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Battlefield Pain Management


MISSION

Pain is experienced throughout the continuum of care. At admission to the ED in theater facilities, 70% of soldiers experience pain of 5 or greater on a Visual Analog Scale of 0-10. Clinical guidelines suggest treating pain at 5 or greater as severe. Despite best efforts of clinicians, inadequate pain control or uncontrolled pain is too frequent especially during the austere environments of evacuation. The overarching goal of this area is to decrease pain wherever possible with special attention/focus on combat related pain and techniques utilized to improve pain control. Our research spans several distinct areas including evaluation of novel therapeutic devices and drugs, and evaluation of the relationship of anesthetic agents and resuscitative fluid requirements and long-term outcomes. We also investigate the molecular mechanisms underlying the effects of anesthetic agents on coagulation and PTSD development and examine methods for emergent management of airways.


PRODUCT EVALUATION

Patients with burn injuries often undergo multiple surgeries, dressing changes, and other painful procedures. Several diverse and innovative pain control measures and products are available, including opioids such as intranasal (IN) morphine, IN dilaudid, early methadone, Actiq, and Ionsys, as well as IN ketamine, regional anesthesia, and nonpharmacological analgesics such as virtual reality. However, pain often has multiple causes and mechanisms, and so a single therapeutic approach is often unable to fully ameliorate pain. Patients receive a “pain soup” of anesthetic and analgesic agents. We are investigating if Virtual Reality (VR) improves pain control during the dressing change. Dressing changes during normal wound care are a great model of pain. Patients receive half their dressing change with a therapeutic agent and half with another method. While receiving VR, patients may think less about pain, be immersed in the VR, and cope with pain better.


ANESTHETICS AND PTSD DEVELOPMENT

Up to 17% of returning OIF/OEF uninjured veterans reported cognitive and psychological symptoms consistent with PTSD. Predisposing factors for PTSD include experiencing a traumatic event, threat of injury or death, and untreated pain; thus almost all deployed service member are at risk for PTSD. Randomized clinical trials of patients whose pain is either adequately controlled or inadequately controlled are not ethical or practical to determine the effect of anesthetic agents and pain control on PTSD development. This leads to reliance on retrospective studies to illuminate the many questions relating pain and PTSD.

Understanding the factors that lead to development of PTSD may allow us to better recognize, manage and prevent this condition that destroys an individual’s ability to function in society as well as the military. This group of studies (both retrospective and prospective portions) will analyze the association of anesthetic and anesthetic regimens on PTSD.

Ketamine is used at low doses as part of a multi-modal anesthesia. However, since ketamine is associated with psychosomatic effects, there was concern that ketamine may increase the risk of developing PTSD. Contrary to expectations, burn patients receiving intra-operative ketamine have a lower prevalence of PTSD compared to soldiers receiving no ketamine during their surgeries, despite having larger burns, higher injury severity scores, undergoing more operations, and spending more time in the ICU. To further understand these results, we are developing a rat model to assess changes in transcription in response to anesthetic exposure. Preliminary results suggest that ketamine may alter genes involved in memory formation.

PAIN CONTROL AND CHRONIC PAIN

Adequate pain management for combat casualties balances requirements for emergent, life-saving care with the need to remove Soldiers from harm’s way. Thus, complete elimination of pain may be impossible until safe evacuation to surgical theatres allows for general anesthesia. Pain is experienced throughout the continuum of care and is tracked from admission to the ED at level 2 and level 3 facilities. At admission to level 2 and level 3 facilities, 308/437 (70.5%) of patients experienced pain of 5 or greater on a Visual Analog Scale of 0-10. Clinical guidelines suggest treating pain at 5 or greater as severe pain and recommend beginning pain treatment at a pain score of 4. Despite the best efforts of clinicians, however, uncontrolled pain is too frequent, especially during the austere environments of evacuation.

Despite marked progress that has been made in combat casualty care and timeliness of medical interventions, the emergent management of pain following battlefield injuries still remains a significant challenge for patients and health care personnel. Adequate pain management for combat casualties balances requirements for life-saving care with the need to remove Soldiers from harm’s way. Thus, complete elimination of pain may be impossible until safe evacuation to surgical theatres allows for general anesthesia. Equally concerning are the obvious gaps in research addressing ways in which rapid control of pain could be accomplished with combat casualties in the battlefield, theater medical care units, during air transport evacuation, and in hospitals along the evacuation chain. Isolated reports do underscore the importance of adequate pain control, but few studies of battlefield casualties actually address pain control issues with a more global perspective.

Recent evidence suggests the hyperstimulation of central neuronal pathways leads to neuropathological remodeling and chronic pain in patients with severe acute unrelieved pain. Also, the stress of combat and prolonged uncontrolled pain and suffering contribute to psychological maladjustment and disorders such as PTSD. Despite this evidence, the physiological and psychosocial consequences of severe pain, including chronic pain and PTSD in the aftermath of battlefield injury, have not been adequately studied in prospective, longitudinal research designs. In collaboration with researchers at the Philadelphia Veterans Affairs Medical Center, WRAMC, and Advanced Regional Anesthesia and Pain Management Initiative, we are determining if early intervention for pain results in more favorable short- and long-term pain control and subsequently lowers rates of disabling pain, PTSD, depression and substance abuse or addiction.

MOLECULAR MECHANISMS OF PAIN AND THERAPEUTICS

The sensation of pain results from the interactions of multiple physiological mechanisms that relay information from the primary afferent neurons to the spinal dorsal horn and ultimately to the pain matrix of the brain. Noxious stimuli, including thermal and mechanical inputs, are detected by nociceptive neurons based upon changes in the environment surrounding the injured tissue. As a consequence of mechanical or thermal injury, multiple signaling pathways are initiated or their functions altered. Signals are transduced via a variety of molecules, including G protein coupled receptors (GPCRs), ligand-gated ion channels, voltage-gated ion channels, and receptor tyrosine kinases (RTKs), and the downstream effectors of these receptors are important for changes in the neurons that result in pain. Transduction through these pathways results in second messenger generation, including cAMP, DAG, and IP3, and initiates kinase cascades which result in altered gene expression, differential function, and production of multiple inflammatory mediators. Levels of neuropeptides, neurotransmitters, cytokines, prostaglandins, hormones, and growth factors, and protons are altered, and changes in these molecules’ concentration and activity result in the sensation of pain in response to a noxious stimulus.

Various anesthetic and analgesic agents function by altering signaling through these pathways. Our goal is to understand the molecular effects of anesthetics and analgesics. Determining the effects of these drugs at the molecular level will provide insight into their mechanisms as well as provide potentially novel targets for additional pharmacological interventions in pain control.

Pain therapeutics are typically screened for efficacy in animal models of human pain conditions, however, the translation of these results into clinical use is slow as only select therapeutics show similar efficacy in both animal models and humans. Testing novel therapeutics on human nociceptors (sensory neurons that specialize in detecting painful stimuli) has the potential to bridge this gap and translate novel pain treatments to the clinic more quickly and efficiently. Human dental pulp is composed of many of the same cells, fibers and nociceptors as other human tissues, thus offering a readily available model for the study of human nociceptors. Using an in vitro superfusion method and ELISA to measure proinflammatory peptide release from human dental pulp, the ability of novel pain therapeutics to reduce pain neurotransmission can be tested non-invasively. Western blotting and fluorescent immunohistochemistry can also be performed on human dental pulp to analyze changes in the expression of proteins and peptides known to be involved in pain processing. Successful therapeutics will be able to reduce pain neurotransmission as measured by proinflammatory peptide release. The results of this study, in collaboration with the results of our animal studies, will allow for a more precise manner of screening potential pain therapeutics for use in our pain patients.

ANESTHETICS AND RESUSCITATIVE FLUIDS

With the recent development and widespread use of tourniquets and hemostatic dressings for compressible hemorrhage control, one current unmet need is for determination of the most efficacious transfusion ratio of FFP:PRBC’s. Fortunately, most casualties receive, at most, 1-4 units of PRBC’s after injury and are not at high risk of presenting or developing a coagulopathy and subsequently dying. Only 5-10% of all combat casualties require massive transfusion (≥ 10 units of PRBCs), and this group constitutes those at risk for hemorrhagic death. Optimal treatment of these severely injured casualties is required.

The purpose of this study is to determine if anesthetic choice affects fluid resuscitation requirements by correlating the current transfusion practices and ratios at the United States Army Institute of Surgical Research [USAISR] with common anesthetic agents, which will result in an understanding of the ideal anesthetic agents and resuscitation fluids combinations for use in burn patients.

FUTURE GOALS

The goals of this area are to improve the quality of life for injured soldiers by improving pain control throughout their recovery period, eliminating PTSD and chronic pain development through controlling early acute pain, and evaluating new products for effective pain relief.

SELECTED PUBLICATIONS

1. Fowler, M., Garza, T., Slater, S., Maani, C., McGhee, L. The Relationship between Pregabalin and Gabapentin on Posttraumatic Stress Disorder in Burned Servicemembers. Epub 2 Jan 2012, J Burn Care Res.

2. Maani, C., Shah, M., Hansen, J., Fowler, M., Maani, E., McGhee, L. Translational Advances in Pain and Anesthesia for Cancer Patients. J Surg Oncol. 2012;105:488–493.

3. Fowler, M., Slater, T., Garza, T., Maani, C., DeSocio, P., Hansen, J., McGhee, L. Relationships Between Early Acute Pain Scores, Autonomic Nervous System Function, and Injury Severity in Wounded Soliders. J. Trauma. 2011 July 71(1): S87-S90.

4. Maani CV, DeSocio PA, Jansen RK, Merrell JD, McGhee LL, Young A, Williams JF, Tyrell K, Jackson BA, Serio-Melvin ML, Blackbourne LH, Renz EM. Use of ultra rapid opioid detoxification in the treatment of US military burn casualties. J Trauma. 2011 Jul;71(1 Suppl):S114-9.

5. Maani, C., Hoffman, H., Fowler, M., Maiers, A., Gaylord, K., DeSocio, C. Combining Ketamine and Virtual Reality Pain Control During Severe Burn Wound Care: One Military and One Civilian Patient. Pain Med. 2011 Apr;12(4):673-8.

6. McGhee, L., Slater, T., Garza, T., Fowler, M., DeSocio, P., Maani, C. The relationship of early pain scores and Post-Traumatic Stress Disorder in Burned Soldiers. J Burn Care Res. 2011 Jan-Feb;32(1):46-51.

7. McGhee LL, Maani CV, Garza TH, DeSocio PA, Gaylord KM, Black IH. The relationship of intravenous midazolam and posttraumatic stress disorder development in burned soldiers. J Trauma. 2009 Apr;66(4 Suppl):S186-90.

8. Maani CV, DeSocio PA, Holcomb JB. Coagulopathy in trauma patients: what are the main influence factors? Curr Opin Anaesthesiol. 2009 Apr;22(2):255-60.

9. McGhee LL, Maani CV, Garza TH, Desocio PA, Gaylord KM, Black IH. The effect of propranolol on posttraumatic stress disorder in burned service members. J Burn Care Res. 2009 Jan-Feb;30(1):92-7.

10. McGhee LL, Maani CV, Garza TH, Gaylord KM, Black IH. The correlation between ketamine and posttraumatic stress disorder in burned service members. J Trauma. 2008 Feb;64(2 Suppl):S195-8; Discussion S197-8.

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