Chronic Opioid Exposure and Peripheral Respiratory Outcomes

In these studies, the hypothesis that chronic opioid exposure promotes peripheral respiratory adverse health outcomes was tested. The first set of clinical studies explored prenatal opioid exposure (POE) and pulmonary outcomes in offspring. The second set of preclinical studies investigated the effects of chronic opioid exposure on airway remodeling, inflammation, pulmonary edema, and lung function, in an adult mouse model. Although we did not use an animal model of POE, our findings that POE influenced respiratory outcomes longitudinally into childhood, inspired preclinical studies for investigation of respiratory disease in a rodent model of chronic opioid exposure. We started with a seven-day model of chronic opioid exposure in mice since it is a widely used protocol for evaluation of physiological opioid dependence. Our first aim was to investigate whether in utero opioid exposure promoted the development of adverse respiratory outcomes within the first five years of childhood. Bioinformatic methods were used to query the 165 million record PearlDiver-Mariner patient database records for adverse respiratory diagnoses after POE. POE significantly impacted the risk for negative respiratory outcomes within the first five years of life, most notably amongst full-term births, although preterm births were also affected. POE resulted in tachypnea and respiratory distress in both groups. Full-term births were at an increased risk for bronchiolitis and apnea, whereas preterm births were at an increased risk for asthma. Full-term infants exposed to prenatal opioids were diagnosed with respiratory outcomes at earlier ages than their unexposed counterparts and appeared more like preterm infants. These data suggest careful monitoring of full-term infants with a history of POE for respiratory outcomes in early life. Findings from the patient database studies inspired additional preclinical studies that had advantages over limitations from the patient data. For example, we were not able to distinguish the effects of individual opioids in our PearlDiver study. With our preclinical mouse model of chronic opioid exposure, we were able to individually study the effects of fentanyl, morphine, and oxycodone separately. We studied the outcomes of pulmonary inflammation, airway remodeling edema, and lung function. Chronic opioid exposure increased inflammation in females, but not general factors associated with tissue remodeling. We observed increased tissue remodeling factor expression in males, but not inflammation. Our model of chronic opioid exposure did not result in pulmonary edema. Indeed, chronic morphine exposure decreased pulmonary vascular permeability in males and females. Chronic fentanyl and oxycodone did not significantly affect pulmonary vascular permeability. Thus, our model of chronic opioid exposure promoted lung inflammation and tissue remodeling in a sex and drug dependent manner but does not directly promote pulmonary edema. Lastly, chronic opioid exposure induced heterogenous changes in lung function in alignment with phenotypes of lung disease. Together, these findings suggest that chronic opioid exposure adversely impacts respiratory health both in developing lungs and in mature lungs. These studies can be used to add to the evidence to search for non-opioid therapies and to guide clinicians to monitor their opioid-prescribed patients for respiratory health outcomes.