Alcohol is one of the most popular substances used worldwide for thousands of years.
Globally, harmful alcohol use continues to be a major public health and economic burden.
The World Health Organization global status report attributed harmful alcohol use to 3
million deaths in 2016.In the United States, alcohol is the most used substance by people
over the age of 12, with alcohol use disorder (AUD) affecting 14.5 million people in this
age group. Hazardous alcohol use is associated with emergency room visits, overdose,
driving fatalities and chronic medical conditions such as liver disease, heart disease,
and hypertension.
Pharmacological interventions for AUD have expanded over the past few decades, including
FDA approved and off-label medications such as naltrexone that have demonstrated efficacy
in reducing alcohol cravings, consumption, and likelihood of relapse. However, the
significant variability in response to treatment fuels ongoing interest in novel
pharmacotherapy for AUD. A common approach involves repurposing readily available
medications based on our understanding of AUD pathophysiology. In this study, we focus on
the orexin system, which has been implicated in behaviors such as feeding, sleep-wake
cycle, motivation, and reward associated with food, sex and substances including alcohol.
The brain neuropeptides orexin A and orexin B originate in the hypothalamus and project
throughout the central nervous system, activating G-protein-coupled receptors orexin 1
and 2 (OX1R and OX2R). While both orexin receptors are involved in addictive behaviors,
OX1R signaling has a stronger association with reward processes whereas OX2R promotes
arousal. Chronic alcohol exposure may lead to neuroadaptations in the orexin system, as
observed in studies showing a positive correlation between orexin levels and severity of
alcohol dependence and distress during alcohol withdrawal. Moreover, multiple animal
studies have demonstrated efficacy of orexin antagonists in reducing alcohol craving,
self-administration, and reinstatement of alcohol use induced by cues and stress.
The orexin antagonist lemborexant is FDA approved for treatment of insomnia. Lemborexant
acts on both OX1R and OX2R and has shown efficacy in sleep initiation and maintenance
compared to placebo on polysomnography and patient-report. It has demonstrated long-term
safety and effectiveness without physical dependence or rebound insomnia. Compared to
suvorexant, another orexin antagonist, lemborexant has greater selectivity and stronger
binding for orexin receptors. Suvorexant has secondary effects on the adenosine receptor
and dopamine transporter whereas lemborexant only has weak binding to melatonin 1. These
differences may increase risk of misuse for suvorexant more than lemborexant. In
addition, Lemborexant's longer half-life (17-19h) may be advantageous for reduction of
cravings during the day.
In people with AUD, insomnia is a common problem that is associated with alcohol craving
and relapse. Standard treatment for AUD with naltrexone improves cravings and other AUD
outcomes, but does not improve sleep. In some cases, naltrexone may have a detrimental
effect on sleep. Lemborexant may be able to target both alcohol craving/urges and
insomnia when added to standard treatment with naltrexone.
