Analgesics in the Pre-hospital Setting: Implications on Hemorrhage Tolerance - Morphine

We are examining how morphine (a commonly used pain medication) will alter responses to simulated blood loss in humans. To simulate blood loss in our research laboratory, participants will complete a test with their lower body in a custom-designed vacuum chamber for a brief period of time.

Pain management on the battlefield is critical for the wellbeing of the soldier. Given that a hemorrhagic injury on the battlefield is virtually always associated with pain, it is paramount that the selected pain medication does not disrupt appropriate physiological mechanisms that are beneficial towards the maintenance of blood pressure and vital organ blood flow during that hemorrhagic insult. Current guidelines for the selection of pain medications of a hemorrhaging soldier are based upon limited scientific evidence, with the vast majority of supporting studies being conducted on anesthetized animals. Thus, the interaction between hemorrhagic shock and pain medications commonly employed on the battlefield is yet to be determined in the conscious humans. With this background, we will test the hypothesis that morphine will impair the capacity for a conscious human to tolerate a hemorrhagic insult. The obtained data will provide the necessary scientific evidence in humans to support the Committee on Tactical Combat Casualty Care (CoTCCC) guidelines on the analgesic of choice for moderate to severe injuries where the casualty is in hemorrhagic shock. Notably, such data will identify the analgesic that least compromises a human's ability to tolerate a hemorrhagic insult, ultimately providing critical information to the combat medic on which analgesic should be employed for such an injury.

Subjects will receive Morphine while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.

Subjects will receive saline while the effects of this drug on tolerance to a hemorrhagic insult will be assessed.

Tolerance to a simulated hemorrhagic challenge will be assessed, for both the placebo and morphine limbs, by causing progressive central hypovolemia via lower-body negative pressure (LBNP). This progressive LBNP challenge will be performed until the onset of syncopal symptoms (defined as: profound bradycardia, a precipitous drop in arterial blood pressure and accompanying narrowing of pulse pressure, a sustained systolic blood pressure less than 80 mmHg, and/or subjective symptoms such as light-headedness, sweating, nausea, or dizziness). The primary variable will be the quantification of LBNP that is required to cause these symptoms. This quantification will be objectively measured via a cumulative stress index which is calculated as the sum of the product of the LBNP level and the duration of each level, until test termination (i.e., 40 mmHg x 3 min + 50 mmHg x 3 min, etc). A larger cumulative stress index represents a greater tolerance

Pain assessments will be conducted using a digital algometer to obtain maximum pain thresholds caused by pressure. This pain assessment technique is conducted by applying the tip of a hand-held digital algometer on the subject's digit. Force is gradually increased and the peak force is recorded when the subject first reports a painful sensation. Removal of the pressure from the algometer immediately relieves the painful sensation and the subject can voluntarily stop the test at any time. This assessment will be performed when the subject has received placebo and morphine.

Inclusion Criteria: Healthy Non-obese (body mass index less than 30 kg/m2) Body mass greater than or equal to 65 kg Exclusion Criteria: Subjects who have cardiac, respiratory, neurological and/or metabolic illnesses Any known history of renal or hepatic insufficiency/disease Pregnancy or breast feeding Current smokers, as well as individuals who regularly smoked within the past 3 years Positive urine drug screen Currently taking pain modifying medication(s)