How does Ramelteon (rozerem) work and why is it not habit-forming?

From the Guidelines

Ramelteon works by selectively binding to melatonin receptors, specifically MT1 and MT2, in the brain, mimicking the effects of natural melatonin to regulate sleep-wake cycles, and its unique mechanism of action is why it is not considered habit-forming. This is in contrast to traditional sleep medications like benzodiazepines and "Z-drugs" that work on GABA receptors, which can lead to tolerance, withdrawal symptoms, and dependence with continued use 1. The evidence from a 2017 clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults supports the use of ramelteon for the treatment of sleep onset disturbance, with minimal potential harms and no evidence of significant difference from placebo for any adverse events 1.

Some key points to consider when prescribing ramelteon include:

• The typical dose is 8 mg taken within 30 minutes before bedtime
• Patients should avoid taking ramelteon with or immediately after a high-fat meal, as this can reduce its effectiveness by delaying absorption
• Ramelteon's targeted action on melatonin receptors helps regulate the body's natural sleep-wake cycle without affecting reward pathways in the brain, which is why the FDA has not classified ramelteon as a controlled substance
• Studies have shown no evidence of withdrawal symptoms or rebound insomnia when stopping the medication, further supporting its safety and lack of habit-forming potential 1.

Overall, the benefits of ramelteon appear to be greater than the minimal potential harms, and based on clinical judgment, the majority of well-informed patients would use ramelteon over no treatment, especially considering its improved sleep latency and low potential for adverse events 1.

From the FDA Drug Label

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and relative selectivity over the MT3 receptor The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates.

Ramelteon works by agonizing melatonin receptors, specifically MT1 and MT2 receptors, which helps regulate the circadian rhythm and promotes sleep. It is not habit-forming because it does not act on GABA receptors or opiate receptors, which are commonly involved in the development of physical dependence and addiction 2. Key points about ramelteon's mechanism of action include:

• High affinity for melatonin MT1 and MT2 receptors
• Relative selectivity over the MT3 receptor
• No appreciable affinity for GABA or opiate receptors
• Does not interfere with the activity of various enzymes and receptors.

From the Research

Mechanism of Action

• Ramelteon works as a highly selective agonist for the melatonin MT1/MT2 receptors, which are believed to mediate the circadian rhythm in mammals 3.
• It has negligible affinity for the MT3 binding sites and other receptors in the brain, including the opiate, dopamine, benzodiazepine, and serotonin receptors 3.
• Ramelteon's primary action in sleep promotion is not a generalized gamma-aminobutyric (GABA)-ergic central nervous system depression, but rather it acts as a melatonergic agonist in the suprachiasmatic nucleus (and at other central nervous system sites) 4.

Efficacy

• Ramelteon has been shown to be effective in reducing sleep latency and increasing total sleep time in patients with chronic insomnia 3, 5, 4, 6.
• It has also been found to improve sleep efficiency and reduce the number of nightly awakenings 4, 7.
• A meta-analysis of 13 trials involving 5812 patients with insomnia found that ramelteon was associated with reduced subjective sleep latency and improved sleep quality, but was not associated with increased subjective total sleep time 7.

Abuse Potential

• Ramelteon has been shown to have no potential for abuse or dependence 3, 5, 4, 6.
• It is not scheduled by the U.S. Drug Enforcement Agency as a controlled substance due to its lack of abuse liability 5.
• Clinical studies have found no evidence of rebound insomnia or abuse potential with ramelteon 6.

Safety and Tolerability

• Ramelteon is generally well tolerated, with the most commonly reported adverse events being somnolence, fatigue, and dizziness 3, 7.
• Adverse events are mostly mild or moderate in nature 3.
• Ramelteon has not been shown to cause withdrawal symptoms or next-morning hangover effects 4, 6.