Opioid Therapy and Sleep Apnea

To the Editor: I enjoyed Dr. Galicia-Castilloâ’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 al ⁷ 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 al ⁸ 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 study ¹² 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.