Combat-related injuries are common among soldiers, and pain is very common after such injuries. The usual (conventional) treatment of pain involves narcotic drugs (opioids), but side effects commonly occur before pain is relieved. The devices used for soldiers to self-dose narcotics are burdensome, and the size and programming of such devices is typically not practical for evacuation from battlefield injury. Narcotics themselves cause potentially dangerous sedation, slowed breathing, nausea, vomiting, itching, urinary retention, and constipation; these symptoms commonly occur before pain is adequately relieved. "Nerve blocks" (as a single-injection) have become an option for pain relief before/during evacuation and transport from a battlefield injury. Nerve blocks act to block pain signals from being carried from the injured arm or leg to the spinal cord and brain. Unfortunately, nerve blocks using typical drugs (local anesthetics, examples of which include Novocain® and Marcaine®) provide pain relief for less than 12 hours. This short duration is not enough time to be practical; a longer duration of pain relief from a nerve block is needed. After surgery to correct orthopaedic injuries, "continuous nerve blocks" have become more common to provide continuous "sensory block" pain relief in the injured (surgically treated) arm or leg. Unfortunately, continuous nerve blocks using typical drugs (for example, the same Marcaine® as above) also create "motor block," in which the arm or leg becomes less mobile. This reduced mobility slows down a soldier's physical therapy and rehabilitation. In this research proposal, we will evaluate four drugs from four different categories of pain relievers. These four drugs (individually) have been shown in civilian studies to make a longer duration of pain relief when given as part of a nerve block with conventional local anesthetics (e.g., Marcaine®). In addition, recent clinical research in civilians has shown that at least two of these four drugs when combined (without local anesthetics) provide pain relief without motor block. Scientific experiments testing whether these four drugs are toxic to nerve cells have been promising, in that the four drugs appear safer to nerve cells than do local anesthetics.

In order to explore the possible drug combinations that can be used to make nerve blocks last 24 hours or more, or to make continuous nerve blocks that relieve severe pain without motor block, it is rational to first test these ideas in an animal model. First, using nerves removed from rats, the drug combinations will be tested to see which combination best blocks electrical impulses "in vitro." After the best combination or combinations are determined using the isolated nerve electrical impulse block model, these same combinations can then be applied to live rats, who after nerve blocks (in the hindlimb) undergo various behavioral tests to determine pain relief and walking function. This research is projected to take approximately 3 years. The best possible drug combinations will be determined for both research goals (the long-duration single-injection nerve block goal with motor block, for pain relief before evacuation and transport; and the continuous nerve block for pain relief without motor block, to promote physical therapy). The partnering researchers (a civilian anesthesiologist and an army anesthesiologist, both of whom specialize in nerve blocks) will work together to advance the outcomes of this "translational" animal research to both civilians undergoing elective surgery, and combat-injured military personnel, respectively. This research will aim to provide meaningful pain relief to soldiers with combat injuries to the arms and/or legs, since these extremities have nerves that are amenable to nerve block by subspecialty-trained anesthesiologists.