Effects of the Opioid Analgesic, Sufentanil, on Components of the Respiratory Cycle after Extremity Trauma and Moderate Conscious Hemorrhage in Rats

Background: Sufentanil (SUF) is 500-fold more potent than morphine but is currently not recommended for use on the battlefield for casualties with shock or respiratory difficulties. However, there have been no controlled, preclinical studies conducted using analgesic doses of SUF to support these guidelines. We previously reported that SUF transiently and moderately depressed respiration rate and tidal volume (TV). The current study was conducted to further evaluate effects of SUF on components of the respiratory cycle after moderate hemorrhage in conscious rats with extremity trauma. Knowledge of specific respiratory-cycle components affected by SUF could provide information concerning SUF mechanisms and sites of action and may provide indices for diagnosis and treatment of compromised respiration. We hypothesized that SUF would negatively impact these respiratory components. Methods: Rats were randomly assigned to receive either 0.9% saline vehicle (VEH), or 1 µg/kg SUF (n=9-10 rats/ group). Rats (male; ~ 380 grams) were surgically implanted with a carotid catheter for hemorrhage and blood sampling. After 24 hours, rats were anesthetized (10 min) to undergo trauma (crushing of the right gastrocnemius and semimembranosus muscles for 30 sec with forceps) and fibula fracture. Rats were allowed to awaken, and 90 min later underwent a conscious hemorrhage (~37% of blood volume during 25 min) within a whole-body plethysmography chamber. After hemorrhage, rats received either VEH orSUF intra-arterially. Respiratory measures were recorded over 1 min intervals and included inspiratory time (Ti, sec), time spent inhaling during each breath; expiratory time (Te, sec), time spent exhaling during each breath); peak inspiratory flow (PIF, ml/sec), maximum inspiratory flow that occurs in one breath; mean inspiratory flow (MIF, equal to TV/Ti, ml/sec); peak expiratory flow (PEF, ml/sec), maximum expiratory flow that occurs in one breath. Data were analyzed via multiway analysis of variance (ANOVA) for repeated measures using PROC GLIMMIX of the Statistical Analysis System with adjustments for multiple comparisons provided via the Hochberg procedure. Results: Compared with VEH, for up to 10 min after SUFinjection Ti was 48% higher (P ≤ 0.025), PIF was 32% lower (P ≤ 0.017), and MIF was 40% lower (P≤0.002). Neither Te nor PEF were affected by SUF (P ≥ 0.18). In SUF-treated rats, PIF and MIF were highly negatively correlated with pCO ₂ (r ≥ -0.91; P ≤ 0.03). This did not occur in VEH-treated rats (r ≤ -0.44; P ≥ 0.24). Summary & Conclusions: Maintaining appropriate respiratory function after trauma and hemorrhage is critical for welfare and survival. At the analgesic dose given ̶ previously shown to ameliorate behavioral indices of pain in rats ̶ SUFhad transient inhibitory effects on inspiration rather than expiration, causing the SUF-induced decrease in respiration rate. Such effects suggest a possible site of action of SUF at the pre-Botzinger Complex, but do not obviate other brainstem nuclei. Moreover, SUF appeared to increase association of inspiratory regulatory mechanisms with blood pCO _2. The minor and transient nature of SUF effects on respiration do not, however, provide evidence for its exclusion as a battlefield pain-relief medication.

Applied Pain Research Program, US Army Clinical and Rehabilitative Medicine, and US Army Combat Casualty Care Research Program, Medical Research and Development Command.

This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.