Pharmacological modulation of heterosynaptic LOng-TErm POtentiation in humans by LOrazepam and METHylphenidat

ISRCTN	ISRCTN88124420
DOI	https://doi.org/10.1186/ISRCTN88124420
Protocol serial number	Tr 236/16-2/LTP-Methyl-Lora
Sponsor	Individual sponsor (Germany)
Funder	German Research Foundation (Deutsche Forschungsgemeinschaft) (Grant ref: Tr236/16-2)

Submission date: 20/08/2007
Registration date: 24/09/2007
Last edited: 24/09/2007

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Signs and Symptoms

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Rolf-Detlef Treede
Scientific

Institute of Physiology and Pathophysiology
The Johannes Gutenberg University of Mainz
Duesbergweg 6
Mainz
55128
Germany

Email	treede@uni-mainz.de

Study information

Primary study design	Interventional
Study design	A double-blind, randomized, placebo-controlled, three-way cross-over study.
Secondary study design	Randomised controlled trial
Scientific title
Study acronym	LOTEPOLOMETH
Study objectives	Long-Term Potentiation (LTP) within the nociceptive system is one of the mechanisms underlying central sensitisation, which accounts for some hyperalgesic pain states in chronic pain patients. In the study we will use a human surrogate model of nociceptive LTP to study the involvement of the GABAergic and the catecholaminergic system in the induction of hyperalgesia following high-frequency electrical stimulation of nociceptive afferents in the skin. We will study the contribution of GABAA-receptors (by lorazepam, a GABAA-receptor agonist) and receptors of catecholamines (by methylphenidat, a dopamine/noradrenaline re-uptake inhibitor) in plastic changes within the nociceptive system, which occur typically after a tissue injury, but in contrast to a real lesion we mimic an injury by high-frequency electrical stimulation of nociceptive afferents in the skin. This conditioning stimulation will lead to pain to light tactile stimuli (dynamic mechanical allodynia) and to an increase of pain to punctuate mechanical pain stimuli (static mechanical hyperalgesia). Both phenomena can typically been found in a subset of neuropathic pain patients.
Ethics approval(s)	The study was approved by the Local Ethics Committee (Ethikkommission der Landesärztekammer Rheinland-Pfalz) on 15 March 2003 (ref: 837.002.03[3664]) and was conducted in accordance with the declaration of Helsinki, the German Medicines Act (AMG), and the guidelines of the International Conference on Harmonisation (ICH) for Good Clinical Practice (GCP).
Health condition(s) or problem(s) studied	Hyperalgesic pain
Intervention	The effect of 40 mg methylphenidate and 2.5 mg lorazepam orally (p.o.) will be compared to placebo in a three-way cross-over design (placebo-methylphenidate-lorazepam). Sensory changes will be determined by Quantitative Sensory Testing (QST) using non-nociceptive and low-intensity painful mechanical and electrical stimuli. The QST-protocol consists of mildly painful and non-painful mechanical and electrical stimuli, which were applied in runs alternating between two skin sites on the forearms (a test site and a control site). In addition, we will apply a moderate painful high-frequency electrical stimulation protocol to induce nociceptive LTP (only at the test site). All test stimuli will last between 0.5 - 2 seconds depending on the modality tested. The QST will be carried out over 30 min before the application of the conditioning stimulus and over 90 min at the beginning and immediately after the stimulus.
Intervention type	Drug
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Methylphenidate, Lorazepam
Primary outcome measure(s)	The following outcomes will be assessed based on the sensory changes determined by QST during the intervention: 1. Spread of the area of dynamic allodynia and static hyperalgesia 2. Combined analgesic and anti-hyperalgesic effect to mechanical and electrical stimuli on the site of conditioning stimulation
Key secondary outcome measure(s)	The following outcomes will be assessed based on the sensory changes determined by QST during the intervention: 1. Anti-hyperalgesic effect to electrical and mechanical test stimuli 2. Analgesic effect to electrical and mechanical test stimuli 3. Anti-wind up pain, tested by mechanical pinprick stimuli
Completion date	01/10/2007

Eligibility

Participant type(s)	Healthy volunteer
Age group	Adult
Sex	All
Target sample size at registration	18
Key inclusion criteria	1. Healthy volunteers of full age 2. Subject familiarized with the experimental procedure prior to experimentation and had given written informed consent 3. At least a 50% increase of pain to pinprick stimuli and a 25% increase of pain to electrical stimuli following high-frequency electrical stimulation in a screening visit
Key exclusion criteria	1. Skin lesions at the test and/or control site 2. Use of any medication within one day prior to study onset except contraceptives 3. Known hypersensitivity to histamine or methylphenidate and lorazepam and their derivates 4. Any history of allergy or drug hypersensitivity 5. Chronic use of analgesics or Central Nervous System (CNS) active drugs 6. Pregnancy or nursing 7. Any acute or chronic disease
Date of first enrolment	01/10/2006
Date of final enrolment	01/10/2007

Locations

Countries of recruitment

Germany

Study participating centre

Institute of Physiology and Pathophysiology

Mainz
55128
Germany

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan