“I need to sleep. I can’t get no sleep.”
— Insomnia, Faithless
Insomnia is an insidious condition. The late Maxi Jazz of Faithless captured its frustration perfectly in their 1995 track Insomnia. Most of us have found ourselves, at some point, desperately wanting to sleep. Yet there is a cruel paradox to insomnia: the more desperately we want sleep to come, the more elusive it seems to become.
We spend around a third of our lives sleeping, and most adults need 7–9 hours of good-quality sleep each night. For many people, however, this is more dream than reality. A study published in 2024, using data from more than 160,000 UK Biobank participants in England, found that 29% reported usually experiencing symptoms of insomnia. The participants were aged 38–71 when assessed, and the data were collected in 2006–2010.1
How we define insomnia is important here. An occasional bad night is different from insomnia disorder. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines this as difficulty sleeping at least three nights a week for at least three months, despite having enough opportunity to sleep, with significant distress or impairment in everyday functioning. The National Institute for Health and Care Excellence (NICE) cites a survey estimate that around one in fourteen UK adults meets these criteria.2
It is tempting to think of insomnia as a modern affliction, brought on by hectic lifestyles, social media and smartphones. Sleeplessness has almost become a metaphor for the pressures of modern life — lying awake while our minds refuse to switch off. The scale of the problem is enormous, and its effects extend well beyond the dark hours. Insomnia can affect how we feel, think and function the following day. It is more than an inconvenience; it is an important public health problem in its own right.2
Many medicines have been used to treat insomnia over the years. Benzodiazepines and the so-called Z-drugs, including zopiclone and zolpidem, boost the action of GABA (gamma-aminobutyric acid), a chemical messenger that makes nerve cells less likely to fire, helping to calm the mind and promote sleep. Sedating antihistamines such as promethazine (Phenergan) work differently, blocking the action of histamine, which helps keep us awake. The downside will be familiar to people who have taken them: their effects may linger into the following day, leaving you drowsy, groggy and feeling as though you’ve done a few rounds with Tyson Fury.3
Perhaps the most extreme example was Michael Jackson. Suffering from chronic insomnia, Jackson was given propofol — a powerful intravenous general anaesthetic normally used for procedures and surgery — by his personal physician in an attempt to make him sleep. On 25 June 2009, Jackson died from acute propofol intoxication, with benzodiazepines also contributing. His death was a tragic reminder of how desperate the search for sleep can become, and how dangerous some attempts to induce it can be.
Medicines are only part of the picture. Cognitive behavioural therapy for insomnia, or CBT-I, is the recommended first treatment for long-term insomnia. It addresses the thoughts and habits that can keep the problem going, although access to it remains uneven.2
A breakthrough in our understanding of sleep came in the late 1990s with the discovery of orexin, a pair of neuropeptides produced by neurons in the lateral hypothalamus of the brain. Orexin binds to two receptors, OX₁R and OX₂R, and has a key role in maintaining wakefulness. This introduced a potentially new approach to treating insomnia. If the action of orexin could be blocked by introducing a molecule to prevent it binding, the wakefulness dial could be turned down without broadly suppressing brain activity. In other words, instead of trying to force the brain to sleep with sedatives, remove one of the signals telling it to stay awake.3
As a scientist, I’m acutely aware that a lot of important discoveries are made by chance. And the orexin story is one of these.
In 1998, Dr Masashi Yanagisawa, a Japanese-American molecular biologist, thought he might have discovered a new target for a weight-loss drug. His team had identified a new pair of peptides in the brain and named them orexins, from the Greek word for appetite. They then genetically engineered mice that couldn’t produce orexin, expecting them to eat less. At first, they didn’t seem to. So Yanagisawa started looking more closely at what the mice were actually doing. Mice are nocturnal, so he bought a Sony camcorder equipped with what was then the new “NightShot” infrared technology and used it to watch them in the dark.
In 1998, Dr Masashi Yanagisawa, a Japanese-American molecular biologist, thought he might have discovered a new target for a weight-loss drug. His team had identified a new pair of peptides in the brain and named them orexins, from the Greek word for appetite. They then genetically engineered mice that couldn’t produce orexin, expecting them to eat less. At first, they didn’t seem to. So Yanagisawa started looking more closely at what the mice were actually doing. Mice are nocturnal, so he bought a Sony camcorder equipped with what was then the new “NightShot” infrared technology and used it to watch them in the dark.
At around the same time, a completely separate line of research was leading in the same direction. Dr Emmanuel Mignot, a sleep researcher at Stanford, had spent years studying narcolepsy in dogs. In 1999, his group identified a mutation in the gene coding for the OX₂R orexin receptor.
The two discoveries clicked neatly into place. Mice that couldn’t produce orexin developed narcolepsy, and dogs with a defective orexin receptor also developed narcolepsy. Orexin was clearly playing an important role in keeping the brain awake.3
For insomnia researchers, this raised an obvious question. Could you temporarily block the same signalling in someone who has difficulty falling or staying asleep? In principle, you would need a drug that blocked the orexin system during the night and then wore off by morning. In practice, finding one was much more difficult.
Among those pursuing the idea were scientists at the Swiss biotechnology company Actelion, founded by the husband-and-wife scientists Jean-Paul and Martine Clozel and their colleagues in 1997. The company began investigating the orexin system soon after its discovery. When Actelion was acquired by Johnson & Johnson in 2017, its drug-discovery operation and early-stage pipeline were spun out into a new company, Idorsia. Importantly, the orexin programme went with it. By then, after years of medicinal chemistry, the researchers had already selected a promising molecule known simply as ACT-541468. That molecule would eventually become daridorexant.4
Getting to that point had been a daunting medicinal-chemistry challenge. The aim was not simply to find a molecule that blocked orexin receptors, but one with the right properties: it needed to enter the brain rapidly (not an easy task), block both OX₁R and OX₂R receptors for long enough to cover a night’s sleep (around 8 hours), and then disappear sufficiently quickly to minimise next-day effects. According to Idorsia, the research programme involved the synthesis of more than 25,000 compounds before the team eventually arrived at daridorexant.
Marketed as Quviviq, daridorexant was approved in the United States in January 2022, followed by the European Union in April 2022 and subsequently Great Britain. It launched in the UK in October 2023.4
Daridorexant belongs to a class of insomnia medicines known as dual orexin receptor antagonists, or DORAs. There are two orexin receptors in the brain, OX₁R and OX₂R, and daridorexant blocks both — hence the term “dual”. By preventing orexin from activating these receptors, it turns down the signalling that helps keep us awake, making it easier for sleep to occur.3
So how well does it work? At three months in one of the main trials, sleep-lab measurements showed that people taking 50 mg daridorexant fell asleep an average of about 12 minutes sooner and spent about 18 minutes less awake during the night than those taking placebo. Patient-reported daytime sleepiness also improved compared with placebo.5
Sleep time is obviously important, but it’s not the whole story. How well people feel they have slept, and how they function the next day, matter too. A follow-up study suggests that the benefits can persist with continued treatment. Participants were followed for up to a year, although the longer-term findings were exploratory.²˒³
Daridorexant is not a cure for insomnia, and it won’t work for everyone. But it does represent a very different way of thinking about the problem. Rather than broadly suppressing brain activity, it targets one of the systems that keeps us awake.
And finally, if daridorexant doesn’t help, please check out some of my other blog posts and I’m sure sleep will come.
Sweet dreams.
References:
1. de Lange MA, Richmond RC, Eastwood SV, Davies NM. Insomnia symptom prevalence in England: a comparison of cross-sectional self-reported data and primary care records in the UK Biobank. BMJ Open. 2024;14: e080479. BMJ
2. NICE. Daridorexant for treating long-term insomnia. Technology appraisal guidance TA922. 18 October 2023. Recommendations, committee discussion and accompanying resource impact report (section 4.1). NICE Report
3. Muehlan C, Roch C, Vaillant C, Dingemanse J. The orexin story and orexin receptor antagonists for the treatment of insomnia. Journal of Sleep Research. 2023;32(6):e 13902. Journal of Sleep Research
4. Idorsia. Daridorexant. Research programme and regulatory history. Accessed 30 September 2026. Idorsia
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 Neurology. 2022;21(2):125–139. Lancet Neurology