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18 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. A2 Zzz 20.3 | September 2011 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 A2 Zzz 20.3 | September 2011 Continued on Page 20 19 Continued from Page 19 20 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 Feb;11(1):35-46. Epub 2006 Dec 1. A2 Zzz 20.3 | September 2011