This project is a series of clinical studies evaluating novel analgesic strategies and therapeutic agents with potential for enhanced efficacy and safety in comparison to standard treatments. Specific objectives of this project are: 1) to evaluate the pain-relieving potential of investigational analgesics which alter either the synthesis or receptor activation of inflammatory and neuroendocrine mediators; 2) to develop novel strategies for preventing pain and optimizing analgesia while minimizing side effect potential for acute pain in ambulatory patients; and 3) to characterize the molecular-genetic responses to surgical stress, acute pain, and inflammation. Subjects in these investigations undergo oral surgery performed with local anesthesia with resultant acute pain, surgical stress and inflammation during the perioperative period as well as for several days. Samples are collected from blood to evaluate systemic responses, from the surgical site to measure local release of inflammatory mediators such as prostaglandins, and by tissue biopsy to measure changes in gene expression due to inflammation. DNA is extacted from blood for selected studies to evaluate genetic differences between individuals that may be associated with inter-individual variations in response to pain and analgesia. Subjects remain at the clinic up to seven hours postoperatively and may return at 24 and 48 hours for additional observations and collection of tissue samples A variety of cultural, psychological and physiological factors contribute to variability in both clinical and experimental contexts. The role of genetic factors in human pain sensitivity is also recognized as an important element. A study evaluating the genetic influences on variability in human pain sensitivity associated with gender, ethnicity, and temperament measured responses to experimental painful thermal and cold stimuli with ratings of pain; temperament dimensions of personality were also evaluated. Loci in the vanilloid receptor subtype 1 gene (TRPV1), delta receptor opioid subtype 1 gene (OPRD) and catechol O-methyltransferase gene (COMT) were genotyped. Female European Americans with a TRPV1 allele and males with low harm avoidance showed longer cold withdrawal times based on classification and regression tree analysis. Gender, an OPRD1 polymorphism and temperament dimensions of personality were primary determinants of heat pain sensitivity. These observations demonstrate that gender, ethnicity and temperament contribute to individual variations in thermal and cold sensitivity through interactions with TRPV1 and OPRD1 genes. We further evaluated the pain sensitivity of normal subjects to experimentally induced pain to delineate individual response patterns; a subset of subjects also underwent standardized oral surgery and the responses to clinically induced inflammatory pain were evaluated. The latency for withdrawal in the cold pressor test exhibited a dichotomous distribution of short and long times. Women exhibited higher responses to cold and thermal stimuli than men. Ethnicity affected pain responses to thermal stimuli and cold stimuli. Neither gender nor ethnicity affected pain responses to clinical pain. Cross-modality comparisons of responses within experimental pain stimuli showed strong correlations but weaker correlations to clinical pain. These findings suggest that background factors and characteristics of experimental pain responses differ from those of clinical pain; therefore experimental pain ratings alone are not sufficient to predict responses to acute clinical acute pain. Given the prominent role of cyclooxygenase (COX) in the inflammatory responses to tissue injury, we investigated expression patterns of COX genes encoding enzymes related to production of inflammatory mediators in a clinical model off tissue injury and their relationship with genetic variation among individuals. Pre- and post-surgical biopsies were taken from patients undergoing third molar removal; the second biopsies were done within the first 4 hours or at 48 hours following surgery. The effects of genetic variation were investigated in the genes for both COX-1 and COX-2. COX-2 expression at early time points was significantly increased but returned to pre-surgical levels with wide variance by 48 hours. COX-1 expression was decrease slightly at early time points but little detectable change was seen at 48 hours. While these observations support the role of COX-2 in acute inflammation and pain as a target for analgesia, they also suggest that wide inter-individual variation in COX-2 expression may influence the analgesic response to selective COX-2 inhibitors. Consistent with these findings are the results of a subsequent study evaluating the effects of a dual COX-1/-2 inhibitor (ibuprofen) and a selective COX-2 ihibitor (rofecoxib) on expression patterns of pro-inflammatory genes related to prostaglandin formation. COX-2 expression at 48 hours varied widely with drug administration: no change in the placebo group but increased COX-2 mRNA from ibuprofen and rofecoxib treatment. Three other enzymes related to PG production were significantly increased and 15-PGDH (related to PG degradation) was significantly decreased in the drug groups This demonstrates that a dual COX-1/COX-2 inhibitor and a selective COX-2 inhibitor change expression patterns of pro-inflammatory genes following tissue injury to stimulate the arachidonic acid cascade and may attenuate the inhibitory actions of these drugs by increased production of PG. We further evaluated gene expression in the arachidonic acid pathway due to tissue injury and inflammation, an NSAID and a coxib in the oral surgery model by use of microarray chips. In post-surgery samples in the placebo group, inflammation related genes were up-regulate from baseline samples whereas these genes were down-regulated or unchanged in the ibuprofen and rofecoxib groups. Differential drug effects were also observed for other genes related to inflammation and coagulation. These results suggest that coxibs and NSAIDs result in differential effects on arachidonic acid cascade gene expression following tissue injury that reflects the inhibition of COX by these drugs.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Intramural Research (Z01)
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Dental & Craniofacial Research
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Wang, Xiao-Min; Wu, Tian-Xia; Hamza, May et al. (2007) Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain 128:136-47
Dworkin, Robert H; Turk, Dennis C; Farrar, John T et al. (2005) Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 113:9-19
Warburton, Gary; Nares, Salvador; Angelov, Nikola et al. (2005) Transcriptional events in a clinical model of oral mucosal tissue injury and repair. Wound Repair Regen 13:19-26
Lee, Y; Rodriguez, C; Dionne, R A (2005) The role of COX-2 in acute pain and the use of selective COX-2 inhibitors for acute pain relief. Curr Pharm Des 11:1737-55
Dionne, Raymond A; Bartoshuk, Linda; Mogil, Jeffrey et al. (2005) Individual responder analyses for pain: does one pain scale fit all? Trends Pharmacol Sci 26:125-30
Dionne, Raymond A; Haynes, Duncan; Brahim, Jaime S et al. (2004) Analgesic effect of sustained-release flurbiprofen administered at the site of tissue injury in the oral surgery model. J Clin Pharmacol 44:1418-24
Ta, Lauren E; Dionne, Raymond A (2004) Treatment of painful temporomandibular joints with a cyclooxygenase-2 inhibitor: a randomized placebo-controlled comparison of celecoxib to naproxen. Pain 111:13-21
Kim, Hyungsuk; Neubert, John K; San Miguel, Anitza et al. (2004) Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 109:488-96
Phero, James C; Becker, Daniel E; Dionne, Raymond A (2004) Contemporary trends in acute pain management. Curr Opin Otolaryngol Head Neck Surg 12:209-16
Gordon, Sharon M; Dionne, Raymond A (2004) The integration of clinical research into dental therapeutics: the role of the astute clinician. J Am Dent Assoc 135:1537-42

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