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Animal models of pain emphasize that small afferent input leads to a facilitated state of hyperalgesia and allodynia. Parallel experimental models in humans have been developed using quantitative sensory testing (QST) and human models using subdermal capsaicin to evoke a state of hyperalgesia and allodynia. Preclinical studies have shown that these hyperpathic states in animals are mediated by a peripheral and spinal pharmacology distinct from that which mediates acute C fiber excitation. Several characteristics are noted: i) Acute high, but not low, threshold afferent input is affected by spinal mu and alpha 2 agonists; ii) A state is induced by small afferent input which is mediated in part by spinal NMDA receptors; and iii) Injured nerves may induce a state mediated in part by spontaneous activity mediated by increased sodium channels. Using the intradermal capsaicin model, we have shown that mu agonism, NMDA receptor antagonism, and sodium channel blockade diminishes the secondary hyperalgesia with minimum effect upon acute thresholds. These experimental pain states are believed to reflect mechanisms underlying components of the post nerve injury pain state. Thus, based on hypotheses derived from our understanding of the pharmacology of afferent processing derived from preclinical work, we plan to define whether I) certain receptor and channel mechanisms influence the experimental human pain models; and 2) certain clinical pain states are mediated by mechanisms which have a comparable pharmacology to experimental human pain models and the corresponding animal model. These studies support the premise that there is a correlation of mechanisms between experimental and clinical states and that experimental models predict clinical efficacy of agents in human pain states. Thus far, these experiments have focused on the effects of single agents on human experimental pain. Future studies are focusing on refining the model to evaluate ED50 of drug potency and than to perform combination studies to determine best drug combinations for pain management.
Publications (Selected From 89 Publications)
Wallace MS, Rauck RL, Deer T. Ziconotide combination intrathecal therapy: rationale and evidence. Clin J Pain. ;26:635-44,2010.
Lawson EF, Wallace MS. Current developments in intraspinal agents for cancer and noncancer pain.Curr Pain Headache Rep.14:8-16, 2010.
Modir JG, Wallace MS. Human experimental pain models. Methods Mol Biol. 617:159-174, 2010.
Burton AW, Deer TR, Wallace MS, Rauck RL, Grigsby E. Considerations and methodology for trialing ziconotide. Pain Physician.13:23-33, 2010.
Thomas JR, Wallace MS, Yocum RC, Vaughn DE, Haller MF, Flament J. The INFUSE-Morphine study: use of recombinant human hyaluronidase (rHuPH20) to enhance the absorption of subcutaneously administered morphine in patients with advanced illness. J Pain Symptom Manage. 38:663-72,2009.
Backonja M, Wallace MS, Blonsky ER, Cutler BJ, Malan P Jr, Rauck R, Tobias J; NGX-4010 C116 Study NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind study. Group. Lancet Neurol. 7:1106-12. 2008.
Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, Golaux B, Abramson I. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers Anesthesiol. 107:785-796, 2007.
Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-dependent pain, allodynia, and hyperalgesia in humans. J Investig Med. 54:238-244, 2006.
Kumar K, Polston GR, Wallace MS. The effect of intravenous ketorolac on capsaicin-induced deep tissue hyperalgesia. Anesth. Analg 103:696-702, 2006.
Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, Fisher R, Bryce DA, Mangieri EA, Luther RR, Mayo M, McGuire D, Ellis D. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA.;291:63-70,2004.
Wallace MS, Barger D, Schulteis G. The effect of chronic oral desipramine on capsaicin-induced allodynia and hyperalgesia: a double-blinded, placebo-controlled, crossover study.Anesth Analg.;95:973-8, 2002.