Reproducibility of the heat/capsaicin skin sensitization model in healthy volunteers
Laura F Cavallone, Karen Frey, Michael C Montana, Jeremy Joyal, Karen J Regina, Karin L Petersen, Robert W Gereau 4th, Laura F Cavallone, Karen Frey, Michael C Montana, Jeremy Joyal, Karen J Regina, Karin L Petersen, Robert W Gereau 4th
Abstract
Introduction: Heat/capsaicin skin sensitization is a well-characterized human experimental model to induce hyperalgesia and allodynia. Using this model, gabapentin, among other drugs, was shown to significantly reduce cutaneous hyperalgesia compared to placebo. Since the larger thermal probes used in the original studies to produce heat sensitization are now commercially unavailable, we decided to assess whether previous findings could be replicated with a currently available smaller probe (heated area 9 cm(2) versus 12.5-15.7 cm(2)).
Study design and methods: After Institutional Review Board approval, 15 adult healthy volunteers participated in two study sessions, scheduled 1 week apart (Part A). In both sessions, subjects were exposed to the heat/capsaicin cutaneous sensitization model. Areas of hypersensitivity to brush stroke and von Frey (VF) filament stimulation were measured at baseline and after rekindling of skin sensitization. Another group of 15 volunteers was exposed to an identical schedule and set of sensitization procedures, but, in each session, received either gabapentin or placebo (Part B).
Results: Unlike previous reports, a similar reduction of areas of hyperalgesia was observed in all groups/sessions. Fading of areas of hyperalgesia over time was observed in Part A. In Part B, there was no difference in area reduction after gabapentin compared to placebo.
Conclusion: When using smaller thermal probes than originally proposed, modifications of other parameters of sensitization and/or rekindling process may be needed to allow the heat/capsaicin sensitization protocol to be used as initially intended. Standardization and validation of experimental pain models is critical to the advancement of translational pain research.
Keywords: central sensitization; experimental pain model; hyperalgesia; peripheral sensitization.
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References
- Dirks J, Petersen KL, Dahl JB. The heat/capsaicin sensitization model: a methodologic study. J Pain. 2003;4(3):122–128.
- Frymoyer AR, Rowbotham MC, Petersen KL. Placebo-controlled comparison of a morphine/dextromethorphan combination with morphine on experimental pain and hyperalgesia in healthy volunteers. J Pain. 2007;8(1):19–25.
- Staud R. Evidence for shared pain mechanisms in osteoarthritis, low back pain, and fibromyalgia. Curr Rheumatol Rep. 2011;13(6):513–520.
- Steyaert A, De Kock M. Chronic postsurgical pain. Curr Opin Anaesthesiol. 2012;25(5):584–588.
- Staud R. Is it all central sensitization? Role of peripheral tissue nociception in chronic musculoskeletal pain. Curr Rheumatol Rep. 2010;12(6):448–454.
- Staud R. Brain imaging in fibromyalgia syndrome. Clin Exp Rheumatol. 2011;29(6 Suppl 69):S109–S117.
- Staud R. Peripheral pain mechanisms in chronic widespread pain. Best Pract Res Clin Rheumatol. 2011;25(2):155–164.
- Graeber MB, Christie MJ. Multiple mechanisms of microglia: a gatekeeper’s contribution to pain states. Exp Neurol. 2012;234(2):255–261.
- Gustorff B, Anzenhofer S, Sycha T, Lehr S, Kress HG. The sunburn pain model: the stability of primary and secondary hyperalgesia over 10 hours in a crossover setting. Anesth Analg. 2004;98(1):173–177. table of contents.
- Petersen KL, Rowbotham MC. A new human experimental pain model: the heat/capsaicin sensitization model. Neuroreport. 1999;10(7):1511–1516.
- Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Effect of systemic adenosine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Reg Anesth Pain Med. 2001;26(5):414–419.
- Dirks J, Fabricius P, Petersen KL, Rowbotham MC, Dahl JB. The effect of systemic lidocaine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Anesth Analg. 2000;91(4):967–972.
- Petersen KL, Maloney A, Hoke F, Dahl JB, Rowbotham MC. A randomized study of the effect of oral lamotrigine and hydromorphone on pain and hyperalgesia following heat/capsaicin sensitization. J Pain. 2003 Sep;4(7):400–406.
- Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515–521.
- Petersen KL, Jones B, Segredo V, Dahl JB, Rowbotham MC. Effect of remifentanil on pain and secondary hyperalgesia associated with the heat – capsaicin sensitization model in healthy volunteers. Anesthesiology. 2001;94(1):15–20.
- Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization. Anesthesiology. 2002;97(1):102–107.
- Hughes A, Macleod A, Growcott J, Thomas I. Assessment of the reproducibility of intradermal administration of capsaicin as a model for inducing human pain. Pain. 2002;99(1–2):323–331.
- Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L, Drewes AM. Assessing efficacy of non-opioid analgesics in experimental pain models in healthy volunteers: an updated review. Br J Clin Pharmacol. 2009;68(3):322–341.
- Oertel BG, Lotsch J. Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research. Br J Pharmacol. 2013;168(3):534–553.
- Yucel A, Miyazawa A, Andersen OK, Arendt-Nielsen L. The effect of heat conditioning of the primary area before and after induction of hyperalgesia by topical/intradermal capsaicin or by controlled heat injury. Somatosens Mot Res. 2001;18(4):295–302.
- Pedersen JL, Kehlet H. Hyperalgesia in a human model of acute inflammatory pain: a methodological study. Pain. 1998;74(2–3):139–151.
- Wang H, Bolognese J, Calder N, et al. Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects. J Pain. 2008;9(12):1088–1095.
- Modir JG, Wallace MS. Human Experimental Pain Models 3: Heat/CapsaicinSensitization and Intradermal Capsaicin Models. In: Szallasi A, editor. Analgesia: Methods and Protocols, Methods in Molecular Biology. Vol. 617. New York: Humana Press; 2010. pp. 169–174.
- Petersen K, Schmelz M. Human Pain Models: Virtues and Limitations; Paper presented at: IASP Refresher Course presented at the 12th World Congress on Pain; August 17–22, 2008; Glasgow, Scotland, UK.
- LaMotte RH, Lundberg LE, Torebjörk HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol. 1992;448:749–764.
- Koltzenburg M, Torebjörk HE, Wahren LK. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain. 1994;117(Pt 3):579–591.
- Hood DD, Curry R, Eisenach JC. Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg. 2003;97(3):810–815.
- Iannetti GD, Zambreanu L, Wise RG, et al. Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans. Proc Natl Acad Sci U S A. 2005;102(50):18195–18200.
- Campbell CM, Bounds SC, Simango MB, et al. Self-reported sleep duration associated with distraction analgesia, hyperemia, and secondary hyperalgesia in the heat-capsaicin nociceptive model. Eur J Pain. 2011;15(6):561–567.
- Eisenach JC, Curry R, Tong C, Houle TT, Yaksh TL. Effects of intrathecal ketorolac on human experimental pain. Anesthesiology. 2010;112(5):1216–1224.
- LaMotte RH, Shain CN, Simone DA, Tsai EF. Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol. 1991;66(1):190–211.
- Moiniche S, Dahl JB, Kehlet H. Time course of primary and secondary hyperalgesia after heat injury to the skin. Br J Anaesth. 1993;71(2):201–205.
- Pedersen JL, Kehlet H. Secondary hyperalgesia to heat stimuli after burn injury in man. Pain. 1998;76(3):377–384.
- Cervero F, Gilbert R, Hammond RG, Tanner J. Development of secondary hyperalgesia following non-painful thermal stimulation of the skin: a psychophysical study in man. Pain. 1993;54(2):181–189.
- Andersen OK, Jensen LM, Brennum J, Arendt-Nielsen L. Evidence for central summation of C and A delta nociceptive activity in man. Pain. 1994;59(2):273–280.
- Gustorff B, Hauer D, Thaler J, Seis A, Draxler J. Antihyperalgesic efficacy of 5% lidocaine medicated plaster in capsaicin and sunburn pain models – two randomized, double-blinded, placebo-controlled crossover trials in healthy volunteers. Expert Opin Pharmacother. 2011;12(18):2781–2790.
- Klein T, Magerl W, Hanschmann A, Althaus M, Treede RD. Antihyperalgesic and analgesic properties of the N-methyl-D-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia. Eur J Pain. 2008;12(1):17–29.
- O’Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH. Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev. 2012;64(4):939–971.
- Torebjörk HE, Lundberg LE, LaMotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol. 1992;448:765–780.
- Jensen MT, Petersen KL. Gender differences in pain and secondary hyperalgesia after heat/capsaicin sensitization in healthy volunteers. J Pain. 2006;7(3):211–217.
- Wallace MS, Schulteis G. Effect of chronic oral gabapentin on capsaicin-induced pain and hyperalgesia: a double-blind, placebo-controlled, crossover study. Clin J Pain. 2008;24(6):544–549.
- Gottrup H, Juhl G, Kristensen AD, et al. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology. 2004;101(6):1400–1408.
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