Purpose <p>Orexin receptor antagonists (ORAs) are a novel class of medications used in the treatment of insomnia. With increasing restrictions on benzodiazepine prescriptions, a rise in ORA overdose is expected. To enable the prediction of clinical severity and formulation of appropriate treatment strategies, we developed a rapid analytical method for detecting ORAs in plasma samples using a Monolithic solid-phase extraction (SPE) and gas chromatography-mass spectrometry (GC–MS).</p> Method <p>Extraction was performed using MonoTip C18. All steps from pretreatment to elution were conducted using centrifugation. Quantification was carried out using GC–MS with temperature-programmed analysis by positive ion electron ionization, using suvorexant-<i>d</i>₆ as the internal standard. The method was applied to plasma samples from actual ORA overdose cases to evaluate its practical applicability.</p> Result <p>The calibration curves demonstrated excellent linearity over the range of 10–2,000&#xa0;ng/mL, with correlation coefficients of at least 0.9999. Reproducibility showed a coefficient of variation (CV) between 0.6% and 6.9%, and recovery rates were over 83%. ORA concentrations in overdose patient samples were successfully quantified using this method.</p> Conclusion <p>MonoTip C18 utilizes a reduced amount of solvent, thereby eliminating the need for evaporation-to-dryness steps. As a result, the entire procedure, encompassing SPE to GC–MS detection, can be completed within 40&#xa0;min. This single protocol is applicable to all ORAs currently available in Japan and is suitable for both clinical and forensic toxicological applications.</p>