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Pulmonary, Critical Care, and Sleep Pearls
]
A 44-Year-Old Woman With Excessive Sleepiness María Paula Tovar-Torres, MD; Cynthia Bodkin, MD; and Ninotchka L. Sigua, MD
A 44-year-old woman was referred by her primary care physician for a polysomnogram for further workup of excessive daytime sleepiness. She reported a 6-month history of uncontrollably falling asleep. She frequently dozed off while watching television, sitting inactive in public places, and talking to people. She had dozed off while driving, but had not had any driving accidents. Her Epworth Sleepiness Scale score was 21 of 24. She admitted to snoring, but no apneas were witnessed by her bed partner. She denied symptoms of morning headaches, gasping for air, leg jerking during sleep, cataplexy, sleep paralysis, hypnagogic hallucinations, gastroesophageal reflux during sleep, or insomnia. She usually went to bed at 10:00 PM and woke up at 9:00 AM. She reported three to four nocturnal awakenings per night. She denied taking naps. Medical history included chronic pain from cervical spinal stenosis, hypothyroidism, hyperlipidemia, depression, restless legs, migraines, and gastroesophageal reflux disease. She had no known cardiac illnesses. Medications included levothyroxine, 50 mg daily; duloxetine, 60 mg daily; cyclobenzaprine, 10 mg tid; omeprazole, 20 mg daily; trazodone, 50 mg daily; gabapentin, 600 mg daily; tolterodine, 2 mg bid; cetirizine, 10 mg daily; extended-release oral morphine sulfate, 15 mg bid; and immediate-release CHEST 2014; 146(6):e204-e207
oral morphine sulfate, 15 mg qid as needed for pain.
Figure 1 – Initial overnight polysomnogram showing respiratory events seen during stage N2 and N3 sleep (300 s/page). SaO2 5 oxygen saturation; ETCO2 5 End-tidal CO2.
e204 Pulmonary, Critical Care, and Sleep Pearls
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146#6 CHEST DECEMBER 2014
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Figure 2 – Respiratory events seen during stage N2 and N3 sleep (60 s/page). See Figure 1 legend for expansion of abbreviations.
Physical Examination Findings
Diagnostic Studies
Significant physical examination findings included BMI of 28.5 kg/m2, a modified Mallampati score of 2, and a neck circumference of 14 in. On general examination, the patient was awake, communicative, and did not appear sleepy during the visit. The rest of the physical examination was unremarkable. Neurologic examination showed no focal findings.
Initial polysomnographic findings are shown in Figures 1 and 2.
What is the diagnosis?
Manuscript received January 27, 2014; revision accepted May 2, 2014. AFFILIATIONS: From the Department of Medicine (Dr Tovar-Torres), Eastern Virginia Medical School, Norfolk, VA; Department of Neurology (Dr Bodkin), Indiana University School of Medicine, Indianapolis, IN; and the Department of Medicine (Dr Sigua), Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Indiana University School of Medicine, Indianapolis, IN. CORRESPONDENCE TO: Ninotchka L. Sigua, MD, 714 N Senate Ave, Ste 120, Indianapolis, IN 46202; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0221
journal.publications.chestnet.org
e205
Diagnosis: Opioid-induced central sleep apnea Discussion The patient’s initial overnight polysomnogram showed sleep-disordered breathing compatible with severe central sleep apnea (CSA). Her overall apnea-hypopnea index (AHI) was 58/h, with a central apnea index of 52.2/h. Capnography was normal. Figures 1 and 2 show repetitive central apneas characterized by cessation of airflow accompanied by lack of respiratory effort on the thoracic and abdominal bands, and cardiogenic oscillations on the capnogram. Reported features of opioidinduced CSA include prolonged periods of hypoventilation resulting in significant hypoxemia, ataxic breathing, and repetitive central apneas. Figure 1 shows typical ataxic breathing with significant respiratory variation in depth and rate associated with frequent respiratory pauses. Respiratory events predominantly occur during non-rapid eye movement sleep and abate during rapid eye movement sleep. Opioidinduced CSA should be distinguished from CheyneStokes respiration. Hallmark features of Cheyne-Stokes respiration include a crescendo-decrescendo breathing pattern with significant periodicity and prolonged cycle time suggestive of prolonged circulation time, with arousals typically occurring during the peak of the respiratory effort rather than at the cessation of the apneas. CSAs are characterized by sleep-disordered breathing associated with diminished or absent respiratory effort on polysomnogram, coupled with symptoms of excessive daytime sleepiness, frequent nocturnal awakenings, or both. Two basic mechanisms that have been described in CSAs include posthyperventilation central apnea and central apnea secondary to hypoventilation. Opioid-induced CSA belongs to the latter group and is a type of hypercapnic CSA due to impairment of central breathing drive thought to be a consequence of the respiratory depressant effects of these medications. The International Classification of Sleep Disorders-2 identifies six different forms of CSAs: primary CSA, CSA due to Cheyne-Stokes breathing pattern, CSA due to a medical condition not CheyneStokes, CSA due to high-altitude periodic breathing, CSA due to drug or substance (which is the case in opioid-induced CSA), and primary sleep apnea of infancy. Treatment of the underlying disorder is essential in nonprimary CSA. The dramatic change in chronic pain management over the last few years has led to an increase in opioid use, e206 Pulmonary, Critical Care, and Sleep Pearls
which has resulted in a surge in the prevalence of opioid-induced CSA. It has been estimated that up to 50% of patients on long-term opioid use have CSA. The exact mechanism of opioid-induced CSA is not well elucidated, but it is thought that opioid use leads to impairment of the hypercapnic and hypoxic ventilatory responses, and the effects are thought to be dose dependent. In a study of 60 patients taking opioid medications long-term, it has been shown that ataxic breathing and central apneas are more prevalent in patient taking opioids at a morphine dose equivalent to ⱖ 200 mg. Recent management guidelines for CSAs state that “literature assessing treatment of CSAs due to drug or substances is markedly limited.” In general, therapeutic strategies for CSAs include positive airway pressure, adaptive servoventilation, and oxygen therapy. The effectiveness of these therapies in opioidinduced CSA has been disappointing, however. CPAP therapy eliminates obstructive apneas but may worsen the central AHI, and adaptive servoventilation may modulate the breathing patterns but does not eliminate ataxic breathing nor significantly impact the AHI. Although reduction of opioid use as a mode of treatment of opioid-associated CSA seems intuitive, this management strategy is not mentioned in the aforementioned guidelines and review articles. Chronicpain guidelines emphasize the importance of a multidisciplinary approach and the use of different treatment options to achieve adequate pain control, trying to avoid, as much as possible, the use and the undesired effects of chronic opioid use. To our knowledge, few cases have documented the complete resolution of CSA after withdrawal of opioids. Our case emphasizes the importance of a multidisciplinary approach to chronic pain and the need to suspect opioids as the etiology of CSA when it presents with ataxic breathing and repetitive central apneas. Clinical Course
Based on the initial polysomnographic findings, recommendation was made to wean the patient off opiates as tolerated. She was able to wean herself completely from narcotics and upon presentation to the sleep clinic, a repeated polysomnogram revealed complete resolution of CSA, with overall AHI of 0/h (Fig 3). This case represents successful treatment of CSA by opioid withdrawal. Despite resolution of CSA, the patient had persistent excessive daytime sleepiness requiring further workup with a multiple sleep-latency test that showed reduced
[
146#6 CHEST DECEMBER 2014
]
Figure 3 – Complete resolution of central sleep apnea with opioid cessation (300 s/page). See Figure 1 legend for expansion of abbreviations.
sleep latency of 4 min 42 s with absence of sleep-onset rapid eye movement periods. She is currently on stimulant medications to control symptoms of daytime sleepiness.
Suggested Readings
Clinical Pearls
Eckert DJ, Jordan AS, Merchia P, Malhotra A. Central sleep apnea: pathophysiology and treatment. Chest. 2007;131(2):595-607.
1. The use of opiates has increased in the last few years and its long-term use has resulted in an upsurge in opioid-induced CSA. 2. Opioid-induced CSA is characterized by ataxic breathing and repetitive central apneas, and is associated with prolonged periods of hypoventilation. 3. Treatment of the underlying disorder is key in the management of nonprimary CSA. 4. For CSA associated with opiates, reduction or discontinuation of these medications by using alternative approaches to chronic pain is warranted to decrease and potentially correct this syndrome.
Novak S, Nemeth WC, Lawson KA. Trends in medical use and abuse of sustained-release opioid analgesics: a revisit. Pain Med. 2004;5(1):59-65. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic & Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.
Walker JM, Farney RJ, Rhondeau SM, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med. 2007;3(5):455-461. Farney RJ, Walker JM, Boyle KM, Cloward TV, Shilling KC. Adaptive servoventilation (ASV) in patients with sleep disordered breathing associated with chronic opioid medications for non-malignant pain. J Clin Sleep Med. 2008;4(4):311-319. Javaheri S, Malik A, Smith J, Chung E. Adaptive pressure support servoventilation: a novel treatment for sleep apnea associated with use of opioids. J Clin Sleep Med. 2008;4(4):305-310. Ramar K. Reversal of sleep-disordered breathing with opioid withdrawal. Pain Pract. 2009;9(5):394-398. American Society of Anesthesiologists Task Force on Chronic Pain Management; American Society of Regional Anesthesia and Pain Medicine. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2010;112(4):810-833. Javaheri S. Central sleep apnea. Clin Chest Med. 2010;31(2):235-248.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
journal.publications.chestnet.org
Institute for Clinical Systems Improvement. Health Care Guideline: Assessment and Management of Chronic Pain. 5th ed. Bloomington, MN: ICSI; 2011. Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep. 2012;35(1):17-40. Davis MJ, Livingston M, Scharf SM. Reversal of central sleep apnea following discontinuation of opioids. J Clin Sleep Med. 2012;8(5):579-580.
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Pulmonary, Critical Care, and Sleep Pearls
]
A 44-Year-Old Woman With Excessive Sleepiness María Paula Tovar-Torres, MD; Cynthia Bodkin, MD; and Ninotchka L. Sigua, MD
A 44-year-old woman was referred by her primary care physician for a polysomnogram for further workup of excessive daytime sleepiness. She reported a 6-month history of uncontrollably falling asleep. She frequently dozed off while watching television, sitting inactive in public places, and talking to people. She had dozed off while driving, but had not had any driving accidents. Her Epworth Sleepiness Scale score was 21 of 24. She admitted to snoring, but no apneas were witnessed by her bed partner. She denied symptoms of morning headaches, gasping for air, leg jerking during sleep, cataplexy, sleep paralysis, hypnagogic hallucinations, gastroesophageal reflux during sleep, or insomnia. She usually went to bed at 10:00 PM and woke up at 9:00 AM. She reported three to four nocturnal awakenings per night. She denied taking naps. Medical history included chronic pain from cervical spinal stenosis, hypothyroidism, hyperlipidemia, depression, restless legs, migraines, and gastroesophageal reflux disease. She had no known cardiac illnesses. Medications included levothyroxine, 50 mg daily; duloxetine, 60 mg daily; cyclobenzaprine, 10 mg tid; omeprazole, 20 mg daily; trazodone, 50 mg daily; gabapentin, 600 mg daily; tolterodine, 2 mg bid; cetirizine, 10 mg daily; extended-release oral morphine sulfate, 15 mg bid; and immediate-release CHEST 2014; 146(6):e204-e207
oral morphine sulfate, 15 mg qid as needed for pain.
Figure 1 – Initial overnight polysomnogram showing respiratory events seen during stage N2 and N3 sleep (300 s/page). SaO2 5 oxygen saturation; ETCO2 5 End-tidal CO2.
e204 Pulmonary, Critical Care, and Sleep Pearls
[
146#6 CHEST DECEMBER 2014
]
Figure 2 – Respiratory events seen during stage N2 and N3 sleep (60 s/page). See Figure 1 legend for expansion of abbreviations.
Physical Examination Findings
Diagnostic Studies
Significant physical examination findings included BMI of 28.5 kg/m2, a modified Mallampati score of 2, and a neck circumference of 14 in. On general examination, the patient was awake, communicative, and did not appear sleepy during the visit. The rest of the physical examination was unremarkable. Neurologic examination showed no focal findings.
Initial polysomnographic findings are shown in Figures 1 and 2.
What is the diagnosis?
Manuscript received January 27, 2014; revision accepted May 2, 2014. AFFILIATIONS: From the Department of Medicine (Dr Tovar-Torres), Eastern Virginia Medical School, Norfolk, VA; Department of Neurology (Dr Bodkin), Indiana University School of Medicine, Indianapolis, IN; and the Department of Medicine (Dr Sigua), Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Indiana University School of Medicine, Indianapolis, IN. CORRESPONDENCE TO: Ninotchka L. Sigua, MD, 714 N Senate Ave, Ste 120, Indianapolis, IN 46202; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0221
journal.publications.chestnet.org
e205
Diagnosis: Opioid-induced central sleep apnea Discussion The patient’s initial overnight polysomnogram showed sleep-disordered breathing compatible with severe central sleep apnea (CSA). Her overall apnea-hypopnea index (AHI) was 58/h, with a central apnea index of 52.2/h. Capnography was normal. Figures 1 and 2 show repetitive central apneas characterized by cessation of airflow accompanied by lack of respiratory effort on the thoracic and abdominal bands, and cardiogenic oscillations on the capnogram. Reported features of opioidinduced CSA include prolonged periods of hypoventilation resulting in significant hypoxemia, ataxic breathing, and repetitive central apneas. Figure 1 shows typical ataxic breathing with significant respiratory variation in depth and rate associated with frequent respiratory pauses. Respiratory events predominantly occur during non-rapid eye movement sleep and abate during rapid eye movement sleep. Opioidinduced CSA should be distinguished from CheyneStokes respiration. Hallmark features of Cheyne-Stokes respiration include a crescendo-decrescendo breathing pattern with significant periodicity and prolonged cycle time suggestive of prolonged circulation time, with arousals typically occurring during the peak of the respiratory effort rather than at the cessation of the apneas. CSAs are characterized by sleep-disordered breathing associated with diminished or absent respiratory effort on polysomnogram, coupled with symptoms of excessive daytime sleepiness, frequent nocturnal awakenings, or both. Two basic mechanisms that have been described in CSAs include posthyperventilation central apnea and central apnea secondary to hypoventilation. Opioid-induced CSA belongs to the latter group and is a type of hypercapnic CSA due to impairment of central breathing drive thought to be a consequence of the respiratory depressant effects of these medications. The International Classification of Sleep Disorders-2 identifies six different forms of CSAs: primary CSA, CSA due to Cheyne-Stokes breathing pattern, CSA due to a medical condition not CheyneStokes, CSA due to high-altitude periodic breathing, CSA due to drug or substance (which is the case in opioid-induced CSA), and primary sleep apnea of infancy. Treatment of the underlying disorder is essential in nonprimary CSA. The dramatic change in chronic pain management over the last few years has led to an increase in opioid use, e206 Pulmonary, Critical Care, and Sleep Pearls
which has resulted in a surge in the prevalence of opioid-induced CSA. It has been estimated that up to 50% of patients on long-term opioid use have CSA. The exact mechanism of opioid-induced CSA is not well elucidated, but it is thought that opioid use leads to impairment of the hypercapnic and hypoxic ventilatory responses, and the effects are thought to be dose dependent. In a study of 60 patients taking opioid medications long-term, it has been shown that ataxic breathing and central apneas are more prevalent in patient taking opioids at a morphine dose equivalent to ⱖ 200 mg. Recent management guidelines for CSAs state that “literature assessing treatment of CSAs due to drug or substances is markedly limited.” In general, therapeutic strategies for CSAs include positive airway pressure, adaptive servoventilation, and oxygen therapy. The effectiveness of these therapies in opioidinduced CSA has been disappointing, however. CPAP therapy eliminates obstructive apneas but may worsen the central AHI, and adaptive servoventilation may modulate the breathing patterns but does not eliminate ataxic breathing nor significantly impact the AHI. Although reduction of opioid use as a mode of treatment of opioid-associated CSA seems intuitive, this management strategy is not mentioned in the aforementioned guidelines and review articles. Chronicpain guidelines emphasize the importance of a multidisciplinary approach and the use of different treatment options to achieve adequate pain control, trying to avoid, as much as possible, the use and the undesired effects of chronic opioid use. To our knowledge, few cases have documented the complete resolution of CSA after withdrawal of opioids. Our case emphasizes the importance of a multidisciplinary approach to chronic pain and the need to suspect opioids as the etiology of CSA when it presents with ataxic breathing and repetitive central apneas. Clinical Course
Based on the initial polysomnographic findings, recommendation was made to wean the patient off opiates as tolerated. She was able to wean herself completely from narcotics and upon presentation to the sleep clinic, a repeated polysomnogram revealed complete resolution of CSA, with overall AHI of 0/h (Fig 3). This case represents successful treatment of CSA by opioid withdrawal. Despite resolution of CSA, the patient had persistent excessive daytime sleepiness requiring further workup with a multiple sleep-latency test that showed reduced
[
146#6 CHEST DECEMBER 2014
]
Figure 3 – Complete resolution of central sleep apnea with opioid cessation (300 s/page). See Figure 1 legend for expansion of abbreviations.
sleep latency of 4 min 42 s with absence of sleep-onset rapid eye movement periods. She is currently on stimulant medications to control symptoms of daytime sleepiness.
Suggested Readings
Clinical Pearls
Eckert DJ, Jordan AS, Merchia P, Malhotra A. Central sleep apnea: pathophysiology and treatment. Chest. 2007;131(2):595-607.
1. The use of opiates has increased in the last few years and its long-term use has resulted in an upsurge in opioid-induced CSA. 2. Opioid-induced CSA is characterized by ataxic breathing and repetitive central apneas, and is associated with prolonged periods of hypoventilation. 3. Treatment of the underlying disorder is key in the management of nonprimary CSA. 4. For CSA associated with opiates, reduction or discontinuation of these medications by using alternative approaches to chronic pain is warranted to decrease and potentially correct this syndrome.
Novak S, Nemeth WC, Lawson KA. Trends in medical use and abuse of sustained-release opioid analgesics: a revisit. Pain Med. 2004;5(1):59-65. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic & Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.
Walker JM, Farney RJ, Rhondeau SM, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med. 2007;3(5):455-461. Farney RJ, Walker JM, Boyle KM, Cloward TV, Shilling KC. Adaptive servoventilation (ASV) in patients with sleep disordered breathing associated with chronic opioid medications for non-malignant pain. J Clin Sleep Med. 2008;4(4):311-319. Javaheri S, Malik A, Smith J, Chung E. Adaptive pressure support servoventilation: a novel treatment for sleep apnea associated with use of opioids. J Clin Sleep Med. 2008;4(4):305-310. Ramar K. Reversal of sleep-disordered breathing with opioid withdrawal. Pain Pract. 2009;9(5):394-398. American Society of Anesthesiologists Task Force on Chronic Pain Management; American Society of Regional Anesthesia and Pain Medicine. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2010;112(4):810-833. Javaheri S. Central sleep apnea. Clin Chest Med. 2010;31(2):235-248.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
journal.publications.chestnet.org
Institute for Clinical Systems Improvement. Health Care Guideline: Assessment and Management of Chronic Pain. 5th ed. Bloomington, MN: ICSI; 2011. Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep. 2012;35(1):17-40. Davis MJ, Livingston M, Scharf SM. Reversal of central sleep apnea following discontinuation of opioids. J Clin Sleep Med. 2012;8(5):579-580.
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