- Email: [email protected]
Opioids and Sleep-Disordered Breathing
Accepted Manuscript Opioids and Sleep Disordered Breathing Dr Emer Van Ryswyk, BMedSci, BMBS, PhD, Professor Nick Antic, MBBS, FRACP, PhD PII:
S0012-3692(16)49109-9
DOI:
10.1016/j.chest.2016.05.022
Reference:
CHEST 491
To appear in:
CHEST
Received Date: 11 March 2016 Revised Date:
19 May 2016
Accepted Date: 23 May 2016
Please cite this article as: Van Ryswyk E, Antic N, Opioids and Sleep Disordered Breathing, CHEST (2016), doi: 10.1016/j.chest.2016.05.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Word Count: 248 for abstract (maximum 250 words) and 3503 for main text (maximum 3,500 words)
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Submitted for: Contemporary Reviews in Sleep Medicine
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Opioids and Sleep Disordered Breathing
4 1st author: Dr Emer Van Ryswyk1, BMedSci, BMBS, PhD
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[email protected]
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2nd author: Professor Nick Antic1, MBBS, FRACP, PhD
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[email protected]
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1. Adelaide Institute for Sleep Health: A Flinders Centre of Research Excellence
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Faculty of Medicine, Nursing and Health Sciences
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The Flinders University of South Australia
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Repatriation General Hospital, C-Block Daws Road, Daw Park,
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c/- Adelaide Sleep Health, SALHN
SA, 5041, AUSTRALIA
Correspondence to: Professor Nick Antic
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Postal Address:
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[email protected]
Conflict of interest: Dr Van Ryswyk has declared that she has no conflict of interest. Professor Antic has received research funding from the National Health and Medical Research Council of Australia, Philips Respironics™ and Fisher and Paykel™, equipment donations from ResMed™, Philips Respironics™ and SomnoMed Limited, and lecture fees and payment for development of educational presentations from ResMed™, Astra Zeneca™ and GSK™.
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1
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ABG = arterial blood gas;
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AHI = apnoea hypopnoea index;
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ASV = adaptive servoventilation;
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BMI = body mass index;
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CDC = Centers for Disease Control and Prevention
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CNCP = chronic non-cancer pain;
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CPAP = continuous positive airway pressure;
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CSA = central sleep apnoea;
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CSR = Cheyne-Stokes respiration (CSR);
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EPAP = expiratory positive airway pressure;
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ESS = Epworth Sleepiness Scale;
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IR = immediate release;
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LVEF = left ventricular ejection fraction;
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NYHA = New York Heart Association;
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OSA = obstructive sleep apnoea;
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PaCO2 = partial pressure of carbon dioxide;
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SDB = sleep disordered breathing;
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ST = spontaneous timed;
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TLR = toll-like receptor.
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ACCEPTED MANUSCRIPT Abstract
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Opioid use for chronic pain analgesia, particularly chronic non-cancer pain (CNCP), has increased
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greatly since the late 1990s, resulting in an increase in opioid-associated morbidity and mortality. A
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clear link between opioid use and sleep disordered breathing (SDB) has been established, with the
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majority of chronic opioid users being affected by the condition, and dose dependent severity apparent
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for some opioids. More evidence is currently needed on how to effectively manage opioid-induced
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SDB. This review summarizes the current state of knowledge relating to management of patients on
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chronic opioid therapy who have SDB. Initial management of the patient on chronic opioid therapy
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with SDB requires thorough biopsychosocial assessment of their need for opioid therapy,
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consideration of reduction, or cessation of the opioid if possible and alternative therapies for treatment
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of their pain. If opioid therapy must be continued, then management of the associated SDB may be
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important. Several small-medium scale studies have examined the efficacy of non-invasive
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ventilation, particularly adaptive servo ventilation (ASV) for treatment of opioid-associated SDB.
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This is particularly because opioids predispose predominantly to central sleep apnoea (CSA), and
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also, to a lesser extent, to obstructive sleep apnoea (OSA). Generally, these studies have found
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positive results in treating opioid-associated SDB with ASV in terms of improving outcome measures
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such as central apnoea index and apnoea hypopnoea index. However, larger studies that measure
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longer term health outcomes, patient sleepiness and compliance are needed. Registries of health
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outcomes of ASV treated patients may assist with future treatment planning.
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Introduction
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In recent years, developed countries have reported a large increase in use of opioid analgesia,
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particularly for management of chronic pain,1 with a doubling of use in the United States (US), and a
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quadrupling of use in Australia (2011-13 compared with 2001-03 use).2 The US in combination with
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Western and Central Europe currently account for 94% of analgesic opioid use in the world.2 This is
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likely to have resulted from many factors, including the release of the joint statement on treatment of
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chronic pain by the American Academy of Pain Medicine and the American Pain Society in 1997.3,4
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This statement indicated that “pain is often managed inadequately, despite the ready availability of
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safe and effective treatments.” 4
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The main indications for prescribing opioids are management of opioid dependency, acute pain,
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terminal pain and chronic non-cancer pain (CNCP).5 Escalations in prescribing of opioids for CNCP
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have been associated with harms, including opioid hyperalgesia, misuse and abuse and a marked
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increase in overdose deaths (more than 100% increase between 1999 and 2009).3,5,1 There is a clear
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link between opioid use and sleep disordered breathing (SDB), with dose dependent severity for
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certain opioids.6 Recent research shows that 70-85% of patients on opioids have SDB, and a high
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proportion of those cases are moderate-to-severe.7-9 Whilst there is a clear link between opioid use and
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SDB, what is much less clear is how to effectively manage this SDB. This review summarizes the
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current state of knowledge relating to management of patients on chronic opioid therapy who have
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SDB.
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Opioids – Effects on respiration
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Opioids act on receptors that are members of the G-protein coupled receptor family.10 Pain,
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respiratory control, stress responses, appetite and thermoregulation are all mediated by the
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endogenous opioid system.10 The brainstem generates respiratory drive, and this drive is influenced by
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conscious inputs from the cortex as well as central and peripheral chemoreceptors that sense changes
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in the chemical constituents of blood.10 Opioid-induced impairment of breathing encompasses central
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depression of respiratory rate, amplitude and reflex responses, reduced brain arousability, as well as
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upper airway dysfunction.10-12 Opioid medications that act on µ-opioid receptors present the
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potentially lethal side effect of respiratory depression, and the development of therapies to reduce this
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side effect is limited because the critical neural sites and mechanisms of action of opioids in causing
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respiratory depression remain unclear.11,12 One particular opioid-sensitive neural site, known as the
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pre-Botzinger complex (preBotC) has been studied closely in recent years as it is believed to have the
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inherent capacity to generate breathing rhythm, and whilst the exact role of this complex is still being
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elucidated, the isolated complex in vitro is being used to develop and test new therapies aiming to
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prevent respiratory depression.10-15
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ACCEPTED MANUSCRIPT 122 Management and assessment of opioid associated breathing requires knowledge of the various
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abnormal breathing patterns that may result from opioid treatment (see Figure 1). These patterns
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include ataxic breathing, Biot’s respiration, Cheyne-Stokes respiration (CSR), obstructive sleep apnea
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(OSA) and central sleep apnea (CSA).7,16-18 Ataxic and Biot’s breathing are sometimes referred to
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interchangeably, although generally ataxic breathing is characterised by irregular frequency and tidal
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volume interspersed with unpredictable pauses in breathing or periods of apnea,19 whereas Biot’s
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breathing refers to a high frequency and regular tidal volume breathing interspersed with periods of
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apnea.19 CSR is characterised by a cyclical crescendo-decrescendo pattern of breathing, followed by
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periods of central apnea.19
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A systematic review, published in 2015, that examined the prevalence of SDB associated with chronic
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opioid therapy, found that generally the prevalence of OSA has been reported to be lower than the
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prevalence of CSA with opioid use (10% vs 60% and 8% vs 30%, respectively), although the exact
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distribution of CSA compared with OSA was difficult to determine.9,20,21 CSA is a term that describes
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a group of conditions characterised by the occurrence of cessations in air flow in the absence of the
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usual corresponding respiratory effort; this contrasts with OSA, in which there is ongoing respiratory
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effort during obstructive respiratory events.22 The systematic review found that hypoxemia is
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frequently associated with opioid use (in 62.5% of studies), although estimation of prevalence of
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hypoxemia during sleep was not possible due to heterogeneity amongst studies.9
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The mechanisms are not fully understood, but it is thought that OSA occurs in some people using
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opioids because of opioid-induced reductions in airway muscle activation.23 CSA is postulated to arise
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from depression of hypoxic and hypercapnic ventilatory drives.24 There is evidence that with chronic
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opioid use, the balance between hypoxic and hypercapnic ventilatory drive changes, such that whilst
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the hypoxic ventilatory drive may recover or be augmented, depression of hypercapnic ventilation
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remains.25 This may explain the characteristic episodes of under-breathing followed by augmentation
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of ventilation in response to hypoxemia that are observed with opioid use.25 Depression of
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hypercapnic drive would explain increases in partial pressure of carbon dioxide (PaCO2) measured in
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a recent study of patients using opioid therapy for chronic pain analgesia; in this prospective study,
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mean (awake) PaCO2 was 44.8 ± 4.1, with median PaCO2 44.9 in the 24 included patients.26 Whilst
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the mean PaCO2 was at the high end of the normal range, worryingly, nine of the participants were
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reported to have hypercapnia (defined as a PaCO2 ≥ 45 mg) on daytime arterial blood gas (ABG)
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measurement, whilst two had even more pronounced hypercapnia.26,27 These findings are concerning
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given that the participants had normal lung function (measured by spirometry) and were previously
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unaware of their hypercapnia. Furthermore, there is no current way of predicting who is at risk of this
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kind of borderline respiratory failure, and at what dose of opioids. Screening all patients on opioid
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therapy using ABG measurement is likely to be impractical, and more research is needed in this area.
159 Given limitations of ABG measurement such as pain and cost, two non-invasive measures of carbon
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dioxide measurement have been increasingly adopted into sleep studies. These measures are
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capnography, otherwise known as end-tidal CO2 (PETCO2) monitoring and transcutaneous CO2
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(PtCO2) monitoring.28 PETCO2 monitoring has been validated as an accurate indicator of arterial CO2
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level in patients who have had endotracheal intubation, and has been used previously for patients with
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OSA. However, when supplemental oxygen or positive airway pressure are utilised, PETCO2
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monitoring is less accurate.29 Difficulties with interpretation of PtCO2 monitoring may be encountered
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with patients with perfusion problems, skin diseases, oedema or hypovolemia.28 Recent studies
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assessing the efficacy of ASV or bilevel ventilation for treatment of opioid-induced SDB (described
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below and in Table 1) did not measure either PETCO2 or PtCO2, so it is important that future studies
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take these measurements.
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Effects of opioid use on driving safety
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Driving safety whilst using opioid therapy is another area of continued uncertainty. A systematic
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review published in 2003 concluded that opioids do not impair driving-related skills in opioid-
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dependent or tolerant patients, in contrast to those who are opioid naïve, who do have dose-related
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impairment in their psychomotor skills related to driving.30 A more recent systematic review found
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that only a subset of patients on opioid therapy, who meet certain criteria may be safe to drive,.31 The
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review suggested that driving may be safe only for those who are taking pharmacologically stable
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doses of opioids, who are not concurrently taking other psychoactive drugs, alcohol or illicit drugs,
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and who do not experience high levels of pain during therapy nor have a substantial sleep disorder,
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psychiatric condition or excessive daytime sleepiness. 31 It is, however, very common that patients
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taking opioid medications are concurrently taking other psychoactive medications. The review
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findings concur with more recent findings from Rose et al (2014), who discovered that their patients,
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recruited from a chronic pain clinic, consistently performed poorly on the 10-minute psychomotor
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vigilance task they administered.26 Compared with healthy controls, who were similar in mean age
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and gender distribution but had lower mean body mass index (BMI), the opioid-using participants in
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the Rose study had significantly higher mean reaction times and more frequent minor lapses.26 More
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research is needed to explore and clarify effects of chronic opioid therapy on driving ability.
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Development of a broadly acceptable driving screening test may prove quite clinically useful.
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Advances in management of patients with opioid induced sleep disordered breathing
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ACCEPTED MANUSCRIPT Recommendations relating to management of opioid-induced SDB are hampered by a lack of research
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on the topic. Details on each of care options and their evidence base are described below.
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Reduction or cessation of opioid therapy – options and considerations
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Assessment of the need for opioids, in conjunction with the individual patient and the opioid
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prescribing practitioner, is an essential part of initial management. Cochrane reviews on use of
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opioids for treatment of rheumatoid arthritis, osteoarthritis (knee and hip), low back pain and
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neuropathic pain have all found that there is insufficient evidence for long term opioid use.32-35
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Common findings were that there is limited evidence (of low-moderate quality) of short term
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analgesic efficacy and that adverse effects are so frequent that they may outweigh any analgesic
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benefit.32-35 Evidence for longer term efficacy was lacking.32-35
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The poor quality evidence for long term efficacy of opioids should be particularly concerning when
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considering the loss of analgesic efficacy due to pharmacologic tolerance or opioid-induced
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hyperalgesia (worsening pain sensitivity in patients chronically exposed to opioids), and the litany of
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associated morbidities and increased risk of mortality with chronic opioid use.36 In addition to SDB,
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adverse effects of opioid use can include addiction, hypogonadism, infertility, immunosuppression,
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falls and fractures in older adults, neonatal abstinence syndrome, cardiac problems such as QT
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prolongation, hyperalgesia, increased emergency department visits, constipation, nausea, vomiting,
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dizziness, drowsiness, respiratory depression and death.5,36 There is evidence that SDB can be
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reversed with cessation of opioids,37 although more research is needed into the relationship between
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appropriate dose reduction and improvements in SDB.
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The CDC Guideline for Prescribing Opioids for Chronic Pain was published in March 2016.38 This
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guideline provides recommendations for clinicians prescribing opioids for chronic pain outside of
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active cancer treatment, palliative care, and end-of-life care, and addresses opioid initiation, selection,
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prescribing and risks. The CDC guidelines recommend that if opioid use is indicated, treatment
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should be initiated with immediate release (IR) preparations rather than extended release/long-acting
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(ER/LA) preparations. This is for a variety of reasons including a lower risk of overdose, and a lack of
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evidence that ER/LA are more effective or safer. The benefits of using IR opioid medications rather
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than ER preparations may include reductions in both respiratory depression and SDB frequency, and
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this is an area that warrants further research. However, the guidelines also state that ER/LA opioids
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may be considered for patients with severe, continuous pain who have received IR opioids daily for at
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least 1 week, so it is possible that those patients who have previously been prescribed ER/LA for
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chronic pain will continue to have ER/LA opioids prescribed, and those with more recent onset
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chronic pain may only be prescribed IR opioids for a short time before moving to ER/LA opioids.
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Thus, clinicians should pay careful attention when prescribing or taking a history of opioid use (e.g.
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ACCEPTED MANUSCRIPT duration of action, dose and frequency) in their patients to make an assessment of how such factors
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may influence their breathing.
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With regards to opioid use in people with SDB, the 2016 CDC guidelines recommend careful
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monitoring and cautious dose titration in mild SDB and avoidance of opioids in patients with
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moderate or severe SDB wherever possible due to the risk of overdose.38 Several other sources of
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information are available on opioid prescribing.5,36,39-41 A key common recommendation is use of non-
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pharmacologic therapies and non-opioid therapies wherever possible for chronic pain, rather than
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routine use of opioids. Such recommendations are highly prudent, although currently available
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alternative therapies, such as antidepressants, anticonvulsant medications, non-steroidal anti-
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inflammatories and acetaminophen (paracetamol) are also somewhat limited by side effects and/or
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lack of evidence for efficacy, so further research is necessary.42-53
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Use of positive pressure ventilation modes for treatment of SDB in chronic opioid use
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Where long term treatment with opioid therapy is continued, treatment of associated SDB is
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important. Small-to-medium scale studies have been conducted on the topic of treatment of opioid
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induced SDB, although there remains a need for research in this area.3,54-60 Table 1 provides details on
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studies that have examined the use of non-invasive positive pressure ventilation modes, including
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continuous positive airwards pressure (CPAP), adaptive-servoventilation, (ASV) and bilevel-
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spontaneous timed (ST) therapy.
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ASV was initially designed for patients with congestive heart failure, although more recently
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indications have extended to cover other causes of CSA, including opioid-induced CSA. ASV allows
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variable inspiratory support, in addition to a fixed or automatic expiratory pressure. In order to
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minimise the risk of chronic hyperventilation, the support in inspiration varies between cycles based
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on the ventilation level measured in the patient.61 In the studies described in Table 1, ASV is
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compared with either CPAP or bilevel-ST. In contrast to ASV, in which variable inspiratory support is
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provided, CPAP splints the airway open by providing a constant stream of positive pressure by
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blowing air through the nose/mouth and into the upper airways. Bi-level therapy uses two levels of
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pressure, an inspiratory pressure and an expiratory pressure; such devices are beneficial to people who
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have difficulty exhaling against standard CPAP pressure. Bi-level with ST machines determine the
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timing of when the user breathes in and out, whereas standard Bi-level machines react to the users’
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breathing.
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The currently available literature points to use of ASV for control of CSA associated with chronic
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opioid use, although, there is a need for further, larger and well-designed studies on this topic. Sample
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sizes of existing studies (Table 1) ranged from six (of which only four received treatment) to 47.57,62
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Generally studies have focused on AHI and CAI measurement rather than patient symptoms. Only
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ACCEPTED MANUSCRIPT two studies measured patient symptoms.56,58 Allatar (2009)58 reported Epworth Sleepiness Scale
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(ESS)63 scores of just four participants, with improvements ranging from 4-9 points with bilevel
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titration. Cao (2014) found that participants were more likely to report feeling more awake and alert
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on ASV-Auto than on bilevel-ST, using their Morning After Patient Satisfaction Questionnaire,
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(which contained questions relating to the patient’s sleep quality on the preceding night).
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Out of six recent studies, five indicated that ASV reduced AHI and CAI significantly, although AHI
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was not consistently reduced below 10/hour. The most recent study demonstrated that the benefits of
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ASV extended beyond the initial titration night into 3 months of home use.54 One of the six studies
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had less positive results.60 In this study, default settings were used (i.e. end positive airway pressure
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[EPAP] of 5.0 cm H2O, minimum pressure support of 3.0 cm H2O, maximum pressure support of 10.0
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cm H2O). As previously pointed out by Cao et al (2014), EPAP set at 5 cm H2O was likely below the
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pressure required to maintain upper airway patency, and therefore residual respiratory events
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remained.56
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Recent results from the Serve HF study are likely to make physicians more reluctant to use ASV
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devices.62 The Serve-HF trial (n = 1325) investigated the effects of ASV in patients with heart failure
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and reduced ejection fraction. Preliminary results of the study were reported in May 2015 with
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increased risk of cardiovascular death in symptomatic chronic heart failure patients with impaired
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LVEF, treated with ASV.61,62 This risk of death occurred despite normalisation of AHI on ASV and
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was constant over time, and was independent of the clinical benefit perceived by the patient.24,28
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Further analyses are in progress to investigate the cause of the increased cardiovascular mortality as
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well as to identify the most and least susceptible subgroups of patients.61 A safety warning was issued
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as a result of the SERVE-HF findings by ResMed™ and this was soon-after communicated by several
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medical organisations, such as the American Academy of Sleep Medicine.61,64 It is now
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contraindicated to implement ASV in patients with chronic symptomatic systolic heart failure (NYHA
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II-IV) with LVEF ≤ 45% and mainly central AHI (≥ 50% central events).
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It is important to note that the SERVE-HF results are not recommended to be extrapolated to other
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patient groups than those defined by the inclusion criteria of the study.61 SERVE-HF participants were
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likely to have significantly more cardiac dysfunction than patients on opiates with SDB. Although, if
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patients have predominantly CSA, an echocardiogram to assess left ventricle function seems prudent
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before using ASV devices in this group, given the SERVE HF findings.
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French experts have recommended setting up comprehensive registries of patients treated with ASV
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for CSA syndromes, in order to study health outcomes.61 Beneficial items to include on such a register
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may be medical history, indication for use of ASV, implementation details (e.g. CPAP failure or first
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line prescription), therapeutic benefit (reductions in abnormal respiratory events, daytime sleepiness
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ACCEPTED MANUSCRIPT and improvements in quality of life), compliance with ASV, and health outcomes such as
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hospitalisations, cardiovascular events and mortality.61
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Future research questions to be answered
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Several unanswered questions remain in relation to management of patients on opioid therapy for
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chronic pain. Research into novel therapies and more robust research into existing alternatives to
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opioid medications are needed. The ultimate goal should be optimal patient analgesia with minimum
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side effects. Recently, research into the pharmacology of opiods has moved from study of
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steroselective neuronal actions, to non-neuronal actions, particularly nonclassic and
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nonstereoselective sites of action.39 It has become apparent that opioids act on the innate immune
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pattern recognition receptors, Toll-like receptors (TLR), and these signaling events modify the
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pharmacodynamics of opioids by stimulating proinflammatory reactivity from glia
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(immunocompetent cells of the central nervous system). Elevated neuronal excitability results from
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the central immune signaling events, leading to heightened pain states and decreases in opioid
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analgesic efficacy.39 Therefore, it may be possible to improve analgesic effects of opiods through co-
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administration of: (a) general glial attenuators, including ibudilast, minocycline, propentofylline, or
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pentoxifylline; (b) glutamate transport enhancers, such as ceftriaxone; (c) with drugs that block pro-
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inflammatory activity, such as interleukin 1 receptor antagonists; (d) drugs that encourage anti-
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inflammatory conditions (e.g. amitriptyline or ultra-low-dose naltrexone/naloxone); (e) a drug that
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blocks TLRs known to trigger the cascade, or (f) a molecule that combines general glial attenuator
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and/or TLR inhibitoin with opioid agonist activity.39 Further research into coadministration of these
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therapies is needed, particularly with respect to the long term systemic immunological consequences.
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More research is also needed into risk factors for hypercapnia in opioid users and specifically which
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target groups should be screened clinically for this pathology.26 It may be useful to develop screening
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tools to aid clinicians with identifying patients on opioid therapy who are at increased risk of SDB,
319
such that they can be referred for formal screening. Further research into opioid dose and CSA,
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including effects of tapering opioid doses, is required.6 Development of widely acceptable driving
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assessments would likely be beneficial for clinicians managing patients on opioid therapy.30,31 For
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pre-existing opioid alternatives, high quality randomised controlled trials with long term follow are
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needed.
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Summary of unanswered questions: •
What opoid doses put patients at risk of SDB?
•
Which patients are at risk of hypercapnia and how can that risk be best predicted?
•
Can effective screening tools be developed to aid clinical identification of those at increased risk of SDB?
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ACCEPTED MANUSCRIPT •
What novel therapies could be used to reduce opioid dose and SDB risk?
•
Do PAP therapies lead to favorable long term health outcomes in opioid-related SDB?
•
How can we better predict driving safety in patients on opioid therapy?
324 Conclusions
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Opioid use increases the likelihood of CSA, and to a lesser extent OSA. Management of patients on
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chronic opioid therapy with SDB is hampered by a lack of high quality evidence. Based on currently
328
available evidence, initial management requires biopsychosocial assessment of the patient and their
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need for opioid therapy, consideration of tapering, or cessation if possible and offering alternative
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therapies for treatment of their pain. Novel alternatives require investigation and currently available
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alternatives require more thorough investigation in high quality randomised controlled trials.
332
Management of SDB is important where opioid therapy is continued. Several small-medium scale
333
studies have examined the efficacy of non-invasive ventilation, particularly adaptive servo ventilation
334
(ASV) for treatment of opioid-associated SDB. Generally, these studies have found positive results in
335
terms of AHI and CAI reduction with use of ASV, but often failed to investigate the impact on patient
336
symptoms, quality of life and health outcomes with long term use. Larger, randomised controlled
337
studies with longer term outcomes are needed for more thorough assessment of the efficacy of ASV
338
for treatment of opioid associated SDB, and registries of health outcomes of ASV treated patients may
339
assist with future treatment planning.
340
Acknowledgements
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Author contributions: EVR and NA discussed potential review content. EVR drafted and revised the
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manuscript. Advice on manuscript content as well as editing was provided by NA. Both authors
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approved the final version of the manuscript.
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Financial/nonfinancial disclosures
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Dr Van Ryswyk has declared that she has no conflict of interest. Professor Antic has received research
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funding from the National Health and Medical Research Council of Australia, Philips Respironics™
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and Fisher and Paykel™, equipment donations from ResMed™, Philips Respironics™ and
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SomnoMed Ltd, and lecture fees and payment for development of educational presentations from
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ResMed™, Astra Zeneca™ and GSK™.
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fibromyalgia in adults. Cochrane Database Syst Rev. 2013; Dec 3(12):CD006044.
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51 Wienecke T, Gotzsche PC. Paracetamol versus nonsteroidal anti-inflammatory drugs for
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52 Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in
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adults. Cochrane Database Syst Rev. 2012; Sep 12(9):CD007400.
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53 Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in adults.
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58 Alattar MA, Scharf SM. Opioid-associated central sleep apnea: a case series. Sleep
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59 Javaheri S, Malik A, Smith J, et al. Adaptive pressure support servoventilation: a novel
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sleep disordered breathing associated with chronic opioid medications for non-malignant
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pain. J Clin Sleep Med. 2008; 4(4):311-319.
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61 Priou P, d'Ortho MP, Damy T, et al. Adaptive servo-ventilation: How does it fit into the
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treatment of central sleep apnoea syndrome? Expert opinions. Rev Mal Respir. 2015;
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32(1):1072-1081.
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62 Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive Servo-Ventilation for Central
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Sleep Apnea in Systolic Heart Failure. N Engl J Med. 2015; 373(12):1095-1105.
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63 Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep. 1992;
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64 American Academy of Sleep Medicine. Special Safety Notice: ASV therapy for central
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sleep apnea patients with heart failure. AASA News Archive, 2015
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Table 1: Studies examining use of positive pressure ventilation for treatment of opioid induced SDB
Retrospective, small scale.
Eligibility: Consecutive patients, referred for evaluation for OSA (2006-2010) and on opioid therapy.
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Outcomes Standard PSG/titration variables, and AHI, CAI, OAI and HI from 3 months of home use. Patient symptoms: not reported. TCO2, end-tidal CO2: not reported.
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Intervention(s) All participants: In randomly allocated order (~1 week apart): (1) CPAP (2) ASV without mandatory pressure support, and (3) ASV manual (pressure support minimum 6cm H2O). Followed by home use of either an ASV device or a CPAP device to use for 3 months, based on PSG review.
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Design and Setting Prospective, multicentre, interventional. Eligibility: Age 21-70, use of opioid analgesia for ≥ 6 months. After a diagnostic PSG, those with AHI ≥ 20 and CAI ≥ 10 or ≥25% of total sleep time below 90% SaO2 were invited to participate further. Setting: 6 sleep clinics. 1 in Canada and 5 in the US. Participants: 34/74 were eligible. 31 completed titration with CPAP, ASV manual and ASV auto. 19 completed 3 months of home treatment with ASV (5 men, 14 women with mean age 52.5± 7.9 years, and mean BMI 30.7± 5.0 kg/m2). Mean morphine equivalent dose: 390.1±338.1 mg.
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Study Shapiro 201554
Setting: Cincinnati, Ohio, US. Participants: 20 total (13 men, and 7 women) with mean age 53 ± 10 and mean
CPAP titration (n = 16), which showed persistent CSA. 4 weeks later, 9/16 underwent a second, equally ineffective CPAP titration.
Standard PSG outcomes were reported, including sleep time, sleep efficiency, AHI, CAI and SpO2.
Study Findings Compared with CPAP: Significant reductions in AHI, CAI and OAI with use of ASV and ASV manual. No differences were detected in ODI, average O2 saturation or minimum O2 saturation with use of ASV and ASV manual. Home Treatment: With ASV use (n = 24), AHI, CAI and OAI were all significantly reduced compared to CPAP (n = 5). ASV were used for almost 50% of the days of home treatment, with ≥ 4 hours use on about 30% of those days. Central apnoeas persisted on CPAP. All central apnoeas were eliminated with ASV.
Patient symptoms:
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Setting: Stanford Sleep Medicine Centre, California, US.
Participants: 18 total: 12 men, 6 women with mean age 52.9 ± 15.3, and mean BMI 30.9 ± 6.7 kg/m2.
Ramar 201257
Opioid use: buprenorphine, naloxone, morphine, oxycodone, oxymorphone, fentanyl, methadone, tramadol, hydrocodone and hydromorphone. Retrospective, medium scale. Eligibility: Baseline AHI ≥ 5/hour. Subsequent CPAP titration showed control of obstructive events but a residual AHI > 5/hour or the persistence of CSA and/or CSR on CPAP. Setting: Center for Sleep Medicine, Mayo
not reported. TCO2, end-tidal CO2: not reported.
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Participants were randomised to one of two groups, then crossed-over into the alternative group:
(1): Bilevel-spontaneous timed (ST) recording with crossover to ASVAuto on a separate night
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CPAP therapy was then abandoned and all 20 participants underwent ASV titration.
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BMI 33 ± 7 kg/m2. 16 had CSA (CAI ≥ 5/hr). 4 had OSA. Opioid use: ≥1 of morphine, oxycodone, fentanyl, methadone, tramadol and hydromorphone. Median morphine equivalent dose 118mg. Prospective, randomised, blinded, crossover. Eligibility: Participants (age ≥ 18 years) who had been receiving chronic opioid therapy (≥ 6 months), and had SDB and CSA (CAI ≥ 5) diagnosed using the 2007 AASM criteria.
(2) ASVAuto with crossover to bilevel-ST on a separate night.
All participants underwent split night studies (diagnostic PSG followed by PSG with CPAP). All participants also underwent ASV titration.
Standard PSG outcomes. TCO2, end-tidal CO2: not reported. Patient symptoms: 2 questionnaires after each PSG: (1) The Morning After Patient Satisfaction Questionnaire, and (2) The PAP Comfort Questionnaire.
Standard PSG outcomes were reported, CSR, CSA, and atrial fibrillation. Patient symptoms: not reported.
Titration with ASVAuto compared with bi-level ST was much more successful. AHI was much more reduced: 2.5 ± 3.5 compared to 16.3 ±2 0.9, as was and CAI (0.4 ± 0.8 versus 9.4 ± 18.8). Patients reported feeling more awake and alert on ASVAuto than bi-level-ST, but there were no differences in the results of the PAP Comfort Questionnaire.
No significant differences were found between the groups in terms of overall ASV success (AHI < 10/hr). ASV was successful in 28 (60%) of patients in the
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Clinic, Minnesota, US.
CHF group: 61 in total. 54 men, 7 women with mean age 70.9 ± 9.4 and mean BMI 30.8 ± 5.8 kg/m2.
Opioid types and dosages not reported. Small scale case series. Eligibility: Patients referred for excessive daytime sleepiness, fatigue and/or snoring who were taking long-acting opioids for treatment of chronic pain.
Setting: Sleep disorder centre, University of Maryland, Baltimore, US. Participants: 6 in total (4 men, 2 women with mean age 56.2 ± 10.7, and mean BMI 31.5 ± 2.6 kg/m2). Participants were taking opioids for 1-15 years prior to referral. Morphine equivalent doses ranged from 120 to 420 mg/day Small scale, retrospective, non-controlled; part of a larger retrospective study on CPAP-emergent CSA Eligibility: Chronic opioid use for pain
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Opioids group: 47 in total. 23 men, 24 women with mean age 59.1 ± 14.2, and mean BMI 33.9 ± 8.0 kg/m2.
All patients had diagnostic PSG and were offered CPAP titration studies (5 took part, 1 declined).
4 patients undertook bilevel titration (5 offered, 1 declined) and used it at home for ≥ 6 months.
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Participants: 2 groups were recruited: patients on opioid therapy (used for > 6 months) and patients with CHF.
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TCO2, end-tidal CO2: bicarbonate levels reported.
All underwent diagnostic PSG, followed by CPAP titration. Because of an increase in
Standard PSG outcomes. Patient symptoms: ESS scores reported. TCO2, end-tidal CO2: Not reported.
Standard PSG/titration variables. Patient symptoms:
opioids group and 43 (71%) of patients in the CHF group. There was also no difference between groups when ASV success was defined as AHI < 5/hr at optimum end-expiratory pressure
ESS scores improved (by 4, 12, 5 and 9) with bilevel titration. AHI severity was reduced from severe to moderate/mild. Time spent at < 90% saturation decreased. Respiratory arousal index decreased. CAI was reduced to 0 in 3/4 cases, and reduced from 331 to 46 in the remaining case Baseline AHI was 70/hr. With CPAP therapy, AHI decreased to 55/hr but CAI increased from 26 to 37/hr. 3
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central apnoea with CPAP use, titration with ASV was undertaken.
Setting: Cincinnati, Ohio, U.S.
Participants: 5 in total: 4 men, 1 woman with mean age 51±4, and mean BMI 31±4 kg/m2.
Mean morphine equivalent dose 252 ± 150 mg. Retrospective study. Eligibility: Prior baseline AHI ≥ 20/hr. Opioids daily for ≥ 6 months.
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Overnight baseline PSG was compared to overnight CPAP titration and ASV titration.
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With ASV titration, mean CAI and OAI were 0 per hour, and mean HI was 13/hour
AHI, CAI, OAI, Mean AHI was 66.6/hr at HI, ODI, mean baseline, 70.1/hr on CPAP SpO2, lowest SpO2 and 54.2/hr with ASV. < 90% and degree When comparing ASV Setting: LDS Hospital, Salt Lake City, of Biot’s with baseline, mean OAI Utah, U.S. respiration. was reduced from 25.8/hr Participants: 22 total. 9 men, 13 women Patient symptoms: to 8.4/hr, whilst mean HI with mean age 50.1 ± 12.6, and mean BMI baseline ESS. increased from 14.5/hr to 32.9±6.1 kg/m2. TCO2, end-tidal 35.7/hr. CO2: not reported. AHI = apnoea hypopnoea index; AASM = American Academic of Sleep Medicine; ASV = adaptive servo-ventilation; BMI = body mass index; CAI = central apnoea index; CPAP = continuous positive airway pressure; CHF = congestive heart failure; CSA = central sleep apnoea; CSR = Cheyne Stokes Respiration; HI = hypopnoea index; H2O = water; OAI = obstructive apnoea index; ODI = oxygen desaturation index; O2 = oxygen; PAP = positive airway pressure; PSG = polysomnogram; SaO2 = arterial oxygen saturation; SpO2 = oxygen saturation using pulse oximetry; SDB = sleep disordered breathing; US = United States. Farney et al 200860
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Baseline ESS. TCO2, end-tidal CO2: not reported.
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management, referred for evaluation of OSA.
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S0012-3692(16)49109-9
DOI:
10.1016/j.chest.2016.05.022
Reference:
CHEST 491
To appear in:
CHEST
Received Date: 11 March 2016 Revised Date:
19 May 2016
Accepted Date: 23 May 2016
Please cite this article as: Van Ryswyk E, Antic N, Opioids and Sleep Disordered Breathing, CHEST (2016), doi: 10.1016/j.chest.2016.05.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Word Count: 248 for abstract (maximum 250 words) and 3503 for main text (maximum 3,500 words)
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Submitted for: Contemporary Reviews in Sleep Medicine
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Opioids and Sleep Disordered Breathing
4 1st author: Dr Emer Van Ryswyk1, BMedSci, BMBS, PhD
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[email protected]
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2nd author: Professor Nick Antic1, MBBS, FRACP, PhD
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[email protected]
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1. Adelaide Institute for Sleep Health: A Flinders Centre of Research Excellence
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Faculty of Medicine, Nursing and Health Sciences
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The Flinders University of South Australia
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Repatriation General Hospital, C-Block Daws Road, Daw Park,
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c/- Adelaide Sleep Health, SALHN
SA, 5041, AUSTRALIA
Correspondence to: Professor Nick Antic
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Postal Address:
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[email protected]
Conflict of interest: Dr Van Ryswyk has declared that she has no conflict of interest. Professor Antic has received research funding from the National Health and Medical Research Council of Australia, Philips Respironics™ and Fisher and Paykel™, equipment donations from ResMed™, Philips Respironics™ and SomnoMed Limited, and lecture fees and payment for development of educational presentations from ResMed™, Astra Zeneca™ and GSK™.
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1
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ABG = arterial blood gas;
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AHI = apnoea hypopnoea index;
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ASV = adaptive servoventilation;
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BMI = body mass index;
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CDC = Centers for Disease Control and Prevention
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CNCP = chronic non-cancer pain;
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CPAP = continuous positive airway pressure;
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CSA = central sleep apnoea;
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CSR = Cheyne-Stokes respiration (CSR);
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EPAP = expiratory positive airway pressure;
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ESS = Epworth Sleepiness Scale;
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IR = immediate release;
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LVEF = left ventricular ejection fraction;
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NYHA = New York Heart Association;
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OSA = obstructive sleep apnoea;
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PaCO2 = partial pressure of carbon dioxide;
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SDB = sleep disordered breathing;
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ST = spontaneous timed;
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TLR = toll-like receptor.
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ACCEPTED MANUSCRIPT Abstract
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Opioid use for chronic pain analgesia, particularly chronic non-cancer pain (CNCP), has increased
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greatly since the late 1990s, resulting in an increase in opioid-associated morbidity and mortality. A
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clear link between opioid use and sleep disordered breathing (SDB) has been established, with the
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majority of chronic opioid users being affected by the condition, and dose dependent severity apparent
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for some opioids. More evidence is currently needed on how to effectively manage opioid-induced
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SDB. This review summarizes the current state of knowledge relating to management of patients on
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chronic opioid therapy who have SDB. Initial management of the patient on chronic opioid therapy
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with SDB requires thorough biopsychosocial assessment of their need for opioid therapy,
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consideration of reduction, or cessation of the opioid if possible and alternative therapies for treatment
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of their pain. If opioid therapy must be continued, then management of the associated SDB may be
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important. Several small-medium scale studies have examined the efficacy of non-invasive
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ventilation, particularly adaptive servo ventilation (ASV) for treatment of opioid-associated SDB.
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This is particularly because opioids predispose predominantly to central sleep apnoea (CSA), and
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also, to a lesser extent, to obstructive sleep apnoea (OSA). Generally, these studies have found
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positive results in treating opioid-associated SDB with ASV in terms of improving outcome measures
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such as central apnoea index and apnoea hypopnoea index. However, larger studies that measure
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longer term health outcomes, patient sleepiness and compliance are needed. Registries of health
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outcomes of ASV treated patients may assist with future treatment planning.
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Introduction
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In recent years, developed countries have reported a large increase in use of opioid analgesia,
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particularly for management of chronic pain,1 with a doubling of use in the United States (US), and a
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quadrupling of use in Australia (2011-13 compared with 2001-03 use).2 The US in combination with
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Western and Central Europe currently account for 94% of analgesic opioid use in the world.2 This is
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likely to have resulted from many factors, including the release of the joint statement on treatment of
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chronic pain by the American Academy of Pain Medicine and the American Pain Society in 1997.3,4
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This statement indicated that “pain is often managed inadequately, despite the ready availability of
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safe and effective treatments.” 4
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The main indications for prescribing opioids are management of opioid dependency, acute pain,
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terminal pain and chronic non-cancer pain (CNCP).5 Escalations in prescribing of opioids for CNCP
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have been associated with harms, including opioid hyperalgesia, misuse and abuse and a marked
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increase in overdose deaths (more than 100% increase between 1999 and 2009).3,5,1 There is a clear
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link between opioid use and sleep disordered breathing (SDB), with dose dependent severity for
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certain opioids.6 Recent research shows that 70-85% of patients on opioids have SDB, and a high
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proportion of those cases are moderate-to-severe.7-9 Whilst there is a clear link between opioid use and
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SDB, what is much less clear is how to effectively manage this SDB. This review summarizes the
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current state of knowledge relating to management of patients on chronic opioid therapy who have
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SDB.
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Opioids – Effects on respiration
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Opioids act on receptors that are members of the G-protein coupled receptor family.10 Pain,
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respiratory control, stress responses, appetite and thermoregulation are all mediated by the
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endogenous opioid system.10 The brainstem generates respiratory drive, and this drive is influenced by
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conscious inputs from the cortex as well as central and peripheral chemoreceptors that sense changes
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in the chemical constituents of blood.10 Opioid-induced impairment of breathing encompasses central
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depression of respiratory rate, amplitude and reflex responses, reduced brain arousability, as well as
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upper airway dysfunction.10-12 Opioid medications that act on µ-opioid receptors present the
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potentially lethal side effect of respiratory depression, and the development of therapies to reduce this
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side effect is limited because the critical neural sites and mechanisms of action of opioids in causing
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respiratory depression remain unclear.11,12 One particular opioid-sensitive neural site, known as the
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pre-Botzinger complex (preBotC) has been studied closely in recent years as it is believed to have the
119
inherent capacity to generate breathing rhythm, and whilst the exact role of this complex is still being
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elucidated, the isolated complex in vitro is being used to develop and test new therapies aiming to
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prevent respiratory depression.10-15
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ACCEPTED MANUSCRIPT 122 Management and assessment of opioid associated breathing requires knowledge of the various
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abnormal breathing patterns that may result from opioid treatment (see Figure 1). These patterns
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include ataxic breathing, Biot’s respiration, Cheyne-Stokes respiration (CSR), obstructive sleep apnea
126
(OSA) and central sleep apnea (CSA).7,16-18 Ataxic and Biot’s breathing are sometimes referred to
127
interchangeably, although generally ataxic breathing is characterised by irregular frequency and tidal
128
volume interspersed with unpredictable pauses in breathing or periods of apnea,19 whereas Biot’s
129
breathing refers to a high frequency and regular tidal volume breathing interspersed with periods of
130
apnea.19 CSR is characterised by a cyclical crescendo-decrescendo pattern of breathing, followed by
131
periods of central apnea.19
132
A systematic review, published in 2015, that examined the prevalence of SDB associated with chronic
133
opioid therapy, found that generally the prevalence of OSA has been reported to be lower than the
134
prevalence of CSA with opioid use (10% vs 60% and 8% vs 30%, respectively), although the exact
135
distribution of CSA compared with OSA was difficult to determine.9,20,21 CSA is a term that describes
136
a group of conditions characterised by the occurrence of cessations in air flow in the absence of the
137
usual corresponding respiratory effort; this contrasts with OSA, in which there is ongoing respiratory
138
effort during obstructive respiratory events.22 The systematic review found that hypoxemia is
139
frequently associated with opioid use (in 62.5% of studies), although estimation of prevalence of
140
hypoxemia during sleep was not possible due to heterogeneity amongst studies.9
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The mechanisms are not fully understood, but it is thought that OSA occurs in some people using
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opioids because of opioid-induced reductions in airway muscle activation.23 CSA is postulated to arise
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from depression of hypoxic and hypercapnic ventilatory drives.24 There is evidence that with chronic
145
opioid use, the balance between hypoxic and hypercapnic ventilatory drive changes, such that whilst
146
the hypoxic ventilatory drive may recover or be augmented, depression of hypercapnic ventilation
147
remains.25 This may explain the characteristic episodes of under-breathing followed by augmentation
148
of ventilation in response to hypoxemia that are observed with opioid use.25 Depression of
149
hypercapnic drive would explain increases in partial pressure of carbon dioxide (PaCO2) measured in
150
a recent study of patients using opioid therapy for chronic pain analgesia; in this prospective study,
151
mean (awake) PaCO2 was 44.8 ± 4.1, with median PaCO2 44.9 in the 24 included patients.26 Whilst
152
the mean PaCO2 was at the high end of the normal range, worryingly, nine of the participants were
153
reported to have hypercapnia (defined as a PaCO2 ≥ 45 mg) on daytime arterial blood gas (ABG)
154
measurement, whilst two had even more pronounced hypercapnia.26,27 These findings are concerning
155
given that the participants had normal lung function (measured by spirometry) and were previously
156
unaware of their hypercapnia. Furthermore, there is no current way of predicting who is at risk of this
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ACCEPTED MANUSCRIPT 157
kind of borderline respiratory failure, and at what dose of opioids. Screening all patients on opioid
158
therapy using ABG measurement is likely to be impractical, and more research is needed in this area.
159 Given limitations of ABG measurement such as pain and cost, two non-invasive measures of carbon
161
dioxide measurement have been increasingly adopted into sleep studies. These measures are
162
capnography, otherwise known as end-tidal CO2 (PETCO2) monitoring and transcutaneous CO2
163
(PtCO2) monitoring.28 PETCO2 monitoring has been validated as an accurate indicator of arterial CO2
164
level in patients who have had endotracheal intubation, and has been used previously for patients with
165
OSA. However, when supplemental oxygen or positive airway pressure are utilised, PETCO2
166
monitoring is less accurate.29 Difficulties with interpretation of PtCO2 monitoring may be encountered
167
with patients with perfusion problems, skin diseases, oedema or hypovolemia.28 Recent studies
168
assessing the efficacy of ASV or bilevel ventilation for treatment of opioid-induced SDB (described
169
below and in Table 1) did not measure either PETCO2 or PtCO2, so it is important that future studies
170
take these measurements.
171 172
Effects of opioid use on driving safety
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Driving safety whilst using opioid therapy is another area of continued uncertainty. A systematic
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review published in 2003 concluded that opioids do not impair driving-related skills in opioid-
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dependent or tolerant patients, in contrast to those who are opioid naïve, who do have dose-related
177
impairment in their psychomotor skills related to driving.30 A more recent systematic review found
178
that only a subset of patients on opioid therapy, who meet certain criteria may be safe to drive,.31 The
179
review suggested that driving may be safe only for those who are taking pharmacologically stable
180
doses of opioids, who are not concurrently taking other psychoactive drugs, alcohol or illicit drugs,
181
and who do not experience high levels of pain during therapy nor have a substantial sleep disorder,
182
psychiatric condition or excessive daytime sleepiness. 31 It is, however, very common that patients
183
taking opioid medications are concurrently taking other psychoactive medications. The review
184
findings concur with more recent findings from Rose et al (2014), who discovered that their patients,
185
recruited from a chronic pain clinic, consistently performed poorly on the 10-minute psychomotor
186
vigilance task they administered.26 Compared with healthy controls, who were similar in mean age
187
and gender distribution but had lower mean body mass index (BMI), the opioid-using participants in
188
the Rose study had significantly higher mean reaction times and more frequent minor lapses.26 More
189
research is needed to explore and clarify effects of chronic opioid therapy on driving ability.
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Development of a broadly acceptable driving screening test may prove quite clinically useful.
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Advances in management of patients with opioid induced sleep disordered breathing
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ACCEPTED MANUSCRIPT Recommendations relating to management of opioid-induced SDB are hampered by a lack of research
194
on the topic. Details on each of care options and their evidence base are described below.
195
Reduction or cessation of opioid therapy – options and considerations
196
Assessment of the need for opioids, in conjunction with the individual patient and the opioid
197
prescribing practitioner, is an essential part of initial management. Cochrane reviews on use of
198
opioids for treatment of rheumatoid arthritis, osteoarthritis (knee and hip), low back pain and
199
neuropathic pain have all found that there is insufficient evidence for long term opioid use.32-35
200
Common findings were that there is limited evidence (of low-moderate quality) of short term
201
analgesic efficacy and that adverse effects are so frequent that they may outweigh any analgesic
202
benefit.32-35 Evidence for longer term efficacy was lacking.32-35
203
The poor quality evidence for long term efficacy of opioids should be particularly concerning when
204
considering the loss of analgesic efficacy due to pharmacologic tolerance or opioid-induced
205
hyperalgesia (worsening pain sensitivity in patients chronically exposed to opioids), and the litany of
206
associated morbidities and increased risk of mortality with chronic opioid use.36 In addition to SDB,
207
adverse effects of opioid use can include addiction, hypogonadism, infertility, immunosuppression,
208
falls and fractures in older adults, neonatal abstinence syndrome, cardiac problems such as QT
209
prolongation, hyperalgesia, increased emergency department visits, constipation, nausea, vomiting,
210
dizziness, drowsiness, respiratory depression and death.5,36 There is evidence that SDB can be
211
reversed with cessation of opioids,37 although more research is needed into the relationship between
212
appropriate dose reduction and improvements in SDB.
213
The CDC Guideline for Prescribing Opioids for Chronic Pain was published in March 2016.38 This
214
guideline provides recommendations for clinicians prescribing opioids for chronic pain outside of
215
active cancer treatment, palliative care, and end-of-life care, and addresses opioid initiation, selection,
216
prescribing and risks. The CDC guidelines recommend that if opioid use is indicated, treatment
217
should be initiated with immediate release (IR) preparations rather than extended release/long-acting
218
(ER/LA) preparations. This is for a variety of reasons including a lower risk of overdose, and a lack of
219
evidence that ER/LA are more effective or safer. The benefits of using IR opioid medications rather
220
than ER preparations may include reductions in both respiratory depression and SDB frequency, and
221
this is an area that warrants further research. However, the guidelines also state that ER/LA opioids
222
may be considered for patients with severe, continuous pain who have received IR opioids daily for at
223
least 1 week, so it is possible that those patients who have previously been prescribed ER/LA for
224
chronic pain will continue to have ER/LA opioids prescribed, and those with more recent onset
225
chronic pain may only be prescribed IR opioids for a short time before moving to ER/LA opioids.
226
Thus, clinicians should pay careful attention when prescribing or taking a history of opioid use (e.g.
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ACCEPTED MANUSCRIPT duration of action, dose and frequency) in their patients to make an assessment of how such factors
228
may influence their breathing.
229
With regards to opioid use in people with SDB, the 2016 CDC guidelines recommend careful
230
monitoring and cautious dose titration in mild SDB and avoidance of opioids in patients with
231
moderate or severe SDB wherever possible due to the risk of overdose.38 Several other sources of
232
information are available on opioid prescribing.5,36,39-41 A key common recommendation is use of non-
233
pharmacologic therapies and non-opioid therapies wherever possible for chronic pain, rather than
234
routine use of opioids. Such recommendations are highly prudent, although currently available
235
alternative therapies, such as antidepressants, anticonvulsant medications, non-steroidal anti-
236
inflammatories and acetaminophen (paracetamol) are also somewhat limited by side effects and/or
237
lack of evidence for efficacy, so further research is necessary.42-53
238
Use of positive pressure ventilation modes for treatment of SDB in chronic opioid use
239
Where long term treatment with opioid therapy is continued, treatment of associated SDB is
240
important. Small-to-medium scale studies have been conducted on the topic of treatment of opioid
241
induced SDB, although there remains a need for research in this area.3,54-60 Table 1 provides details on
242
studies that have examined the use of non-invasive positive pressure ventilation modes, including
243
continuous positive airwards pressure (CPAP), adaptive-servoventilation, (ASV) and bilevel-
244
spontaneous timed (ST) therapy.
245
ASV was initially designed for patients with congestive heart failure, although more recently
246
indications have extended to cover other causes of CSA, including opioid-induced CSA. ASV allows
247
variable inspiratory support, in addition to a fixed or automatic expiratory pressure. In order to
248
minimise the risk of chronic hyperventilation, the support in inspiration varies between cycles based
249
on the ventilation level measured in the patient.61 In the studies described in Table 1, ASV is
250
compared with either CPAP or bilevel-ST. In contrast to ASV, in which variable inspiratory support is
251
provided, CPAP splints the airway open by providing a constant stream of positive pressure by
252
blowing air through the nose/mouth and into the upper airways. Bi-level therapy uses two levels of
253
pressure, an inspiratory pressure and an expiratory pressure; such devices are beneficial to people who
254
have difficulty exhaling against standard CPAP pressure. Bi-level with ST machines determine the
255
timing of when the user breathes in and out, whereas standard Bi-level machines react to the users’
256
breathing.
257
The currently available literature points to use of ASV for control of CSA associated with chronic
258
opioid use, although, there is a need for further, larger and well-designed studies on this topic. Sample
259
sizes of existing studies (Table 1) ranged from six (of which only four received treatment) to 47.57,62
260
Generally studies have focused on AHI and CAI measurement rather than patient symptoms. Only
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ACCEPTED MANUSCRIPT two studies measured patient symptoms.56,58 Allatar (2009)58 reported Epworth Sleepiness Scale
262
(ESS)63 scores of just four participants, with improvements ranging from 4-9 points with bilevel
263
titration. Cao (2014) found that participants were more likely to report feeling more awake and alert
264
on ASV-Auto than on bilevel-ST, using their Morning After Patient Satisfaction Questionnaire,
265
(which contained questions relating to the patient’s sleep quality on the preceding night).
266
Out of six recent studies, five indicated that ASV reduced AHI and CAI significantly, although AHI
267
was not consistently reduced below 10/hour. The most recent study demonstrated that the benefits of
268
ASV extended beyond the initial titration night into 3 months of home use.54 One of the six studies
269
had less positive results.60 In this study, default settings were used (i.e. end positive airway pressure
270
[EPAP] of 5.0 cm H2O, minimum pressure support of 3.0 cm H2O, maximum pressure support of 10.0
271
cm H2O). As previously pointed out by Cao et al (2014), EPAP set at 5 cm H2O was likely below the
272
pressure required to maintain upper airway patency, and therefore residual respiratory events
273
remained.56
274
Recent results from the Serve HF study are likely to make physicians more reluctant to use ASV
275
devices.62 The Serve-HF trial (n = 1325) investigated the effects of ASV in patients with heart failure
276
and reduced ejection fraction. Preliminary results of the study were reported in May 2015 with
277
increased risk of cardiovascular death in symptomatic chronic heart failure patients with impaired
278
LVEF, treated with ASV.61,62 This risk of death occurred despite normalisation of AHI on ASV and
279
was constant over time, and was independent of the clinical benefit perceived by the patient.24,28
280
Further analyses are in progress to investigate the cause of the increased cardiovascular mortality as
281
well as to identify the most and least susceptible subgroups of patients.61 A safety warning was issued
282
as a result of the SERVE-HF findings by ResMed™ and this was soon-after communicated by several
283
medical organisations, such as the American Academy of Sleep Medicine.61,64 It is now
284
contraindicated to implement ASV in patients with chronic symptomatic systolic heart failure (NYHA
285
II-IV) with LVEF ≤ 45% and mainly central AHI (≥ 50% central events).
286
It is important to note that the SERVE-HF results are not recommended to be extrapolated to other
287
patient groups than those defined by the inclusion criteria of the study.61 SERVE-HF participants were
288
likely to have significantly more cardiac dysfunction than patients on opiates with SDB. Although, if
289
patients have predominantly CSA, an echocardiogram to assess left ventricle function seems prudent
290
before using ASV devices in this group, given the SERVE HF findings.
291
French experts have recommended setting up comprehensive registries of patients treated with ASV
292
for CSA syndromes, in order to study health outcomes.61 Beneficial items to include on such a register
293
may be medical history, indication for use of ASV, implementation details (e.g. CPAP failure or first
294
line prescription), therapeutic benefit (reductions in abnormal respiratory events, daytime sleepiness
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ACCEPTED MANUSCRIPT and improvements in quality of life), compliance with ASV, and health outcomes such as
296
hospitalisations, cardiovascular events and mortality.61
297
Future research questions to be answered
298
Several unanswered questions remain in relation to management of patients on opioid therapy for
299
chronic pain. Research into novel therapies and more robust research into existing alternatives to
300
opioid medications are needed. The ultimate goal should be optimal patient analgesia with minimum
301
side effects. Recently, research into the pharmacology of opiods has moved from study of
302
steroselective neuronal actions, to non-neuronal actions, particularly nonclassic and
303
nonstereoselective sites of action.39 It has become apparent that opioids act on the innate immune
304
pattern recognition receptors, Toll-like receptors (TLR), and these signaling events modify the
305
pharmacodynamics of opioids by stimulating proinflammatory reactivity from glia
306
(immunocompetent cells of the central nervous system). Elevated neuronal excitability results from
307
the central immune signaling events, leading to heightened pain states and decreases in opioid
308
analgesic efficacy.39 Therefore, it may be possible to improve analgesic effects of opiods through co-
309
administration of: (a) general glial attenuators, including ibudilast, minocycline, propentofylline, or
310
pentoxifylline; (b) glutamate transport enhancers, such as ceftriaxone; (c) with drugs that block pro-
311
inflammatory activity, such as interleukin 1 receptor antagonists; (d) drugs that encourage anti-
312
inflammatory conditions (e.g. amitriptyline or ultra-low-dose naltrexone/naloxone); (e) a drug that
313
blocks TLRs known to trigger the cascade, or (f) a molecule that combines general glial attenuator
314
and/or TLR inhibitoin with opioid agonist activity.39 Further research into coadministration of these
315
therapies is needed, particularly with respect to the long term systemic immunological consequences.
316
More research is also needed into risk factors for hypercapnia in opioid users and specifically which
317
target groups should be screened clinically for this pathology.26 It may be useful to develop screening
318
tools to aid clinicians with identifying patients on opioid therapy who are at increased risk of SDB,
319
such that they can be referred for formal screening. Further research into opioid dose and CSA,
320
including effects of tapering opioid doses, is required.6 Development of widely acceptable driving
321
assessments would likely be beneficial for clinicians managing patients on opioid therapy.30,31 For
322
pre-existing opioid alternatives, high quality randomised controlled trials with long term follow are
323
needed.
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Summary of unanswered questions: •
What opoid doses put patients at risk of SDB?
•
Which patients are at risk of hypercapnia and how can that risk be best predicted?
•
Can effective screening tools be developed to aid clinical identification of those at increased risk of SDB?
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ACCEPTED MANUSCRIPT •
What novel therapies could be used to reduce opioid dose and SDB risk?
•
Do PAP therapies lead to favorable long term health outcomes in opioid-related SDB?
•
How can we better predict driving safety in patients on opioid therapy?
324 Conclusions
326
Opioid use increases the likelihood of CSA, and to a lesser extent OSA. Management of patients on
327
chronic opioid therapy with SDB is hampered by a lack of high quality evidence. Based on currently
328
available evidence, initial management requires biopsychosocial assessment of the patient and their
329
need for opioid therapy, consideration of tapering, or cessation if possible and offering alternative
330
therapies for treatment of their pain. Novel alternatives require investigation and currently available
331
alternatives require more thorough investigation in high quality randomised controlled trials.
332
Management of SDB is important where opioid therapy is continued. Several small-medium scale
333
studies have examined the efficacy of non-invasive ventilation, particularly adaptive servo ventilation
334
(ASV) for treatment of opioid-associated SDB. Generally, these studies have found positive results in
335
terms of AHI and CAI reduction with use of ASV, but often failed to investigate the impact on patient
336
symptoms, quality of life and health outcomes with long term use. Larger, randomised controlled
337
studies with longer term outcomes are needed for more thorough assessment of the efficacy of ASV
338
for treatment of opioid associated SDB, and registries of health outcomes of ASV treated patients may
339
assist with future treatment planning.
340
Acknowledgements
341
Author contributions: EVR and NA discussed potential review content. EVR drafted and revised the
342
manuscript. Advice on manuscript content as well as editing was provided by NA. Both authors
343
approved the final version of the manuscript.
344
Financial/nonfinancial disclosures
345
Dr Van Ryswyk has declared that she has no conflict of interest. Professor Antic has received research
346
funding from the National Health and Medical Research Council of Australia, Philips Respironics™
347
and Fisher and Paykel™, equipment donations from ResMed™, Philips Respironics™ and
348
SomnoMed Ltd, and lecture fees and payment for development of educational presentations from
349
ResMed™, Astra Zeneca™ and GSK™.
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Table 1: Studies examining use of positive pressure ventilation for treatment of opioid induced SDB
Retrospective, small scale.
Eligibility: Consecutive patients, referred for evaluation for OSA (2006-2010) and on opioid therapy.
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Outcomes Standard PSG/titration variables, and AHI, CAI, OAI and HI from 3 months of home use. Patient symptoms: not reported. TCO2, end-tidal CO2: not reported.
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Intervention(s) All participants: In randomly allocated order (~1 week apart): (1) CPAP (2) ASV without mandatory pressure support, and (3) ASV manual (pressure support minimum 6cm H2O). Followed by home use of either an ASV device or a CPAP device to use for 3 months, based on PSG review.
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Design and Setting Prospective, multicentre, interventional. Eligibility: Age 21-70, use of opioid analgesia for ≥ 6 months. After a diagnostic PSG, those with AHI ≥ 20 and CAI ≥ 10 or ≥25% of total sleep time below 90% SaO2 were invited to participate further. Setting: 6 sleep clinics. 1 in Canada and 5 in the US. Participants: 34/74 were eligible. 31 completed titration with CPAP, ASV manual and ASV auto. 19 completed 3 months of home treatment with ASV (5 men, 14 women with mean age 52.5± 7.9 years, and mean BMI 30.7± 5.0 kg/m2). Mean morphine equivalent dose: 390.1±338.1 mg.
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Study Shapiro 201554
Setting: Cincinnati, Ohio, US. Participants: 20 total (13 men, and 7 women) with mean age 53 ± 10 and mean
CPAP titration (n = 16), which showed persistent CSA. 4 weeks later, 9/16 underwent a second, equally ineffective CPAP titration.
Standard PSG outcomes were reported, including sleep time, sleep efficiency, AHI, CAI and SpO2.
Study Findings Compared with CPAP: Significant reductions in AHI, CAI and OAI with use of ASV and ASV manual. No differences were detected in ODI, average O2 saturation or minimum O2 saturation with use of ASV and ASV manual. Home Treatment: With ASV use (n = 24), AHI, CAI and OAI were all significantly reduced compared to CPAP (n = 5). ASV were used for almost 50% of the days of home treatment, with ≥ 4 hours use on about 30% of those days. Central apnoeas persisted on CPAP. All central apnoeas were eliminated with ASV.
Patient symptoms:
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Setting: Stanford Sleep Medicine Centre, California, US.
Participants: 18 total: 12 men, 6 women with mean age 52.9 ± 15.3, and mean BMI 30.9 ± 6.7 kg/m2.
Ramar 201257
Opioid use: buprenorphine, naloxone, morphine, oxycodone, oxymorphone, fentanyl, methadone, tramadol, hydrocodone and hydromorphone. Retrospective, medium scale. Eligibility: Baseline AHI ≥ 5/hour. Subsequent CPAP titration showed control of obstructive events but a residual AHI > 5/hour or the persistence of CSA and/or CSR on CPAP. Setting: Center for Sleep Medicine, Mayo
not reported. TCO2, end-tidal CO2: not reported.
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Participants were randomised to one of two groups, then crossed-over into the alternative group:
(1): Bilevel-spontaneous timed (ST) recording with crossover to ASVAuto on a separate night
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BMI 33 ± 7 kg/m2. 16 had CSA (CAI ≥ 5/hr). 4 had OSA. Opioid use: ≥1 of morphine, oxycodone, fentanyl, methadone, tramadol and hydromorphone. Median morphine equivalent dose 118mg. Prospective, randomised, blinded, crossover. Eligibility: Participants (age ≥ 18 years) who had been receiving chronic opioid therapy (≥ 6 months), and had SDB and CSA (CAI ≥ 5) diagnosed using the 2007 AASM criteria.
(2) ASVAuto with crossover to bilevel-ST on a separate night.
All participants underwent split night studies (diagnostic PSG followed by PSG with CPAP). All participants also underwent ASV titration.
Standard PSG outcomes. TCO2, end-tidal CO2: not reported. Patient symptoms: 2 questionnaires after each PSG: (1) The Morning After Patient Satisfaction Questionnaire, and (2) The PAP Comfort Questionnaire.
Standard PSG outcomes were reported, CSR, CSA, and atrial fibrillation. Patient symptoms: not reported.
Titration with ASVAuto compared with bi-level ST was much more successful. AHI was much more reduced: 2.5 ± 3.5 compared to 16.3 ±2 0.9, as was and CAI (0.4 ± 0.8 versus 9.4 ± 18.8). Patients reported feeling more awake and alert on ASVAuto than bi-level-ST, but there were no differences in the results of the PAP Comfort Questionnaire.
No significant differences were found between the groups in terms of overall ASV success (AHI < 10/hr). ASV was successful in 28 (60%) of patients in the
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Clinic, Minnesota, US.
CHF group: 61 in total. 54 men, 7 women with mean age 70.9 ± 9.4 and mean BMI 30.8 ± 5.8 kg/m2.
Opioid types and dosages not reported. Small scale case series. Eligibility: Patients referred for excessive daytime sleepiness, fatigue and/or snoring who were taking long-acting opioids for treatment of chronic pain.
Setting: Sleep disorder centre, University of Maryland, Baltimore, US. Participants: 6 in total (4 men, 2 women with mean age 56.2 ± 10.7, and mean BMI 31.5 ± 2.6 kg/m2). Participants were taking opioids for 1-15 years prior to referral. Morphine equivalent doses ranged from 120 to 420 mg/day Small scale, retrospective, non-controlled; part of a larger retrospective study on CPAP-emergent CSA Eligibility: Chronic opioid use for pain
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Opioids group: 47 in total. 23 men, 24 women with mean age 59.1 ± 14.2, and mean BMI 33.9 ± 8.0 kg/m2.
All patients had diagnostic PSG and were offered CPAP titration studies (5 took part, 1 declined).
4 patients undertook bilevel titration (5 offered, 1 declined) and used it at home for ≥ 6 months.
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Participants: 2 groups were recruited: patients on opioid therapy (used for > 6 months) and patients with CHF.
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TCO2, end-tidal CO2: bicarbonate levels reported.
All underwent diagnostic PSG, followed by CPAP titration. Because of an increase in
Standard PSG outcomes. Patient symptoms: ESS scores reported. TCO2, end-tidal CO2: Not reported.
Standard PSG/titration variables. Patient symptoms:
opioids group and 43 (71%) of patients in the CHF group. There was also no difference between groups when ASV success was defined as AHI < 5/hr at optimum end-expiratory pressure
ESS scores improved (by 4, 12, 5 and 9) with bilevel titration. AHI severity was reduced from severe to moderate/mild. Time spent at < 90% saturation decreased. Respiratory arousal index decreased. CAI was reduced to 0 in 3/4 cases, and reduced from 331 to 46 in the remaining case Baseline AHI was 70/hr. With CPAP therapy, AHI decreased to 55/hr but CAI increased from 26 to 37/hr. 3
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central apnoea with CPAP use, titration with ASV was undertaken.
Setting: Cincinnati, Ohio, U.S.
Participants: 5 in total: 4 men, 1 woman with mean age 51±4, and mean BMI 31±4 kg/m2.
Mean morphine equivalent dose 252 ± 150 mg. Retrospective study. Eligibility: Prior baseline AHI ≥ 20/hr. Opioids daily for ≥ 6 months.
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Overnight baseline PSG was compared to overnight CPAP titration and ASV titration.
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With ASV titration, mean CAI and OAI were 0 per hour, and mean HI was 13/hour
AHI, CAI, OAI, Mean AHI was 66.6/hr at HI, ODI, mean baseline, 70.1/hr on CPAP SpO2, lowest SpO2 and 54.2/hr with ASV. < 90% and degree When comparing ASV Setting: LDS Hospital, Salt Lake City, of Biot’s with baseline, mean OAI Utah, U.S. respiration. was reduced from 25.8/hr Participants: 22 total. 9 men, 13 women Patient symptoms: to 8.4/hr, whilst mean HI with mean age 50.1 ± 12.6, and mean BMI baseline ESS. increased from 14.5/hr to 32.9±6.1 kg/m2. TCO2, end-tidal 35.7/hr. CO2: not reported. AHI = apnoea hypopnoea index; AASM = American Academic of Sleep Medicine; ASV = adaptive servo-ventilation; BMI = body mass index; CAI = central apnoea index; CPAP = continuous positive airway pressure; CHF = congestive heart failure; CSA = central sleep apnoea; CSR = Cheyne Stokes Respiration; HI = hypopnoea index; H2O = water; OAI = obstructive apnoea index; ODI = oxygen desaturation index; O2 = oxygen; PAP = positive airway pressure; PSG = polysomnogram; SaO2 = arterial oxygen saturation; SpO2 = oxygen saturation using pulse oximetry; SDB = sleep disordered breathing; US = United States. Farney et al 200860
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Baseline ESS. TCO2, end-tidal CO2: not reported.
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management, referred for evaluation of OSA.
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