GABAergic Modulation in Pain Transmission in Human: Effect of the GABAA Agonist Clobazam on Peripheral and Central Sensitisation
Condition: Neuropathic Pain
MeSH terms: Neuralgia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed 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 :

        1. 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.

        2. 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.
    

Intervention name(s): Clonazepam; Tolterodine; clobazam
Intervention type(s): Drug; Drug; Drug
Intervention description(s): clonazepam, 1 mg, single oral dose; Tolterodine 1,37mg, single oral dose; clobazam 20 mg, single oral dose
Intervention MeSH terms: Clonazepam; Clobazam; Tolterodine Tartrate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science