Residual excessive daytime sleepiness in patients treated for obstructive sleep apnea: guidance for assessment, diagnosis, and management

Figures & data

Figure 1. Residual EDS in adults with OSA: diagnosis and management. CPAP, continuous positive airway pressure; EDS, excessive daytime sleepiness; OSA, obstructive sleep apnea

Table 1. Risk factors for EDS in patients with OSA based on a combination of available studies.^a

Risk Factor	Odds Ratio	p-value
Diabetes [4]	6.9	<0.001
Baseline^b EDS [4,18]	1.3–5.1^c	<0.001
Not getting enough sleep [5]	4.6	<0.001
Heart disease [4]	2.9	0.004
Awaken with leg cramps [5]	2.4	<0.001
Chronic pain [18]	2.3	0.008
COPD [5]	2.0	0.01
Wake up too early [5]	1.8	0.002
Wake up during night [5]	1.8	0.001
Respiratory disease [5]	1.8	0.003
Depression [18]	1.8	0.059
Habitual snorer [5]	1.6	0.005
Trouble falling asleep [5]	1.5	0.055
Asthma [5]	1.2	0.015

^aBudhiraja et al. [18], n = 1,105; Koutsourelakis et al. [4], n = 208; Kapur et al. [5], n = 6,440. ^bPre-CPAP treatment. ^cOdds of experiencing residual EDS after CPAP treatment.

COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; EDS, excessive daytime sleepiness; OSA, obstructive sleep apnea.

Table 2. Tools for evaluating EDS

Tools	Characteristics Assessed	Findings Suggestive of EDS	Utility	Administrator
Self-report measures
Epworth Sleepiness Scale (ESS)	Sleep propensity in daily situations (trait sleepiness)	Score >10	To assess for and/or diagnose EDS	Any HCP
Stanford Sleepiness Scale (SSS)	Degree of sleepiness at point in time (state sleepiness)	Score >3	Not ideal for clinical purposes	Any HCP
Karolinska Sleepiness Scale (KSS)	Degree of sleepiness at point in time (state sleepiness)	Score ≥7	Not ideal for clinical purposes	Any HCP
Objective measures
Multiple Sleep Latency Test (MSLT)	Ability to fall asleep	Mean sleep latency <8 minutes^a	To make a differential diagnosis (e.g. rule out EDS associated with narcolepsy) To confirm severity of EDS to justify pharmacotherapy	Sleep specialist
Maintenance of Wakefulness Test (MWT)	Ability to stay awake	Mean sleep latency ≤19 minutes^a	To characterize response to wake-promoting treatment To evaluate functional severity of EDS (i.e. if patient’s ability to remain awake is a safety risk)	Sleep specialist
Oxford Sleep Resistance (OSLER) Test	Ability to stay awake	N/A^b	Simplified behavioral-based version of the MWT	Sleep specialist
Psychomotor Vigilance Test (PVT)	Sustained vigilance (reaction time; lapses in attention)	N/A^c	To evaluate functional severity of EDS (i.e. if patient’s ability to remain awake is a safety risk)	Sleep specialist
Actigraphy	Graphical summary of sleep and wakefulness patterns; estimates of sleep parameters (e.g. sleep latency, TST, WASO, SE)	N/A	To improve diagnostic accuracy (e.g. rule out insufficient sleep as cause of EDS)	Sleep specialist

^aThresholds to determine EDS based on mean sleep latency on the MWT and MSLT are not well established as mean sleep latency can vary with methodological differences and individual differences in sleep tendency [36]. ^bNo standard cutoff; however, OSLER test mean sleep latency has been shown to be consistent with MWT mean sleep latency. ^cNo standard cutoff; however, patients with EDS have been shown to have lower reaction times, greater variability in reaction times across a task, and longer and more frequent lapses [37].

EDS, excessive daytime sleepiness; HCP, health care provider; SE, sleep efficiency; TST, total sleep time; WASO, wake after sleep onset.

Table 3. Differential diagnosis of EDS

Suboptimal treatment of OSA
Inadequate adherence
Non-normalization of breathing (AHI)
Inappropriate ventilatory support
Lifestyle factors
Insufficient sleep
Diet
Exercise
Sleep disorders
Narcolepsy (type 1 or 2)
Idiopathic hypersomnia
Kleine-Levin syndrome
Circadian rhythm sleep-wake disorders
Restless legs syndrome
Periodic limb movement disorder
Psychiatric disorders
Depression
Anxiety
Substance use
Medical disorders
Diabetes
Hypothyroidism
Renal disease
Hepatic encephalopathy
Cancer
Inflammatory conditions
Encephalitis
Neurodegenerative conditions
Head trauma
Stroke
Medications
Alpha-2 antagonists^a
Antihistamines^b
Anxiolytics
Antidepressants^c
Anticonvulsants
Antidiarrhea agents
Antiemetics
Antimuscarinics/antispasmodics
Antiparkinsonian agents
Antipsychotics
Antitussives
Barbiturates
Benzodiazepines
Genitourinary smooth muscle relaxants
Mood stabilizers
Opioids
Sedative-hypnotics
Skeletal muscle relaxants

^aClonidine and methyldopa [67].

^bFirst-generation antihistamines; sedation is infrequent with second-generation antihistamines [67].

^cSedating antidepressants include tricyclics (amitriptyline, imipramine, nortriptyline, etc), tetracyclics (trazadone and mirtazapine), paroxetine, citalopram, fluvoxamine, brexanolone, and esketamine [67].

AHI, apnea hypopnea index; EDS, excessive daytime sleepiness; OSA, obstructive sleep apnea.

Table 4. Pharmacotherapy options for EDS in OSA

Agent	Dosing	Side Effects	Drug Interactions/Contraindications
FDA-approved
Modafinil (Provigil®) [78]	200 mg/day Administer once daily in morning	Serious rash, including Stevens-Johnson syndrome Headache Nausea Nervousness Rhinitis Diarrhea Back pain Anxiety Insomnia Dizziness Dyspepsia	Steroidal contraceptive Cyclosporine CYP2C19 substrates (e.g. omeprazole, phenytoin, diazepam)
Armodafinil (Nuvigil®) [79]	150 or 250 mg/day Administer once daily in morning	Serious rash, including Stevens-Johnson syndrome Headache Nausea Dizziness Insomnia	Steroidal contraceptive Cyclosporine CYP2C19 substrates (e.g. omeprazole, phenytoin, diazepam)
Solriamfetol (Sunosi™) [80]	37.5, 75, or 150 mg/day Initiate at 37.5 mg/day Administer once daily on waking	Headache Nausea Decreased appetite Insomnia Anxiety	Monoamine oxidase inhibitors Drugs that increase blood pressure and/or heart rate Dopaminergic drugs
Off-label
Pitolisant (Wakix®) [81]	17.8 to 35.6 mg/day^a Initiate at 8.9 mg/day Administer once daily in morning	Insomnia Nausea Anxiety QT interval prolongation	Patients with severe hepatic impairment CYP2D6 inducers CYP3A4 substrates, including hormonal contraceptives
Methylphenidate (Ritalin® or Concerta®) [82,83]	Ritalin® 5, 10, or 20 mg/day Administer 20–30 mg 2 or 3 times daily, preferably 30–45 min before meals (maximum dose of 60 mg/day) Concerta® extended-release 18, 27, 36, and 54 mg/day Initiate at 36 mg/day (adults) Administer once daily in the morning	Tachycardia Palpitations Headache Insomnia Anxiety Hyperhidrosis Weight loss Decreased appetite Dry mouth Nausea Abdominal pain	Monoamine oxidase inhibitors Antihypertensive drugs Halogenated anesthetics
Amphetamines (e.g. Adderall® [84] and Dexedrine® [85])	5 to 60 mg/day Initiate at 10 mg/day Administer at the lowest effective dose and adjust on an individual patient basis Administer in divided doses; first dose upon awakening with subsequent doses at intervals of 4 to 6 h Avoid late evening doses due to resulting insomnia	Hypertension Tachycardia Myocardial infarction Stroke New/worsened psychiatric symptoms Peripheral vasculopathy Seizures Serotonin syndrome Dizziness Insomnia Tremor Headache Vision blurred Dry mouth Gastrointestinal disturbances Anorexia/weight loss	Patients with advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma, or agitated states Patients with history of drug abuse Monoamine oxidase inhibitors Acidifying agents, adrenergic blockers, alkalinizing agents, tricyclic antidepressants, CYP2D6 inhibitors, serotonergic drugs, antihistamines, antihypertensives, chlorpromazine, ethosuximide, haloperidol, lithium carbonate, meperidine, methenamine therapy, norepinephrine, phenobarbital, phenytoin, propoxyphene, proton pump inhibitors, veratrum alkaloids

^aNote that these doses are FDA-approved for patients with narcolepsy. In patients with OSA, pitolisant has been tested in Europe at doses of 5, 10, and 20 mg/day; treatment was initiated at 5 mg/day [86]. EDS, excessive daytime sleepiness; FDA, Food & Drug Administration; OSA, obstructive sleep apnea.

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