Effects of GABA-a-Agonists on Pain Mechanisms: An Experimental Study in Healthy Volunteers
Condition: Pain
Study type: Interventional
Phase: Phase 3

Summary: 
      The investigators will use an intradermal capsaicin injection in the forearm to induce a
      state of localized pain. This localized pain will be measured by different means, and
      analysed locally and distally by so called quantitative sensory testing. The primary endpoint
      of measure is the difference in pain perception with and without
      benzodiazepines/GABA-Agonists around the injection point of capsaicin. The secondary
      endpoints are to measure pain modulation locally and distally by different quantitative tests
      as electricity, pressure pain thresholds, and ice water tests.

      The investigators' hypothesis is that clobazam induces higher pain thresholds as placebo and
      less sedation than the control medication clonazepam.
    

Detailed description: 
      Background

      Neuropathic and nociceptive pain are linked to plastic changes of the central nervous system.
      These lead to lower pain thresholds. An important component of this neuronal plasticity is a
      diminished inhibition-control of the neurons on the level of the spine, where an alpha-3
      subunit of the glycine receptor plays an important role. Modulation of this receptor subunit
      with specific and non-specific GABA-Agonists produce antinociception. The new fact is, that a
      subunit specific medication does not induce sedation in animals. The relationship of pain
      modulation and Gaba-Agonists is not well studied in humans. The benzodiazepine used in pain
      therapy in humans is clonazepam, which induces a strong sedation, reason why it is not much
      used in a chronic pain setting. Clobazam is another GABA-Agonist, which is less sedative. To
      our knowledge its effects on pain modulation has never been studied in humans.

      Objective

      The aim is an analysis and description of clobazam on the central pain mechanisms. We will
      use well known quantitative sensory testing methods therefore.

      The primary objective is to gather data about potential clinical use of clobazam in pain
      therapy. The secondary aim would be to do the same tests on new specific alpha-3 agonists,
      which are being developed by pharmaceutical industry.

      Methods

      Quantitative sensory testing is being made after eliciting an area of hyperalgesia on the
      forearm by capsaicin.

      The area of hyperalgesia around the injection point will be the primary issue of this study.

      The medication given to our patients will be a cross-over, double blind randomized
      administration of clobazam, clonazepam (positive control) and tolterodine (active placebo).
      Quantitative sensory testing will be made before and after study medication administration.

      The quantitative sensory testing consists of the area of hyperalgesia around capsaicin
      injection point, pressure pain elicited with an electronic pressure algometer, ice-water
      testing of the hand, single and multiple electrical skin and muscle stimulation,
      pressure-cuff algometry and the side effects of the administered medication with psychomotor
      testing.

      Before we start the study protocol each patient will have a blood sample drawn for genetic
      testing of the different cytochrome subunits (CYP P450 2C19, 3A4).
    

Intervention name(s): clobazam; clonazepam; tolterodine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): test substance; positive control; active placebo
Intervention MeSH terms: Clonazepam; Clobazam; Tolterodine Tartrate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: healthy study subjects, no disease