Orexin: The New Kid on the Insomnia Block

CONFERENCE REPORTER

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Dual orexin receptor antagonists (DORAs), the newest kid on the insomnia treatment block, do not adversely effect sleep architecture, explained Paul P. Doghramji, MD, at the 2023 Annual Psychiatric Times™ World CME Conference. He also explained DORAs do not have rebound insomnia, tolerance issues, or withdrawal symptoms. Doghramji, Senior Family Physician at Collegeville Family Practice, told attendees how orexins work, and then reviewed the currently available DORAs.

Paul Doghramji, MD

Suvorexant was the first DORA on the market, approved in 2014 for difficulties with sleep onset and/or maintenance, he said. Available in 5, 10, 15, and 20 mg doses, Doghramji finds most patients do best at the 20 mg dose but suggested starting with the 10 mg dose. It has a half-life of 15 hours and a Tmax of 2 hours. The most common adverse effects in trials were somnolence, headache, abnormal dreams, dry mouth, cough, and upper respiratory infection. Interestingly, the adverse events rate were in a 2 to 1 ratio of women to men, Doghramji explained. There were no differences in psychomotor or morning driving performance when compared with placebo. Doghramji shared highlights of an interesting study, in which there were significant improvements in both total sleep time and wake after sleep for patients with insomnia and mild to moderate Alzheimer in the suvorexant group as compared with the placebo group.¹

Next on the scene was lemborexant, Doghramji said, which was approved for difficulties with sleep onset and/or maintenance. It is available in 5 mg and 10 mg doses; Doghramji noted it is better to start with the 5 mg dose, and if the desired effect is not realized, move to the higher dose. Lemborexant has more effect on orexin 2 than orexin 1, he explained, with a Tmax of 1-3 hours and a half-life of 17-19 hours. Doghramji noted that because it induces CYP2B6, which impacts the area under the curve for bupropion, patients on both drugs will need a higher dose of bupropion. The most common adverse effects in trials were somnolence/fatigue, he said. Doghramji noted research indicates it is safe in mild obstructive sleep apnea, and no difference in middle of the night auditory awakening threshold or morning cognitive performance, body sway, and driving performance when compared with placebo. In one study, lemborexant showed an improvement in sleep latency to persistent sleep almost as good if not better than zolpidem.² In addition to sustained efficacy, he also explained patients reported improved fatigue during the day, which he said is an important indicator of treatment success.^3,4

Approved in 2022, daridorexant is the most recent DORA approved for difficulties with sleep onset and/or maintenance, Doghramji said. Daridorexant is available in 25 mg and 50 mg doses. It has a Tmax of 1-2 hours and a half-life of 8h, which he noted is about half that of the other DORAs. Compared to placebo after 4 days of treatment there was no morning driving impairment, and he said safety as been demonstrated in mild obstructive sleep apnea and moderate chronic obstructive pulmonary disease. Interestingly, the most common adverse effects are nasopharyngitis and headache, he said, but somnolence and fatigue were also reported.

In addition to improving latency to persistent sleep and wake after sleep onset, Deradoorian was found to improve daytime function, Doghramji told attendees. He explained the Insomnia Daytime Symptoms and Impacts Questionnaire was created and validated according to FDA guidelines to assess and evaluate daytime functioning in individuals with insomnia disorder. At the 50 mg dose daridorexant improved the IDSIQ sleepiness domain at months 1 and 3, with clinically meaningful at month 3.^5,6

Doghramji told attendees there are 2 emerging DORAs: seltorexant and vornorexant. Seltorexant is a selective orexin-2 receptor antagonist and is currently in phase 3 trials as an adjunctive therapy to antidepressants for patients with major depressive disorder and insomnia symptoms, he said. On the other hand, vornorexant is a balanced dual orexin antagonist that showed significant improvement in sleep latency to persistent sleep and wake after sleep onset.

Visit PsychiatricTimes.com regularly for more breaking news from the 2023 Annual Psychiatric Times™ World CME Conference. Email us at PTEditor@mmhgroup.com if you would like to share your thoughts and insights gleaned from this or other conferences.

References

1. Herring WJ, Ceesay P, Snyder E, et al. Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial. Alzheimers Dement. 2020;16(3):541-551.

2. Rosenberg R, Murphy P, Zammit G, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial JAMA Netw Open. 2019;2(12):e1918254. Published 2019 Dec 2.

3. Kärppä M, Yardley J, Pinner K, et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep. 2020;43(9):zsaa123.

4. Chepke C, Jain R, Rosenberg R, et al. Improvement in fatigue and sleep measures with the dual orexin receptor antagonist lemborexant in adults with insomnia disorder. Postgrad Med. 2022;134(3):316-325.

5. Mignot E, Mayleben D, Fietze I, et al. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials .Lancet Neurol. 2022;21(2):125-139.

6. Hudgens S, Phillips-Beyer A, Newton L, Seboek Kinter D, Benes H. Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Patient. 2021;14(2):249-268.