero within this time, and a minimum regimen prop osed, with half the dose being given during the first week followed by a quarter of the dose for the second week and then discontinuation at D14. Nonetheless, if subjects wished to discontinue benzodiazepines more rapidly, they were encouraged to do so. During the third phase (assessment phase; D15-D45), subjects continued captodiamine or placebo treatment was continued in the absence of benzodiazepines. From the assessment visit at D45 until the final study visit at D60 (post-treatment phase), all treatment was discontinued.

Outcome assessments were made at D0, D15, D21, D45 and D 60. The primary outcome criterion was the extent of withdrawal symptoms over the treatment period as assessed with the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ).[40] This scale evaluates twenty clinical signs of withdrawal, each scored between 0 and 2 (0 = absence of symptoms; 1 = moderate symptoms; 2 = severe symptoms). The total score thus obtained ranged from 0 to 100, with a higher score indicating more intense withdrawal.

Secondary outcome assessments included autoevalua tion of tension, anxiety, drowsiness and physical and mental slowness, performed with 10cm Visual Analogue Scales (VAS). Each scale was calibrated from 0 (absence of symptom) to 100 (maximal possible intensity of symptom). The investigator measured intensity of anxiety symptoms with the Hamilton Anxiety Rating Scale (HARS)[41] at D0, D14 and D45. At these time-points, subjects completed the Spiegel sleep quality questionnaire.[42] In order to assess the impact of treatment on cognitive function, visual reaction time was measured and a divided attention test (DADS - Divided Attention Driving Simulator) performed at D0 and D45. Visual Reaction Time was determined using an EAP apparatus taking 32 consecutive measures. After exclusion of the minimal and maximal values, a mean value of the remaining thirty measures was calculated. From the DADS, the number of errors and number of lapses of lane maintenance were recorded. Finally, subjects were asked to rate their satisfaction with study treatment on a semi-quantitative 5 point scale.

Safety assessments included routine clinical examin ation with determination of heart rate and blood pressure. At the same time, urinary screening for benzo diazepines was performed in order to check subject compliance at fortnightly intervals throughout the study.

The data was analysed for the intent-to-treat popula tion, defined as all subjects randomised and receiving at least one dose of study treatment. Categorical variables were compared with the c[2] test and quantitative variables using Student's t-test, the Mann-Whitney U-test or analysis of variance with repeated measures as appropriate. A probability level of < 0.05 was taken to be statistically significant. When multiple comparisons were made, the significance threshold was adjusted using the Bonnefoi correction, for example in the case of five parallel comparisons, the probability level was reduced to 0.01. No a priori power calculations were performed.

The study was conducted according to the Declaration of Helsinki (Hong Kong Amendment), Good Clinical Practices (European Guidelines) and pertinent national legal and regulatory requirements. Written informed consent was obtained from each subject. Subjects were free to withdraw from the study at any time for any reason, without effect on their medical care. The protocol was submitted to and approved by the ethics committee of Grenoble, France.

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