Opioids and Respiratory Depression: The Impact on the Sleep Study

Kathryn Hansen, BS, CPC, CPMA, REEGT

Integration Consultants, LLC

Sleep Education Partners

Executive Director – Kentucky Sleep Society

Executive Director – Society of Behavioral Sleep Medicine

Director of Education – American Academy of Sleep Disorders Disciplines

Indications for opioid therapy are changing

▪Management of opioid dependence

▪Acute pain

▪Terminal pain

▪Less so for chronic non-cancer pain

▪Anesth Analg 2015;120:1273–85

▪ Alcohol1

▪ Herbals2

▪ Dietary supplements2

▪ Homeopathic preparations3

▪ Melatonin2

▪ OTC sleep aids1

▪ Sedating antidepressants4

▪ Sedative-hypnotics5

▪ Marijuana

▪ Opioids

What Do People Take to Try to Improve Their Sleep?

1. Ancoli-Israel S, Roth T. Sleep. 1999;22(suppl 2):S347-S353. 2. Larzelere MM, Wiseman P.

Prim Care Clin Office Pract. 2002;29:339-360. 3. Neubauer DN. Clinical Cornerstone. 2003;5:16-27;

4. Wagner J et al. Neuropsychiatry. 1998;32:680-691. 5. Mitler MM. Sleep. 2000;23(suppl 1):S39-S47.

Sleep apnea terminology

▪Apnea: No airflow for 10 or more seconds▪Hypopnea: Reduced airflow for 10 or more seconds with ≥ 4% oxygen desaturation (CMS) or 3% (AASM)▪AHI = Apnea-Hypopnea Index▪Apneas + Hypopneas / Total sleep time (in hours)

▪ODI = Oxygen Desaturation Index▪Number of 4% desaturations/hour of recording▪Measured with overnight pulse oximetry

▪ American Academy of Sleep Medicine (AASM)

(B) Central Sleep Apnea (CSA)

A pattern of breathing characterized by a normal deep inspiratory cycle interchanged with complete cessation of breathing.

It is typically caused by problems with how the brain controls breathing rather than an occlusion of the airway.

(A) Obstructive Sleep Apnea (OSA)

▪The absence of airflow due to an occlusion in the upper airway that lasts at least 10 seconds despite a continual effort to breathe.

Cheyne Stokes Respiration (CSR)a variation of central sleep apnea

CSR is characterized by recurrent central apneas during sleep alternating with a crescendo-decrescendo pattern of tidal volume. Most often seen in association with congestive heart failure or stroke.

Opioids do not cause CSR

Pathophysiology of CSA

▪Goal of ventilatory control is homeostasis of: PaCO2, PaO2 and blood PH

▪Main sensors:▪Peripheral chemoreceptors (carotid, aortic)▪Central chemoreceptors (ventral surface of medulla)

▪CSA results from an instability of ventilatory control

Pathophysiology of CSAChemical Control of Breathing

▪Peripherally at Carotid Body via PaO2 and PaCO2

▪Medullary neurons responds to CO2 via shifts in H+ concentration

▪Hypercapnic Ventilatory Response▪Hypoxic Ventilatory Response

Case Study (pg. 1)

▪2013: 61 year-old man with witnessed apnea, loud snoring and daytime sleepiness (ESS 13/24). Wakes up 4-5 times/night.

▪Gained 15 pounds over past two years. Hypertension and mood disorder.

▪Multiple back surgeries. Back injury in 1987 and 1997. Intrathecal pain pump (dilaudid) for 3 years. BMI 29, neck 16 inches, BP 160/94, RR 18, pulse 63, O2 sat 97%, Mallampati Class 3

▪Meds: clonazepam prn, mirtazapine qhs, losartan, labetalol, omeprazole, intrathecal dilaudid.

Case Study (pg. 2)

▪Polysomnography July 2013▪ Stage N1 9%, Stage N2 81%, No Stage N3, ↓REM 10% (2 REM episodes)

▪ Sleep efficiency 83%

▪ 272 central apneas, 2 mixed apneas, no obstructive apneas, 16 hypopneas

▪ O2 saturation nadir 89%

▪ No Cheyne Stokes breathing, mild ataxia of respiration, soft snoring

▪ AHI 46 (AHI in REM 13, AHI in NREM 50)

▪ SEVERE CENTRAL SLEEP APNEA probably related to opioid

▪Titration Study ▪ Using adaptive servo-ventilation. AHI reduced to 1.5 at Max Pressure 25 cm H2O, EPAP 5

to 15 cm H2O, Pressure support 0 to 20 cm H2O , auto rate

Case Study (pg. 3)

▪6 weeks f/u: Usage of ASV 96%, average 5 hours/33 minutes with “average AHI” of 6.3/hour, resting “much better”, wakes up 1-2/night. ESS 12

▪6 month f/u: Usage 99%, 5 hours/49 minutes, occasional nap in afternoon while using ASV. ESS 12. Remains on dilaudid via pump

▪ 1.5 year f/u in 2015. Usage 98%, average 6 hours/49 minutes. “average AHI 7.5, ESS 11. now has pacemaker, diabetes, and echocardiogram shows LV EF 65%. ↓Max EPAP to 12 and ↓Max PS to 12 (in view of “expert” recommendations after SERVE-HF clinical trial and ↑ mortality using ASV with CHF and EF < 45%)

▪2 year f/u in 2016: 100%, 6 hours/26 min, “AHI” is 3.3

Opioid-Induced Sleep-Related Breathing Disorders

▪Obstructive sleep apnea—longer events

▪Complex sleep apnea (OSA with CSA during titration)

▪Central sleep apnea—intermittent events or as form of periodic breathing

▪Ataxic breathing—variations in cycle length and air flow magnitude

▪Sleep-related hypoventilation (with or without awake hypoventilation)

▪Low respiratory rate

Modified from Sleep Medicine Pearls, Third Edition, R. Berry and M Wagner (2015)

The Making of the Opioid Crisis

▪ 1980: NEJM publishes a letter to the editor that becomes known as Porter and Jick with title “Addiction is Rare in Patients Treated with Narcotics.”

▪ 1984 Purdue releases MSContin, a timed-release morphine marketed for cancer patients

▪ 1996 Purdue releases OxyContin, timed-release oxycodone, marketed for chronic pain patients.

Pain in the late 90s

▪ American Academy of Pain Medicine and American Pain Society: “pain is often managed inadequately, despite the ready availability of safe and effective treatments” (1997).

▪ This report downplayed the risk of adverse respiratory effects of long term opioid use (more details later)

▪ The VA system spearheaded the campaign to make pain the “5th vital sign,” meaning that it had to be assessed at every patient encounter.

▪ Doctors who declined to write prescriptions for narcotics were given bad reviews on patient satisfaction surveys.

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Opioid Crisis Today

▪ (2008) Drug Overdose Deaths, mostly from opioids, surpass auto fatalities as leading cause of accidental death

▪ (2012) Hydrocodone is the number one prescribed medication in America

▪ (2012) The Kentucky General Assembly passed HB 1 that focuses on the regulation of pain clinics and prescription drug abuse in Kentucky.

▪ There is little scientific evidence that the use of opioids effectively controls non-cancer type pain.

▪ Editorial by Lee-Iannotti J, Parish JM. The epidemic of opioid use: implications for the sleep physician. J Clin Sleep Med 2014;10(6):645-646.

Indications for opioid therapy are changing

▪Management of opioid dependence

▪Acute pain

▪Terminal pain

▪Less so for chronic non-cancer pain

▪Anesth Analg 2015;120:1273–85

Opioids and Respiratory Control

▪Opioids decrease central respiratory drive, with a resultant decrease in tidal volume, respiratory rate, and minute ventilation. (TV x RR = MV)

▪Significant alterations and irregularity in breathing

▪The mechanism of central apneas associated with chronic opioid use is unknown but may be due in part to the respiratory instability caused by a paradoxical

▪↓central hypercarbic ventilatory drive and

▪↑peripheral hypoxemic ventilatory drive

▪ which may result in an increased loop gain.

Teichtahl H et al. Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients. Chest 2005;128:1339-47

3 Types of Sleep Disordered Breathing (SDB)

▪(A) Obstructive Sleep Apnea (OSA)

▪(B) Central Sleep Apnea (CSA)

▪(C) Hypoventilation Syndromes

All 3 types of SDB may occur with chronic opioid use

Cheyne Stokes Respiration (CSR)a variation of central sleep apnea

CSR is characterized by recurrent central apneas during sleep alternating with a crescendo-decrescendo pattern of tidal volume. Most often seen in association with congestive heart failure or stroke.

Opioids do not cause CSR

Hypercapnic Ventilatory Response As a Function of State

Hypoxic Ventilatory Response as a function of State

1997 report downplayed the risk of adverse respiratory effects of long term opioid use

▪“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.”

▪American Academy of Pain Medicine and American Pain Society. The use of opioids for chronic pain. Clin J Pain 1997;13:6-8.

Sleep-Disordered Breathing Associated with Long-Term Opioid Therapy 2003

▪3 cases of SDB described

▪ In contrast to typical OSA:

▪More severe in NREM sleep▪“Ataxic breathing” pattern with irregular respiratory pauses and gasping during NREM sleep

▪Prolonged periods of obstructive hypoventilation lasting at least 5 minutes resulting in progressive hypoxemia & not present in REM sleep

▪Ineffectiveness of nasal CPAP

▪Farney RJ, Walker JM, et al. Chest 2003: 123(2): 632-639.

SDB,

not responsive to CPAP, resolves in REM

Farney CHEST 2003

Variations of ataxic breathing

Farney RJ, et al, J Clin Sleep Med 2008; 4: 311–319

Opioid-induced ataxic and cluster breathing.

The respiratory pattern is characterized by a highly irregular rhythm, varying in rate and amplitude …There are a few scattered central apneas with a “cluster” pattern

Anesth Analg 2015;120:1273–85

Variations of ataxic breathing

Farney RJ, et al, J Clin Sleep Med 2008; 4: 311–319

(C) Hypoventilation with chronic opioid use

▪Rose AR, et al. Sleep disordered breathing and chronic respiratory failure in patients with chronic pain on long term opioid therapy. J Clin Sleep Med. 2014; 10(8):847-852.

▪ In this prospective study, mean (awake) PaCO2 was 44.8 ± 4.1, with median PaCO2 44.9 in the 20 patients who permitted ABG.

▪Hypercapnia (defined as a PaCO2 ≥ 45 mg) was seen in 9/20 and PaCO2 >50 was seen in 2/20. All had relatively unremarkable pulmonary function tests

▪Depression of hypercapnic drive would explain increases in PaCO2 measured in this study of patients using opioid therapy for chronic pain analgesia.

Diagnostic Testing (1)

▪Diagnosis of SDB in patients chronically using opioids requires a high index of suspicion and a PSG.

▪None of the available screening questionnaires for OSA have been validated in identifying SDB in patients who chronically use opioids, and no such instruments exist for detection of CSA in the general population.

▪Adding to the uncertainty is the relative lack of outcome data in patients with opioid-associated SDB.

-Sleep-disordered breathing in patients chronically using opioids, Shafazand S., UpToDate with this topic last updated: Apr 27, 2016.

Treatment of CSA due to chronic opioid use

▪Lower the opioid dose

▪Avoid concomitant drugs ▪ benzodiazepines and alcohol

▪Positive Airway Pressure Therapy

Troitino A, Labedi N, Kufel T, El-Solh AA. Positive airway pressure therapy in patients with opioid-related central sleep apnea. Sleep Breath 2014; 18:367.

▪Systematic review of various PAP modalities from five studies and a total of 127 patients

▪BPAP with backup rate, with and without supplemental oxygen, eliminated central apneas in 62 percent of patients, and adaptive servo-ventilation (ASV) was successful in 58 percent of participants.

▪CPAP and/or oxygen are not effective.

Behavioral aspects of medication treatment for insomnia

▪Medications for insomnia: A brief review

▪Medications as a form of behavioral intervention

▪What the patient brings

▪What the provider brings

▪Take home points

Therefore: SDB with Chronic Opioids

▪The prevalence of SDB in those receiving chronic opioids is high.

▪The prevalence of CSA is much higher than in the general population (24%).

▪The SDB associated with opioids includes OSA, CSA, hypoventilation and ataxic breathing or some combination.

▪The usual risk factors seen in patients with OSA are not reliably predictive in patients with opioid-related SDB.

▪The possibility of CSA and other disturbances should be considered in any person being treated with chronic opioids, especially if the MEDD ≥ 200 mg/d

Risk Factors for CSA with chronic opioid use

▪Low to low-normal body mass index

▪Daily dose of opioid greater than 200 mg morphine dose equivalents

▪Another risk factor identified in some but not all studies include concomitant use of benzodiazepine.

▪(2016) FDA requires "black box warning“ for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use.

Wang D, et al. Chest 2005; 128:1348.

Walker JM, et al. J Clin Sleep Med 2007; 3:455.

Walker JM, Farney RJ. Curr Pain Headache Rep 2009; 13:120.

Clinicians’ and patients’ choices in evidence-based medicine1

Clinical stateand circumstances

Research evidence

Clinical expertise

Patients’preferencesand actions

1DaCruz, BMJ 2002;324:674.

Does Marijuana Help Sleep?

▪Prevailing view: yes

▪Study - University of Michigan concluded that depending on how frequently an individual uses marijuana, it may not help them sleep at all.

▪ It may actually worsen their sleep quality.

▪The study recruited 98 subjects who were divided into three groups: daily marijuana users, non-daily marijuana users, and a non-user control group.

Marijuana and Sleep

▪Researchers found:▪that that the daily-use group had higher levels of insomnia (almost 40 percent)

compared to non-daily users (10 percent) and the control group (20 percent).

In Conclusion: SDB with Chronic Opioids (1)

▪The prevalence of SDB in those receiving chronic opioids is high.

▪The prevalence of CSA is much higher than in the general population (24%).

▪The SDB associated with opioids includes OSA, CSA, hypoventilation and ataxic breathing or some combination.

▪The usual risk factors seen in patients with OSA are not reliably predictive in patients with opioid-related SDB.

▪The possibility of CSA and other disturbances should be considered in any person being treated with chronic opioids, especially if the MEDD ≥ 200 mg/d

In Conclusion: SDB with Chronic Opioids (2)

▪ In contrast to OSA, there are presently no guidelines or standards regarding indications for performing PSG in patients who use opioids.

▪Diagnosis of SDB in patients chronically using opioids requires a high index of suspicion and a PSG with attention to clinical symptoms, known risk factors, and high-risk comorbid conditions.

▪Therapy for CSA related to opioid usually requires ASV or BPAP with a backup rate.

▪There are many limitations to the published studies, and the clinical outcomes of patients with documented CSA due to opioids are not known.

Thank you

kathrynhk@msn.com

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