Opioid-induced respiratory depression (ORID) is the hallmark of opioid overdose and a major risk factor for death due to fentanyl. While repeat opioid use (ROU) elevates the risk of death, understanding its influence over breathing and its control has been poorly resolved. We developed a mouse model of ROU involving daily fentanyl use (5 days). We examined how ROU impacted breathing and activity from the preBötzinger complex (preBötC), a brainstem network critical to inspiratory rhythmogenesis. Acute fentanyl use caused a profound metabolic crisis during ORID involving a mismatch between ventilation and oxygen consumption. Our findings also revealed a crucial distinction in respiratory responses to ROU. Most mice (77%) had an adaptive ventilatory response, indicative of the development of tolerance to OIRD following ROU, and the relationship between ventilation and oxygen consumption improved during OIRD. However, in 23% of mice, the adaptive response failed to emerge, underscoring the heterogeneity in ventilatory and metabolic outcomes. Following ROU, rhythmogenesis in the preBötzinger complex was less sensitive to μ-opioid receptor agonism, indicating that adaptation to ROU involves centrally-mediated changes in the inspiratory medullary network. These findings reveal a series of physiological changes following ROU, typically resulting in improved ventilation and oxygenation during ORID. Such changes—or lack thereof—may contribute to the unpredictable nature of overdose susceptibility among opioid users. It has been well documented in the literature that one factor that can alter opioid overdose susceptibility in repeat users is the context of drug administration. Despite ROU increasing tolerance to opioid effects, taking opioids in an environmental context where they have not previously been administered the drug results in a loss of tolerance and an increase in opioid overdose susceptibility. While Context-Dependent Tolerance to overdose susceptibility and analgesia has been well described in the literature, Context-Dependent Tolerance to OIRD, and the neural mechanisms that support it have not been investigated. The Locus Coeruleus (LC) is a principal source of noradrenergic neuromodulation that can influence breathing responses to blood gas deviations. It is also involved with cue-reward associative relationships, Opioid Use Disorder, and opioid withdrawal. Using fiber photometry and simultaneous whole-body plethysmography in a mouse model of repeat fentanyl administration, we tested the hypothesis that ROU leads to context-based tolerance to OIRD supported by LC activity. The development of tolerance to OIRD coincided with enhanced LC activity coupled with transient increases in breathing. Changing the context of fentanyl use to a context not previously associated with the drug altered LC activity and its correlation with transient increases in breathing and reduced the tolerance to OIRD that developed with ROU. Optogenetic activation of the LC minimized OIRD magnitude in fentanyl-naïve subjects. These findings underscore the importance of the LC in facilitating OIRD tolerance from learned associations during ROU. Failure to establish such associations and the corresponding LC activity may increase susceptibility to overdose and death among chronic opioid users.