Pain

Updated 11/26/07

1. Regulation of Beta-Defensin Expession in Oral Epithelia

B. A. Dale-Crunk, Ph.D, M. R.. Byers, Ph.D.,et al.

Antimicrobial peptides of the human beta-defensin (hBDs) family are recognized as important components of the innate immune responses of oral epithelia as well as epithelia throughout the body.  These peptides may be particularly important in the oral cavity where microbial flora are present in high numbers at all times.  The overall working hypothesis for this project is that b-defensins, and other antimicrobial peptides, aid the oral health in two main ways, first, by their direct antimicrobial activity, and second, by their cytokine-like functions to stimulate other cells within the tissue to respond appropriately to the microbial challenge.  Further, the innate immune mechanisms that function within the oral soft tissue are also reflected in the tooth pulp; that b-defensins are expressed in odontoblasts; that b-defensins expressed in oral epithelium vs. tooth pulp are different and reflect regional differences in their function; that b-defensins mediate communication between epithelial cells and dendritic cells in oral mucosa, the primary cells that bridge innate and adaptive immunity; and between odontoblasts and dendritic cells.  The goal of this project is to put our work on b-defensin expression and regulation in oral epithelial cells into a more biological framework by taking advantage of two systems, cellular interactions in oral soft tissue and in tooth pulp.  These studies will investigate expression of b-defensins and exploration of their role as functional mediators of cell interactions.  Investigations include (1) influence of epithelial b-defensins on specific lineages of] DCs; (2) co-culture of epithelial cells and dedritic cells, (3) characterization of b-defensin expression in an odontoblast cell line and (4) characterization of b-defensin expression in a dental pulp organ culture system.

2. Subgroups of FMS: Symptoms, Beliefs & Tailored Treatments (C)

D.C. Turk, Ph.D., J. Robinson, M.D., Ph.D.

Fibromyalgia syndrome (FMS) is a prevalent, chronic musculoskeletal pain disorder.  Despite extensive research, the etiology and pathophysiologic mechanisms of FMS are not well understood, and no treatment has been shown to be universally effective.  In this project, we propose that FMS is a complex disorder involving multiple factors, both physical and psychosocial-behavioral.  In our previous research, we have demonstrated that FMS patients are heterogeneous in the psychosocial-behavioral axis and can be classified into three distinct subgroups on a basis of their psychosocial-adaptation to symptoms.  In this project, we will extend our previous research and attempt to match treatments to patients’ psychosocial-behavioral characteristics.  Specifically, we will test the efficacy of uniquely tailored treatments for each psychosocial subgroup.  Three groups of FMS patients will be treated with one of three treatment protocols with a standard physical therapy and varying psychological treatments.  A total of 312 FMS patients will undergo a six half-day interdisciplinary treatment sessions consisting of physical therapy and psychological treatments.  All protocols include a standardized physical therapy but include either cognitive-behavioral treatment outcome study, interpersonal skill training, or supportive counseling.  In addition, to the treatment outcome study, various symptoms of FMS will be assessed prospectively in the patient natural habitats to better understand covariations of FMS symptoms.  The repeated daily monitoring using the ratings compared to retrospective reports.  Overall, the results of these studies should establish the benefit of matching treatments to subject characteristics, and enhance our understanding of the roles of cognitive-affective-behavioral adaptation of FMS patients.

3.  Optimizing the Control of pain from Severe Burns (C)

D. Patterson, Ph.D.; S R. Sharar, MD; D. Heimbach, MD., J Doctor, Ph.D.

The primary long term objective of this project is to improve pain control and reduce resulting disability in all age groups of burn survivors (e.g., pediatric, adult, and elderly).  This will be accomplished by determining the optimal combinations of Opioid analgesics, anxiolytics and psychological approaches, and matching treatments with patient characteristics that may predict thrapeutic effects.  Because extensive burn injuries are clearly an etiology of acute pain that produce substantial challenges in its treatment, the results will be generalizable to other causes of pain.  A second primary objective will be to determine how pain and other factors related to burn injuries influence long term physical and psychological adjustment.  To accomplish these objectives, the investigators will conduct six studies, of which four have randomized, controlled designs, one has an observational methodology and one uses longitudinal measurement.  These studies will specifically 1) investigate the synergistic effects of a benzodiasipine (lorzepam) and a psychological technique (hypnosis) in reducing burn pain and stress level, relative to the individual use of such techniques, as well as opioid analgesics alone and 1a) introduce and test a new set of variables for their ability to predict the analgesic effects of the modalities used (e.g. Opioid analgesic, lorazepam, hypnosis, virtual reality), 2 provide the first controlled study of the use of virtual reality in reducing pain from skin graft dressing changes, 3) continue previous studies in order to gain a large enough sample to determine the effects that opioid pain medication scheduling has on acute pain levels in pediatric patients, 4) continue with previous studies in order to produce the first controlled pediatric burn pain study comparing the use of anxiolytics and Opioid analgesics, 5) perform the first even prospective analyses of the Opioid analgesic needs of elderly burn patients, and 6) test a predictive model for determining the longitudinal impact of burn injuries on psychological adjustment and health outcome.  The anticipated benefits of this project will be that they will provide information enabling health care professionals to treat acute pain more effectively across the life span.  This will not only reduce unnecessary suffering, but might improve health outcomes by minimizing the deleterious effects of acute pain.

4. Subjective and Neuroimaging Assessment of Combined Opioid and Virtual Reality Analgesia (C)

S. R. Sharar, M.D.T. Richards, Ph.D.

Painful medical procedures that do not warrant general anesthesia or deep sedation, yet require potent analgesia in awake and cooperative patients, are increasing in scope and number and exceed our specialty’s resources to provide direct  care.  Awake patients undergoing painful procedures such as wound debridement, post-injury or post-operative physical therapy, cancer-related oncology procedures, or limited surgical procedures may benefit from the thoughtful combination of pharmacologic and non-pharmacologic analgesic techniques.  Concrete evidence supporting this potentially widely applicable combined analgesic approach is lacking, but is best provided by anesthesiologists whose knowledge and training are best suited for such investigation.  We propose to explore the efficacy, safety, and mechanism of one particularly promising combination -- systemic opioids + attentional distraction with immersive, interactive virtual reality (VR) – each of which alone can provide measurable analgesia for procedural pain.  We propose to test the specific hypotheses: (1) that combined opioid + VR therapies act synergistically to effect clinically superior analgesia compared to either treatment alone, and (2) that functional neuroimaging of these therapies, alone and in combination, will demonstrate specific patterns of brain activation in the ‘pain matrix’ that explain their relative analgesic effects.  Results from these studies will provide evidence for procedural analgesic strategies that maximize clinical and economic benefits, as well as provide valuable preliminary data for future clinical trials in procedural pain.  Furthermore, these results will allow our specialty to positively impact conscious, procedural analgesic care outside of the operating room, whether or note we are directly involved in such patient care.

5. A Pilot Study of Virtual Reality Analgesia for Cancer Pain in the Elderly (C)

S. R. Sharar, M.D., H Hoffman, Ph.D

The proposed research -- investigating the potential clinical application of immersive virtual reality (VR) analgesia in the treatment of oncology procedure-related pain in the elderly -- directly addresses the Palliative Care, End-of-Life Care, Pain Relief.  It also addresses overlapping issues in both (1) cancer pain management and (2) pain management in the aging population through the novel application of VR, a technique well-suited for short periods of cognitive distraction from pain (i.e., during procedural pain), but never before applied to elderly patients in any medical setting.  The investigative approach utilizes a previously established protocol to study simulated lumbar puncture pain in healthy volunteers, and capitalizes on the strengths of a multidisciplinary team whose individual members are nationally recognized in their fields.

A comparative efficacy and safety of various types of audio/visual distraction analgesia techniques is requisite before a thoughtful clinical trial can commence.  VR analgesia is an emerging technology, with the UW established as the field leader.  To date, VR analgesia has been applied in experimental and clinical studies in pediatric, and to a lesser extent young adult, age groups, but never before in the elderly, who due to cognitive and sensory changes inherent to aging, may respond differently to VR.  Thus, pilot project funding by SCAP will allow the first comprehensive study of pain modulation by VR and related distraction techniques in the previously neglected elderly population, and provide critical preliminary data requisite for future funding proposals (e.g., to NIH and AFAR) that will address its potential clinical use specifically in cancer, but also in other medical settings where pain is a daily challenge for this expanding demographic group and their care providers.

6. Assessment of Patient Recall/Awareness of Prehospital Endotracheal  Intubation (C)

S. R. Sharar, M.D.

This application proposes performance of two related and complementary projects relevant to field airway management in critically ill patients.  Both projects address endotracheal intubation issues (one in adults, one in children), both utilize unique and sizeable data available as a result of Medic One’s proactive airway management policies, and both share budgeted resources in an efficient manner that allows completion of two projects for a cost similar to that for one project alone.  Lastly, results from both proposed projects will have likely clinical application in establishing safe and effective airway management recommendations, both locally and nationally. 

  (1) Emergent endotracheal intubation is a painful, yet life-saving procedure that is often performed in the prehospital and emergency room settings without the benefit of adequate analgesic, sedative or amnestic medications because of cardiovascular side effects associated with these agents.  Awareness (or recall) of pain or other unpleasant events associated with emergent intubation in these two settings has both potential psychologic and liability implications.  However, the true incidence of this complication is unknown; hence, the indications and clinical guidelines for its prevention and treatment are undefined. Knowledge of its incidence and settings may alter prehospital care guidelines in a way that will improve patient care.

  (2) Long-standing clinical practice teaches that children under ~10 years of age who require endotracheal intubation should receive an uncuffed tube, due to considerations of anatomy and potential complications unique to the pediatric age group.  This practice has recently been questioned in the inpatient setting, due to increasing recognition of potential complications of uncuffed tubes in critically ill children, and has resulted in a change in clinical practice (i.e., placement of cuffed tubes) in the inpatient setting.  However, the relative frequency and magnitude of complications related to cuffed v. uncuffed tubes placed in the prehospital setting is unknown.  Knowledge of these relative complications may alter prehospital care guidelines in a way that will improve patient care.

7. Ketorolac in Surgical Infants: Pharmacokinetics/Analgesia (C)

A.M. Lynn, M.D.

The live birth rate in the United States in 1990 was 4,158,212.  Major congenital defects that will require surgical corrections or palliation in the first year of life will affect 0.02% (for tracheoesophageal fistula) or 0.04% for imperforate anus as reported in the Congenital Malformations surveillance 1982-1985 from the Center for Disease Control (CDC) in 1988.  Infants affected by these major congenital defects necessitating surgery in infancy comprise an orphan population of less that 100,000.  For these infants, surgery offers the best (or only) potential for correction and a good quality of life.  Postoperative pain control should be given to these infants, as it would be adults undergoing similar surgeries, despite their limited ability to communicate their needs.

Infants and children first received the label therapeutic orphans in 1968 when Shirkey pointed out they were excluded from the labeling of most drugs.  Kauffman’s editorial in 1991 presented the lack of rigorous study of drugs in infants and children as a continuing problem.  More recently in 1996 Kauffman, Cote, and others anticipated the “adoption” of the pediatric therapeutic orphan, as the Food and Drug Administration implemented a more proactive stand encouraging pediatric investigation of pharmacologic agents.

* (C) denotes clinical investigation.

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