E Editorial
Sleep, Pain, and Breathing David R. Hillman, MB
S
leep and pain have a difficult, multidimensional relationship. Pain disturbs sleep.1–4 Disturbed sleep aggravates pain.5–8 Treatment of sleep disorders can reduce pain.9 Relieving pain can improve sleep although, as shown by Correa and colleagues10 in this issue of Anesthesia & Analgesia, where opioids are involved this is not uniformly the case. Sleep is a vulnerable state for breathing. Ventilatory drive is reduced because of loss of the stimulatory effects of wakefulness, accompanied by reduction in hypercapnic and hypoxic responsiveness. Sleep depresses muscle activation, reflex gain, and arousal responses. These changes are more prominent in rapid eye movement than non-rapid eye movement sleep. Upper airway obstruction and/or hypoventilation occur in predisposed subjects.11 This makes sleep of enormous relevance to anesthesiologists, as these state-related physiological changes are also present during anesthesia. Knowledge of breathing behavior during sleep is helpful in predicting likely behavior under drug-induced sedation. Furthermore, it is important to appreciate the potential for sleep to potentiate the effects on breathing of drugs that depress ventilatory drive.12 It is only now that these relationships are becoming widely appreciated. In a 1997 consensus statement, the American Academy of Pain Medicine and American Pain Society took it upon themselves to announce that “withholding the appropriate use of opioids from a patient who is experiencing pain on the basis of respiratory concerns is unwarranted.”13 They did so because they contended “it is now accepted by practitioners of the specialty of pain medicine that respiratory depression induced by opioids tends to be a short-lived phenomenon, generally only occurs in the opioid-naive patient and is antagonized by pain.” Predictably, the number of opioid prescriptions written exploded in the years that followed. Sadly, so did the number of opioid-related deaths. The compounding effects of sleep on the ventilatory depressant effects of opioids were not considered at the time of the statement. This appears to have been a fatal flaw in the guidance.12
From the Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Australia. Accepted for publication January 13, 2015. Funding: No external funding. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the author. Address correspondence to David R. Hillman, MB, Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Australia. Address e-mail to [email protected]. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000666
1182 www.anesthesia-analgesia.org
The review of Correa et al.10 helps make this clear. As they point out, adequate breathing during wakefulness does not provide any assurance that it will be adequate during sleep. This wake-sleep dichotomy in breathing behavior is self-evident in the case of snoring and obstructive sleep apnea (OSA). While more subtle, it is also evident with sleep hypoventilation and central sleep apnea, the particular focus of the article by Correa et al..10 The stimulatory effect of wakefulness on ventilation and muscle activation acts both to ensure a patent upper airway and to augment ventilatory drive and dampen oscillations in it. It has long been understood that the breathing periodicity (Cheyne-Stokes ventilation) associated with heart failure is more prominent during sleep than wakefulness. So, it appears, is breathing periodicity from other causes including those associated with neurologic disease, high altitude, and opioid use.14–17 Opioids have complex effects on breathing that are particularly prominent (and may only be clinically evident) during sleep. They reduce upper airway muscle activation, predisposing to snoring and upper airway obstruction (i.e., OSA).18 They depress hypoxic and hypercapnic ventilatory drive, particularly in opioid-naive subjects, leading to hypoventilation.19 With chronic opioid use, breathing periodicity becomes evident, particularly if doses are high.16,17 This breathing periodicity can take the form of regular waxing and waning of ventilatory drive or more ataxic breathing patterns with irregularly placed central apneas and hypopneas. While common among chronic opioid users, the mechanism of this periodicity is not well understood. Teichtahl et al.20 present some evidence to suggest that the mechanism may relate to chronic opioid use changing the balance between hypoxic and hypercapnic ventilatory drive. With chronic opioid use, hypoxic ventilatory drive may recover, or even be augmented, while the opioids still depress hypercapnic ventilatory drive. If so, this would help explain recurrent periods of under-breathing terminated by augmentation of ventilation once stimulated by sufficient hypoxemia. The review of Correa et al.10 is a timely reminder that the relationships among sleep, anesthesia, and breathing go well beyond consideration of OSA and its perioperative implications. Awareness of sleep-related breathing disorders and their physiologic basis helps inform anesthesiology practice. The presence of such disorders indicates increased vulnerability to breathing disturbances when under the influence of opioids and sedative drugs. Conversely, observation of these disturbances in patients not previously known to have a sleep-related breathing disorder should alert anesthesiologists in their role as perioperative physicians to that possibility. E June 2015 • Volume 120 • Number 6
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Sleep, Pain, and Breathing
DISCLOSURES
Name: David R. Hillman, MB. Contribution: This author wrote the manuscript. Attestation: David R. Hillman approved the final manuscript. Conflicts of Interest: David R. Hillman received honoraria from ResMed, received research funding from ResMed, received honoraria from Philips Healthcare, and received honoraria from SomnoMed. RECUSE NOTE
Dr. David R. Hillman is the Section Editor for Respiration and Sleep Medicine for Anesthesia & Analgesia. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Hillman was not involved in any way with the editorial process or decision. REFERENCES 1. Kelly GA, Blake C, Power CK, O’Keeffe D, Fullen BM. The association between chronic low back pain and sleep: a systematic review. Clin J Pain 2011;27:169–81 2. McCracken LM, Iverson GL. Disrupted sleep patterns and daily functioning in patients with chronic pain. Pain Res Manag 2002;7:75–9 3. Tang NK, Wright KJ, Salkovskis PM. Prevalence and correlates of clinical insomnia co-occurring with chronic back pain. J Sleep Res 2007;16:85–95 4. Theadom A, Cropley M, Humphrey KL. Exploring the role of sleep and coping in quality of life in fibromyalgia. J Psychosom Res 2007;62:145–51 5. Okifuji A, Hare BD. Do sleep disorders contribute to pain sensitivity? Curr Rheumatol Rep 2011;13:528–34 6. Onen SH, Alloui A, Gross A, Eschallier A, Dubray C. The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. J Sleep Res 2001;10:35–42 7. Schuh-Hofer S, Wodarski R, Pfau DB, Caspani O, Magerl W, Kennedy JD, Treede RD. One night of total sleep deprivation promotes a state of generalized hyperalgesia: a surrogate pain model to study the relationship of insomnia and pain. Pain 2013;154:1613–21
June 2015 • Volume 120 • Number 6
8. Tiede W, Magerl W, Baumgärtner U, Durrer B, Ehlert U, Treede RD. Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers. Pain 2010;148:36–42 9. Roehrs TA; Workshop Participants. Does effective management of sleep disorders improve pain symptoms? Drugs 2009;69 Suppl 2:5–11 10. Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic opioid use and central sleep apnea: a review of prevalence, mechanisms, and perioperative considerations. Anesth Analg 2015;120:1273–85 11. White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 2005;172:1363–70 12. Walker JM, Farney RJ, Rhondeau SM, Boyle KM, Valentine K, Cloward TV, Shilling KC. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007;3:455–61 13. The use of opioids for the treatment of chronic pain. A consensus statement from the American Academy of Pain Medicine and the American Pain Society. Clin J Pain 1997;13:6–8 14. Hermann DM, Bassetti CL. Sleep-related breathing and sleep-wake disturbances in ischemic stroke. Neurology 2009;73:1313–22 15. Insalaco G, Romano S, Salvaggio A, Pomidori L, Mandolesi G, Cogo A. Periodic breathing, arterial oxyhemoglobin saturation, and heart rate during sleep at high altitude. High Alt Med Biol 2012;13:258–62 16. Mogri M, Khan MI, Grant BJ, Mador MJ. Central sleep apnea induced by acute ingestion of opioids. Chest 2008;133:1484–8 17. Webster LR, Choi Y, Desai H, Webster L, Grant BJ. Sleep disordered breathing and chronic opioid therapy. Pain Med 2008;9:425–32 18. Hajiha M, DuBord MA, Liu H, Horner RL. Opioid recep tor mechanisms at the hypoglossal motor pool and effects on tongue muscle activity in vivo. J Physiol 2009;587:2677–92 19. Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology 2010;112:226–38 20. Teichtahl H, Wang D, Cunnington D, Quinnell T, Tran H, Kronborg I, Drummer OH. Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients. Chest 2005;128:1339–47
www.anesthesia-analgesia.org 1183
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Sleep, Pain, and Breathing David R. Hillman, MB
S
leep and pain have a difficult, multidimensional relationship. Pain disturbs sleep.1–4 Disturbed sleep aggravates pain.5–8 Treatment of sleep disorders can reduce pain.9 Relieving pain can improve sleep although, as shown by Correa and colleagues10 in this issue of Anesthesia & Analgesia, where opioids are involved this is not uniformly the case. Sleep is a vulnerable state for breathing. Ventilatory drive is reduced because of loss of the stimulatory effects of wakefulness, accompanied by reduction in hypercapnic and hypoxic responsiveness. Sleep depresses muscle activation, reflex gain, and arousal responses. These changes are more prominent in rapid eye movement than non-rapid eye movement sleep. Upper airway obstruction and/or hypoventilation occur in predisposed subjects.11 This makes sleep of enormous relevance to anesthesiologists, as these state-related physiological changes are also present during anesthesia. Knowledge of breathing behavior during sleep is helpful in predicting likely behavior under drug-induced sedation. Furthermore, it is important to appreciate the potential for sleep to potentiate the effects on breathing of drugs that depress ventilatory drive.12 It is only now that these relationships are becoming widely appreciated. In a 1997 consensus statement, the American Academy of Pain Medicine and American Pain Society took it upon themselves to announce that “withholding the appropriate use of opioids from a patient who is experiencing pain on the basis of respiratory concerns is unwarranted.”13 They did so because they contended “it is now accepted by practitioners of the specialty of pain medicine that respiratory depression induced by opioids tends to be a short-lived phenomenon, generally only occurs in the opioid-naive patient and is antagonized by pain.” Predictably, the number of opioid prescriptions written exploded in the years that followed. Sadly, so did the number of opioid-related deaths. The compounding effects of sleep on the ventilatory depressant effects of opioids were not considered at the time of the statement. This appears to have been a fatal flaw in the guidance.12
From the Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Australia. Accepted for publication January 13, 2015. Funding: No external funding. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the author. Address correspondence to David R. Hillman, MB, Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Australia. Address e-mail to [email protected]. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000666
1182 www.anesthesia-analgesia.org
The review of Correa et al.10 helps make this clear. As they point out, adequate breathing during wakefulness does not provide any assurance that it will be adequate during sleep. This wake-sleep dichotomy in breathing behavior is self-evident in the case of snoring and obstructive sleep apnea (OSA). While more subtle, it is also evident with sleep hypoventilation and central sleep apnea, the particular focus of the article by Correa et al..10 The stimulatory effect of wakefulness on ventilation and muscle activation acts both to ensure a patent upper airway and to augment ventilatory drive and dampen oscillations in it. It has long been understood that the breathing periodicity (Cheyne-Stokes ventilation) associated with heart failure is more prominent during sleep than wakefulness. So, it appears, is breathing periodicity from other causes including those associated with neurologic disease, high altitude, and opioid use.14–17 Opioids have complex effects on breathing that are particularly prominent (and may only be clinically evident) during sleep. They reduce upper airway muscle activation, predisposing to snoring and upper airway obstruction (i.e., OSA).18 They depress hypoxic and hypercapnic ventilatory drive, particularly in opioid-naive subjects, leading to hypoventilation.19 With chronic opioid use, breathing periodicity becomes evident, particularly if doses are high.16,17 This breathing periodicity can take the form of regular waxing and waning of ventilatory drive or more ataxic breathing patterns with irregularly placed central apneas and hypopneas. While common among chronic opioid users, the mechanism of this periodicity is not well understood. Teichtahl et al.20 present some evidence to suggest that the mechanism may relate to chronic opioid use changing the balance between hypoxic and hypercapnic ventilatory drive. With chronic opioid use, hypoxic ventilatory drive may recover, or even be augmented, while the opioids still depress hypercapnic ventilatory drive. If so, this would help explain recurrent periods of under-breathing terminated by augmentation of ventilation once stimulated by sufficient hypoxemia. The review of Correa et al.10 is a timely reminder that the relationships among sleep, anesthesia, and breathing go well beyond consideration of OSA and its perioperative implications. Awareness of sleep-related breathing disorders and their physiologic basis helps inform anesthesiology practice. The presence of such disorders indicates increased vulnerability to breathing disturbances when under the influence of opioids and sedative drugs. Conversely, observation of these disturbances in patients not previously known to have a sleep-related breathing disorder should alert anesthesiologists in their role as perioperative physicians to that possibility. E June 2015 • Volume 120 • Number 6
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Sleep, Pain, and Breathing
DISCLOSURES
Name: David R. Hillman, MB. Contribution: This author wrote the manuscript. Attestation: David R. Hillman approved the final manuscript. Conflicts of Interest: David R. Hillman received honoraria from ResMed, received research funding from ResMed, received honoraria from Philips Healthcare, and received honoraria from SomnoMed. RECUSE NOTE
Dr. David R. Hillman is the Section Editor for Respiration and Sleep Medicine for Anesthesia & Analgesia. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Hillman was not involved in any way with the editorial process or decision. REFERENCES 1. Kelly GA, Blake C, Power CK, O’Keeffe D, Fullen BM. The association between chronic low back pain and sleep: a systematic review. Clin J Pain 2011;27:169–81 2. McCracken LM, Iverson GL. Disrupted sleep patterns and daily functioning in patients with chronic pain. Pain Res Manag 2002;7:75–9 3. Tang NK, Wright KJ, Salkovskis PM. Prevalence and correlates of clinical insomnia co-occurring with chronic back pain. J Sleep Res 2007;16:85–95 4. Theadom A, Cropley M, Humphrey KL. Exploring the role of sleep and coping in quality of life in fibromyalgia. J Psychosom Res 2007;62:145–51 5. Okifuji A, Hare BD. Do sleep disorders contribute to pain sensitivity? Curr Rheumatol Rep 2011;13:528–34 6. Onen SH, Alloui A, Gross A, Eschallier A, Dubray C. The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. J Sleep Res 2001;10:35–42 7. Schuh-Hofer S, Wodarski R, Pfau DB, Caspani O, Magerl W, Kennedy JD, Treede RD. One night of total sleep deprivation promotes a state of generalized hyperalgesia: a surrogate pain model to study the relationship of insomnia and pain. Pain 2013;154:1613–21
June 2015 • Volume 120 • Number 6
8. Tiede W, Magerl W, Baumgärtner U, Durrer B, Ehlert U, Treede RD. Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers. Pain 2010;148:36–42 9. Roehrs TA; Workshop Participants. Does effective management of sleep disorders improve pain symptoms? Drugs 2009;69 Suppl 2:5–11 10. Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic opioid use and central sleep apnea: a review of prevalence, mechanisms, and perioperative considerations. Anesth Analg 2015;120:1273–85 11. White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 2005;172:1363–70 12. Walker JM, Farney RJ, Rhondeau SM, Boyle KM, Valentine K, Cloward TV, Shilling KC. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007;3:455–61 13. The use of opioids for the treatment of chronic pain. A consensus statement from the American Academy of Pain Medicine and the American Pain Society. Clin J Pain 1997;13:6–8 14. Hermann DM, Bassetti CL. Sleep-related breathing and sleep-wake disturbances in ischemic stroke. Neurology 2009;73:1313–22 15. Insalaco G, Romano S, Salvaggio A, Pomidori L, Mandolesi G, Cogo A. Periodic breathing, arterial oxyhemoglobin saturation, and heart rate during sleep at high altitude. High Alt Med Biol 2012;13:258–62 16. Mogri M, Khan MI, Grant BJ, Mador MJ. Central sleep apnea induced by acute ingestion of opioids. Chest 2008;133:1484–8 17. Webster LR, Choi Y, Desai H, Webster L, Grant BJ. Sleep disordered breathing and chronic opioid therapy. Pain Med 2008;9:425–32 18. Hajiha M, DuBord MA, Liu H, Horner RL. Opioid recep tor mechanisms at the hypoglossal motor pool and effects on tongue muscle activity in vivo. J Physiol 2009;587:2677–92 19. Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology 2010;112:226–38 20. Teichtahl H, Wang D, Cunnington D, Quinnell T, Tran H, Kronborg I, Drummer OH. Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients. Chest 2005;128:1339–47
www.anesthesia-analgesia.org 1183
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
