INTRODUCTION — Excessive daytime sleepiness (EDS) is one of the most common symptoms reported by patients with obstructive sleep apnea (OSA). While successful treatment of OSA with positive airway pressure (PAP) therapy or other modalities typically improves sleep quality, a small proportion of patients continue to experience EDS despite adequate therapy.
The evaluation and management of residual sleepiness in adults with OSA is discussed here. Primary therapy for OSA (eg, PAP, oral appliances, or, occasionally, surgery) is discussed separately. (See "Management of obstructive sleep apnea in adults".)
DEFINITION AND PATHOGENESIS — Residual excessive sleepiness (RES) in patients with obstructive sleep apnea (OSA) refers to the subjective complaint of excessive daytime sleepiness (EDS) that is present even when breathing and oxygenation parameters during sleep are normalized by successful OSA therapy. EDS is defined as the inability to maintain wakefulness and alertness during the major waking episodes of the day, with sleep occurring unintentionally or at inappropriate times [1].
Although the definition of RES is agreed upon, the entity itself is not universally accepted, as some experts feel that the prevalence of EDS in patients with successfully treated OSA simply reflects a prevalent complaint in the general population (ie, a population of patients with a genetic predisposition to excessive sleepiness) [2-4].
The pathogenesis of RES in patients with adequately treated OSA is likely multifactorial. Sleep fragmentation caused by repeated episodes of pharyngeal collapse and arousal is thought to be the most important mechanism. Additional factors may include abnormal sleep architecture, activation of the hypothalamic pituitary adrenal axis, and chronic inflammation and cytokine production. Experimental studies in animals have suggested that intermittent nocturnal hypoxia may cause irreversible cellular injury in regions of the brain that control sleep wake regulation [5-7], but it is not known whether this is contributory in humans. The degree of nocturnal hypoxia has been inconsistently associated with measures of daytime sleepiness in observational studies [8-12]. Disruption of sleep due to positive airway pressure therapy is also thought to be a cause.
PREVALENCE — Most patients with OSA who are treated with continuous positive airway pressure (CPAP) or other primary therapies (eg, mandibular advancement device) experience improvement in sleepiness when adherent to therapy. However, a minority experience residual sleepiness. The reported prevalence of residual sleepiness in patients adequately treated with CPAP ranges from 6 to 14 percent [8,13], although rates as high as 55 percent have been reported [12]. The prevalence of residual sleepiness decreases with increasing nightly CPAP use [13]. There is no gender predominance.
RISK FACTORS — Risk factors for residual sleepiness in OSA are poorly studied and not well defined but may include the following:
●Severe excessive daytime sleepiness at diagnosis - Several studies have demonstrated residual sleepiness was associated with a higher Epworth excessive daytime sleepiness score (calculator 1) and slightly lower apnea hypopnea index (AHI) on presentation [8,12,13].
●Other possible risk factors include [8,11,13]:
•Younger age (eg, <55 years, although the threshold is poorly defined)
•Lower mean night duration of continuous positive airway pressure (CPAP) usage
•Side effects from CPAP usage (eg, aerophagia, facial discomfort)
•Select sleep-related parameters (eg, reduced nocturnal sleep latency, periodic limb movement)
•Depression
Baseline severity of OSA does not appear to be a risk factor for residual sleepiness in OSA patients on adequate CPAP therapy. In one large study, patients with moderate OSA at baseline (defined as an AHI between 15 and 30 events per hour) were twice as likely to complain of residual sleepiness than those with severe OSA (AHI >30 events per hour) [13]. In the same study, body mass index (BMI) and medical comorbidities such as hypertension and diabetes were not associated with residual sleepiness.
EVALUATION — Before making the diagnosis of residual excessive daytime sleepiness and considering wake-promoting agents in patients with OSA, the clinician should take steps to do the following (algorithm 1):
●Confirm the diagnosis of OSA
●Confirm adherence to the prescribed therapy
●Exclude other competing etiologies of excessive sleepiness
●Ensure that patients are receiving adequate OSA therapy (eg, positive airway pressure, oral appliances)
Treatment with wakefulness-promoting agents should not be considered until this evaluation is complete.
Revisit the diagnosis — Clinical evaluation of residual daytime sleepiness in patients with OSA who are receiving therapy usually starts with ensuring that the diagnosis of OSA is correct. The clinician should reassess for the symptoms of OSA and review diagnostic data from home or in-laboratory tests (ie, polysomnography). A detailed approach to the clinical presentation and diagnosis of OSA is provided separately. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)
When the diagnosis of OSA is clear, it is imperative that adherence to therapy be assessed. (See 'Ensure adherence to treatment' below.)
Ensure adherence to treatment — All patients with OSA who have excessive daytime sleepiness (EDS) despite therapy should be assessed for adherence to their therapy. Most patients with OSA show improvement in daytime sleepiness after successful treatment with continuous positive airway pressure (CPAP) or other primary OSA therapies (eg, mandibular advancement device [MAD]). However, up to 30 percent of patients with OSA do not use their CPAP every night, and among those patients, mean nightly use is less than four hours per night.
Patients (and their bed partner) should be asked directly regarding frequency and duration of nightly use. In addition, objective measurements of adherence are available through CPAP telemonitoring [14]. Most newer CPAP devices have data interrogation capability that allows the clinician to determine hours of nightly use and assess other issues that may be contributing to sleepiness such as efficacy of CPAP therapy, airway leak, and insufficient sleep. However, such data is generally unavailable for those wearing oral devices (eg, MAD) such that the clinician may be reliant upon self-reported adherence from the patient; insertable monitoring capability is not typically available [15]. (See "Downloading data from positive airway pressure devices in adults".)
Once the evaluation for adherence is completed, we suggest the following:
●For patients who are not adherent, there are a variety of interventions that can help promote CPAP use, including troubleshooting device side effects, behavioral therapy, and engagement tools [16]. A detailed approach to treating nonadherence is discussed separately. (See "Assessing and managing nonadherence with continuous positive airway pressure (CPAP) for adults with obstructive sleep apnea".)
●For patients who are adherent, alternate etiologies for EDS despite therapy should be sought. (See 'Exclude alternative etiologies' below.)
Exclude alternative etiologies — Patients with OSA who have residual sleepiness on therapy to which they are adherent should be re-evaluated for additional causes of EDS. This is the most challenging step in the evaluation of residual EDS in patients with OSA receiving therapy. Specifically, clinicians should inquire about common causes of EDS. As an example, clinicians should request that the patients keep a sleep journal to elicit poor sleep habits or insufficient sleep EDS and inquire about EDS that may be due to depression, medication side, effects and other comorbid medical and psychiatric disorders all of which are listed in the table (table 1).
In most cases, ruling out other significant causes of EDS is determined by history and examination. Further testing including multiple sleep latency testing and laboratory tests (eg, blood count, thyroid function tests, vitamin D level, testosterone level, iron studies, Epstein-Barr virus antibodies) may be performed depending upon the suspicion for specific etiologies. The etiologies and approach to a patient with EDS are discussed separately. (See "Approach to the patient with excessive daytime sleepiness", section on 'Initial evaluation'.)
Patients with a suspected etiology for their residual sleepiness should be investigated for that etiology while patients in whom there is no clear alternate etiology should have the adequacy of their OSA therapy evaluated. (See 'Evaluate adequacy of therapy' below.)
Evaluate adequacy of therapy — Clinicians should elicit a history of weight gain or medication changes which can contribute to inadequate therapy. If inadequate therapy is suspected or if the patient is adhering to primary therapy and no alternative causes of EDS have been identified, we typically prefer to repeat in-laboratory polysomnography (with the patient wearing their device) to assess whether the primary OSA therapy (ie, CPAP, oral appliance) is indeed adequate, although using a home sleep apnea test (eg, WatchPAT) may also be feasible [17]. Adequate primary therapy is defined as the minimal pressure setting required to resolve all apneas, hypopneas, snoring, and arousals related to these events, in all stages of sleep and in all sleep positions [17,18]. (See "Home sleep apnea testing for obstructive sleep apnea in adults", section on 'Type 3 devices (portable devices)'.)
For patients deemed to be on inadequate therapy, reasons for persistently abnormal parameters should be sought. This includes weight gain, a poorly fitting mandibular device, inadequate CPAP titration leading to residual respiratory events, CPAP mask or mouth leaks, and treatment-emergent central sleep apnea. Noteworthy, is that OSA may be adequately treated with CPAP in the sleep laboratory but worsened in the home environment due to environmental allergies or use of sedatives or alcohol. Such issues may be suspected when disparate results occur between data derived from the device used at home and data derived from in-laboratory assessment. Titration and optimization of CPAP therapy is discussed in detail separately. (See "Titration of positive airway pressure therapy for adults with obstructive sleep apnea".)
Patients with OSA deemed to have adequate therapy, who still complain of burdensome EDS, and in whom alternative etiologies have been excluded are candidates for a trial of adjunctive stimulant pharmacotherapy. (See 'Treatment' below.)
Diagnosis — RES in patients with OSA is defined as the subjective complaint of EDS that is present even when breathing and oxygenation parameters during sleep are normalized by successful OSA therapy. The diagnosis of RES is dependent upon the confirmation of the diagnosis of OSA, the exclusion of alternate etiologies for excessive sleepiness, and the assurance of adherence to therapy that is adequate. (See 'Revisit the diagnosis' above and 'Ensure adherence to treatment' above and 'Exclude alternative etiologies' above and 'Evaluate adequacy of therapy' above.)
TREATMENT — RES in patients with adequately treated OSA, in whom other etiologies of excessive daytime sleepiness (EDS) have been excluded should be assessed for the severity of their sleepiness so that a decision can be made regarding the prescription of wakefulness promoting agents.
EDS is defined as the inability to maintain wakefulness and alertness during the major waking episodes of the day, with sleep occurring unintentionally or at inappropriate times [1]. In practice, EDS is often measured using the Epworth Sleepiness Scale (ESS), with scores greater than 10 generally considered abnormal (calculator 1). However, the ESS does not capture all facets of sleepiness, and some patients who are sleepy may have a normal ESS score.
Wakefulness promoting agents
Patient selection — For patients with adequately-treated OSA who have persistent burdensome daytime sleepiness, and in whom alternative causes of daytime sleepiness have been excluded, we suggest a trial of a wakefulness-promoting agent [17,19]. However, the use of wakefulness-promoting agents in this population is controversial, and the level of daytime sleepiness at which a trial of stimulant therapy is warranted has not been well-defined.
The decision to prescribe a wakefulness-promoting medication is generally based upon the subjective impact of patient symptoms on their activities of daily living in conjunction with the ESS score (calculator 1). Symptoms that might prompt a trial of a wakefulness-promoting agent include but are not limited to falling asleep at work or while driving, and significant fatigue or sleepiness affecting quality of life and work productivity. Although no single best cut-off value on the ESS has been determined, we believe that an ESS score of 10 or higher is a reasonable threshold for initiating a treatment trial.
Choosing an agent — Available agents include modafinil, armodafinil, and solriamfetol. Choosing among the available agents is individualized and depends upon physician and patient preference as well as cost and the presence of cardiovascular comorbidities. While all agents have been shown to improve EDS in randomized trials, modafinil and armodafinil are not approved in Europe for this indication, and are therefore, not reimbursable. Solriamfetol is, however approved and reimbursable. In the United States, modafinil and armodafinil are more frequently prescribed, and depending upon insurance, modafinil may be less expensive. Solriamfetol may be less suitable for those with cardiovascular disorders as it can dose-dependently increase blood pressure such that only the lower dose has been approved for use in both Europe and the United States [20,21]. Stimulants such as methylphenidate and amphetamines are not typically prescribed and their use is discouraged in patients with OSA because of the increased cardiovascular risk associated with their use. In addition, modafinil and armodafinil decrease the effectiveness of oral contraception and are contraindicated by some supervisory agencies during pregnancy. (See "Obstructive sleep apnea in pregnancy".)
Modafinil and armodafinil — These agents are available in the United States but are not approved in Europe.
Dosing — Modafinil is typically started at 100 or 200 mg orally each morning for the first week and then titrated up to 300 or 400 mg in the next two to three weeks, as needed. Armodafinil can be started at 150 mg once daily and titrated up to 250 mg once daily, as needed. Both agents are given once in the morning and typically promote wakefulness into the early evening without disrupting nighttime sleep. Patients with persistent afternoon sleepiness may benefit from divided dosing with, for example, modafinil 200 mg in the morning and 200 mg in the early to mid-afternoon. Patients generally notice a response within days of initiation or increasing a dose.
Side effects — The most common side effect of modafinil and armodafinil is headache, reported in 15 to 20 percent of patients treated with these agents compared with 8 to 10 percent of patients treated with placebo [22-25]. While some patients tolerate this side effect, cessation of the medication may be necessary, which may justify a trial on another wakefulness-promoting agent. Other side effects are uncommon, but include nausea, dry mouth, anorexia, back pain, anxiety, insomnia, rhinitis, and diarrhea.
Serious and life-threatening rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported [25,26]. Most rashes have occurred within the first five weeks of therapy, although rare cases have occurred after long-term use. Rare cases of multi-organ hypersensitivity reactions in association with modafinil or armodafinil use and isolated cases of angioedema and anaphylactoid reactions with armodafinil have also been reported [25]. Such hypersensitivity reactions typically present with fever and rash associated with organ-system dysfunction. Thus, patients should be advised to discontinue modafinil or armodafinil at the first sign of rash.
Adverse cardiovascular effects can occur with modafinil and armodafinil (eg, chest pain, hypertension, palpitations), although cardiovascular adverse effects are presumed to be less common with these drugs than with stimulants such as amphetamines [27,28]. However, data to support significant cardiovascular risk is lacking. Although one 12-week randomized trial reported no difference between those receiving armodafinil compared with placebo in rates of newly diagnosed hypertension or worsening of baseline hypertension [24], anecdotal evidence exists [29]. Regardless, the FDA has issued a warning regarding this potential side effect and the European Commission have not approved these medications for residual sleepiness in patients with OSA because of this adverse cardiovascular risk. In patients with a cardiovascular disorder (eg, hypertension, angina, a recent history of myocardial infarction, or left ventricular hypertrophy) we do not initiate these therapies unless the patient is stable from a cardiovascular standpoint. If prescribed, patients should be seen within one week for cardiovascular assessment and followed routinely thereafter.
Modafinil and armodafinil may decrease the effectiveness of hormonal contraception, and premenopausal women should be advised about alternative, nonhormonal methods of contraception. One case report also suggested an increased risk of congenital malformations [30]. (See "Contraception: Counseling and selection".)
Unlike amphetamines, addiction or tolerance to these agents has not been reported.
Efficacy — The effectiveness of modafinil and its active R-enantiomer, armodafinil for treatment of residual sleepiness in patients with adequately-treated OSA has been examined in multiple randomized trials [22-25,31-38]. In general, these agents improve objective and subjective measures of daytime sleepiness but adverse effects are tripled when compared with placebo. In addition, the response is variable and there are no predictors to determine who responds and who does not. Armodafinil and modafinil have never been directly compared.
●One meta-analysis of 1479 patients with OSA and residual sleepiness on adequate CPAP adherence reported that compared with placebo, wakefulness-promoting agents (modafinil and armodafinil) resulted in a decreased ESS score by 2.5 points, increased sleep latency in the maintenance of wakefulness test (MWT) by 2.7 minutes, and increased the reporting of minimal improvement on the Clinical Global Impression of Change scale (CGI-C) by 26 percent (CGI-C is a scale of symptom improvement reported by clinicians at follow-up) [23]. There was a trend for decreased continuous positive airway pressure (CPAP) use with treatment that was not significant. Another meta-analysis showed similar results [25].
●A double-blind crossover trial randomly assigned 157 patients with OSA who had persistent daytime sleepiness despite adequate conventional therapy to receive modafinil (titrated upward from 200 to 400 mg) or placebo once daily for four weeks [22]. EDS resolved in a greater proportion of patients in the modafinil group than in the placebo group (51 versus 27 percent), as measured by the ESS. A subsequent analysis that pooled data from this trial with data from another trial [22,33], found that modafinil improved productivity, activity, and vigilance compared with placebo [36].
●Armodafinil appears to be similarly effective, according to randomized trials [24,37,38]. In one randomized trial, armodafinil resulted in an increase in the MWT sleep latency by 2.3 minutes compared with a reduction by 1.3 minutes in the placebo group. Armodafinil also improved the CGI-C (7 versus 53 percent), episodic secondary memory, patient-estimated wakefulness, and fatigue compared with placebo. Armodafinil did not adversely affect nocturnal CPAP use. Armodafinil was found in another randomized trial to improve driving task performance at three months but not at six months; the ESS score, however, did not change [38].
It is believed that modafinil and armodafinil act on the central nervous system to enhance alertness. Most likely, these medications enhance dopamine signaling, but the precise mechanism of effect is unknown.
Solriamfetol — Solriamfetol is an oral selective dopamine and norepinephrine reuptake inhibitor with wake-promoting effects. Solriamfetol has been shown to improve wakefulness in patients with narcolepsy [39] and in patients with residual sleepiness in OSA despite CPAP therapy [20,21,40]. Solriamfetol at the 150 mg dose was approved by the US Food and drug Administration (FDA) and by the European Commission for use for both populations. The higher dose of 300 g daily is not approved due to an observed dose-dependent increase in the mean blood pressure and heart rate. Side effects, are similar to modafinil [41]. Detailed descriptions of these studies are provided separately. (See "Treatment of narcolepsy in adults", section on 'Solriamfetol'.)
Solriamfetol has not been compared with other agents, and patients should be monitored in a similar fashion to those taking modafinil or armodafinil. (See 'Follow up' below.)
Other agents — Other stimulants such as amphetamines or methylphenidate have been used occasionally, but published data to support their use are nonexistent. In addition, their side effect profile prohibits their routine use; serious adverse effects include systemic and pulmonary hypertension, tachycardia, loss of appetite, mood changes, tolerance, and addiction.
Although caffeine intake is generally higher in patients with OSA than in those without OSA [42], one trial in healthy individuals showed that high doses of caffeine (600 mg) were required for maintaining alertness during sleep deprivation. Although alertness was similar to that achieved with 200 or 400 mg of modafinil, side effects were commonly reported with caffeine and the long term effects of this degree of caffeine is unknown.
Pitolisant, a selective histamine receptor-3 antagonist has also been studied and further data and regulatory approvals are pending before it can be routinely administered:
●One study preliminarily investigated a randomized (3:1) trial of 268 patients with OSA who declined or were non-adherent to CPAP [43]. Pitolisant resulted in a reduction in the ESS score and the Pichot fatigue score when compared with placebo. Performance on the Maintenance of Wakefulness Test was not improved. Adverse effects were no different between the groups and no significant cardiovascular side effects were reported.
●The effect of pitolisant in OSA patients with residual daytime sleepiness who are adherent to CPAP was studied in 244 patients who were randomized to pitolisant or placebo [44]. Pitolisant reduced the ESS compared with placebo (-2.6). In addition, the rate of responders to pitolisant therapy, as defined by an ESS ≤10 or change in ESS ≥3, was higher with pitolisant than placebo (71 versus 54 percent). Adverse effects were higher with pitolisant (eg, headache, insomnia) but no serious cardiovascular effects were reported.
Follow up — Within the first two weeks, patients should be evaluated for efficacy, adverse effects, and adherence to their primary therapy (eg, effect on CPAP or mandibular advancement device use). A response should be noticed within a few days of initiation and titrated within the subsequent four to six weeks, at which point a decision should be made about continuing or discontinuing therapy.
●Assessment of efficacy is focused on the subjective sense of improved wakefulness and the ESS score (calculator 1). Patients generally report improvement within days of starting therapy or increasing a dose. Medications can be titrated according to the response. (See 'Dosing' above.)
●Side effects may also be noted during this period. Specifically, clinicians should ask about cardiovascular side effects such as chest pain and hypertension. Some adverse effects may be late and occur weeks after initiation (eg, rashes). (See 'Side effects' above.)
●Patients should be encouraged to continue to use their primary mode of OSA therapy (eg, positive airway pressure [PAP] therapy or mandibular advance devices). Some studies suggest that reduced daytime sleepiness due to modafinil therapy prompts patients to reduce their use of CPAP [31,32], while other studies suggest that modafinil does not alter CPAP use [22,33].
Treatment of comorbidities — In patients with adequately-treated OSA who have residual sleepiness, maximizing therapy for comorbid diseases that can affect sleep including obesity, depression, anxiety, diabetes, hypothyroidism, alcoholism, and anemia is appropriate. Care should be taken when selecting medications for mood disorders since some antidepressants, for example, can interfere with sleep or cause weight gain (eg, mirtazapine). Working with a psychiatrist for medication selection is suggested. (See "Unipolar major depression in adults: Choosing initial treatment" and "Diagnostic approach to anemia in adults" and "Treatment of primary hypothyroidism in adults" and "Obesity in adults: Overview of management".)
FUTURE THERAPIES — Several molecules are potential candidates for the promotion of wakefulness. These include agents that target inflammatory cytokines (eg, etanercept) [45] and agents that target the orexin/hypocretin system [46].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sleep-related breathing disorders in adults".)
SUMMARY AND RECOMMENDATIONS
●While most patients with obstructive sleep apnea (OSA) experience improved sleep quality and alertness in response to treatment with positive airway pressure (PAP) therapy or other modalities, a small proportion of patients continue to experience residual symptoms of excessive daytime sleepiness (EDS). (See 'Introduction' above.)
●Residual excessive sleepiness (RES) in patients with OSA refers to the subjective complaint of EDS that is present even when breathing and oxygenation parameters during sleep are normalized by successful OSA therapy. EDS is defined as the inability to maintain wakefulness and alertness during the major waking episodes of the day, with sleep occurring unintentionally or at inappropriate times. The pathogenesis of RES is poorly understood and likely multifactorial (eg, sleep fragmentation, abnormal sleep architecture, activation of the hypothalamic pituitary adrenal axis, chronic inflammation). (See 'Definition and pathogenesis' above.)
●Residual sleepiness is reported by approximately 6 to 14 percent of patients with adequately treated OSA. Risk factors for residual sleepiness are not well defined but may include severe EDS at presentation, younger age, lower mean duration of continuous PAP (CPAP) usage, side effects from CPAP usage, select sleep-related parameters (eg, reduced nocturnal sleep latency, periodic limb movement), and depression. (See 'Prevalence' above.)
●Clinical evaluation of residual daytime sleepiness in patients with OSA who are receiving therapy usually starts with ensuring that the diagnosis of OSA is correct. We typically reassess patients for the symptoms of OSA and review diagnostic data from home or in-laboratory devices (ie, polysomnography). (See 'Revisit the diagnosis' above and "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)
When the diagnosis of OSA is assured, we suggest the following (algorithm 1):
•Patients should be assessed for adherence to their therapy by questioning them (and their bed partner) directly regarding frequency and duration of device use and, for those on PAP, by interrogating device data which records hours of nightly use, effectiveness, and airway leak. Obtaining information via telemonitoring may also be useful. (See "Assessing and managing nonadherence with continuous positive airway pressure (CPAP) for adults with obstructive sleep apnea".)
•Patients should also be evaluated for alternative causes of EDS, including insufficient sleep, EDS due to depression, medication side effects, and comorbid medical and psychiatric disorders (table 1). In most cases, ruling out other significant causes of EDS is determined by history and examination and obtaining a self-reported sleep diary from the patient. Further testing including multiple sleep latency testing and laboratory tests (eg, blood count, thyroid function tests, testosterone level, iron studies, Epstein-Barr virus antibodies) may be performed depending upon the suspicion for specific etiologies. (See 'Exclude alternative etiologies' above and "Approach to the patient with excessive daytime sleepiness", section on 'Initial evaluation'.)
•If inadequate therapy is suspected or no alternative explanations can be found, we typically prefer to perform in-laboratory sleep testing (with the patient wearing their device) to formally assess the adequacy of primary therapy. Alternatively, home sleep apnea testing while using their device (eg, WatchPAT) is also an option. For patients deemed to have inadequate therapy, reasons for persistently abnormal parameters should be sought. This includes weight gain, a poorly fitting mandibular device, inadequate CPAP titration leading to residual respiratory events, CPAP mask or mouth leaks, and treatment-emergent central sleep apnea. (See 'Evaluate adequacy of therapy' above.)
•When patients with adequately-treated OSA in whom alternative etiologies for EDS have been excluded still complain of burdensome EDS, residual sleepiness is of unclear etiology and patients may be eligible for adjunctive pharmacotherapy with a wakefulness-promoting agent. (See 'Diagnosis' above and 'Definition and pathogenesis' above.)
●Adjunctive pharmacotherapy for residual sleepiness in patients with adequately-treated OSA is controversial, and the level of daytime sleepiness at which a trial of stimulant therapy is warranted has not been well-defined. We typically use the patient’s subjective symptoms and an Epworth Sleepiness scale score ≥10 (calculator 1) to identify suitable candidates. (See 'Treatment' above.)
•For patients with adequately-treated OSA who have persistent, burdensome daytime sleepiness in whom alternative causes of daytime sleepiness have been excluded, we suggest a four to six-week trial of a wakefulness-promoting agent (Grade 2C). Randomized trials have demonstrated improved objective and subjective measures of daytime sleepiness with these agents in this population compared with placebo. However, this benefit may occur at the expense of adverse effects including headache, nausea, dry mouth, anorexia, back pain, anxiety, insomnia, rhinitis, diarrhea, rash (including Stevens-Johnson syndrome and toxic epidermal necrolysis), and hypertension. (See 'Wakefulness promoting agents' above and 'Patient selection' above and 'Efficacy' above.)
•Among the available agents, we suggest agents that have demonstrated efficacy in randomized placebo-controlled trials (Grade 2C). These include modafinil, armodafinil, or solriamfetol. Choosing among these three agents is individualized and depends upon physician and patient preference as well as cost, and the presence of cardiovascular conditions. Alternatives are limited. Other stimulants such as amphetamines or methylphenidate have been used occasionally. However, there are no data to support their efficacy and the side effect profile often prohibits their routine use (eg, systemic and pulmonary hypertension, tachycardia, loss of appetite, mood changes, tolerance, and addiction). Caffeine and pitolisant are other options, but experience is even more limited. (See 'Modafinil and armodafinil' above and 'Solriamfetol' above and 'Other agents' above.)
•Within the first two weeks, patients should be evaluated for efficacy, adverse effects, and adherence to their primary therapy (eg, effect on CPAP or mandibular advancement device use). A response should be noticed within a few days of initiation and titrated within the subsequent four to six weeks, at which point a decision should be made about continuing or discontinuing therapy. (See 'Follow up' above.)
●In patients with adequately-treated OSA who have residual sleepiness, maximizing therapy for comorbid diseases that can affect sleep including obesity, depression, anxiety, diabetes, hypothyroidism, alcoholism, and anemia is appropriate. (See 'Treatment of comorbidities' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Charles W Atwood, Jr, MD, who contributed to an earlier version of this topic review.
