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Long-Term Opioid Drug Treatment and Sleep-Disordered Breathing
By Regina Patrick, RST, RPSGT
I
n 1997, the American Academy of Pain Medicine (AAPM) and
the American Pain Society (APS) released a joint consensus
statement concerning the respiratory effect of opioid drugs:
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 occurs only in the
opioid-naive patient, and is antagonized by pain. Therefore,
withholding the appropriate use of opioids from a patient
who is experiencing pain on the basis of respiratory concerns
is unwarranted.1
After the consensus statement, the prescriptions for opioid
drugs greatly increased by 235 to 1403 percent (depending
on the drug) as scientists believed that respiratory depression
(i.e., decrease in respiratory rate and/or respiratory effort) was
a temporary adverse effect in people receiving long-term opioid
treatment.2 However, some recent research indicates that
respiratory depression associated with long-term opioid therapy
is not temporary.
Drugs such as morphine and codeine that are derived
from the juice of the opium poppy are called opiates. Natural
chemicals (e.g., the enkephalins and endorphins) or synthetic
chemicals (e.g., methadone) that mimic the actions of morphine
are called opioid drugs, which are used for their analgesic
(i.e., pain-relieving) effects. Some commonly used opioids are
methadone, hydrocodone, oxycodone, and fentanyl.
Pain is a sensation of localized discomfort, distress or agony
resulting from the stimulation of nociceptive (i.e., pain-sensing)
nerves.3 Specialized receptors, called nociceptors (from the
Latin noci - meaning “to injure”), are located on the terminals
of the axons of nociceptive neurons. Nociceptors become
activated by physical stimuli (e.g., pressure, temperature, electrical) or chemical stimuli (e.g., toxic substances, inflammatory
substances) that cause injury or inflammation of body tissues.
Pain usually subsides as an injury heals. Pain that persists six
or more months after the onset of an injury or after an injury
heals is considered chronic.4 Chronic pain may be intermittent
or continuous. Even with appropriate treatment, many chronic
pain sufferers subjectively feel pain to the point. It negatively
impacts their physical and psychological health, their ability to
function at work or school, and their ability to perform other
social activities.
Regina Patrick, RST, RPSGT
Regina Patrick, RST, RPSGT, has been in
the sleep field for more than 20 years and
works as a sleep technologist at the
Wolverine Sleep Disorders Center in
Tecumseh, Mich.
The perception of pain begins when trauma to a tissue stimulates nociceptors. This causes a nociceptive neuron to increase
its firing rate. These signals are relayed down the axon of the
nociceptive neuron toward the spinal cord. At the spinal cord,
the axonal terminal of the nociceptive neuron synapses with the
processes of neurons in the dorsal horn (a horn-shaped region
of gray matter in the rear [i.e., dorsal] portion of the spinal cord).
The dorsal horn neurons relay the signals toward the brain, where
they are then relayed to different areas such as the primary and
secondary somatosensory cortices (which play a role in the
conscious awareness of pain in the skin, joints, muscle and
viscera); the thalamus (which mediates deep, poorly localized
pain); the hypothalamus (which releases various substances such
as the endorphins that play a role in pain perception); the superior
colliculus (which plays a role in the affective aspects of pain [i.e.,
as unpleasant stimulus]); and the amygdala (which is thought to
affect the emotional response to pain).5
Opioid drugs bind to opioid receptors on the axonal terminals
of nociceptive neurons. One type of opioid receptor, the mu (μ)
receptor, primarily mediates the analgesic (i.e., pain-relieving)
effect of opioid drugs. When opioid drugs bind to μ receptors,
they inhibit the firing rate of the nociceptive neuron. This in turn
reduces the signals relayed to the spinal cord and to the brain. The
result is the decreased perception of pain.
In the brainstem, μ receptors are present on the same groups
of nerve cells (i.e., nuclei) involved in respiration and in sleep. The
inhibitory effect of the drugs on these neurons may allow opioid
drugs to depress respiration and alter ventilatory responses to
hypercapnia and hypoxia during wake and during sleep.1,6 People
receiving long-term opioid treatment for pain management have
been noted to have ataxic breathing, obstructive sleep apnea
(OSA), central sleep apnea, Cheyne-Stokes respiration, and Biot’s
(pronounced “BEE-ohz”) respiration.1,7-10
Ataxic breathing is an erratic breathing pattern in which
a person takes breaths of variable depth and rate that are
irregularly intermixed with pauses and with increasing periods
of apnea. It is typically seen in people who have had a stroke
or trauma to the medulla.
OSA results from the blockage (i.e., obstruction) of the upper
airway by airway tissues (e.g., tonsils, fat) during sleep. Since
airflow ceases (i.e., apnea) or is greatly reduced, a person’s blood
oxygen level falls. Meanwhile, the person makes increasingly
strong respiratory efforts to overcome the blockage and restore
airflow. The person ultimately awakens briefly to take some
fast, deep breaths, which restores the blood oxygen level. Once
restored, the person promptly falls back asleep. However, this
may set the stage for another apnea episode to occur.
Central sleep apnea occurs when the respiratory center does
not send signals to initiate inspiration and expiration. Unlike
OSA, there is no respiratory effort to breathe during a central
sleep apnea episode. Central sleep apnea can result from
neurological damage or as a result of faulty feedback between
the systems involved in the respiratory drive.
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Cheyne-Stokes respiration is a rhythmic pattern of
increasingly shallow breaths (often to the point of apnea),
followed by increasingly deeper breaths. Cheyne-Stokes
respiration reflects an instability in the feedback mechanisms
that control the respiratory response to blood level changes
in oxygen and carbon dioxide. For example, an exaggerated
response to a small decrease in the blood oxygen level triggers
deep, fast breaths to increase the perceived low oxygen level,
and a small increase in the blood oxygen triggers shallow
breaths to reduce the perceived excessive oxygen level. The
depth of breathing consequently waxes and wanes.
Biot’s respiration is reminiscent of Cheyne-Stokes respiration,
but irregular periods of apnea alternate with several breaths of
identical depth, rather than the waxing and waning breaths as
in Cheyne-Stokes respiration.
The most common sleep-related breathing disorder in people
receiving long-term opioid therapy is OSA, followed by central
sleep apnea.9,10 OSA is typically treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure
(BPAP) therapy. In these treatments, pressurized air is blown
through a mask that covers the nose or the nose and mouth.
The pressure of the air pushes against the upper airway tissues
to prevent their collapsing into the airway during sleep. In
CPAP therapy, a person inhales and exhales against one (i.e.,
continuous) pressure. In BPAP therapy, a person inhales at one
pressure and exhales against a slightly lower pressure.
A more recently developed positive airway pressure treatment
is adaptive servoventilation (which is used for sleep-disordered
breathing involving central sleep apnea). Rather than using one
pressure (as in CPAP) or two pressures (as in BPAP), an adaptive servoventilation machine continually adjusts the amount of
inspiratory pressure on a breath-by-breath basis. The frequent
adjustments in the inspiratory pressure can help to stabilize
the breathing pattern in a person who has sleep-disordered
breathing that involves central apneas (e.g., Cheyne-Stokes
respiration).
When the AAPM and APS issued their joint consensus
statement in 1997, there had been no prospective randomized
studies performed that supported or refuted the statement.11
In 2003, the first report of sleep-disordered breathing in
people receiving long-term opioid therapy appeared in the
medical literature. That year, Robert Farney and colleagues
reported their findings, using three patients as examples of
what they had noted for some time.1 The three patients had
been on long-term opioid therapy for various pain conditions.
The opioid drugs used among the three were hydrocodone,
morphine sulfate, methadone, and fentanyl. All three patients
had sleep apnea symptoms such as excessive daytime sleepiness, witnessed apnea, and snoring. Farney noted the following
polysomnographic features among the patients in the study:
severe obstructive respiratory events during non-rapid eye
movement (NREM) sleep; prolonged obstructive hypoventilation episodes that were associated with gradually progressive
severe hypoxemia (occurring exclusively during NREM sleep);
Biot’s respiration (one patient); and frequent central apneas
(one patient). None of the patients had clinical conditions such
as congestive heart failure or pulmonary disease that are normally associated with central sleep apnea, and all patients had a
normal wake SaO2 (93 percent or greater). Farney believed the
only explanation for the abnormal breathing was the prolonged
use of opioid therapy. In addition, the patient who had frequent
central apneas had previously undergone a polysomnographic
study and was successfully treated for OSA, but had not been
treated with opioids at the time. However, by the time of the
2005 study, the patient had been on opioid therapy for some
time, indicating that the patient’s frequent central apneas
developed after beginning opioid therapy.
Since the 2003 Farney study, other scientists have similarly
noted sleep-disordered breathing in patients receiving longterm opioid therapy. For example, in a 2005 study, Wang and
colleagues found that 30 percent of methadone maintenance
treatment patients had a central apnea index (CAI, the number of central apneas per hour of sleep) greater than 5 events
per hour and that the blood level of methadone was the only
variable significantly associated with the CAI.6 In addition, the
methadone maintenance treatment patients had a reduced ventilatory response to hypercapnia. Lynn Webster and colleagues
in a 2008 study found that 75 percent of chronic pain patients
who had received around-the-clock methadone or other opioid
therapy for at least six months had an apnea-hypopnea index
(AHI, the number of apneas or hypopneas per hour of sleep)
greater than five events per hour; that a direct relation existed
between the AHI and the dosage of methadone (but not the
other opioids); and that a direct relation existed between the
CAI and the dosage of methadone.10 Mogri and colleagues in
2009 noted a high prevalence of sleep apnea among 98 patients
who were on long-term opioid therapy: 36 percent of the patients had obstructive sleep apnea; 24 percent had central sleep
apnea; 21 percent had combined obstructive and central sleep
apnea; and 15 percent had no sleep apnea.9 The sleep apnea in
the remaining four percent was classified as indeterminate. Two
patients had hypoxemia during wake or sleep-related hypoxemia in the absence of sleep apnea.
The opioid-induced inhibition of signals from the carotid
body (a small mass of cells that contains μ receptors and is
found in the bifurcation of each carotid artery) may play a role
in the blunted respiratory response to hypoxia (e.g., a greater
decrease in blood oxygen needs to occur before the respiratory
center triggers rapid, deep breathing).11 This blunted response
can allow low blood levels of oxygen to persist during wake
and sleep.1 Other research shows a blunted response to hypercapnia (e.g., a greater-than-normal increase in carbon dioxide
needs to occur before the respiratory center triggers rapid, deep
breathing), reflecting inhibitory effect of μ receptors on the
respiratory center neurons in the brain.6 Since a blunted respiratory response to hypoxia and hypercapnia can set the stage
for hypoxemia and central apneas, the effectiveness of CPAP
treatment may be reduced in people with sleep-disordered
breathing who are on long-term opioid therapy.
In some people who have Cheyne-Stokes respiration and
cardiac or pulmonary disorders (e.g., congestive heart failure or
emphysema, respectively), adaptive servoventilation effectively
restores a regular breathing pattern. However, the effectiveness
of this therapy for resolving central sleep apnea and CheyneStokes respiration in people receiving long-term opioid therapy
was first investigated in a 2008 study by Farney and colleagues.8
In this study, subjects underwent a night of CPAP therapy and a
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night of adaptive ventilation therapy, and the results were compared. At baseline, the study participants had an AHI of nearly
67 events per hour. With CPAP treatment, the AHI increased
to 70 events per hour; however, with adaptive servoventilation, the AHI fell to 54 events per hour and the CAI fell from
26 events per hour to about 16 events per hour. Eighty-two
percent of the patients had Biot’s respiration, which persisted
with servoventilation therapy. Farney concluded that adaptive
servoventilation was insufficient in treating these patients. In
contrast to Farney, Javaheri and colleagues found that adaptive
servoventilation effectively treated sleep-disordered breathing in
patients who were receiving long-term opioid therapy.12 In Javaheri’s study, adaptive servoventilation reduced the patients’ AHI
from 70 to 13 events per hour and eliminated central apneas.
The number of pain management centers is increasing rapidly
as scientists gain new information about the chemical mediation of pain and as new drugs and treatments (e.g., spinal cord
stimulation) are developed and introduced to the market. Pain
medicine physicians aggressively monitor patients on long-term
opioid therapy for addiction and other adverse effects of the
drugs. Screening and treating these patients for sleep-disordered
breathing may be another factor that needs to be addressed.
Some research suggests that people receiving long-term opioid
therapy have an increased risk of unexpected death. It is possible
that this is a consequence of undiagnosed sleep-disordered
breathing.12 Therefore, assessing patients on long-term opioid
therapy for sleep-disordered breathing may be beneficial in
reducing negative consequences of an undiagnosed sleep-related
breathing disorder.
8. 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 Aug 15;4(4):311-9.
9. Mogri M, Desai H, Webster L, Grant BJ, Mador MJ.
Hypoxemia in patients on chronic opiate therapy with and
without sleep apnea. Sleep Breath. 2009 Mar;13(1):49-57.
Epub 2008 Aug 6.
10. Webster LR, Choi Y, Desai H, Webster L, Grant BJ. Sleepdisordered breathing and chronic opioid therapy. Pain Med.
2008 May-Jun;9(4):425-32.
11. 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
Aug 15;3(5):455-61.
12. 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
Aug 15;4(4):305-10. 
REFERENCES
1. Farney RJ, Walker JM, Cloward TV, et al. Sleep-disordered
breathing associated with long-term opioid therapy. Chest.
2003 Feb;123(2):632-9.
2. Morgenthaler TI. The quest for stability in an unstable
world: Adaptive servoventilation in opioid-induced
complex sleep apnea syndrome. J Clin Sleep Med. 2008
Aug 15;4(4):321-3.
3. Dorland WAN, editor. Dorland’s Illustrated Medical
Dictionary. 28th ed. Philadelphia: WB Saunders
Company; 1994.
4.
BehaveNet. DSM-IV & DSM-IV-TR: Pain disorder
[Internet]. Bellevue (WA): BehaveNet; 2011 [cited
2011 June]. Available from: http://www.behavenet.com/
capsules/disorders/paindisorder.htm.
5.
Mycek M, Harvey RA, Champ PC. Pharmacology. 2nd ed.
Philadelphia: Lippincott-Raven Publishers; 1997.
6. Wang D, Teichtahl H, Drummer O, et al. Central sleep
apnea in stable methadone maintenance treatment
patients. Chest. Sep 2005;128(3):1348-56.
7. Wang D, Teichtahl H. Opioids, sleep architecture
and sleep-disordered breathing. Sleep Med Rev. 2007
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