GABAergic Modulation in Pain Transmission in Human: Effect of the GABAA Agonist Clobazam on Peripheral and Central Sensitisation

University Hospitals (UH)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Neuropathic Pain

Treatments

Drug: Clonazepam

Drug: Tolterodine

Drug: clobazam

Study type

Interventional

Funder types

Other

Identifiers

NCT01291316

GABA-SPUM

Details and patient eligibility

About

In animal, the GABAergic system modulates central sensitisation, which is a key phenomenon in pain processing. The development of GABAA agonists targeting the subunits of the GABAA receptor implicated in nociception, but not the subunit implicated in sedation is attractive as it opens new perspectives of testing the role of GABAergic modulation of pain processing in human volunteers. The purpose of this subproject is to test the effect of the specific α2 and α3 agonist but sparing α1 effect TPA023 on a human model of peripheral and central sensitisation and to correlate its pharmacodynamic effect with the pharmacokinetic of the compound.

The results would contribute to clarify the potential role of these α2/α3 agonist but sparing α1drugs in clinical pain conditions.

Full description

Objectives:

To assess the effect of the GABAA agonist clobazam on central sensitisation (change in the size of the area of secondary hyperalgesia) in healthy volunteers.
To assess the effect of the GABAA agonist clobazam on peripheral sensitisation.
To assess the effect of the GABAA agonist clobazam on sedation.
To correlate the pharmacokinetic of clobazam to its effect (PK-PD modelling)
To describe the role of the polymorphisms of CYP450 2C19 in the pharmacokinetic and dynamic of clobazam.

Methodology :

phase II , exploratory, three arms randomised placebo-controlled, double blind cross-over study in healthy volunteers

Number of patients : 25

Test product,Dose, Route of administration :

Clobazam,20 mg,oral intake

Duration of treatment :

Single dose administration of each compound

Reference therapy :

Clonazepam 1mg, oral intake Tolterodine 1, 37mg, oral intake

Other therapy :

Flumazenil 0.2mg, intravenous

Efficacy evaluation :

Determination of the impact of clobazam:
- on the size of the area of secondary hyperalgesia induced by an UVB irradiation of the skin (sunburn model). The area is mapped with an electronical Von Frey filament
- on the pain threshold (heat, static and mechanical threshold) in the primary and secondary area of hyperalgesia
- on the nociceptive flexion reflex
- on tolerance pain threshold (cold pressor test)
- on the degree of sedation measured by saccadic eye movements, digit substation symbols test (DSST) and numerical rating scale.
Determination of the concentration-time curve of clobazam and PK-PD modelling.

Statistical Methods :

Based on the results of a previous study done in our unit, assessing the effect of the association of paracetamol and ketorolac on the sunburn model30, the number of volunteers required to detect a 30% reduction in the area of hyperalgesia is 4830. However we chose a lower intensity of UVB irradiation than in previous studies. Using a dose of irradiation of 3 med , this number falls to 18, adopting a 5% level for statistical significance and a 80% power. Taking these two results in account we will go for 25 volunteers.

Data will be analysed by multifactorial analysis of variance (MANOVA) and by analysis of variance (ANOVA) with repeated measures In the case of withdrawal, the data obtained will not be used in the analysis. Data set will however be completed by enrolling a substitute volunteer.

Enrollment

25 patients

Sex

Male

Ages

18 to 60 years old

Volunteers

Accepts Healthy Volunteers

Inclusion criteria

Male subject, age between 18 and 60 year old
Caucasian
Type 3 skin phototype
Non smoker or moderate smoker (< 10 cigarettes/day)
No clinically abnormal findings on history and/or on physical examination
Presence of an area of secondary hyperalgesia after UVB irradiation

Exclusion criteria

Any concomitant illness
Current or past history of drug and alcohol abuse or current intake of more than 3 glasses of alcohol a day or more than 21 glasses of alcohol per week
Psychotropic drug intake during the last month
Sun allergy or any skin disease
Current and regular intake of any drugs that might affect nociception Paracetamol, or NSAIDS with a short half lives are permitted but should be stopped at least 48 h before the UVB session