Effect of the Kv7-channel Opener Flupirtine on the Excitability of Human Peripheral Myelinated Axons in Vivo

Evaluation of the Effect of the K+-Channel Opener Flupirtine on the Excitability of Human Peripheral Myelinated Axons in Vivo: a Randomised Controlled Trial

Slow axonal Kv7 potassium channels are found along unmyelinated axons and at the nodes of Ranvier of myelinated axons in peripheral nerve. As such the pharmacological activation of Kv7 channels offers a potential means of reducing the excitability of peripheral axons. To determine whether this is the case for human peripheral myelinated axons, the effect of the Kv7 channel agonist flupirtine on the electrical excitability of A fibres was examined in both isolated segments of human sural nerve in vitro and in motor axons of the median nerve supplying abductor pollicus brevis in vivo. Axonal excitability was assessed in 21 human sural nerve fascicles in vitro and in 20 volunteers in vivo using threshold tracking in QTRAC (© Institute of Neurology, London, UK). Strength-duration time constant, rheobase current, relative refractory period (RRP), post spike superexcitability at 5 and 7 ms and threshold electrotonus over the 90 100 ms period were used as indices of electrical excitability. In addition, suppression of ectopic discharge in a model of upper limb ischaemia.

Study Overview

• Status: Completed
• Conditions: Pain; Axonal Change, Neuronal
• Intervention / Treatment: Drug: flupirtine

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bavaria
    • Munich, Bavaria, Germany, 80336
      • Multidisciplinary Pain Unit Department of Anaesthesiology University of Munich Pettenkoferstr. 8a

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• voluntarily
• age > 18 years old

Exclusion Criteria:

• current use of medication (e.g. analgetics, antiepileptics, antidepressants, etc.)
• prevailing organic disease (e.g. diabetes, vascular or neurologic illness, etc.)
• previous physical trauma of the forearm (e.g. burning, surgery)
• primary organ failure
• pregnancy and lactation

Study Plan

How is the study designed?

Design Details

• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Placebo first; Volunteers receive placebo first and after a cross-over period of at least 7 days flupirtine second. On the days of the experiment outcome is taken as the change in excitability from Baseline (all measures before intervention) to a timepoint two hours after intervention	Drug: flupirtine; Potassium channel opener (SNEPCO); Other Names: brand names: Trancopal Dolo, Katadolon
EXPERIMENTAL: Flupirtine first; Volunteers receive flupirtine first and after a cross-over period of at least 7 days placebo second. On the days of the experiment outcome is taken as the change in excitability from Baseline (all measures before intervention) to a timepoint two hours after intervention	Drug: flupirtine; Potassium channel opener (SNEPCO); Other Names: brand names: Trancopal Dolo, Katadolon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Axonal Excitability as assessed with QTrac	The primary outcome parameter of axonal excitability was the relative refractory period (RRP) as assessed with threshold tracking techniques. Strength-duration time constant, rheobase current, refractoriness determined at 2 and 2.5 ms, superexcitability at 7 ms and threshold electrotonus over the 90 100 ms period were used as secondary outcome measures.	Change of neuronal excitability from Baseline (before) to two hours after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ectopic Discharge	Further secondary outcome measures were power content for the surface EMG and the ranked summed scores for the McGill pain questionnaire.	Change of neuronal excitability from Baseline (before) to two hours after intervention

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich
• Investigators: Principal Investigator: Dominik Irnich, MD, PhD, Multidisciplinary Pain Unit Department of Anaesthesiology University of Munich Pettenkoferstr. 8a D-80336 Munich

Publications and helpful links

General Publications

• Fleckenstein J, Sittl R, Averbeck B, Lang PM, Irnich D, Carr RW. Activation of axonal Kv7 channels in human peripheral nerve by flupirtine but not placebo - therapeutic potential for peripheral neuropathies: results of a randomised controlled trial. J Transl Med. 2013 Feb 8;11:34. doi: 10.1186/1479-5876-11-34.

Helpful Links

• Homepage of the respective Journal

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (ACTUAL): July 1, 2010
• Study Completion (ACTUAL): August 1, 2010

Study Registration Dates

• First Submitted: October 10, 2011
• First Submitted That Met QC Criteria: October 10, 2011
• First Posted (ESTIMATE): October 12, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): January 13, 2015
• Last Update Submitted That Met QC Criteria: January 12, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: human; neuropathy; myelinated nerve; axonal excitability; ectopic discharge; flupirtine
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Flupirtine
• Other Study ID Numbers: EudraCT 2007-007314-10