Author: Thomas Altree
Altree, Thomas, 2024 The effects of reboxetine and morphine on sleep and breathing in obstructive sleep apnea and chronic obstructive pulmonary disease, Flinders University, College of Medicine and Public Health
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Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) are common respiratory diseases that cause significant symptom burden. OSA is characterized by repetitive pharyngeal airway narrowing and collapse, resulting in hypoxia, hypercapnia, and arousals during sleep. COPD is a small airways disease characterized by airflow obstruction and persistent respiratory symptoms, including breathlessness. Sleep disruption is common in both conditions, and currently available treatments are often incompletely effective.
Drugs initially developed for different purposes have shown therapeutic promise in both conditions. Antimuscarinics combined with noradrenergic reuptake inhibitors have been investigated as novel pharmacotherapy for OSA, but the optimal agents have yet to be determined. Morphine, originally developed for analgesia, was subsequently observed to relieve breathlessness, leading to its use in COPD. However, therapeutic responses vary, and the underlying effects on sleep, breathing and next day alertness in COPD are incompletely understood. In both conditions, clinical trials to investigate the effects of these potential pharmacotherapies are required.
Recent findings indicate that noradrenergic and muscarinic processes are important in pharyngeal muscle control, one of four key OSA endotypes. To date, reductions in OSA severity have only been detected when noradrenergic agents, such as reboxetine, are combined with an antimuscarinic. However, antimuscarinics cause significant side effects, and it is unclear if reboxetine alone is efficacious. Accordingly, in study one, I conducted a three-way, placebo-controlled, randomized trial, to determine if reboxetine alone reduces OSA severity. Reboxetine reduced OSA severity as measured by the apnea-hypopnea index (AHI). Reboxetine combined with the antimuscarinic oxybutynin did not cause additional reductions in AHI. Mechanistically, reboxetine improved pharyngeal collapsibility and respiratory control (loop gain), another important OSA endotype. These findings represent the first evidence that reboxetine alone reduces OSA severity, and provide insight into the role of noradrenergic agents on pharyngeal stability during sleep.
In COPD, breathlessness is common and can contribute to sleep disruption. Opioid analgesics, such as low-dose morphine, are included in international COPD guidelines for symptomatic relief of chronic breathlessness. Morphine is a central nervous system depressant, and as such may cause sedation and respiratory depression. Thus, there are significant safety concerns. The effects of morphine on sleep, breathing and next-day function have not been rigorously investigated in COPD.
My second project analyzed sleep questionnaire data from a placebo-controlled, randomized trial of low-dose morphine for breathlessness in ~150 people with COPD. After one week, there were no differences in perceived daytime sleepiness. This reassuring neutral effect persisted after four weeks. Additionally, participants who reported reduced breathlessness with morphine at four weeks also had improvements in sleep quality, raising a potential novel relationship between sleep and breathlessness which may be mediated by morphine.
In my third project, a placebo-controlled, randomized, cross-over trial, I aimed to objectively measure the sleep-related effects of morphine in COPD. After three daily 20mg doses, morphine did not affect sleep efficiency or the AHI, but reduced rapid eye movement sleep, respiratory rate, oxygenation and raised carbon dioxide levels during sleep. Despite these changes, there were no effects on next morning alertness or breathlessness.
Keywords: Obstructive sleep apnea, sleep disordered breathing, chronic obstructive pulmonary disease, pharmacotherapy, opioids, respiratory, sleep, breathlessness
Subject: Medical Science thesis
Thesis type: Doctor of Philosophy
Completed: 2024
School: College of Medicine and Public Health
Supervisor: Professor Danny Eckert