Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing

Intermountain Sleep Disorder Center, Pulmonary Division, LDS Hospital, Salt Lake City, UT 84143, USA.
Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine (Impact Factor: 3.05). 08/2007; 3(5):455-61.
Source: PubMed


Chronic opioid therapy for pain management has increased dramatically without adequate study of potential deleterious effects on breathing during sleep.
A retrospective cohort study comparing 60 patients taking chronic opioids matched for age, sex, and body mass index with 60 patients not taking opioids was conducted to determine the effect of morphine dose equivalent on breathing patterns during sleep.
The apnea-hypopnea index was greater in the opioid group (43.5/h vs 30.2/h, p < .05) due to increased central apneas (12.8/h vs 2.1/h; p < .001). Arterial oxygen saturation (SpO2) in the opioid group was significantly lower during both wakefulness (difference 2.1%, p < .001) and non-rapid eye movement (NREM) sleep (difference 2.2%, p < .001) but not during rapid eye movement (REM) sleep (difference 1.2%) than in the nonopioid group. Within the opioid group, and after controlling for body mass index, age, and sex, there was a dose-response relationship between morphine dose equivalent and apnea-hypopnea (p < .001), obstructive apnea (p < .001), hypopnea (p < .001), and central apnea indexes (p < .001). Body mass index was inversely related to apnea-hypopnea index severity in the opioid group. Ataxic or irregular breathing during NREM sleep was also more prevalent in patients who chronically used opioids (70% vs 5.0%, p < .001) and more frequent (92%) at a morphine dose equivalent of 200 mg or higher (odds ratio = 15.4, p = .017).
There is a dose-dependent relationship between chronic opioid use and the development of a peculiar pattern of respiration consisting of central sleep apneas and ataxic breathing. Although potentially significant, the clinical relevance of these observations remains to be established.

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Available from: Robert Farney, Jun 07, 2014
    • "In conclusion, the present results provide a mechanism for the respiratory disturbances induced by opioids in the KF, whereby opioids hyperpolarized KF neurons and suppressed post-inspiration. This process may be especially involved in upper airway disturbances caused by opioids (Savilampi et al. 2014) that will impact patients with impaired upper airway function, such as sleep apnoea (Walker et al. 2007). In this study, the sensitivity of μ opioid receptors on KF neurons to agonists was similar to that of neurons in other brain slice preparations and would be activated by clinically relevant circulating concentrations of morphine. "
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    ABSTRACT: Opioid-induced respiratory effects include aspiration and difficulty swallowing, suggesting impairment of the upper airways. The pontine Kölliker-Fuse (KF) controls upper airway patency and regulates respiration, in particular the inspiratory/expiratory phase transition. Given the importance of the KF in coordinating respiratory pattern, the mechanisms of mu opioid receptor activation in this nucleus were investigated at the systems and cellular level. In anesthetized, vagi-intact rats, injection of opioid agonist DAMGO or [Met(5) ]enkephalin (ME) into the KF reduced respiratory frequency and amplitude. The mu opioid agonist DAMGO applied directly into the KF of the in situ arterially perfused working heart-brainstem preparation of rat resulted in robust apneusis (lengthened low amplitude inspiration due to loss of post-inspiratory drive) that was rapidly reversed by the opioid antagonist naloxone. In brain slice preparations, activation of mu opioid receptors on KF neurons hyperpolarized a distinct population (61%) of neurons. As expected, the opioid-induced hyperpolarization reduced the excitability of the neuron in response to either current injection or local application of glutamate. In voltage-clamp recordings the outward current produced by the opioid agonist ME was concentration-dependent, reversed at the potassium equilibrium potential and was blocked by BaCl2 , characteristics of a G protein-coupled inwardly rectifying potassium (GIRK) conductance. The clinically used drug morphine produced an outward current in KF neurons with similar potency to morphine-mediated currents in locus coeruleus brain slice preparations. Thus, the population of KF neurons that are hyperpolarized by mu opioid agonists are likely mediators of the opioid-induced loss of post-inspiration and induction of apneusis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · The Journal of Physiology
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    • "To produce the analgesic effect, the opioid attaches to opioid receptors, where it modulates pain by inhibiting and/or opening voltage-gated calcium and/or potassium channels. The decrease in neuronal excitability within pathways and nuclei that are related to nociception translates into diminished pain sensation (Bessler, Shavit, Mayburd, Smirnov, & Beilin, 2006; Gupta & Weber, 2006; Gutstein & Akil, 2005; Teichtahl et al., 2005; Walker et al., 2007). Although all opioids are associated with pain control, the opioids that bind primarily to the mu receptors have the strongest analgesic effect and the greatest potential for central nervous system depression. "

    Full-text · Dataset · May 2013
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    • "Due to its all-inclusive definition (predominance of obstructive apneas during diagnostic testing, appearance of central apneas during PAP therapy) complex sleep apnea likely represents a common phenotypic manifestation of a group of conditions. Mechanisms that are postulated in the development of CompSAS include elevated chemoreceptor sensitivity [6], decreased arousal threshold [7], prolonged circulation time [8], and use of opioid medications [9]. This multitude of pathways leading to CompSAS, and the improvement of some of these mechanisms with time on treatment [10] likely results in the dynamic phenotype, with the improvement or disappearance CompSAS activity in some patients [11–15], and its appearance de novo in others [14]. "
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    ABSTRACT: Background: The definition of complex sleep apnea (CompSAS) encompasses patients with obstructive sleep apnea (OSA) who develop central apnea activity upon restitution of airway patency. Presence of arterial hypertension (HTN), coronary artery disease (CAD) and heart failure (HF) have been proposed as risk factors for CompSAS among OSA patients. Using our database of patients with CompSAS, we examined the prevalence of these risk factors and defined other clinical characteristics of patients with CompSAS. Methods: Through retrospective search of the database, we examined the medical and clinical characteristics of consecutive patients diagnosed with CompSAS between 11/1/2006 and 6/30/2011 at NorthShore University HealthSystem. Results: One hundred and fifty patients with CompSAS were identified. Among patients included in the study, 97 (64.7 %) had at least one risk factor for CompSAS, while 53 (35.3 %) did not have any of them. Prevalence of low left ventricular ejection fraction and hypocapnia were low. Therapeutic interventions consisted of several positive airway pressure therapies, mainly adaptive servo ventilation. A hundred and ten patients (73.3 %) complied with recommended therapy and improved clinically. Conclusions: Although most patients with CompSAS have cardiac comorbidities, about one third of patients do not have any risk factors of CompSAS prior to sleep testing. Further research on factors involved in development of CompSAS will allow for better tailoring of therapy to pathophysiology involved in an individual case.
    Full-text · Article · Feb 2013 · Sleep And Breathing
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