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To the Editor: I enjoyed Dr. Galicia-Castillo’s article about long-term opioid therapy in older adults,1 which reaffirmed the imperative to “start low and go slow” to minimize the risk of addiction. However, the article missed an opportunity to raise awareness regarding another extremely important side effect of chronic prescription opioid consumption, that of ingestion prior to sleep, with consequent cessation of breathing leading to death.
According to the Drug Enforcement Administration,2 most narcotic deaths are a result of respiratory depression. And the American Pain Society has stated, “No patient has succumbed to [opioid] respiratory depression while awake.”3
Dr. Galicia-Castillo noted that the prevalence of central sleep apnea in chronic opioid users is 24%, based on a review by Correa et al.4 As alarming as this number is, other investigators have estimated it to be even higher—as high as 50% to 90%.5
Walker et al,6 in a study of 60 patients, found that the higher the opioid dose the patients were on, the more episodes of obstructive sleep apnea and central sleep apnea per hour they had. Yet prescribing a low dose does not adequately protect the chronic opioid user. Farney et al7 reported that oxygen saturation dropped precipitously—from 98% to 70%—15 minutes after a patient took just 7.5 mg of hydrocodone in the middle of the night. Mogri et al8 reported that a patient had 91 apnea events within 1 hour of taking 15 mg of oxycodone at 2 am.
Opioids, benzodiazepines, barbiturates, and ethanol individually and additively suppress medullary reflex ventilatory drive during sleep, especially during non–rapid-eye-movement (non-REM) sleep.6 During waking hours, in contrast, there is redundant backup of cerebral cortical drive, ensuring that we keep breathing. Therefore, people are most vulnerable to dying of opioid ingestion during sleep.
Moreover, oxygen desaturation during episodes of sleep apnea may precipitate seizures (which may be lethal) or coronary vasospasm with consequent malignant arrhythmias and myocardial ischemia.
Continuous positive airway pressure protects against obstructive sleep apnea, but not against central sleep apnea.9
Patients need to be aware of the danger, and physicians need to consider the pharmacokinetic profiles of the opioid preparations they prescribe. If patients are taking an opioid that has a short half-life, such as immediate-release oxycodone, they should not take it within 5 hours of sleep. Longer-lasting preparations need a longer interval, and some, such as extended-release tramadol, may need to be taken only on awakening.
Safe sleep can be facilitated by medications that are sedating but do not compromise ventilation. Optimal agents also enhance restorative REM and stage III and IV deep-sleep duration, and some may have the additional benefit of reducing the risk of cancer.10,11 Such agents may include baclofen, cyproheptadine, gabapentin, mirtazepine, and melatonin. Nonpharmacologic measures include sleep hygiene, aerobic exercise, and cognitive behavioral therapy.
A retrospective study12 found that 301 (60.4%) of 498 patients who died while on opioid therapy and whose death was judged to be related to the opioid were also taking benzodiazepines. Patients who take opioids should avoid taking benzodiazepines, barbiturates, or alcohol before going to sleep, and physicians should be extremely cautious about prescribing benzodiazepines and barbiturates to patients who are on opioids.
- Galicia-Castillo M. Opioids for persistent pain in older adults. Cleve Clin J Med 2016; 83:443–451.
- Drug Enforcement Administration. Drugs of Abuse. 2005 Edition. Washington, DC: US Government Printing Office, 2005:19.
- American Pain Society, Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 4th ed. Glenview, IL: American Pain Society, 1999:30.
- Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic opioid use and central sleep apnea: a review of the prevalence, mechanisms, and perioperative considerations. Anesth Analg 2015; 120:1273–1285.
- Panagiotou I, Mystakidou K. Non-analgesic effects of opioids: opioids’ effects on sleep (including sleep apnea). Curr Pharm Des 2012; 18:6025–6033.
- 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; 3:455–461. Erratum in J Clin Sleep Med 2007; 3:table of contents.
- Farney RJ, Walker JM, Cloward TV, Rhondeau S. Sleep-disordered breathing associated with long-term opioid therapy. Chest 2003; 123:632–639.
- Mogri M, Khan MI, Grant BJ, Mador MJ. Central sleep apnea induced by acute ingestion of opioids. Chest 2008; 133:1484–1488.
- Guilleminault C, Cao M, Yue HJ, Chawla P. Obstructive sleep apnea and chronic opioid use. Lung 2010; 188:459–468.
- Kao CH, Sun LM, Liang JA, Chang SN, Sung FC, Muo CH. Relationship of zolpidem and cancer risk: a Taiwanese population-based cohort study. Mayo Clin Proc 2012; 87:430–436.
- Kripke DF. Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit. F1000Res 2016; 5:918.
- Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011; 171:686–691.
To the Editor: I enjoyed Dr. Galicia-Castillo’s article about long-term opioid therapy in older adults,1 which reaffirmed the imperative to “start low and go slow” to minimize the risk of addiction. However, the article missed an opportunity to raise awareness regarding another extremely important side effect of chronic prescription opioid consumption, that of ingestion prior to sleep, with consequent cessation of breathing leading to death.
According to the Drug Enforcement Administration,2 most narcotic deaths are a result of respiratory depression. And the American Pain Society has stated, “No patient has succumbed to [opioid] respiratory depression while awake.”3
Dr. Galicia-Castillo noted that the prevalence of central sleep apnea in chronic opioid users is 24%, based on a review by Correa et al.4 As alarming as this number is, other investigators have estimated it to be even higher—as high as 50% to 90%.5
Walker et al,6 in a study of 60 patients, found that the higher the opioid dose the patients were on, the more episodes of obstructive sleep apnea and central sleep apnea per hour they had. Yet prescribing a low dose does not adequately protect the chronic opioid user. Farney et al7 reported that oxygen saturation dropped precipitously—from 98% to 70%—15 minutes after a patient took just 7.5 mg of hydrocodone in the middle of the night. Mogri et al8 reported that a patient had 91 apnea events within 1 hour of taking 15 mg of oxycodone at 2 am.
Opioids, benzodiazepines, barbiturates, and ethanol individually and additively suppress medullary reflex ventilatory drive during sleep, especially during non–rapid-eye-movement (non-REM) sleep.6 During waking hours, in contrast, there is redundant backup of cerebral cortical drive, ensuring that we keep breathing. Therefore, people are most vulnerable to dying of opioid ingestion during sleep.
Moreover, oxygen desaturation during episodes of sleep apnea may precipitate seizures (which may be lethal) or coronary vasospasm with consequent malignant arrhythmias and myocardial ischemia.
Continuous positive airway pressure protects against obstructive sleep apnea, but not against central sleep apnea.9
Patients need to be aware of the danger, and physicians need to consider the pharmacokinetic profiles of the opioid preparations they prescribe. If patients are taking an opioid that has a short half-life, such as immediate-release oxycodone, they should not take it within 5 hours of sleep. Longer-lasting preparations need a longer interval, and some, such as extended-release tramadol, may need to be taken only on awakening.
Safe sleep can be facilitated by medications that are sedating but do not compromise ventilation. Optimal agents also enhance restorative REM and stage III and IV deep-sleep duration, and some may have the additional benefit of reducing the risk of cancer.10,11 Such agents may include baclofen, cyproheptadine, gabapentin, mirtazepine, and melatonin. Nonpharmacologic measures include sleep hygiene, aerobic exercise, and cognitive behavioral therapy.
A retrospective study12 found that 301 (60.4%) of 498 patients who died while on opioid therapy and whose death was judged to be related to the opioid were also taking benzodiazepines. Patients who take opioids should avoid taking benzodiazepines, barbiturates, or alcohol before going to sleep, and physicians should be extremely cautious about prescribing benzodiazepines and barbiturates to patients who are on opioids.
To the Editor: I enjoyed Dr. Galicia-Castillo’s article about long-term opioid therapy in older adults,1 which reaffirmed the imperative to “start low and go slow” to minimize the risk of addiction. However, the article missed an opportunity to raise awareness regarding another extremely important side effect of chronic prescription opioid consumption, that of ingestion prior to sleep, with consequent cessation of breathing leading to death.
According to the Drug Enforcement Administration,2 most narcotic deaths are a result of respiratory depression. And the American Pain Society has stated, “No patient has succumbed to [opioid] respiratory depression while awake.”3
Dr. Galicia-Castillo noted that the prevalence of central sleep apnea in chronic opioid users is 24%, based on a review by Correa et al.4 As alarming as this number is, other investigators have estimated it to be even higher—as high as 50% to 90%.5
Walker et al,6 in a study of 60 patients, found that the higher the opioid dose the patients were on, the more episodes of obstructive sleep apnea and central sleep apnea per hour they had. Yet prescribing a low dose does not adequately protect the chronic opioid user. Farney et al7 reported that oxygen saturation dropped precipitously—from 98% to 70%—15 minutes after a patient took just 7.5 mg of hydrocodone in the middle of the night. Mogri et al8 reported that a patient had 91 apnea events within 1 hour of taking 15 mg of oxycodone at 2 am.
Opioids, benzodiazepines, barbiturates, and ethanol individually and additively suppress medullary reflex ventilatory drive during sleep, especially during non–rapid-eye-movement (non-REM) sleep.6 During waking hours, in contrast, there is redundant backup of cerebral cortical drive, ensuring that we keep breathing. Therefore, people are most vulnerable to dying of opioid ingestion during sleep.
Moreover, oxygen desaturation during episodes of sleep apnea may precipitate seizures (which may be lethal) or coronary vasospasm with consequent malignant arrhythmias and myocardial ischemia.
Continuous positive airway pressure protects against obstructive sleep apnea, but not against central sleep apnea.9
Patients need to be aware of the danger, and physicians need to consider the pharmacokinetic profiles of the opioid preparations they prescribe. If patients are taking an opioid that has a short half-life, such as immediate-release oxycodone, they should not take it within 5 hours of sleep. Longer-lasting preparations need a longer interval, and some, such as extended-release tramadol, may need to be taken only on awakening.
Safe sleep can be facilitated by medications that are sedating but do not compromise ventilation. Optimal agents also enhance restorative REM and stage III and IV deep-sleep duration, and some may have the additional benefit of reducing the risk of cancer.10,11 Such agents may include baclofen, cyproheptadine, gabapentin, mirtazepine, and melatonin. Nonpharmacologic measures include sleep hygiene, aerobic exercise, and cognitive behavioral therapy.
A retrospective study12 found that 301 (60.4%) of 498 patients who died while on opioid therapy and whose death was judged to be related to the opioid were also taking benzodiazepines. Patients who take opioids should avoid taking benzodiazepines, barbiturates, or alcohol before going to sleep, and physicians should be extremely cautious about prescribing benzodiazepines and barbiturates to patients who are on opioids.
- Galicia-Castillo M. Opioids for persistent pain in older adults. Cleve Clin J Med 2016; 83:443–451.
- Drug Enforcement Administration. Drugs of Abuse. 2005 Edition. Washington, DC: US Government Printing Office, 2005:19.
- American Pain Society, Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 4th ed. Glenview, IL: American Pain Society, 1999:30.
- Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic opioid use and central sleep apnea: a review of the prevalence, mechanisms, and perioperative considerations. Anesth Analg 2015; 120:1273–1285.
- Panagiotou I, Mystakidou K. Non-analgesic effects of opioids: opioids’ effects on sleep (including sleep apnea). Curr Pharm Des 2012; 18:6025–6033.
- 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; 3:455–461. Erratum in J Clin Sleep Med 2007; 3:table of contents.
- Farney RJ, Walker JM, Cloward TV, Rhondeau S. Sleep-disordered breathing associated with long-term opioid therapy. Chest 2003; 123:632–639.
- Mogri M, Khan MI, Grant BJ, Mador MJ. Central sleep apnea induced by acute ingestion of opioids. Chest 2008; 133:1484–1488.
- Guilleminault C, Cao M, Yue HJ, Chawla P. Obstructive sleep apnea and chronic opioid use. Lung 2010; 188:459–468.
- Kao CH, Sun LM, Liang JA, Chang SN, Sung FC, Muo CH. Relationship of zolpidem and cancer risk: a Taiwanese population-based cohort study. Mayo Clin Proc 2012; 87:430–436.
- Kripke DF. Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit. F1000Res 2016; 5:918.
- Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011; 171:686–691.
- Galicia-Castillo M. Opioids for persistent pain in older adults. Cleve Clin J Med 2016; 83:443–451.
- Drug Enforcement Administration. Drugs of Abuse. 2005 Edition. Washington, DC: US Government Printing Office, 2005:19.
- American Pain Society, Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 4th ed. Glenview, IL: American Pain Society, 1999:30.
- Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic opioid use and central sleep apnea: a review of the prevalence, mechanisms, and perioperative considerations. Anesth Analg 2015; 120:1273–1285.
- Panagiotou I, Mystakidou K. Non-analgesic effects of opioids: opioids’ effects on sleep (including sleep apnea). Curr Pharm Des 2012; 18:6025–6033.
- 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; 3:455–461. Erratum in J Clin Sleep Med 2007; 3:table of contents.
- Farney RJ, Walker JM, Cloward TV, Rhondeau S. Sleep-disordered breathing associated with long-term opioid therapy. Chest 2003; 123:632–639.
- Mogri M, Khan MI, Grant BJ, Mador MJ. Central sleep apnea induced by acute ingestion of opioids. Chest 2008; 133:1484–1488.
- Guilleminault C, Cao M, Yue HJ, Chawla P. Obstructive sleep apnea and chronic opioid use. Lung 2010; 188:459–468.
- Kao CH, Sun LM, Liang JA, Chang SN, Sung FC, Muo CH. Relationship of zolpidem and cancer risk: a Taiwanese population-based cohort study. Mayo Clin Proc 2012; 87:430–436.
- Kripke DF. Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit. F1000Res 2016; 5:918.
- Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011; 171:686–691.
