Acetazolamide as an Adjunct to CPAP Treatment: A Case of Complex Sleep Apnea in a Patient on Long-Acting Opioid Therapy

Abstract

A 41-year-old white woman on long-acting opioid therapy was diagnosed with moderate obstructive sleep apnea. On initiation of continuous positive airway pressure (CPAP), she manifested severe central apnea that was unresponsive to supplemental oxygen and interfered with CPAP titration. Acetazolamide, 250 mg, nightly at bedtime was initiated, and CPAP titration was repeated. On acetazolamide, optimal CPAP pressure was obtained with no manifestation of clinically significant central respiratory disturbance. This case suggests that acetazolamide may be an effective adjunct to positive airway pressure therapy in patients on long-acting opioids. A need exists for examination of acetazolamide in this capacity.

Citation:

Glidewell RN; Orr WC; Imes N. Acetazolamide as an adjunct to CPAP treatment: a case of complex sleep apnea in a patient on long-acting opioid therapy. J Clin Sleep Med 2009;5(1):63-64.

Acetazolamide is an effective treatment for central sleep apnea in heart failure, at high altitude, and in its idiopathic form.¹ Chronic opioid use is a risk factor for complex sleep apnea syndrome, a term referring to a subset of patients with obstructive sleep apnea who manifest respiratory control dysfunction and central apnea on continuous positive airway pressure (CPAP).² Recent evidence indicates effective treatment of complex sleep apnea syndrome using adaptive servoventilation.³ However, recent trials investigating the efficacy of adaptive servoventilation the for management of complex sleep apnea syndrome associated with chronic opioid use have produced mixed results.^3,4 We report the use of acetazolamide as an adjunct to positive airway pressure (PAP) therapy for complex sleep apnea syndrome related to opioid therapy.

REPORT OF CASE

A 41-year-old woman with a body mass index of 31 was referred for evaluation of insomnia and daytime sleepiness. She was receiving opioid treatment (hydrocodone, transdermal fentanyl) for tarsal tunnel syndrome. She presented with an Epworth Sleepiness Scale score of 17. She had no evidence of systolic or diastolic heart dysfunction. The patient underwent an initial split-night polysomnogram. Respiratory events were scored using current American Academy of Sleep Medicine rules.

Baseline data (Table, Column 1) documented moderate obstructive sleep apnea with central apneas occurring at a rate of 7 per hour. No mixed apneas or periodic breathing were present. Titration using CPAP and bilevel PAP, as well as supplemental oxygen therapies, was attempted. Although these therapies improved the patient’s obstructive apnea, a startling increase in central apnea was observed, and severe hypoxemia persisted (Table, Column 2). No difference was noted in central apneas when comparing CPAP and bilevel PAP.

Table 1.

Polysomnographic Diagnostic and CPAP Titration Findings Before and After Treatment With Acetazolamide

PSG parameter	Testing conditions
	Initial diagnostic PSGa	Initial CPAP titration	Optimal CPAP+ acetazolamideb	Follow-upc
Obstructive AHI, no./h	27	12	0	0
CAI, no./h	7	66	1	17
Total AHI	34	78	1	17
RERA index, no./h	7	0	4	0
RDI, no./h	41	78	5	17
Percentage of sleep time with SaO2 less than
90%	88	57	0	0.1
85%	5	6	0	0
Mean SaO2, %	88	89	94	94
Lowest O2 value, %	78	74	93	82
AI, no./hd	18	0	1	0

^aDuration of baseline polysomnography (PSG) was 140 minutes.

^bOptimal continuous positive airway pressure (CPAP), 9 cm h₂o, and acetazolamide, 250 mg, at bedtime for 7 days.

^cFive-month follow-up on CPAP without acetazolamide (off acetazolamide for 7 days).

^dNumber of arousals per hour of sleep not related to respiratory events.

Abbreviations: AHI, apnea-hypopnea index; CAI, central apnea index; RERA, respiratory event-related arousals; RDI, respiratory disturbance index.

Acetazolamide, 250 mg, at bedtime nightly prior to bedtime was initiated. Follow-up polysomnography was conducted after 1 week of treatment. With an optimal CPAP pressure of 9 cm h₂o, obstructive events and hypoxemia were eliminated. Central events and respiratory event-related arousals were reduced to clinically acceptable rates (Table, Column 3).

Clinical follow-up after 5 weeks on combined therapy revealed minor improvement in subjective complaints of daytime sleepiness, as indicated by persistent elevation in the Epworth Sleepiness Scale score (12/24). After 5 months, acetazolamide treatment was discontinued for 1 week, and a follow-up polysomnogram was conducted with the patient remaining on CPAP at 9 cm H₂O. No snoring, obstructive events, respiratory event-related arousals, or hypoxemia were recorded. Central events were recorded at a rate of 17 per hour and were unresponsive to treatment with supplemental oxygen (Table, Column 4).

DISCUSSION

The respiratory effects of acetazolamide are well established. Acetazolamide administration in humans has been shown to inhibit the ventilatory response of the peripheral chemoreceptors but to enhance central chemosensitivity to CO₂.^5,6 Furthermore, in a dog model, metabolic acidosis induced by acetazolamide has been shown to lower the PETCO₂ apnea threshold and widen the difference between the eupneic and the PETCO₂ apnea thresholds.⁷ The resulting effects of acetazolamide are to decrease the susceptibility to develop apneas, hypopneas, and periodic breathing.^5–7

Opioid therapy appears to have altered the CO₂ apnea threshold in this patient, resulting in an increase in central apneas upon introduction of positive airway pressure. Whether by altered chemosensitivity or enhanced ventilatory drive via metabolic acidosis and decreasing the CO₂ apnea threshold, acetazolamide effectively counteracted the respiratory effect of opioids. It was expected and observed that, with the addition of acetazolamide, we could effectively titrate CPAP to relieve obstructive sleep apnea. Some evidence suggests that central apnea manifesting upon introduction of CPAP therapy may spontaneously resolve in the initial weeks of therapy. However, return of central apneas after removal of acetazolamide in this case suggests the respiratory effect of long-term opioid therapy persists.

Sleep apnea is implicated as a possible mechanism for increased mortality among patients treated with opioids.⁴ With this in mind, the prevalence of sleep apnea in patients treated with opioids (30% to 90%) and the dramatic increase in the therapeutic use of opioids in the past decade make finding effective treatments for sleep apnea in this population a timely clinical challenge for sleep and pain medicine providers.^3,4 Positive response to the adjunctive use of acetazolamide in this case suggests that acetazolamide may have utility in the broader management of complex sleep apnea syndrome related to chronic opioid therapy.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.