Activation of A-delta-fibres and C-fibres in a First Degree Thermal Injury in Volunteers

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to measure reaction times and thermal detection thresholds to CO2 laser stimulation of the skin, before and after a first degree thermal injury, in the primary and secondary hyperalgesia area, in order to investigate whether different nerve-fiber classes are activated in the post-injury phase. The study results are expected to uncover existence of a peripheral inflammatory input contributing to secondary hyperalgesia.

Detailed Description
-----------------
BACKGROUND The conduction speed of peripheral nerve fibers depends on the nerve diameter. The conduction velocity of large myelinated fibers are 50 - 120 m/s, while for the smaller myelinated A-delta- and unmyelinated C-fibers, they are in the range of 5-10 m/s, and 0.5-1 m/s, respectively. Applying short laser pulses with a high energy density and synchronization, simple reaction times can be used to determine the type of fiber class that has been activated. Research from the group of Plaghki and colleagues has shown that when stimulating surface areas are between 15 and 50 sq.mm at a supra-threshold intensity for activating A-delta-fibers, a typical bimodal response pattern is observed with a first peak centered around 400 ms and a second around 850 ms. Whereas the early peak is due to activation of A-delta-fibers, the second peak is caused by C-fiber activation. HYPOTHESIS Following a mild thermal skin injury (47ºC, 420 s, 9.0 or 12.5 sq.cm area) the injured area is associated with erythema and an increased sensitivity, i.e. pain is easily evoked by mechanical and thermal stimuli in the primary hyperalgesia area. In normal skin surrounding the injury mechanical and thermal allodynia and hyperalgesia, are present. Innocuous stimuli in this secondary hyperalgesia area may elicit pain. This is believed to be a central process suggested by pioneering research in the 1980s and 1990s. The term for this phenomenon is heterosynaptic central facilitation meaning that innocuous stimuli may activate normally high-threshold nociceptive dorsal horn neurons leading to allodynia. This conversion of an innocuous stimulus in normal skin just outside of the injury, to a pain generating stimulus, is the result of a change in the sensory processing within the CNS. This processing is probably regulated by spino-bulbo-spinal loops including the rostral ventro-medial medulla (RVM) and locus coeruleus (LC). The study hypotheses are, first, that the reaction times at the thermal injury site (i.e. primary hyperalgesia area) are changed compared to the pre-injury level. Second, that the sensory changes in the secondary hyperalgesia area, following a thermal injury, are not exclusively centrally mediated, but that also changes in peripheral afferents, e.g. A-delta-fibers (AMH type I) are demonstrable by assessments of reaction times to CO2 laser pulses. A well-known alternative to laser stimulation is the use of a contact thermode with a much larger stimulation area, i.e. 2.5 to 16 sq.cm. The substantially larger area of the contact thermode, combined with a slower heating rate, compared to the laser stimulus (< 0.5 sq.cm, 10 ms), may induce pronounced spatial and temporal summation, interfering with accurate interpretation of sensory data. A recent method-comparison study in patients with postherpetic neuralgia, comparing assessments obtained by a contact thermode (9 sq.cm) and by laser stimuli (< 0.25 sq.mm), indicates that the laser method is more sensitive and specific in detecting thermal sensory abnormalities. Since the laser stimulus gives a steeper slope of heating profile and a more synchronized activation of warmth- and heat-sensitive small fibers, i.e. C- and A-delta-fibers, in the skin laser stimulation is the preferred method in the present study. CLINICAL IMPLICATIONS The propensity for developing secondary hyperalgesia may reflect a predisposition for developing persistent postsurgical pain. It has been estimated that 2-10% of patients undergoing otherwise uncomplicated surgical procedures will suffer from persistent postsurgical pain. Investigating the pathophysiological mechanisms behind secondary hyperalgesia may therefore increase our understanding of the transition to chronic pain and thereby improve our management strategies for this large patient group.

Official Title
-----------------
Activation of A-delta-fibres and C-fibres in a First Degree Thermal Injury in Volunteers

Conditions
-----------------
Healthy Subjects

Intervention / Treatment
-----------------
* Device: CO2-Laser stimulation (Laser Stimulation Device, SIFEC)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: healthy right-handed males non-smokers (due to fluctuating skin temperatures in smokers) normal thermal perception (warmth detection threshold [WDT], cool detection threshold [CDT] and heat pain threshold [HPT]) familiarized with the thermal injury and quantitative sensory testing understands written and verbal study information in Danish understands written and verbal study information in English Exclusion Criteria: lesions on the lower leg unable to cooperate with the sensory testing suspected neurological disease hereditary predisposition to peripheral neurological disease inability to develop secondary hyperalgesia area (non-responder)14 small-area responder (secondary hyperalgesia area < 36 cm2) participated in pharmacological trials during the preceding 4 weeks participated in a thermal-injury trial during the preceding 8 weeks intake of any medication during the preceding 48 hours intake of prescription drugs during the preceding 7 days

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Thermal Injury<br>A first degree heat injury is induced by a contact thermode (12.5 cm2; 47C; 420 s) applied at the skin at the lower leg. CO2-Laser stimulation (Laser Stimulation Device, SIFEC) | Device: CO2-Laser stimulation (Laser Stimulation Device, SIFEC)<br>* Laser stimuli are evenly applied in 15 spots (each 6 mm in diameter) in the primary hyperalgesic zone (application zone of the contact thermode) and in the secondary hyperalgesic zone (1 cm outside the application zone of the contact thermode).<br>|
| Sham Comparator: Sham Injury<br>A sham injury is induced by a contact thermode (12.5 cm2; 38C; 420 s) applied at the skin at the lower leg. CO2-Laser stimulation (Laser Stimulation Device, SIFEC) is used to assess | Device: CO2-Laser stimulation (Laser Stimulation Device, SIFEC)<br>* Laser stimuli are evenly applied in 15 spots (each 6 mm in diameter) in the primary hyperalgesic zone (application zone of the contact thermode) and in the secondary hyperalgesic zone (1 cm outside the application zone of the contact thermode).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in distribution of reaction times assessed by laser stimuli in the thermal injury area (the primary hyperalgesia area) comparing post-injury values with pre-injury, baseline values. | Assessments are performed at Baseline, 1 h post-thermal injury and 24 h post-thermal injury. Changes compared to Baseline are analyzed. | 24 hours | 
| Changes in distribution of reaction times assessed by laser stimuli in the secondary hyperalgesia area comparing post-injury values with pre-injury, baseline values. | Assessments are performed at Baseline, 1 h post-thermal injury and 24 h post-thermal injury. Changes compared to Baseline are analyzed. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in thermal pain thresholds assessed by laser stimuli in the thermal injury area (the primary hyperalgesia area) comparing post-injury values with pre-injury, baseline values. | Assessments are performed at Baseline, 1 h post-thermal injury and 24 h post-thermal injury. Changes compared to Baseline are analyzed. | 24 hours | 
| Changes in thermal pain thresholds assessed by laser stimuli in the secondary hyperalgesia area comparing post-injury values with pre-injury, baseline values. | Assessments are performed at Baseline, 1 h post-thermal injury and 24 h post-thermal injury. Changes compared to Baseline are analyzed. | 24 hours | 
| Thermal detection thresholds assessed by laser stimuli in the thermal injury area (the primary hyperalgesia area) comparing post-injury values with pre-injury, baseline values. |  | Baseline, 1 h post-thermal injury; 24 h post-thermal injury | 
| Changes in thermal detection thresholds assessed by laser stimuli in the secondary hyperalgesia area comparing post-injury values with pre-injury, baseline values. | Assessments are performed at Baseline, 1 h post-thermal injury and 24 h post-thermal injury. Changes compared to Baseline are analyzed. | 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heat Injury, Humans, Laser Stimulation, Quantitative Sensory Testing, Reaction Time, Secondary Hyperalgesia, Thermal Thresholds