Research

My research interest is injury and its clinical sequela--pain and wound healing--and the interaction of the inflammatory response and nervous system in pain. My lab is presently employing clinical and molecular biological techniques to investigate the cellular mechanisms underlying tissue injury, and the factors contributing to differential pain experience. Clinical investigations are aimed at understanding mechanisms of acute and chronic pain, and developing new methods of pain control. Specific research interests are translational and clinical studies that evaluate novel therapeutic agents and permit examination of molecular responses to pain and analgesia. Previous studies have evaluated pain mechanisms in human subjects by correlating biomarkers and pain report.

Current Research

One of our areas of focus is mechanisms of mucosal injury arising from immune dysfunction, such as mucositis from immunosuppressive conditions and cancer treatments.

Mucositis is a painful consequence of cancer therapy that affects the entire alimentary tract, affecting the GI (oral and gut) mucosa. While it is difficult to produce oral mucositis in rodents without direct injury, rodent gut mucosa may give insights into the pathogenesis of mucositis in the gut that may be extrapolated to oral mucosa. We are examining mucosal inflammation in a rodent colitis model using various chemotherapeutic agents. Vincristine is a chemotherapeutic drug associated with peripheral neuropathy and mucositis in humans, and has been demonstrated to cause neurotoxicity and pain behavior in rats. We examined mucosal inflammation and pain behavior in male Sprague-Dawley rats by administering vincristine or matching vehicle via intraperitoneal (IP) injection (50 ug/kg) daily for 10 days. Pain-related behavior was evaluated by testing mechanical allodynia (in response to application of von Frey hairs to the flank and to the plantar surface of the hind paw) and cold allodynia in response to acetone applied to the plantar surface of the hind paw on days 0, 4, 7, and then weekly thereafter until day 49. Gut mucosa was collected at day 50, subdivided according to anatomic location and assayed for an array of cytokines spanning those representing early inflammatory signaling to tissue degradation. Escape behavior in response to flank and hindpaw probing did not differ between control and vincristine-treated rats. Cold withdrawal response scores increased in vincristine-treated rats at day 4 through the remainder of the observation days, with a trend towards separation between the two groups that did not reach statistical significance. Cytokine concentrations in colonic tissue were not different between control and drug-treated groups, and were below the level of detection in jejunal tissue. The chemokine fractalkine (P = 0.033) and cytokines IL-6 (P = 0.036), IL-10 (P = 0.002), and were significantly elevated in the ilium of vincristine-treated rats as compared to controls. There were no differences between the two groups for levels of IFN-gamma, IL-1-beta, or TNF-alpha. MMP2 as a measure of protease activity was higher in the drug versus control group, but not statistically significant. No stool changes were noted within or between groups over time, and no animals lost weight. Differential expression of some inflammatory mediators in rat gut mucosa by drug group suggests mucotoxicity by vincristine is detectable in this model.

In a prospective, observational study of patients undergoing cancer therapy, mucositis was observed in 73% of patients. Plasma TNF-alpha concentrations varied within normal range. Salivary TNF-alpha levels were significantly elevated post-chemotherapy as compared to BL (P = .017). Elevated salivary, but not plasma, TNF-alpha suggest a local mucosal inflammatory response, and are supportive of our choice of a topical intervention targeting TNF-alpha for patients with mucositis resulting from cancer therapy in our current Phase I/II study of mucositis in cancer patients. We plan correlative studies between these patients undergoing head and neck radiation and in non-human primate radiation studies.

In addition to mechanistic investigations, current clinical studies also include clinical trials for acute and chronic pain. We are studying the pain relieving effects of a topical gel for toothache, the efficacy of duloxentine for chronic orofacial pain, and molecular-genetic correlates to acute pain and stress.

Recently Completed Studies

Clinical studies recently completed include a study to reduce opioid CNS effects. Opioids frequently produce adverse CNS side effects in ambulatory settings, providing a rationale for improving opioid analgesia by minimizing adverse effects. In this pilot study, we tested the hypothesis that an efflux activator improves the tolerability and safety of oxycodone without impairing analgesia. Healthy subjects (N=65) undergoing third molar removal were randomly allocated to receive 500 mg oral LNS-5662 or matching placebo at 1 hr prior to surgery. All subjects received 10 mg oral oxycodone immediately prior to surgery. As expected, pupil size decreased with increasing oxycodone plasma concentration. Oxycodone concentrations did not differ between groups prior to surgery, at 1 hr, or at 4 hr. Total Nausea and Vomiting Score (TNVS) was calculated for the time from dosing through 24 hr. More subjects in the LNS-5662 group (67%) than in the placebo group (56%) experienced “no” nausea or vomiting. Median TNVS was 0.39 (LNS-5662) and 0.56 (placebo). No subjects in the LNS-5662 group experienced the most severe level of nausea or vomiting vs 3 in the placebo group. Fewer subjects in the LNS-5662 group (33.3%) than the placebo group (43.8%) requested anti-emetic, and the placebo group tended to request anti-emetic sooner (280 vs 306 min). Importantly, the LNS-5662 treated group had lower mean pain intensity than the placebo group. All subjects except one requested additional analgesic doses; there was no difference in median time to request for a second analgesic (120 and 131 min, respectively). LNS-5662 given 1 hr prior to oxycodone may ameliorate the severity of nausea and vomiting while not interfering with analgesic efficacy.

We also examined a new drug to reverse local anesthesia. A Phase 2 study of pediatric patients (n=152, 4-11 y/o) evaluated the safety and efficacy of a new formulation of phentolamine mesylate (PM), a short-term, nonspecific alpha-adrenergic blocker and vasodilator, as an anesthetic reversal agent. The hypothesis that local maxillary or mandibular injections of PM would shorten the duration of unwanted soft tissue anesthesia (STA) after routine local oral anesthesia was tested. The prolonged duration of STA can lead to accidental lip, cheek and tongue biting among children. Eligible subjects received local anesthesia using standard clinical techniques and anesthetics containing a vasoconstrictor preceding routine dental restorative or periodontal maintenance procedures. Following completion of the procedure, subjects with STA were randomized to receive PM or control (sham injection) in a 2:1 allocation ratio, respectively, stratified according to the location of the dental procedure (mandible or maxilla) and study site. PM was injected into the same site(s) as the local anesthetic. Subjects who weighed >/=15 to < 30 kg received 0.2 mg; those >/=30 kg received 0.2 or 0.4 mg. The duration of STA was measured by a standardized lip tapping procedure. PM reduced the median time required for recovery from STA in the lip by 75 minutes (55.6%) compared with sham injection