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

Respiratory and sedative effects of clobazam and clonazepamin volunteers

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

1 The respiratory and psychomotor effects of two benzodiazepines used mainly asanticonvulsants were compared in healthy volunteers, using a double-blind placebocontrolled design.2 Clobazam (10 and 20 mg) produced significantly fewer psychomotor side effects thanclonazepam (0.5 and 1 mg). Neither drug at either dose affected the ventilatory responseto 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 considerablyless sedating than clonazepam. Further investigation is required into the tolerance profileof both drugs in patients.

Keywords clobazam clonazepam ventilatory response to CO2 psychomotor tests

Introduction

Clobazam and clonazepam are benzodiazepineswidely used as adjunctive therapy in epilepsy.There are numerous reports in the literatureconcerning the effects of these drugs individuallyand in comparison with other benzodiazepines(Gudgeon & Hickey, 1981; Hindmarch, 1979).Cull & Trimble (1985) compared the two agentsin volunteers, but the same subjects did notreceive both clonazepam and clobazam. Further-more, the benzodiazepine was administeredchronically over a 2 week period and only asingle dose of each drug was included.Clobazam has a 1-5 structure, unlike the

classical 1-4 structure possessed by clonazepamand most other benzodiazepines including dia-zepam. This seems to confer unusual propertiessuch as enhancement at low dosage of psycho-motor performance which is normally depressedby these drugs. It is less sedative than typical1-4 benzodiazepines in chronic dosage (Cull &Trimble, 1985).

In order to determine the selectivity of thesetwo drugs, at conventional starting doses, theyhave been compared in a range of psychomotor

tests, using a double-blind crossover design.Some oral benzodiazepines depress the ventila-tory response to carbon dioxide (Pleuvry et al.,1980; Rudolph et al., 1978; Utting & Pleuvry,1975), but little work has been done in thisrespect with clonazepam and clobazam. Thus,the ventilatory response to carbon dioxide hasbeen investigated. The correlation betweenchanges in performance and plasma drugs con-centration has also been determined.

Methods

Clobazam and clonazepam were administeredto healthy volunteers in a five period, double-blind, crossover study. The doses selected wererecommended starting doses for adult patientswith epilepsy (British National Formulary, 1989).The treatments were presented as identicalopaque capsules containing clobazam 10 or 20mg, clonazepam 0.5 or 1 mg or placebo andadministered in a random sequence.

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Volunteers

Ten volunteers (six male) aged 22-37 years,55-85 kg were assessed by medical examinationwith biochemical and haematological screening.The details of the study were explained andwritten informed consent was obtained. Any-one taking regular medication (with the excep-tion of oral contraceptives), smokers and womenwho were pregnant or intended to becomepregnant were excluded. The experiment hadapproval from the University Ethics Committee.The subjects were fasted from the night before

dosage and fruit juice only was allowed on thefollowing morning not less than 2 h before in-gestion of the drug capsules. Food and fluidwere permitted 4 h after ingestion of the cap-sules, but the subjects were asked to abstainfrom coffee and alcohol from the day beforeand until 24 h after dosage. Each volunteer wasasked to attend on five separate occasions andreceived the treatments described. At least 7days elapsed between successive treatments.

Psychomotor performance Psychomotor per-formance was assessed using the 'Leeds Psycho-motor Tester'. Two tests were carried out in-dependently. In the choice reaction time testthe subject was required to scan a semi-circleof six lights each adjacent to a correspondingbutton. The lights were illuminated individuallyon a random basis. As soon as the subject de-tected a light he lifted his finger from the baseposition button and, as quickly as possible, wasexpected to press the appropriate responsebutton thus extinguishing the light. This pro-vided the total response time (light on to lightoff) and the recognition component (light on tofinger lifted). The difference between the twowas designated movement time. Thirty stimuliwere presented. The critical flicker fusionthreshold (CFFT) (Hindmarch, 1979) was usedas an index of arousal. The subjects were re-quired to detect flicker in a set of four lightemitting diodes in foveal fixation at 1 m. Amean of six thresholds was taken, three withgradually increasing frequency of flicker wherethe point that perceived flickering stops wasrecorded and three with a decreasing frequencyof flicker where the point that perceived flicker-ing starts was recorded.The digit symbol substitution test (Wechsler,

1944) involved substituting symbols for digitsaccording to the code given in the box at thetop of the page. The number of symbols cor-rectly substituted in a 90 s period was counted.The volunteers reported their subjective con-

dition on visual analogue scales. Sedation was

measured using a 100 mm scale marked at oneend 'wide awake' and at the other 'nearly asleep';similarly coordination was registered betweenextremes of 'well co-ordinated' and 'clumsy'.

Postural sway Subjects were asked to stand onan electronic sway meter. This consisted of awooden circular platform resting on a resilientrubber plate, into which had been embeddedfour pressure transducers spaced 900 apart. Cut-out shapes attached to the top of the platformensured that the subjects' feet were positionedconsistently so that measurements were repeat-able. This resembled the equipment used byPatat & Foulhoux (1986).

Volunteers were asked to stand erect andmotionless for two 1 min periods, onewith eyes open and one with eyes closed. Theoutput from the pressure transducers was re-corded as a variable line in the anterior-posteriorand left-right directions on two separate record-ing potentiometers (Rikadenki). This contrastswith the computerised system used by Patat& Foulhoux (1986) who required a complexanalysis of the components of postural devia-tion. Each potentiometer record was analysedvia a graphics tablet attached to an Apple IIcomputer. By tracing the potential record, theprogram calculated the mean deviation from astraight line joining the start and stop potentials.This value was used to represent the relativesway of the individual. The machine was cali-brated by determining the potential changeproduced by a 1 kg mass placed over each swaysensor.

Ventilatory response to C02 The ventilatoryresponse to CO2 was measured using a Bellclosed circuit spirometer (Ealing). The soda limecanister was removed from the spirometer circuitand the cylinder filled with 5% CO2 in oxygen.Following a maximal expiration, the subjectwas connected to the spirometer and after initialdeep inspiration, was allowed to breathe quietlyinto the apparatus. Rebreathing took place fornot more than 4 min.Gases were sampled at the mouthpiece and

measured continuously by an infrared analyser(Morgan) before being returned to the circuit.The CO2 analyser was connected to a recordingpotentiometer (Rikadenki). End tidal pCO2(Kpa) was measured from the trace. Minutevolume was plotted against end tidal pCO2.The slope of the best straight line and the 30 1min-' volume intercept were calculated. Thismethod was based on that of Read (1967) withcertain modifications. Read (1967) used an initialconcentration of 7% C02, thus equilibrium

Anticonvulsant benzodiazepines in volunteers 171

occurred more rapidly and end tidal pCO2 moreclosely mirrored brain tissue pCO2. However,in our previous experience this had proved ex-tremely stressful to volunteers, often inducingheadaches and dyspnoea.

Blood pressure and pulse rate Systolic and dia-stolic blood pressure were measured using theCopal printing/auto-inflation digital sphygmo-manometer. The same arm was used for allreadings and the same observer made allmeasurements. It was attempted to ensure thatthe positioning of the arm cuff was identical oneach occasion. Readings were taken at stage 1and stage 5.

Timing A blood sample was taken via acatheter inserted into an arm vein and all thetests described above were performed shortlybefore drug administration, half hourly for thenext 2 h and then at hourly intervals until 8 hafter administration. Blood clotting in thecatheter was prevented by flushing with hep-arinised saline (2u ml- 1) after each sample hadbeen taken. The catheter was removed at 8 h.A further set of tests were performed 24 h afterdrug administration and a 10 ml blood samplewas taken by venepuncture. Blood was collectedin potassium oxalate tubes, mixed and centri-fuged. The plasma was removed and stored at-20° C until assayed for benzodiazepines.

Assays Clobazam was extracted from plasmaand plasma concentrations measured by. themethod of Caccia et al. (1979) using gas chro-matography with electron capture. There werecertain modifications. The stationary phase was(3%) SP2250DA on 80/100 Supelcoport, usingN2 as the carrier gas. Elution time for clobazamwas 8 min. Diazepam was used as internal stan-dard. Drug recovery using this method was 86+ 4 (% ± s.d., n = 4) and was consistent forhigh and low concentrations of the drug.Clonazepam was assayed by a modification of

the method of Badcock & Pollard (1982) usingdiazepam as internal standard. The stationaryphase was 3% SP2150DA on 100/120 Supelco-port as the support, with N2 as the carrier gasflowing at 60 ml min1. Drug recovery was 80.9+ 9.0 (% ± s.d., n = 4) at both high and lowconcentrations.

N-desmethylclobazam was assayed under thesame conditions by a modification of the methodof Greenblatt (1979). Retention time for N-desmethylclobazam was 14 min.

Statistics

Measurements of response at each time wereexpressed as the difference between the post-and pre-treatment (zero time) values. In thepreliminary analysis measurement from dif-ferent times were pooled and differences due totreatments were assessed without regard to time.Similarly, differences due to time were assessedwithout regard to treatments. If either revealedsignificance (P < 0.05) then differences due totreatment were assessed separately at each time.Since the sequence of treatment was random,the effects of treatments and sequence couldnot be resolved. Significance was judged fromthe variance ratio (F) derived from analysis ofvariance.

Results

Significant effects of clobazam compared withplacebo were found on four of- the sixteen tests(CFlFT, visual analogue scales and L-R posturalsway). Significant effects of clonazepam werefound on nine of the sixteen tests.The results for critical flicker fusion threshold

are shown in Figure 1. Subjects given placeboshowed a decrease in threshold frequencythroughout the experimental day. This was notsignificant at any one time and had returned tocontrol values by the following morning. Similarresults were obtained from subjects givenclobazam 10 mg. The higher dose of clobazamproduced a significantly (P < 0.05) greater de-crease than placebo over the first 2 h. Clona-zepam 0.5 mg also tended to decrease flickerfusion threshold but this failed to reach signifi-cance compared with placebo. The higher doseof clonazepam caused a decrease in the thresholdfrequency for most of the day, with a deficit stillapparent the next morning. This was signifi-cantly different from placebo at 1-7 h and fromclobazam 20 mg at 2 and 5 h. Other pairwisecomparisons were not made.There was a slight increase in recognition

time over the day in placebo-treated subjects(Figure 2). Neither dose of clobazam producedchanges that were significantly different fromplacebo, although low dose clobazam tendedto shorten recognition time. The low dose ofclonazepam tended to increase recognition timebut only 1.0 mg clonazepam produced a signifi-cant increase above placebo and above clobazam20 mg. Recovery after the second hour wasrapid.As with the previous two tests, subjects given

placebo showed a decrease in their performance

172 J. D. Wildin et al.

U

4 5Tinw (b),

7

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. ; ;3: ,I ; fjL.._: i :i 1

'I I-:* e-% 1-

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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 fromplacebo.

in the DSST throughout the trial day (Figure3). Neither dose of clobazam further affectedperformance in this test. Both doses of clonaze-pam significantly reduced performance, withthe higher dose having a greater and more persis-tent effect. This significantly exceeded the effectof the higher dose of clobazam at 1, 2 and 4 h.

Subjects receiving placebo generally improvedin wakefulness during the day (Figure 4)-peakscoinciding with lunch and the end of the experi-mental day. Similar results were obtained forsubjects given clobazam 10 mg. Higher dose

clobazam, and both doses of clonazepam de-creased subjective feelings of wakefulness.Some subjects receiving clonazepam 1 mg hadto be awakened to undertake tests. A similarpattern of effects was seen with the dexterityscale except that low doses of clobazam tendedto improve dexterity.

Postural sway

Measurements of postural sway with eyes openand eyes closed showed very similar results, and

Anticonvulsant benzodiazepines in volunteers

14~~~~~~~~320 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.

.0

I4- 8h 7 8124

h -tFigure 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. Asignificant increase in sway after clobazam wasobserved at one time point only (1 h, 10 mg).Clonazepam lower dose significantly increasedanterior-posterior postural sway at 1 h, andwith the higher dose this effect persisted for5 h (Figure 5). Left-right sway was less adverselyaffected with high dose clonazepam increasingsway for only the first 3 h.

Ventilatory response to CO2

In the doses used, neither clobazam nor clona-zepam produced any effect on the slope or the

intercept of the ventilation (I min-') (%) CO2-'curve. Similarly, no effects on pulse, bloodpressure or body temperature were seen.

Plasma concentrations

After clobazam, maximal plasma concentrationswere reached at 1.3 ± 0.2 h (10 mg) and at 1.6

0.3 h (20 mg). After clonazepam maximalconcentrations were reached at 2.2 ± 0.3 h(0.5 mg) and at 2 ± 0.6 h (1.0 mg). Theseresults are shown in Figure 6. The ratio of thearea under the concentration-time curves(AUCO, 24) high dose/low dose was 2.31 ± 0.78

15

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-

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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.Two subjects showed very low concentrationsof clonazepam after the 0.5 mg dose. They wereexcluded from the pharmacokinetic analysis.The concentrations of N-desmethylclobazamwere low in all subjects and did not exceed 200ng ml-'.

Discussion

Clobazam had little or no effect on a wide rangeof psychomotor and subjective tests, when com-pared with placebo. In some cases the effect ofclobazam was to improve the score (e.g. 10 mgclobazam on recognition time and visual ana-logue scale for dexterity), when compared withplacebo. Several volunteers taking clobazamspontaneously reported not drowsiness but amild sense of detachment. These results supportprevious work by other workers (Parrott, 1982;Robinson et al., 1981; Steiner-Chaskel & Lader,1981).The tests differed in their sensitivity to the

effects of these drugs. For example, althoughrecognition time was affected markedly byclonazepam, the movement time was not signi-ficantly prolonged. This demonstrates that oncethe light was perceived the subject had no signi-ficant deficit in his motor ability.The greatest persistence of clonazepam effects

was seen in the flicker fusion (CFF) test (Figure1). This contrasts with the brief duration of

effect and rapid recovery seen with recognitiontime (Figure 2). The CFF response appeared toparallel the plasma concentration of clonazepam(Figure 6b). Other responses (DSST, recognitiontime) waned whilst the concentration remainedhigh. This may indicate that acute tolerance,which has been recognised with other benzo-diazepines (Crawford et al., 1987), develops tothe effects of clonazepam on some functions butnot on others. Alternative explanations are lesslikely. The rapid waning of the effect of 1 mgclonazepam on recognition time (Figure 2) isunlikely to be caused by the concentration fallingbelow a critical threshold since the mean con-centration at 3 h exceeded that at 2 h (Figure6b). Similarly, a more rapid fall in the concen-tration of drug in venous plasma than in brainwould lead to the unexpected presence of psycho-motor effects rather than early recovery. Withinsubject correlations between plasma concentra-tions and effect were generally very weak. Thissupports previous findings by Congdon & For-sythe (1980) who found that in patients, dosewas unrelated to effect in terms of seizure scores,and Froscher & Engels (1986) who observed indiscussion following a paper on tolerance toclonazepam that there was no correlation be-tween clonazepam serum levels and side effects.The mild effects of clobazam made concentra-tion/effect analysis impractical. Graphical plotsof response (DSST, recognition time) againstplasma concentration of clonazepam were pre-pared in the expectation of observing a hyster-

0

Anticonvulsant benzodiazepines in volunteers

600

C

0

a)

c0

0

EnN-0

0

500

400

300

200

a

4 5

Time (h)

b

4-

P4_

a)

C

coCL

a)

N

0

-0 1 2 3 4 5 6 7 8 11 24

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Figure 6 (a) Plasma concentrations (ng ml-' + s.c. mean) of clobazam (10 and 20 mg) after oral dosein 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

subject only. Generally there was a lack ofobservations during the rising phase of plasmaconcentration. As with clobazam, correlationbetween effect and the concentration of itsmajor metabolite (N-desmethylclobazam) was

not assessed. Pullar et al. (1987) showed thatonly small amounts (100-200 ng ml-') of N-desmethylclobazam were to be expected from a

single dose of clobazam. Comparable plasmaconcentrations to these have been shown toproduce virtually no effect on psychomotorperformance in humans (Davies et al., 1985).

Further work with higher doses of clobazam isnecessary before concentration/response rela-tionships can be described.

Neither drug at either dose had any effect on

the ventilatory response to CO2 despite the factthat many of the recipients of clonazepam 1 mghad to be awakened to undertake the tests. Thissuggests that the displacement of the ventilatoryresponse to CO2 seen with other benzodiaze-pines is not simply due to sedation as has beensuggested for some other drugs (Eddy et al.,1970).The doses given in this study are those given

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176 J. D. Wildin et al.

in the first weeks of anti-epileptic therapy, whendrugs are being introduced to the patient, andwhen adverse effects are most likely to be re-ported. Clobazam maintenance therapy oftenremains around the 20 mg day-' mark forpatients with epilepsy, and so this dose couldbe considered therapeutic. The relative lack ofeffect from clobazamn in this study suggests thatpatients should have few problems relating toCNS depression with this drug. Clonazepam bycontrast appears likely to produce a higher in-cidence of drowsiness and sedation during thefirst few weeks of therapy. Unless tolerance tothese effects is substantial it is likely that CNS

depression caused by clonazepam will increaseas the dose is increased towards the usual adultdaily maintenance dose of 4-8 mg (BritishNational Formulary, 1989).

It is concluded that clobazam is relatively freefrom CNS depressant actions when comparedwith clonazepam at the doses recommended forthe commencement of anti-epileptic drug treat-ment.The authors would like to thank Miss J. Preece forassistance in performing the assays for clobazam andclonazepam, Mrs K. Bond for word-processing thetext, and Hoechst UK Ltd for financial support forthe study.

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(Received 16 May 1989,accepted 10 October 1989)