Electrical Intra-cutaneous Half-sine Stimulation for Optimized Preferential C-fiber Activation
Condition: Pain Perception; Secondary Hyperalgesia
MeSH terms: Hyperalgesia
Study type: Interventional

Summary: 
      This exploratory study is to improve an established pain model by a new stimulation profile
      that allows preferential activation of C fibers that are of main clinical interest in chronic
      pain and also to generate a stable secondary hyperalgesia, which is of particular interest in
      the actual research of acute and chronic pain. It is to investigate if the specific
      activation of afferent sensory fibers and expected lower current intensities makes it more
      comfortable for the participant as motor neuron activation is much less pronounced at low
      current intensities. Therefore it compares the area under the curve (AUC) of hyperalgesia
      during electrical, intracutaneous 25 ms half-sine wave stimulation at a pain level of the
      numeric rating scale (NRS) of 6 out of 10 for 65 minutes compared to 500 µs rectangular
      pulses.
    

Detailed description: 
      Nociceptors in the epidermis are responsible for peripheral pain perception. Mechanical,
      thermal as well as chemical stimuli can trigger action potentials in nociceptors and thereby
      pain. Regarding pain, polymodal and "silent" C-fibers are of special interest. Slower
      depolarisation via sine and half-sine currents preferentially stimulate C-fibers compared to
      rectangular shaped currents. This study is to compare the development of central
      sensitization comparing the half-sine wave and the rectangular stimulation, hypothesizing
      that preferential C fiber stimulation through half-sine currents facilitate the development
      of secondary hyperalgesia.

      This exploratory study is to improve an established pain model by a new stimulation profile
      that allows preferential activation of C fibers that are of main clinical interest in chronic
      pain and also to generate a stable secondary hyperalgesia, which is of particular interest in
      the actual research of acute and chronic pain. It is to investigate if the specific
      activation of afferent sensory fibers and expected lower current intensities makes it more
      comfortable for the participant as motor neuron activation is much less pronounced at low
      current intensities. Therefore it compares the area under the curve (AUC) of hyperalgesia
      during electrical, intracutaneous 25 ms half-sine wave stimulation at a pain level of the
      numeric rating scale (NRS) of 6 out of 10 for 65 minutes compared to 500 µs rectangular
      pulses.

      Every volunteer will have two appointments. There will be a "washout" period of at least two
      weeks between the two appointments. On each day two microdialysis catheters containing
      internally a stainless steel wire will be inserted intracutaneously on the volar surface of
      the adominant forearm for a length of approximately 10 mm and at a distance of 5 mm. Before
      insertion, the catheters are filled with 0.9% saline and after insertion a continuous flow of
      0.4 μl/min will be ensured by a syringe pump (Perfusor®) to facilitate conduction and to
      protect the tissue from potential local pH changes by the direct current. Alternating
      polarity of the both pulses is used to ensure charge-balanced stimulation.

      It is randomly assigned which current form is applied on the first and on the second trial.
      Subsequently, the stainless steel wire serving as electrodes of the current generator (for 25
      ms half-sine stimulation the Digitimer DS5; Digitimer Ltd, Hertfordshire, United Kingdom; and
      for 500 µs rectangular stimulation the Digitimer DS7A; Digitimer Ltd, Hertfordshire, United
      Kingdom) are connected. The rectangular pulses are generated by the Digitimer DS7A, which
      works in combination with a pulse generator (PG 1, Rimkus Medizintechnik, Parsdorf, Germany)
    

Intervention name(s): Study Intervention: 25 ms half-sine wave stimulation; Control Intervention: 500 µs rectangular shaped stimulation
Intervention type(s): Diagnostic Test; Diagnostic Test
Intervention description(s): Part I: Threshold detection and Flare response: 6 pulses of 25 ms half-sine are given at 2 Hz each, increasing current intensity (mA) until detection threshold, pain threshold and pain level (3 out of 10 NRS) are reached. Determined intensity values reapplied during 214 impulses. Line scan to visualize changes in local skin blood flow done. Part II: Hyperalgesia, Allodynia, Pain and flare response of 65 minutes. Baseline assessment of local skin perfusion and spatial extent of allodynia by using cotton swab and pinprick hyperalgesia. Current intensity is reapplied, adjusted until pain level of 6 reached. After 5 minutes axon reflex flare, allodynia and secondary hyperalgesia are measured and repeated proximal every 10 minutes with last measurement after 65 minutes. In first 15 minutes current intensity is adapted to maintain NRS level of 6. During this 65 minutes' period, 25 ms half-sine is administered continuously.; Part I: Threshold detection and Flare response: 6 pulses of 500 µs rectangular shaped stimulation are given at 2 Hz each, increasing current intensity (mA) until detection threshold, pain threshold and pain level (3 out of 10 NRS) are reached. Determined intensity values reapplied during 214 impulses. Line scan to visualize changes in local skin blood flow done. Part II: Hyperalgesia, Allodynia, Pain and flare response of 65 minutes. Baseline assessment of local skin perfusion and spatial extent of allodynia by using cotton swab and pinprick hyperalgesia. Current intensity is reapplied, adjusted until pain level of 6 reached. After 5 minutes axon reflex flare, allodynia and secondary hyperalgesia are measured and repeated proximal every 10 minutes with last measurement after 65 minutes. In first 15 minutes current intensity is adapted to maintain NRS level of 6. During this 65 minutes' period, 500 µs rectangular shaped stimulation is administered continuously.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: randomized, crossover, single-blinded experimental proof of concept investigation in healthy volunteers
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: C-fiber activation; evoked pain; hyperalgesia; allodynia; half-sine stimulation; 25ms HS stimulation; pain perception; nociceptors; rectangular current stimulation; electrical pain model; numeric rating scale (NRS)