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

This study has been completed.
Sponsor:
Information provided by:
University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier:
NCT01011036
First received: November 6, 2009
Last updated: August 10, 2010
Last verified: August 2010
History of Changes
  Purpose

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 Intervention Phase
Pain
 Drug: clobazam
Drug: clonazepam
Drug: tolterodine
 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Effects of Gaba-a-Agonists on Pain Mechanisms: An Experimental Study in Healthy Volunteers

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University Hospital Inselspital, Berne:

Primary Outcome Measures:
  • area of hyperalgesia on the forearm [ Time Frame: 11.2010 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Diffuse noxious inhibition control [ Time Frame: 11.2010 ] [ Designated as safety issue: No ]
  • Pressure cuff algometry [ Time Frame: 11.2010 ] [ Designated as safety issue: No ]
  • pressure pain [ Time Frame: 11.2010 ] [ Designated as safety issue: No ]
  • electrical stimulation-temporal summation [ Time Frame: 11.2010 ] [ Designated as safety issue: No ]
  • psychomotor testing [ Time Frame: 11.2010 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Pharmacodynamic study: Measurement of pharmacodynamic behaviour of our 3 tested substances in relation to sedation score. [ Time Frame: 11.2010 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 17
Study Start Date: December 2009
Study Completion Date: June 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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).

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01011036

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

No publications provided

Responsible Party: Dr. med. Pascal Vuilleumier, Inselspital Bern, Institut für Anästhesiologie und Schmerztherapie
ClinicalTrials.gov Identifier: NCT01011036     History of Changes
Other Study ID Numbers: 152/09, SNF SPUM no.33CM30_124117
Study First Received: November 6, 2009
Last Updated: August 10, 2010
Health Authority: Switzerland: Ethikkommission
Switzerland: Swissmedic

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

Additional relevant MeSH terms:
Clobazam
Clonazepam
Tolterodine
GABA-A Receptor Agonists
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
GABA Modulators
 GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
GABA Agonists

ClinicalTrials.gov processed this record on May 21, 2013