Respiratory and Sedative Effects of Clobazam and Clonazepam in Volunteers

Br. J. clin. Pharmac. (1990), 29, 169-177

Respiratory and sedative effects of clobazam and clonazepam in volunteers

J. D. WILDIN, B. J. PLEUVRY, G. E. MAWER, T. ONON & L. MILLINGTON Department of Physiological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT

1 The respiratory and psychomotor effects of two benzodiazepines used mainly as anticonvulsants were compared in healthy volunteers, using a double-blind placebo controlled design. 2 Clobazam (10 and 20 mg) produced significantly fewer psychomotor side effects than clonazepam (0.5 and 1 mg). Neither drug at either dose affected the ventilatory response to C02. 3 Although clonazepam produced significant effects on psychomotor performance, these did not correlate with plasma drug concentration. 4 Our studies provide further evidence that at the doses chosen clobazam is considerably less sedating than clonazepam. Further investigation is required into the tolerance profile of both drugs in patients. Keywords clobazam clonazepam ventilatory response to CO2 psychomotor tests

Introduction Clobazam and clonazepam are benzodiazepines tests, using a double-blind crossover design. widely used as adjunctive therapy in epilepsy. Some oral benzodiazepines depress the ventila- There are numerous reports in the literature tory response to carbon dioxide (Pleuvry et al., concerning the effects of these drugs individually 1980; Rudolph et al., 1978; Utting & Pleuvry, and in comparison with other benzodiazepines 1975), but little work has been done in this (Gudgeon & Hickey, 1981; Hindmarch, 1979). respect with clonazepam and clobazam. Thus, Cull & Trimble (1985) compared the two agents the ventilatory response to carbon dioxide has in volunteers, but the same subjects did not been investigated. The correlation between receive both clonazepam and clobazam. Further- changes in performance and plasma drugs con- more, the benzodiazepine was administered centration has also been determined. chronically over a 2 week period and only a single dose of each drug was included. Clobazam has a 1-5 structure, unlike the classical 1-4 structure possessed by clonazepam Methods and most other benzodiazepines including diazepam. This seems to confer unusual properties Clobazam and clonazepam were administered such as enhancement at low dosage of psycho- to healthy volunteers in a five period, double- motor performance which is normally depressed blind, crossover study. The doses selected were by these drugs. It is less sedative than typical recommended starting doses for adult patients 1-4 benzodiazepines in chronic dosage (Cull & with epilepsy (British National Formulary, 1989). Trimble, 1985). The treatments were presented as identical In order to determine the selectivity of these opaque capsules containing clobazam 10 or 20 two drugs, at conventional starting doses, they mg, clonazepam 0.5 or 1 mg or placebo and have been compared in a range of psychomotor administered in a random sequence. 169 170' J. D. Wildin et al.

Volunteers measured using a 100 mm scale marked at one end 'wide awake' and at the other 'nearly asleep'; Ten volunteers (six male) aged 22-37 years, similarly coordination was registered between 55-85 kg were assessed by medical examination extremes of 'well co-ordinated' and 'clumsy'. with biochemical and haematological screening. The details of the study were explained and Postural sway Subjects were asked to stand on written informed consent was obtained. Any- an electronic sway meter. This consisted of a one taking regular medication (with the excep- wooden circular platform resting on a resilient tion of oral contraceptives), smokers and women rubber plate, into which had been embedded who were pregnant or intended to become four pressure transducers spaced 900 apart. Cut- pregnant were excluded. The experiment had out shapes attached to the top of the platform approval from the University Ethics Committee. ensured that the subjects' feet were positioned The subjects were fasted from the night before consistently so that measurements were repeat- dosage and fruit juice only was allowed on the able. This resembled the equipment used by following morning not less than 2 h before in- Patat & Foulhoux (1986). gestion of the drug capsules. Food and fluid Volunteers were asked to stand erect and were permitted 4 h after ingestion of the cap- motionless for two 1 min periods, one sules, but the subjects were asked to abstain with eyes open and one with eyes closed. The from coffee and alcohol from the day before output from the pressure transducers was re- and until 24 h after dosage. Each volunteer was corded as a variable line in the anterior-posterior asked to attend on five separate occasions and and left-right directions on two separate record- received the treatments described. At least 7 ing potentiometers (Rikadenki). This contrasts days elapsed between successive treatments. with the computerised system used by Patat & Foulhoux (1986) who required a complex Psychomotor performance Psychomotor per- analysis of the components of postural devia- formance was assessed using the 'Leeds Psycho- tion. Each potentiometer record was analysed motor Tester'. Two tests were carried out in- via a graphics tablet attached to an Apple II dependently. In the choice reaction time test computer. By tracing the potential record, the the subject was required to scan a semi-circle program calculated the mean deviation from a of six lights each adjacent to a corresponding straight line joining the start and stop potentials. button. The lights were illuminated individually This value was used to represent the relative on a random basis. As soon as the subject de- sway of the individual. The machine was cali- tected a light he lifted his finger from the base brated by determining the potential change position button and, as quickly as possible, was produced by a 1 kg mass placed over each sway expected to press the appropriate response sensor. button thus extinguishing the light. This pro- vided the total response time (light on to light Ventilatory response to C02 The ventilatory off) and the recognition component (light on to response to CO2 was measured using a Bell finger lifted). The difference between the two closed circuit spirometer (Ealing). The soda lime was designated movement time. Thirty stimuli canister was removed from the spirometer circuit were presented. The critical flicker fusion and the cylinder filled with 5% CO2 in oxygen. threshold (CFFT) (Hindmarch, 1979) was used Following a maximal expiration, the subject as an index of arousal. The subjects were re- was connected to the spirometer and after initial quired to detect flicker in a set of four light deep inspiration, was allowed to breathe quietly emitting diodes in foveal fixation at 1 m. A into the apparatus. Rebreathing took place for mean of six thresholds was taken, three with not more than 4 min. gradually increasing frequency of flicker where Gases were sampled at the mouthpiece and the point that perceived flickering stops was measured continuously by an infrared analyser recorded and three with a decreasing frequency (Morgan) before being returned to the circuit. of flicker where the point that perceived flicker- The CO2 analyser was connected to a recording ing starts was recorded. potentiometer (Rikadenki). End tidal pCO2 The digit symbol substitution test (Wechsler, (Kpa) was measured from the trace. Minute 1944) involved substituting symbols for digits volume was plotted against end tidal pCO2. according to the code given in the box at the The slope of the best straight line and the 30 1 top of the page. The number of symbols cor- min-' volume intercept were calculated. This rectly substituted in a 90 s period was counted. method was based on that of Read (1967) with The volunteers reported their subjective con- certain modifications. Read (1967) used an initial dition on visual analogue scales. Sedation was concentration of 7% C02, thus equilibrium Anticonvulsant benzodiazepines in volunteers 171 occurred more rapidly and end tidal pCO2 more Statistics closely mirrored brain tissue pCO2. However, in our previous experience this had proved ex- Measurements of response at each time were tremely stressful to volunteers, often inducing expressed as the difference between the post- headaches and dyspnoea. and pre-treatment (zero time) values. In the preliminary analysis measurement from different times were pooled and differences due to Blood pressure andpulse rate Systolic and dia- treatments were assessed without regard to time. stolic blood pressure were measured using the Similarly, differences due to time were assessed Copal printing/auto-inflation digital sphygmo- without regard to treatments. If either revealed manometer. The same arm was used for all significance (P < 0.05) then differences due to readings and the same observer made all treatment were assessed separately at each time. measurements. It was attempted to ensure that Since the sequence of treatment was random, the positioning of the arm cuff was identical on the effects of treatments and sequence could each occasion. Readings were taken at stage 1 not be resolved. Significance was judged from and stage 5. the variance ratio (F) derived from analysis of variance. Timing A blood sample was taken via a catheter inserted into an arm vein and all the Results tests described above were performed shortly before drug administration, half hourly for the Significant effects of clobazam compared with next 2 h and then at hourly intervals until 8 h placebo were found on four of- the sixteen tests after administration. Blood clotting in the (CFlFT, visual analogue scales and L-R postural catheter was prevented by flushing with hep- sway). Significant effects of clonazepam were arinised saline (2u ml- 1) after each sample had found on nine of the sixteen tests. been taken. The catheter was removed at 8 h. The results for critical flicker fusion threshold A further set of tests were performed 24 h after are shown in Figure 1. Subjects given placebo drug administration and a 10 ml blood sample showed a decrease in threshold frequency was taken by venepuncture. Blood was collected throughout the experimental day. This was not in potassium oxalate tubes, mixed and centri- significant at any one time and had returned to fuged. The plasma was removed and stored at control values by the following morning. Similar -20° C until assayed for benzodiazepines. results were obtained from subjects given clobazam 10 mg. The higher dose of clobazam produced a significantly (P < 0.05) greater de- Assays Clobazam was extracted from plasma crease than placebo over the first 2 h. Clona- and plasma concentrations measured by. the zepam 0.5 mg also tended to decrease flicker method of Caccia et al. (1979) using gas chro- fusion threshold but this failed to reach signifi- matography with electron capture. There were cance compared with placebo. The higher dose certain modifications. The stationary phase was of clonazepam caused a decrease in the threshold (3%) SP2250DA on 80/100 Supelcoport, using frequency for most of the day, with a deficit still N2 as the carrier gas. Elution time for clobazam apparent the next morning. This was signifi- was 8 min. Diazepam was used as internal stan- cantly different from placebo at 1-7 h and from dard. Drug recovery using this method was 86 clobazam 20 mg at 2 and 5 h. Other pairwise + 4 (% ± s.d., n = 4) and was consistent for comparisons were not made. high and low concentrations of the drug. There was a slight increase in recognition Clonazepam was assayed by a modification of time over the day in placebo-treated subjects the method of Badcock & Pollard (1982) using (Figure 2). Neither dose of clobazam produced diazepam as internal standard. The stationary changes that were significantly different from phase was 3% SP2150DA on 100/120 Supelco- placebo, although low dose clobazam tended port as the support, with N2 as the carrier gas to shorten recognition time. The low dose of flowing at 60 ml min1. Drug recovery was 80.9 clonazepam tended to increase recognition time + 9.0 (% ± s.d., n = 4) at both high and low but only 1.0 mg clonazepam produced a signifi- concentrations. cant increase above placebo and above clobazam N-desmethylclobazam was assayed under the 20 mg. Recovery after the second hour was same conditions by a modification of the method rapid. of Greenblatt (1979). Retention time for N- As with the previous two tests, subjects given desmethylclobazam was 14 min. placebo showed a decrease in their performance 172 J. D. Wildin et al.

4 5 7 Tinw (b), Figure 1 Changes in critical flicker fusion threshold (Hz ± s.e. mean) after placebo (A), clobazam 10 (0), 20 mg (0) and clonazepam 0.5 (e), 1 mg (u) in 10 subjects. * indicates a significant (P < 0.05) difference from placebo.

I- r 9 i.jL ; ; 3: ,I'I; fI-:* e-% 1- ._: . i :i 1 .. .3 4.'5 . 7 Th.li.1 .11 Figure 2 Changes in recognition time (s ± s.e. mean) after placebo (A), clobazam 10 (0), 20 mg (0) and clonazepam 0.5 (0), 1 mg (-) in 10 subjects. * indicates a significant (P < 0.05) difference from placebo.

in the DSST throughout the trial day (Figure clobazam, and both doses of clonazepam de- 3). Neither dose of clobazam further affected creased subjective feelings of wakefulness. performance in this test. Both doses of clonaze- Some subjects receiving clonazepam 1 mg had pam significantly reduced performance, with to be awakened to undertake tests. A similar the higher dose having a greater and more persis- pattern of effects was seen with the dexterity tent effect. This significantly exceeded the effect scale except that low doses of clobazam tended of the higher dose of clobazam at 1, 2 and 4 h. to improve dexterity. Subjects receiving placebo generally improved in wakefulness during the day (Figure 4)-peaks Postural sway coinciding with lunch and the end of the experimental day. Similar results were obtained for Measurements of postural sway with eyes open subjects given clobazam 10 mg. Higher dose and eyes closed showed very similar results, and Anticonvulsant benzodiazepines in volunteers 173

14~~~~~~~~32 0 1 2 3 4 -5 8 7 Time tlh) Figure 3 Changes in DSST (no. of symbols substituted ± s.e. mean) after placebo (A), clobazam 10 (0), 20 mg (0) and clonazepam 0.5 (0), 1 mg (e) in 10 volunteers. * indicates a significant (P < 0.05) difference from placebo.

I -J5 E ; :3 - R'157

& ,-a I - 7 .0 4- 8h 8124 h -t Figure 4 Changes in subjective assessment by visual analogue scale of wakefulness (mm ± s.e. mean) by placebo (A), clobazam 10 (0) and 20 mg (0), and clonazepam 0.5 (0), 1 mg (m) in 10 volunteers. * indicates a significant (P < 0.05) difference from placebo. hence only the eyes open results are shown. A intercept of the ventilation (I min-') (%) CO2-' significant increase in sway after clobazam was curve. Similarly, no effects on pulse, blood observed at one time point only (1 h, 10 mg). pressure or body temperature were seen. Clonazepam lower dose significantly increased anterior-posterior postural sway at 1 h, and Plasma concentrations with the higher dose this effect persisted for 5 h (Figure 5). Left-right sway was less adversely After clobazam, maximal plasma concentrations affected with high dose clonazepam increasing were reached at 1.3 ± 0.2 h (10 mg) and at 1.6 sway for only the first 3 h. 0.3 h (20 mg). After clonazepam maximal concentrations were reached at 2.2 ± 0.3 h Ventilatory response to CO2 (0.5 mg) and at 2 ± 0.6 h (1.0 mg). These results are shown in Figure 6. The ratio of the In the doses used, neither clobazam nor clona- area under the concentration-time curves zepam produced any effect on the slope or the (AUCO, 24) high dose/low dose was 2.31 ± 0.78 174 J. D. Wildin et al.

Figure 5 Changes in sway with eyes open in the anterior-posterior plane by placebo (A), clobazam 10 (o) and 20 mg (0), and clonazepam 0.5 (-) and 1 mg (v). * significantly different from placebo (P < 0.05). Sway is measured as the mean deviation from a mean point in arbitrary units ± s.e. mean (n = 10). In this plane a 1 kg mass at the extremity of the platform produced a deviation of 1.916 units. for clobazam and 2.4 ± 0.98 for clonazepam. effect and rapid recovery seen with recognition Two subjects showed very low concentrations time (Figure 2). The CFF response appeared to of clonazepam after the 0.5 mg dose. They were parallel the plasma concentration of clonazepam excluded from the pharmacokinetic analysis. (Figure 6b). Other responses (DSST, recognition The concentrations of N-desmethylclobazam time) waned whilst the concentration remained were low in all subjects and did not exceed 200 high. This may indicate that acute tolerance, ng ml-'. which has been recognised with other benzodiazepines (Crawford et al., 1987), develops to the effects of clonazepam on some functions but Discussion not on others. Alternative explanations are less likely. The rapid waning of the effect of 1 mg Clobazam had little or no effect on a wide range clonazepam on recognition time (Figure 2) is of psychomotor and subjective tests, when com- unlikely to be caused by the concentration falling pared with placebo. In some cases the effect of below a critical threshold since the mean con- clobazam was to improve the score (e.g. 10 mg centration at 3 h exceeded that at 2 h (Figure clobazam on recognition time and visual ana- 6b). Similarly, a more rapid fall in the concen- logue scale for dexterity), when compared with tration of drug in venous plasma than in brain placebo. Several volunteers taking clobazam would lead to the unexpected presence of psycho- spontaneously reported not drowsiness but a motor effects rather than early recovery. Within mild sense of detachment. These results support subject correlations between plasma concentra- previous work by other workers (Parrott, 1982; tions and effect were generally very weak. This Robinson et al., 1981; Steiner-Chaskel & Lader, supports previous findings by Congdon & For- 1981). sythe (1980) who found that in patients, dose The tests differed in their sensitivity to the was unrelated to effect in terms of seizure scores, effects of these drugs. For example, although and Froscher & Engels (1986) who observed in recognition time was affected markedly by discussion following a paper on tolerance to clonazepam, the movement time was not signi- clonazepam that there was no correlation be- ficantly prolonged. This demonstrates that once tween clonazepam serum levels and side effects. the light was perceived the subject had no signi- The mild effects of clobazam made concentra- ficant deficit in his motor ability. tion/effect analysis impractical. Graphical plots The greatest persistence of clonazepam effects of response (DSST, recognition time) against was seen in the flicker fusion (CFF) test (Figure plasma concentration of clonazepam were pre- 1). This contrasts with the brief duration of pared in the expectation of observing a hyster- Anticonvulsant benzodiazepines in volunteers 175

a 600

500

C 400 0

300 a) c 0 0 E 200 nN -0 0

4 5 Time (h) b

P 4_C

CLco

0 a)

-0 1 2 3 4 5 6 7 8 11 24 Time (h)

Figure 6 (a) Plasma concentrations (ng ml-' + s.c. mean) of clobazam (10 and 20 mg) after oral dose in 10 volunteers and (b) plasma concentrations of clonazepam (ng ml-' ± s.e. mean) (0.5 and 1 mg) after oral dose in 10 volunteers. esis loop. However, this was observed in one Further work with higher doses of clobazam is subject only. Generally there was a lack of necessary before concentration/response rela- observations during the rising phase of plasma tionships can be described. concentration. As with clobazam, correlation Neither drug at either dose had any effect on between effect and the concentration of its the ventilatory response to CO2 despite the fact major metabolite (N-desmethylclobazam) was that many of the recipients of clonazepam 1 mg not assessed. Pullar et al. (1987) showed that had to be awakened to undertake the tests. This only small amounts (100-200 ng ml-') of N- suggests that the displacement of the ventilatory desmethylclobazam were to be expected from a response to CO2 seen with other benzodiaze- single dose of clobazam. Comparable plasma pines is not simply due to sedation as has been concentrations to these have been shown to suggested for some other drugs (Eddy et al., produce virtually no effect on psychomotor 1970). performance in humans (Davies et al., 1985). The doses given in this study are those given 176 J. D. Wildin et al. in the first weeks of anti-epileptic therapy, when depression caused by clonazepam will increase drugs are being introduced to the patient, and as the dose is increased towards the usual adult when adverse effects are most likely to be re- daily maintenance dose of 4-8 mg (British ported. Clobazam maintenance therapy often National Formulary, 1989). remains around the 20 mg day-' mark for It is concluded that clobazam is relatively free patients with epilepsy, and so this dose could from CNS depressant actions when compared be considered therapeutic. The relative lack of with clonazepam at the doses recommended for effect from clobazamn in this study suggests that the commencement of anti-epileptic drug treat- patients should have few problems relating to ment. CNS depression with this drug. Clonazepam by The authors would like to thank Miss J. Preece for contrast appears likely to produce a higher in- assistance in performing the assays for clobazam and cidence of drowsiness and sedation during the clonazepam, Mrs K. Bond for word-processing the first few weeks of therapy. Unless tolerance to text, and Hoechst UK Ltd for financial support for these effects is substantial it is likely that CNS the study.

References

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