Activation of A-delta-fibres and C-fibres in a First Degree Thermal Injury in Volunteers
NCT ID: NCT02442726
Last Updated: 2015-12-03
Study Results
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Basic Information
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COMPLETED
NA
18 participants
INTERVENTIONAL
2015-05-31
2015-11-30
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
BASIC_SCIENCE
SINGLE
Study Groups
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Thermal Injury
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)
CO2-Laser stimulation (Laser Stimulation Device, SIFEC)
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).
Sham Injury
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
CO2-Laser stimulation (Laser Stimulation Device, SIFEC)
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).
Interventions
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CO2-Laser stimulation (Laser Stimulation Device, SIFEC)
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).
Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
30 Years
MALE
Yes
Sponsors
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University of Copenhagen
OTHER
Responsible Party
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mads u werner
MD, PhD, DMSc
Principal Investigators
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Mads U Werner, MD, DMSc
Role: PRINCIPAL_INVESTIGATOR
Neuroscience Center, Copenhagen University Hospital, Denmark
Ron Kupers, MSc
Role: STUDY_CHAIR
Panum Institute, Copenhagen University, Denmark
Henrik Kehlet, MD, DMSc
Role: STUDY_CHAIR
JMC, Copenhagen University Hospital, Denmark
Locations
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BRAINLab, Department of Neuroscience and Pharmacology, Panum Institute
Copenhagen, , Denmark
Countries
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References
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Pedersen JL, Kehlet H. Hyperalgesia in a human model of acute inflammatory pain: a methodological study. Pain. 1998 Feb;74(2-3):139-51. doi: 10.1016/s0304-3959(97)00160-7.
Naert ALG, Kehlet H, Kupers R. Characterization of a novel model of tonic heat pain stimulation in healthy volunteers. Pain. 2008 Aug 15;138(1):163-171. doi: 10.1016/j.pain.2007.11.018. Epub 2008 Jan 22.
Pedersen JL, Kehlet H. Secondary hyperalgesia to heat stimuli after burn injury in man. Pain. 1998 Jun;76(3):377-384. doi: 10.1016/S0304-3959(98)00070-0.
Torebjork HE, LaMotte RH, Robinson CJ. Peripheral neural correlates of magnitude of cutaneous pain and hyperalgesia: simultaneous recordings in humans of sensory judgments of pain and evoked responses in nociceptors with C-fibers. J Neurophysiol. 1984 Feb;51(2):325-39. doi: 10.1152/jn.1984.51.2.325.
Cook AJ, Woolf CJ, Wall PD. Prolonged C-fibre mediated facilitation of the flexion reflex in the rat is not due to changes in afferent terminal or motoneurone excitability. Neurosci Lett. 1986 Sep 25;70(1):91-6. doi: 10.1016/0304-3940(86)90443-x.
Woolf CJ, Wall PD. Relative effectiveness of C primary afferent fibers of different origins in evoking a prolonged facilitation of the flexor reflex in the rat. J Neurosci. 1986 May;6(5):1433-42. doi: 10.1523/JNEUROSCI.06-05-01433.1986.
Torebjork HE, Lundberg LE, LaMotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol. 1992 Mar;448:765-80. doi: 10.1113/jphysiol.1992.sp019069.
LaMotte RH, Lundberg LE, Torebjork HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol. 1992 Mar;448:749-64. doi: 10.1113/jphysiol.1992.sp019068.
Werner MU, Petersen KL, Rowbotham MC, Dahl JB. Healthy volunteers can be phenotyped using cutaneous sensitization pain models. PLoS One. 2013 May 9;8(5):e62733. doi: 10.1371/journal.pone.0062733. Print 2013.
Franz M, Spohn D, Ritter A, Rolke R, Miltner WHR, Weiss T. Laser heat stimulation of tiny skin areas adds valuable information to quantitative sensory testing in postherpetic neuralgia. Pain. 2012 Aug;153(8):1687-1694. doi: 10.1016/j.pain.2012.04.029. Epub 2012 May 31.
Arendt-Nielsen L, Chen AC. Lasers and other thermal stimulators for activation of skin nociceptors in humans. Neurophysiol Clin. 2003 Dec;33(6):259-68. doi: 10.1016/j.neucli.2003.10.005.
Martinez V, Ammar SB, Judet T, Bouhassira D, Chauvin M, Fletcher D. Risk factors predictive of chronic postsurgical neuropathic pain: the value of the iliac crest bone harvest model. Pain. 2012 Jul;153(7):1478-1483. doi: 10.1016/j.pain.2012.04.004. Epub 2012 May 2.
Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006 May 13;367(9522):1618-25. doi: 10.1016/S0140-6736(06)68700-X.
Johansen A, Schirmer H, Stubhaug A, Nielsen CS. Persistent post-surgical pain and experimental pain sensitivity in the Tromso study: comorbid pain matters. Pain. 2014 Feb;155(2):341-348. doi: 10.1016/j.pain.2013.10.013. Epub 2013 Oct 18.
Plaghki L, Mouraux A. How do we selectively activate skin nociceptors with a high power infrared laser? Physiology and biophysics of laser stimulation. Neurophysiol Clin. 2003 Dec;33(6):269-77. doi: 10.1016/j.neucli.2003.10.003.
Ravn P, Frederiksen R, Skovsen AP, Christrup LL, Werner MU. Prediction of pain sensitivity in healthy volunteers. J Pain Res. 2012;5:313-26. doi: 10.2147/JPR.S33925. Epub 2012 Aug 29.
Other Identifiers
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H-2-2014-002
Identifier Type: -
Identifier Source: org_study_id