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Effects of GABA-a-Agonists on Pain Mechanisms: An Experimental Study in Healthy Volunteers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01011036
Recruitment Status : Completed
First Posted : November 11, 2009
Last Update Posted : August 11, 2010
Information provided by:
University Hospital Inselspital, Berne

Brief 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.

Condition or disease Intervention/treatment Phase
Pain Drug: clobazam Drug: clonazepam Drug: tolterodine Phase 3

Detailed Description:


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.


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.


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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Effects of Gaba-a-Agonists on Pain Mechanisms: An Experimental Study in Healthy Volunteers
Study Start Date : December 2009
Actual Primary Completion Date : April 2010
Actual Study Completion Date : June 2010

Arm Intervention/treatment
1 Drug: clobazam
test substance

Drug: clonazepam
positive control

Drug: tolterodine
active placebo

2 Drug: clobazam
test substance

Drug: clonazepam
positive control

Drug: tolterodine
active placebo

3 Drug: clobazam
test substance

Drug: clonazepam
positive control

Drug: tolterodine
active placebo

Primary Outcome Measures :
  1. area of hyperalgesia on the forearm [ Time Frame: 11.2010 ]

Secondary Outcome Measures :
  1. Diffuse noxious inhibition control [ Time Frame: 11.2010 ]
  2. Pressure cuff algometry [ Time Frame: 11.2010 ]
  3. pressure pain [ Time Frame: 11.2010 ]
  4. electrical stimulation-temporal summation [ Time Frame: 11.2010 ]
  5. psychomotor testing [ Time Frame: 11.2010 ]
  6. Pharmacokinetic study: plasmatic concentration measured in regular intervals with blood samples, starting at time zero and ending at time plus 24h after drug administration. [ Time Frame: 11.2010 ]
  7. Pharmacodynamic study: Measurement of pharmacodynamic behaviour of our 3 tested substances in relation to sedation score. [ Time Frame: 11.2010 ]
  8. Pharmacogenetic study: Measurement of subtype cytochrome P450 CYP3A4 and CYP2C19 by metabolites of midazolam and omeprazol. Genotyping of cytochrome P450 CYP3A4 and CYP 2C19. [ Time Frame: 11.2010 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • European males
  • 18-55 years old
  • non smoking status or less than 10 cigarettes per day
  • no disease

Exclusion Criteria

  • any medication
  • any drug abuse
  • diseases of any type

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01011036

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Dep of Anesthesiology and Pain Therapy, University Hospital Bern
Bern, Switzerland, 3010
Sponsors and Collaborators
University Hospital Inselspital, Berne
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Study Director: Michele Curatolo, Professor University of Bern
Principal Investigator: Pascal H Vuilleumier, Dr med University of Bern

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Dr. med. Pascal Vuilleumier, Inselspital Bern, Institut für Anästhesiologie und Schmerztherapie Identifier: NCT01011036     History of Changes
Other Study ID Numbers: 152/09
SNF SPUM no.33CM30_124117
First Posted: November 11, 2009    Key Record Dates
Last Update Posted: August 11, 2010
Last Verified: August 2010

Keywords provided by University Hospital Inselspital, Berne:
healthy study subjects, no disease

Additional relevant MeSH terms:
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Tolterodine Tartrate
GABA-A Receptor Agonists
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Urological Agents
GABA Modulators
GABA Agents
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
GABA Agonists