P-098 - (Poster #98) Bedside Suite of Aggregated Technologies to Monitor and Characterize Post-operative Respiratory Depression in the Clinical and Research Milieu – The Data Acquisition Module (DAM)

Background: Pain intricately modulates breathing through complex neural and chemical pathways. In states of acute pain, the body often triggers slow, deep respiration, linked to both analgesia and parasympathetic activation, as an adaptive response. However, when opioids are used to manage this pain, the suppression of excitatory neurons in the brainstem pre-Bötzinger complex (preBötC) can dangerously prolong the inspiratory rhythm. This disruption prolongs the inter-burst interval. While slow, deep breathing is associated with analgesia and parasympathetic tone, plausibly an evolutionary adaptation, the mechanism has the potential to become a life-threatening complication of both clinical and illicit opioid use. The brainstem nucleus tractus solitarius (NTS) integrates input from central and peripheral chemoreceptors, including the carotid body glomus cells, which sense hypoxia via ion channels like BK, TASK-1, and TASK-3. These channels initiate feedback that drives respiration via afferents to the NTS. In the context of chronic pain, opioids can compound respiratory depression by acting on the medulla and peripheral chemoreceptors. Hypoventilation can result, leading to hypercapnia, acidosis, hypoxemia and subsequent tissue hypoxia, precursors to fatal respiratory arrest. ENA-001, a BK-channel inhibitor, selectively stimulates the carotid body to restore peripheral respiratory drive and rhythmogenesis, bypassing central opioid suppression while preserving analgesia.

Purpose/Objectives: The purpose of this abstract is to theoretically explore the physiological link between slow, deep breathing and pain relief in the context of OIRD and provide a theoretical basis how ENA-001 can preserve this analgesia-associated breathing pattern while reversing its life-threatening consequences. We hypothesize that the carotid body is the link between paced slow deep breathing (by virtue of its effect on blood PaO2, PaCO2, and pH bathing the carotid body) and the opioid system in the brainstem, particularly the endogenous kappa-opioid dynorphin peptide family. ENA-001 offers a novel solution by stimulating the carotid body, thereby restoring respiratory drive without antagonizing central opioid receptors or compromising analgesic efficacy. We aim to bridge the mechanistic understanding of respiratory modulation with the clinical need for safer opioid use, positioning ENA-001 as a targeted therapy that uncouples respiratory rescue from analgesia reversal.

Methods: Given the relatively well-known bidirectional relationship between pain and respiration: changes in respiration often occur in response to pain; and reduction of pain can occur in response to changes in respiration, we employ a theoretical and integrative framework to explore the link among slow, deep breathing, analgesia, and OIRD, with a focus on the potential role of ENA-001 in restoring respiratory drive while preserving opioid-mediated pain relief.

Results: The brainstem respiratory network comprises several interconnected networks, including the preBötC, which generates inspiratory rhythm; the retrotrapezoid/parafacial respiratory group (RTN/pFRG), involved in expiratory patterning and CO₂ chemosensitivity; and the post-inspiratory complex (PiCo), which coordinates post-inspiratory activity (Ramirez et al., 2021). These centers are modulated by descending projections from the dorsolateral pons, particularly the Kölliker-Fuse and parabrachial nuclei (KFPN). Opioids exert inhibitory effects across multiple levels of this network, notably suppressing neuronal activity in the preBötC, PiCo, and KFPN (Lalley, 2003; Levitt et al., 2015; Montandon & Horner, 2014; Prkic et al., 2012; Saunders et al., 2022). Building on this mechanistic understanding of opioid action within the brainstem respiratory network, attention has turned to novel therapeutic interventions capable of restoring respiratory drive without compromising analgesia. Evidence supporting the safety and efficacy of ENA-001 derived from extensive preclinical investigations across multiple species and completed human studies, with current targeted indications including post-operative respiratory depression in both hospital and ambulatory settings, as well as community-based opioid overdose provide the infrastructure for the framework. Simultaneously, we consider the analgesia-promoting effects of slow breathing mechanisms of OIRD, suggesting a shared physiological pathway between respiratory modulation and pain control. Building on this, we incorporate published mechanistic data on ENA-001 to propose a pharmacological strategy that restores respiratory rhythm via peripheral input, independent of central opioid pathways. We synthesize existing findings from pharmacology, respiratory neurobiology, and pain science to model how ENA-001 could support ventilatory recovery without reversing analgesia. By exploring the convergence of preclinical and clinical literature, this conceptual framework offers a novel interpretation of OIRD not only as a pathological state but also as a maladaptive exaggeration of an evolutionarily conserved pain-relieving mechanism, potentially correctable via targeted peripheral intervention.

Conclusions/Implications for future research and/or clinical care: This theoretical framework supports the link between depth of breathing and analgesia. Further, the framework suggests that agents which act to restore respiratory drive (obtunded by opioid action) without compromising analgesia may have applications in clinical practice. Further preclinical and clinical studies are needed to fully articulate this action, and ultimate clinical import.