Some articles on orexin and insomnia (I'm not a medic):

http://www.newscientist.com/article/mg19325894.900-narcolepsy-hints-at-drug-for-insomniacs.html

http://www.eurekalert.org/pub_releases/2007-10/plos-ifs101007.php

http://www.eurekalert.org/pub_releases/2010-09/nifp-wuy092110.php

http://www.cell.com/neuron/retrieve/pii/S0896627306003692

http://www.eurekalert.org/pub_releases/2006-05/cp-nme052506.php

http://www.biologynews.net/archives/2008/01/02/researchers_reverse_effects_of_sleep_deprivation.html

Regards,

Joachim

Interesting question, but I am afraid data available do not allow to accurately predict if orexin antagonization may provide remedy against insomnia or not. However, considering that the current knowledge indicates that orexin is involved in the control of the transition between sleep-wake states, and not in the drive (tendency, need) to sleep, my opinion is that antagonizing orexinergic signaling will lead to a direct transition from wakefulness to REM sleep (as observed in narcolepsy where orexin levels are very low compared to physiological levels). Such sleep will not be as physiological as normal sleep (that follows the sequence NREM-REM), and will probably affect brain circuitry, and have tremendous long term undesired effects. May be narcolepsy will be part of them.. So it would not be suitable to use orexin against insomnia. Besides, although the pathophysiology of insomnia is not well understood, I would consider molecules more linked to drive (tendency) to sleep (adenosine mostly).

Suvorexant is currently under review by the FDA in the United States as a sleep aid, following good results in stage III clinical trials. These orexin antagonists do increase total REM sleep time in several experiments, and some side effects related to that could include more hypnogogic hallucinations or sleep paralysis (but these haven't been reported in the data to my knowledge). The biggest question that remains is why orexin antagonism by almorexant or suvorexant does NOT cause cataplexy in any animal or human data released so far, unlike double orexin receptor mutants. It could be such a phenotype is hard to elicit in the lab (no emotionally charged components, for example), or it may be that drug antagonism is such a short-term, incomplete blockade that cataplexy is not developed. Maybe taking a high dose of suvorexant and then staying awake and going to a party could lead to a catapletic attack? Right now, that may be the biggest worry for these drugs, but there is no published evidence that cataplexy develops.

Have you noticed that none of the studies carried out so far in humans mentions the effects of these substances on REM sleep latency? I would be curious to know the data.

Treating insomnia in clinical trials and getting proper results is one thing, it's another to study the efficacy of such a novel drug in your everyday work. I am a little sceptical about its effects on patients with e.g. psychophysiological insomnia which account for a large portion of insomniacs.

I would also be curious about the effects of on sleep efficiency in narcoleptic patients, as paradoxical as it may sound at first?

A randomized clinical trial of Suvorexant, an Orexin (hypocretin) receptor antagonist for treatment of insomnia has provided Class I evidence that it improves sleep efficiency over 4 weeks in non-elderly adult patients. Suvorexant indeed provides a novel approach in treating insomnia.

I couldn't have access to the original data, but according to Medscape Medical News interview of Dr. Joseph Herring (http://www.medscape.com/viewarticle/775292) "a total of 228 patients completed the study... all doses of suvorexant were more effective than placebo for SE (average sleep efficiency) (P < .01)". Doesn't look very promising to me.. P

There is at least one recently published RCT entitled as: "Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men." http://www.ncbi.nlm.nih.gov/pubmed/23372274

that study included healthy individuals.

However, we as clinicians should be very cautious about its efficacy and adverse effects. when zoplidem was introduced, it had been emphasized about its safety and lack of dependency.

The dual orexin receptor antagonist (DORA) compounds suveroxant and almorexant which bind to the OX1R and OX2R receptors, antagonize hypothalamic orexin A or B and tend to block the stimulation of the brain's arousal system. These compounds are thought to present as a new class of insomnia treatments however, their wide use seem to be practiced with caution. Post marketing surveillance is expected to highlight details on their efficacy and safety in real life setting.

Moreover, something interesting is that chronic insomnia as well as inefficient sleep (in long run) are shown to potentially hasten the progress towards neurodegenerative disorders such as Alzheimer’s in potentially vulnerable brains. The role of orexin in promoting this process has recently been discussed in literature. In addition to the role of orexin antagonism in treating insomnia, the question whether antagonizing orexin receptors can be a possible future target to slowdown progression to Alzhiemer’s diseasein those at risk ( e.g. those with genetic predisposition) remains an interesting topic…

Anyway, these new medications seem to offer new options to treat insomnia with perhaps no / or minimal risk for dependence

DORAs could represent a significant breakthrough in the pharmacological treatment of insomnia but there are still grey areas regarding its safety. For instance, although cataplexy was not seen in clinical trials, a paper published in the March issue of Sleep report that almorexant in a murine model of narcolepsy. There were also evidence of REM sleep promoting effects of almorexant in healthy subjects as well as in insomniac patients (shortened REM latency and/or increase time spent in REM sleep). Another potential issue is weight gain (orexine decrease food intake). I was also surprised that surevoxant did not increase slow wave activity in the study performed in healthy subjects (the same was observed with SB649868 in a noise model of insomnia) I would be interested if anyone knows other papers who deal with the effects of DORAs on NREM sleep spectral power.

http://www.ncbi.nlm.nih.gov/pubmed/23449602

http://www.ncbi.nlm.nih.gov/pubmed/20376002

http://www.nature.com/clpt/journal/v91/n6/full/clpt2011370a.html

http://www.ncbi.nlm.nih.gov/pubmed/22237311

http://www.ncbi.nlm.nih.gov/pubmed/23372274

http://www.ncbi.nlm.nih.gov/pubmed/23197752

Is there any head to head study of DORAs vs melatonin (or its agonists)?