Activation of A-delta-fibres and C-fibres in a First Degree Thermal Injury in Volunteers
Condition: Healthy Subjects
Study type: Interventional

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.
    

Intervention name(s): CO2-Laser stimulation (Laser Stimulation Device, SIFEC)
Intervention type(s): Device
Intervention description(s): 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).
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Heat Injury; Humans; Laser Stimulation; Quantitative Sensory Testing; Reaction Time; Secondary Hyperalgesia; Thermal Thresholds