Background and objectives Residual sleepiness can occur in adult patients with obstructive sleep apnea (OSA) despite adequate treatment with continuous positive airway pressure (CPAP). Various wake-promoting agents (WPAs) have been shown to reduce residual sleepiness in CPAP-treated patients with OSA. This systematic review and network meta-analysis aimed to compare the efficacy and safety of WPAs in this setting. Methods We searched MEDLINE, Scopus, and ClinicalTrials.gov up to 9 January 2025 for randomized controlled trials (RCTs) examining WPAs for treating sleepiness in patients with OSA. Included were all RCTs that explored the efficacy and/or safety of any approved WPAs (i.e., modafinil, armodafinil, solriamfetol, or pitolisant) in patients with OSA (aged <InlineEquation ID="IEq1"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="40263_2025_1175_Article_IEq1.gif" Format="GIF" Height="15" Rendition="HTML" Resolution="72" Type="Linedraw" Width="19" /> </InlineMediaObject> <EquationSource Format="TEX">$\ge$</EquationSource> <EquationSource Format="MATHML"><math> <mo>≥</mo> </math></EquationSource> </InlineEquation> 18 years) treated with CPAP but who are still sleepy [Epworth sleepiness scale (ESS) score ≥10]. Studies that were conducted in patients whose comorbidities cause daytime somnolence [i.e., psychiatric conditions (other than depression), other sleep disorders, medical or surgical conditions], open label extension studies, and studies published in a language other than English were excluded. The primary outcomes included ESS, maintenance of wakefulness test (MWT), and adverse events. Two authors independently assessed the risk of bias using the revised Cochrane risk-of-bias tool for randomized trials 2.0. Results In total, 14 RCTs studying four WPAs (total N = 2969) including modafinil (six RCTs; 200–400 mg/day), armodafinil (four RCTs; 150–250mg/day), solriamfetol (two RCTs; 37.5–300 mg/day), and pitolisant (two RCTs; 5–40 mg/day) were included. Solriamfetol, modafinil, and armodafinil were efficacious in reducing subjective sleepiness as measured by ESS [mean difference (95% confidence interval) at <InlineEquation ID="IEq2"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="40263_2025_1175_Article_IEq2.gif" Format="GIF" Height="15" Rendition="HTML" Resolution="72" Type="Linedraw" Width="19" /> </InlineMediaObject> <EquationSource Format="TEX">$\le$</EquationSource> <EquationSource Format="MATHML"><math> <mo>≤</mo> </math></EquationSource> </InlineEquation> 4 weeks: −3.84 (−5.60, −2.07), −2.44 (−3.38, −1.49), and −2.41 (−3.60, −1.21) for solriamfetol, modafinil, and armodafinil, respectively; at > 4 weeks: −4.11 (−6.14, −2.08), −2.88 (−3.85, −1.91), −2.46 (−3.68, −1.24) for solriamfetol, armodafinil, and modafinil, respectively] and clinical global impression of change, as well as the objective MWT [at <InlineEquation ID="IEq3"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="40263_2025_1175_Article_IEq3.gif" Format="GIF" Height="15" Rendition="HTML" Resolution="72" Type="Linedraw" Width="19" /> </InlineMediaObject> <EquationSource Format="TEX">$\le$</EquationSource> <EquationSource Format="MATHML"><math> <mo>≤</mo> </math></EquationSource> </InlineEquation> 4 weeks: 11.66 min (9.70, 13.61), 3.61 min (2.48, 4.73), and 2.52 min (1.27, 3.76) for solriamfetol, modafinil, and armodafinil, respectively; at > 4 weeks: 10.34 min (4.16, 16.52) for solriamfetol]. Pitolisant showed later improvements in ESS [at > 4 weeks: −2.70 (−3.66, −1.73)], with limited data on MWT. Sensitivity analyses restricted to U.S. Food and Drug Administration-approved solriamfetol dosages (37.5–150 mg/day) still showed higher efficacy, but lower anxiety risk. Conclusions Among all WPAs, solriamfetol demonstrated the highest efficacy on ESS and MWT, with the latter being significant. Modafinil demonstrated the best clinician impression, albeit not statistically significant. All four WPAs were associated with a low risk of serious or adverse events. Registration PROSPERO registration number, CRD42022359237

Comparative Efficacy and Safety of Multiple Wake-Promoting Agents for the Treatment of Residual Sleepiness in Obstructive Sleep Apnea Despite Continuous Positive Airway Pressure: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

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2025年4月10日

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Pongsakorn Tanayapong,
Visasiri Tantrakul,
Somprasong Liamsombut,
Sukanya Siriyotha,
Gareth McKay,
John Attia,
Ammarin Thakkinstian

摘要

Background and objectives

Residual sleepiness can occur in adult patients with obstructive sleep apnea (OSA) despite adequate treatment with continuous positive airway pressure (CPAP). Various wake-promoting agents (WPAs) have been shown to reduce residual sleepiness in CPAP-treated patients with OSA. This systematic review and network meta-analysis aimed to compare the efficacy and safety of WPAs in this setting.

Methods

We searched MEDLINE, Scopus, and ClinicalTrials.gov up to 9 January 2025 for randomized controlled trials (RCTs) examining WPAs for treating sleepiness in patients with OSA. Included were all RCTs that explored the efficacy and/or safety of any approved WPAs (i.e., modafinil, armodafinil, solriamfetol, or pitolisant) in patients with OSA (aged $\ge$ $\geq$ 18 years) treated with CPAP but who are still sleepy [Epworth sleepiness scale (ESS) score ≥10]. Studies that were conducted in patients whose comorbidities cause daytime somnolence [i.e., psychiatric conditions (other than depression), other sleep disorders, medical or surgical conditions], open label extension studies, and studies published in a language other than English were excluded. The primary outcomes included ESS, maintenance of wakefulness test (MWT), and adverse events. Two authors independently assessed the risk of bias using the revised Cochrane risk-of-bias tool for randomized trials 2.0.

Results

In total, 14 RCTs studying four WPAs (total N = 2969) including modafinil (six RCTs; 200–400 mg/day), armodafinil (four RCTs; 150–250mg/day), solriamfetol (two RCTs; 37.5–300 mg/day), and pitolisant (two RCTs; 5–40 mg/day) were included. Solriamfetol, modafinil, and armodafinil were efficacious in reducing subjective sleepiness as measured by ESS [mean difference (95% confidence interval) at $\le$ $\leq$ 4 weeks: −3.84 (−5.60, −2.07), −2.44 (−3.38, −1.49), and −2.41 (−3.60, −1.21) for solriamfetol, modafinil, and armodafinil, respectively; at > 4 weeks: −4.11 (−6.14, −2.08), −2.88 (−3.85, −1.91), −2.46 (−3.68, −1.24) for solriamfetol, armodafinil, and modafinil, respectively] and clinical global impression of change, as well as the objective MWT [at $\le$ $\leq$ 4 weeks: 11.66 min (9.70, 13.61), 3.61 min (2.48, 4.73), and 2.52 min (1.27, 3.76) for solriamfetol, modafinil, and armodafinil, respectively; at > 4 weeks: 10.34 min (4.16, 16.52) for solriamfetol]. Pitolisant showed later improvements in ESS [at > 4 weeks: −2.70 (−3.66, −1.73)], with limited data on MWT. Sensitivity analyses restricted to U.S. Food and Drug Administration-approved solriamfetol dosages (37.5–150 mg/day) still showed higher efficacy, but lower anxiety risk.

Conclusions

Among all WPAs, solriamfetol demonstrated the highest efficacy on ESS and MWT, with the latter being significant. Modafinil demonstrated the best clinician impression, albeit not statistically significant. All four WPAs were associated with a low risk of serious or adverse events.

Registration

PROSPERO registration number, CRD42022359237