Real-world clinical outcomes of daridorexant in chronic insomnia disorder refractory to previous pharmacological treatment

Chronic insomnia disorder (CID) is among the most prevalent sleep-wake disorders worldwide and is associated with substantial functional impairment, including daytime fatigue, cognitive dysfunction, affective disturbances, and diminished quality of life. CID is defined by persistent difficulty initiating or maintaining sleep, or early-morning awakening with inability to resume sleep, occurring at least three times per week for ≥3 months. CID frequently co-occurs with psychiatric and medical comorbidities. Conventional pharmacological treatments, including benzodiazepines, non-benzodiazepine hypnotics, and sedating antidepressants, are often limited by concerns regarding tolerance, dependence, residual sedation, and cognitive adverse effects. Dual orexin receptor antagonists (DORAs) have emerged as a novel therapeutic strategy targeting the neurobiological mechanisms underlying hyperarousal. Daridorexant, a selective antagonist of orexin-1 and orexin-2 receptors, promotes sleep by attenuating wake-promoting signaling without inducing generalized central nervous system depression. Randomized clinical trials have demonstrated its efficacy and favorable safety profile; however, real-world evidence remains limited.

Objectives: To evaluate the real-world effectiveness and tolerability of daridorexant in patients diagnosed with CID refractory to previous pharmacological treatments, using validated patient-reported outcome measures.

Methods: A prospective, multicentre, real-world study was conducted over a 6-month period in a consecutive non-probabilistic sample of patients treated at Infanta Elena University Hospital, Madrid and at Santa Lucía University Hospital, Cartagena. All patients initiating daridorexant for clinically diagnosed CID were included. Treatment response was assessed using the Insomnia Severity Index (ISI) and the PROMIS Sleep Disturbance (SD) scale at basal and months 1, 3 and 6. Additional data regarding adverse events and concomitant psychopharmacological treatments were collected. Changes in concomitant medication burden were assessed through comparison of defined daily doses (DDDs) before and after daridorexant initiation. Data were analyzed using SPSS version 20.0 (IBM Corp., Armonk, NY, USA). Distribution normality was assessed using the Shapiro–Wilk test. Changes in ISI and PROMIS SD scores from baseline to follow-up were analyzed using paired-samples t-tests or Wilcoxon signed-rank tests, as appropriate. Two-tailed p values < 0.05 were considered statistically significant.

Results: 42 patients (76% women), mean age 52.7± 2.6 years were included. The mean daily dose of daridorexant was (45.8± 3.9mg). A clinically meaningful improvement was observed after treatment with daridorexant, reflected by a reduction in ISI total scores (19.4±3.8 vs 11.2±4.1; p < 0.001) and in PROMIS SD scores (67.3±5.4 vs 58.1±6.2; p<0.001) indicating decreased insomnia severity and improved sleep quality. A significant reduction in concomitant psychopharmacological burden was observed following daridorexant after 6 months, as reflected by lower cumulative DDDs (2.1±1.1 vs 1.4±0.9; p=0.03). This reduction was primarily driven by decreased use of benzodiazepines, suggesting a potential sparing effect of daridorexant on conventional hypnotic treatment. Mild adverse events were reported in 13.3% of patients, with no serious adverse events.

Conclusions: daridorexant was associated with significant improvements in insomnia severity and sleep-related outcomes as assessed by validated patient-reported measures. The treatment demonstrated an excellent tolerability profile, supporting its utility as an effective therapeutic option for chronic insomnia in routine clinical practice. Prospective longitudinal studies with larger samples are warranted to further characterize its long-term effectiveness and safety.

References

No references