Suvorexant

First-approved DORA (Merck 2014, FDA-cleared, AASM-recommended), with the deepest post-market dataset of the class — and the longest half-life (~12 hr) of the three approved DORAs, which translates to measurably more next-day grogginess than daridorexant (8 hr) without proportionally better sleep effects. For Dylan: SKIP-FOR-NOW. He doesn't have insomnia, and if a DORA is ever needed, daridorexant is the better-fit tool for a brain-priority 20yo. The one genuine future-interest signal: Lucey 2023 showed suvorexant lowered CSF amyloid-β in healthy older adults overnight — preliminary, single small trial, healthy 50-70yo population, NOT a Dylan-relevant decision input today, but worth tracking for a 30-year-AD-prevention thesis.

Suvorexant is a competitive, reversible antagonist at both orexin receptors (OX1 and OX2) — the original "DORA," and the molecule that proved the orexin-blockade mechanism could be commercialized for insomnia.

The orexin system in plain English: Orexin (also called hypocretin) is a hypothalamic neuropeptide that functions as the brain's "stay awake" master switch. Orexin neurons in the lateral hypothalamus fire vigorously during wakefulness, fall silent during sleep, and project to every wake-promoting nucleus — locus coeruleus (norepinephrine), tuberomammillary nucleus (histamine), raphe (serotonin), VTA (dopamine), basal forebrain (acetylcholine). Block orexin and the wake systems lose their drive; sleep is permitted, not forced.

Two receptor subtypes:

• OX1 (HCRTR1): preferential for orexin-A, concentrated in locus coeruleus → arousal/vigilance/sympathetic tone.
• OX2 (HCRTR2): binds both orexin-A and orexin-B, concentrated in tuberomammillary nucleus → wakefulness/histamine cascade. OX2 blockade is the dominant sleep-promoting pathway.

Suvorexant-specific PK features:

• Half-life ~12 hours (median 12, range 9-15). This is the central separator from daridorexant (8 hr) and the central similarity to lemborexant (17-19 hr — actually longer). 12 hr means significant overlap into the morning, especially in users dosed late or in CYP3A4-slow phenotypes.
• Tmax ~2 hours (delayed by food — high-fat meals push Tmax to ~3.5 hr and reduce Cmax modestly; Merck label says take on empty stomach).
• CYP3A4 dominant metabolism (>95%) with minor CYP2C19 contribution. Two main hydroxy metabolites (M9 and M17), both inactive.
• Highly protein-bound (~99.5%) — dosing not affected by typical protein-binding shifts but theoretically relevant in severe hypoalbuminemia.
• No clinically significant active metabolites at therapeutic doses.

Architecture: PSG studies show suvorexant preserves REM and N3 sleep (similar to daridorexant), distinguishing it from Z-drugs/benzos which suppress both. This is the mechanistic core of why DORAs are class-superior for brain-priority users — the type of sleep is preserved, not just the quantity.

Why suvorexant is the "old" DORA: Approved August 2014 (FDA), first-in-class, developed by Merck. The 12-hour half-life reflects the original engineering target — Merck wanted "lasts the night" without realizing the next-day cognitive cost would become a market vulnerability when Eisai (lemborexant 2019, 17-19 hr — even worse) and Idorsia (daridorexant 2022, 8 hr — the answer) entered the class. Suvorexant has the longest real-world data tail (~12 years post-market), the most insurance coverage, and the lowest cash price after generics began appearing in late 2024 / early 2025 — but the cognitive-cost profile is the worst-of-three on the dimension Dylan cares about.