Side effects of<unk>  (at doses of 15–20mg) include somnolence (7% vs. 3% for placebo) and headaches (7% vs. 6% for placebo). Somnolence with<unk>  appears to be dose-dependent, with rates of 2% at 10mg, 5% at 20mg, 10–12% at 40mg, and 11–12% at 80mg, relative to 0.4% for placebo. Less common side effects (at 15–20mg) may include dizziness (3% vs. 2% for placebo), abnormal dreams (2% vs. 1% for placebo), diarrhea (2% vs. 1% for placebo), dry mouth (2% vs. 1% for placebo), upper respiratory tract infection (2% vs. 1% for placebo), and cough (2% vs. 1% for placebo). High doses of<unk>  (80mg) have also been found to produce greater incidences of dizziness (5% vs. 0% for placebo) and abnormal dreams (5% vs. 1% for placebo). Less commonly,<unk>  may cause sleep paralysis, hypnagogic and hypnopompic hallucinations, and complex sleep behaviors (0.2–0.6% vs. 0% for placebo). Complex sleep behaviors include sleepwalking, sleep-driving, and engaging in other activities while not completely awake (e.g., making or eating food, making phone calls, and having sex). Other narcoleptic-like symptoms such as cataplexy (sudden weakness or paralysis) may also rarely occur.<unk>  may sometimes cause worsening of depression or suicidal ideation. A dose-dependent increase in suicidal ideation as assessed with the Columbia Suicide Severity Rating Scale was seen with<unk>  in clinical trials although rates were very low (0.2% (1/493) at low doses (15–20mg) and 0.4% (5/1291) at high doses (30–40mg) relative to 0.1% (1/1025) for placebo). It has also been stated however that suicidal ideation was reported in 0% to 1.6% of people taking 10 to 20mg and 3.4% to 8.2% taking 40 to 80mg relative to 0% to 0.3% with placebo. Suicidal ideation with<unk>  is considered to be mild. In any case, caution is warranted in use of<unk>  in people with depression, and people with worsening depression or suicidal thoughts should be promptly evaluated. Besides the clinical trial data, a case report of rapidly worsened depression and onset of suicidal ideation with<unk>  has been published. The next-day effects of<unk>  have been studied. Besides the side effect of daytime somnolence,<unk>  may dose-dependently reduce alertness and motor coordination and impair driving ability. It may also increase the risk of falling asleep while driving. Driving ability was found to be impaired at doses of 20 and 40mg in clinical studies. Driving impairment may also occur with lower doses of<unk>  due to variations in individual sensitivity to the medication. In three of four studies, 30mg<unk>  had no influence on next-day memory or balance, whereas in the remaining study, there was a decrease in morning word recall with 40mg and an increase in body sway with 20 and 40mg doses. In another study in elderly people who were awakened in the night, impaired balance was present at 1.5hours after taking 30mg<unk>  whereas memory was unaffected. A 2017 systematic review and meta-analysis of<unk>  for the treatment of insomnia found that the medication significantly increased the rate of somnolence by 3.5-fold, daytime sleepiness/sedation by 3.1-fold, fatigue by 2.1-fold, abnormal dreams by 2.1-fold, and dry mouth by 2.0-fold. Conversely,<unk>  did not significantly differ from placebo in the rates of any other assessed adverse effects. This included back pain, diarrhea, dizziness, falls, headache, car accidents/traffic violations, nasopharyngitis, nausea, potential drug misuse, suicidal ideation, complex sleep behaviors, hypnagogic or hypnopompic hallucinations, and sleep paralysis. The overall risk of any adverse event was increased 1.07-fold while discontinuation due to adverse events was unchanged ( = 0.93, 95% 0.60 to 1.44). Tolerance, dependence, withdrawal, and rebound effects do not appear to occur with<unk>  in the treatment of insomnia at studied doses. In three-month clinical studies, no rebound insomnia as assessed by measures of sleep onset or maintenance was observed with discontinuation of<unk>  at doses of 15 to 40mg. Similarly, no withdrawal effects were observed with discontinuation of<unk>  at these doses. However, in other reports, some tolerance as assessed by diminishing somnolence and rebound insomnia upon discontinuation has been noted. The orexin neuropeptides augment the signaling of the mesolimbic dopamine reward pathway and are thought to potentiate hedonic tone. Conversely, low orexin signaling may result in low hedonic tone and orexin receptor antagonists are of interest for the potential treatment of addiction. In line with these findings,<unk>  and other orexin receptor antagonists have not shown misuse liability in animal studies in rats and non-human primates. Paradoxically however, orexin receptor antagonists, including<unk> , lemborexant, and daridorexant, have consistently shown drug-liking responses in human studies of recreational sedative users. In any case,<unk>  at higher-than-approved doses (40, 80, and 150mg vs. 20mg maximum recommended dose) showed similar drug liking to the Z-drug zolpidem (15 and 30mg) in such individuals. On the other hand, it showed lower misuse potential on all other measures (including an overall rate of misuse potential adverse event of 58% for zolpidem and 31% for<unk> . In another study,<unk>  at a dose of 150mg showed greater drug liking than daridorexant (50mg) but similar drug liking to zolpidem (30mg) and higher doses of daridorexant (100–150mg) in recreational sedative users. There was no apparent dose–response relationship for positive measures of misuse potential with<unk> , in contrast to zolpidem. In the phase III clinical trials, misuse potential adverse events were reported in 3.0% with placebo, 4.1% with 15 or 20mg<unk> , and 2.6% with 30 or 40mg<unk> . The misuse liability of<unk>  is considered to be at most modest, and further research is needed to characterize the misuse potential of orexin receptor antagonists. In any case,<unk>  is a controlled substance in the United States due to concerns about the possibility of misuse. Besides its subjective side effects,<unk>  has been found to cause dose-dependent increases in serum cholesterol levels in clinical trials. These changes in cholesterol levels were +1.2mg/dL at 10mg, +2.3mg/dL at 20mg, +3.1mg/dL at 40mg, and +6.0mg/dL at 80mg relative to –3.7mg/dL for placebo. Although the increases in cholesterol levels with approved doses of<unk>  (10–20mg) are small, they could be important over a long duration of treatment. Early studies in rodents found that orexins (derived from Greek "orexis" meaning "appetite") stimulate appetite, feeding behavior, and weight gain while orexin receptor antagonists block these effects. However, subsequent animal studies were more mixed, with the effects being limited and depending on the animal strain. In humans, orexin receptor antagonists including<unk>  have not been found to affect body weight in rigorous clinical trials that lasted up to 12 to 14months.
Suvorexant
Icatibant
Veristrat
Seltorexant
Daridorexant
Rimegepant
Atogepant
Ubrogepant