6/5/2017. Mellar P Davis MD FCCP FAAHPM Geisinger Medical Center Danville, PA

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1 Mellar P Davis MD FCCP FAAHPM Geisinger Medical Center Danville, PA Opioids adversely influence respiration in five distinct ways Opioids cause complex sleep disordered breathing consisting of central sleep apnea (CSA) and obstructive sleep apnea (OSA) Clinically opioids worsen pre-existing sleep disordered breathing (SDB) Recent studies have shown increased morbidity and mortality in patients receiving opioids for chronic non-cancer pain and chronic obstructive pulmonary disease (COPD)which appear to be related to cardiovascular events, not overdose Recommendations regarding management of SDB on opioids are not well developed and there is little trials data to give evidence to management 1

2 Breathlessness or dyspnea is a subjective experience of breathing discomfort with qualitatively distinct sensations that vary in intensity and from patient to patient The relief from breathlessness at the end of life is a critically important qualitative measure. Refractory breathlessness which is breathlessness that persists despite aggressive pulmonary rehabilitation, optimal bronchial dilatation and meticulous treatment of concurrent morbidities is palliated by morphine. Morphine modestly reduces the subjective severity of breathlessness. Unfortunately, opioids have not been shown to improve activities of daily living or function limited by breathless Two recent systematic reviews of randomized trials have gauged the benefits of opioids in reducing breathlessness in patients with COPD and advanced cardiopulmonary disease. Patients (n=797) had reduced dyspnea with a NNT of

3 The design of the opioid trials was centered on efficacy and not safety. Both showed improvements in dyspnea but not function. None of the studies involved assessment of patients for SDB. Almost all were less than 4 weeks in duration and a significant number were single dose studies. Safety was not well described Apnea is defined as the absence of air flow for at least 10 seconds while hypopnea is 50% or greater reduction in air flow for 10 seconds with a 4% reduction in oxygen saturation or a 3% desaturation with subsequent arousal. Obstructive sleep apnea is separated from central sleep apnea by the presence of respiratory effort during the period of reduced airflow. Obstructive sleep apnea is caused by recurrent upper airway collapse during inspiration SDB is clinically and diagnostically defined as an AHI >5. Mild SDB is an AHI ( episodes per hour) of 5-15, moderate and severe >30 Complex sleep disordered breathing consists of both CSA and OSA 3

4 Patient with a pre-existing cardiovascular disease and SDB have higher healthcare costs and a greater risk for adverse cardiovascular events with an odds ratio (OR) of 4.1 (95%CI ) compared with matched controls without SDB The number of obstructive events and the degree of hypoxemia during sleep strongly predicts for occurrence of an arrhythmia Those with SBD and comorbid COPD (overlap syndrome) or those with cardiovascular disease are at greater risk of for arrhythmias at night. The overlap syndrome compounds the risk of nocturnal arrhythmias relative to COPD or SDB alone. Those with the overlap syndrome have a 2.5- fold greater risk of tachyarrhythmias relative to those with OSA alone The prevalence of SDB is higher in patients who have chronic pain than in the normal population. The prevalence of OSA in patients with chronic spinal pain is 13.8%. Sleep disordered breathing occurs more frequently in individuals with temporomandibular joint disease or who have chronic headaches of all types (tension, migraine and cluster) 4

5 One mechanisms behind the arrhythmias at night relates to the dispersion of the QTc interval (differences between maximum and minimum QTc intervals over time). QTc intervals were found to lengthen with OSA and hypoxia. QTc dispersions were positively associated with the severity of the AHI (r=0.913, p<0.001 and were a direct marker of arrhythmia risk. Most sudden cardiac deaths from arrhythmias in individuals without SDB occur during the day with a nadir between midnight and 6AM. However, 50% of sudden deaths in those with SDB occur between midnight and 6am, a reversal of the common timing of sudden cardiac death Sleep disordered breathing has been associated with risk factors for cardiovascular disease. OSA is associated with increased risks of uncontrolled hypertension leading to a greater prevalence for myocardial infarction and strokes as well as deep venous thrombosis, all of which may cause sudden death. Hypertension, myocardial infarctions, strokes and deep venous thrombosis are related to increased sympathetic tone caused by SDB and hypoxia which is reduced by positive airway pressure 5

6 Opioids delay inspiration through hyperpolarization of pre-botzinger complex neurons thereby slowing respiratory rate by delaying inspiration Tidal volume compensatorially increases when doses are low thereby maintaining minute ventilation which is lost with higher opioid doses An inspiratory cycle is missed (called quantal breathing or integer multiples of the control period of breathing in the absence of the opioid Opioids are not associated with Cheyne -Stokes respiration Hypoxic drive is depressed to a greater extent than hypercapnic drive and suppression is longer lasting Opioids blunt responses to hypoxia by binding to mu receptors within the Nucleus Tractus Solitarius thus blocking neurotransmission from Glomus cells to the medulla Breath to breath tidal volume variability and delayed hyperventilation response to rising pco2 levels suggests both a central and peripheral opioid effect Blunted respiratory response to context cues ( breath holding) 6

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8 Respiratory drive is maintained by cortical activity while awake but during non-rapid eye movement sleep (NREM sleep), respiratory drive is maintained by metabolic drive (O2 and CO2) During rapid eye movement sleep (REM) by the medial pontine reticular group of neurons In both REM sleep and NREM sleep ventilatory responses to CO2 are blunted, responses to hypoxia are better maintained. During REM sleep, breathing becomes more variable (less rhythmic) and intercostal muscles become atonic Intermittent and sometimes severe hypoxemia can occur during REM sleep particularly if there is diaphragmatic impairment. Hypoxia becomes quite severe if the diaphragm is compromised by obesity, rib cage, deformity or COPD During REM sleep, there is a greater dependence on the chemoreceptor centers within and around the retrotrapezoid neuron complex (RTN) to maintain respiration 8

9 The respiratory rate is normally reduced during REM sleep but further reduced with opioid therapy due to opioid receptors on the NTS. REM sleep is a vulnerable time for opioidrelated impaired breathing; some Individuals with SDB depend on arousal at night to reinstate wakeful- related cerebral cortex respiratory drive to compensate for hypoxemia. Opioids blunt this compensatory arousal which reduces waking after sleep onset (WASO) episodes. This may improve sleep subjectively but will worsen or prolong hypoxemia during sleep, potentially leading to arrhythmias Opioid receptors on the mechanosensory neurons in upper airways activate laryngeal adductor and pharyngeal constrictors and depress laryngeal abductor muscles resulting in a decreased the upper airway caliber causing increased airway resistance. Upper airway dilator muscles become less active during REM sleep, when OSA most often occurs. The addition of benzodiazepines to opioids aggravates induced airway obstruction 9

10 Higher potency opioids such as the phenylpiperdine class (fentanyl) more profoundly reduce upper airway discharges control upper airway patency. This results in inspiratory glottic closure and increased airway resistance during inspiration. 30% of individuals on methadone maintenance therapy have CSA which only weakly correlated with dose, age and BMI 35% of patients on methadone maintenance therapy, have OSA which correlated with BMI and longer duration of maintenance therapy 46% of patients on opioids for chronic pain had severe SDB (AHI>30). 46% had mild day time increases in Paco2 which became more prevalent with increasing doses 75% of patients on a mean morphine equivalent dose of 266 mg, a median dose 187 mg per day, had a AHI > 5, 39% has OSA, 24% CSA and 8% both CSA and OSA. Severe SDB (AHI>30) was occurred in approximately 40%. The AHI worsened with the addition of muscle relaxants to opioid therapy. Combinations of methadone and benzodiazepines was highly associated with CSA 10

11 A comparison of patients on opioid therapy for chronic pain and a similar cohort of patients with chronic pain not on opioids found a AHI of 41 in those on opioids and 22 in those not on opioids (p=0.018). In a subset who underwent opioid taper, the AHI decreased to (p<0.01). Central sleep apnea resolved off opioids. Hypoxia during REM sleep which had occurred in 27% of individuals before opioid taper also improved significantly (p<0.01) Author (Reference) Numbers Benefits / Risks NNT Comments Elkstrom M N=271 Dyspnea relief 7-9 All but I study< 30 days in duration Barnes H Systematic review Dyspnea relief 9-10 All but I study< 30 of 26 studies with N=526 days in duration Vozoris NT N=130,979 Risks HR/NNH Opioid Matched-cohort study Hospitalizations HR1.5 / NNH 66 Short-acting opioids COPD/pneumonia related mortality All-cause mortality HR 4.79 /NNH 77 Short-acting opioids HR 3.38 / NNH 28 Mortality related to cardiac events Vozoris NT N=22,912 Hospitalizations HR 1.73 /NNH 71 Morphine dose<30mg/day Matched-cohort study COPD/pneumonia related mortality All-cause mortality HR 7.55 / NNH 71 Morphine dose<30mg/day HR 5.19 / NNH 17 Morphine dose<30mg/day There is a narrow therapeutic index between benefits and mortality when opioids are used to treat breathlessness or pain in patients with COPD. This influences our choices of analgesics and should be used to inform our patients about benefits and risks. We cannot assume that there is a safe dose of opioid until longer randomized trials are completed. 11

12 It should not be assumed that the morbidity and mortality risk of opioids in COPD is the same as that which occurs in the addiction maintenance population or in the chronic noncancer pain population. Methadone maintenance reduces mortality from addiction by reducing the use of street drugs Individuals with the overlap syndrome and a subset with SDB alone have daytime fatigue, daytime sleepiness, reduced cognitive function and frequently complain of insomnia Patients may also complain of WASO as a compensatory mechanism. Therefore, if one only treats the complaint, it would seem reasonable to prescribe a sedative at night and an opioid for breathlessness which would reduce breathlessness and WASO but deepen nocturnal hypoxia, worsen SDB and increase the risk for nocturnal arrhythmias 12

13 The STOP BANG questionnaire, although originally validated to screen for sleep apnea in perioperative setting, has been used in numerous studies to screen for OSA outside of the perioperative setting with high sensitively for moderate to severe sleep apnea. This screening tool may be useful in screening patients for the presence of sleep apnea Do Not Start an Opioid in a Patient with COPD Without a Clear Indication This may appear self-evident but most patients with COPD in the Ontario study were given an opioid not for dyspnea but for chronic noncancer musculoskeletal pain, an indication which has recently been questioned When Opioids Are Necessary for Advanced Cancer Pain and Survival Expectations Are Months to a Year or More, Monitor the Patient with COPD for a Sleep Disordered Breathing and Nocturnal Hypoxemia. It is not known if it is the degree of hypoxemia at night or the severity of the SDB as measured by the AHI that predisposes patients to respiratory and cardiovascular adverse events. It may be that the obstructive episodes at night predispose patients to pneumonia and COPD exacerbations while hypoxia causes arrhythmia. 13

14 Use an Opioid -Sparing Strategy for Pain Management and Avoid Benzodiazepines The level of evidence for opioid-sparing strategies is derived largely from nonrandomized trials and should be validated in randomized prospective studies. The evidence is also mixed with some negative studies Regional blocks, radiation and palliative surgery reduce pain and opioid requirements If a 24- hour sustained release opioid is used, one study suggested that it be given in the morning to avoid peaked plasma levels at night Consider Positive Airway Pressure for Those with COPD Overlap Syndrome and SDB on Opioids The level of evidence is derived from nonrandomized prospective and retrospective studies and so should be validated in randomized trials Efforts to manage CSA on opioids by continuous positive airway pressure (CPAP) have largely been unsuccessful whereas OSA responds relatively well The American Academy of Sleep Medicine guidelines do not make recommendations as to which positive airway pressure method should be used for CSA CPAP is generally less expensive than bi-level positive airway pressure (BiPAP) and adaptive servoventilation (ASV). Therefore, CPAP should be tried first and BiPAP and ASV used for individuals not responding to CPAP 14

15 A recent review six studies which explored the use of ASV for opioid induced SDB found in five of the six studies a reduction in both the AHI and central apnea index. The sixth demonstrated long-term benefits beyond 3 month. However, ASV should not be used for patients with congestive heart failure and an ejection fraction of <40; ASV increases mortality in these patients. Increased overdose deaths may be related to prescriptions of opioids given to patients with undiagnosed SDB- are these overdoses or are these individuals who follow a physician s order with unsuspected SDB? There are large gaps in evidence particularly regarding the benefits of positive pressure support and clinical outcomes- Does positive pressure support are night reduce opioid mortality? Who would benefit? 15