Journal of Sleep Disorders & Therapy
Open Access

Comparative Outcomes of Melatonin Agonists and Orexin Antagonists in Sleep Disorders

Ruby James^{* *}Correspondence: Ruby James, Department of Psychiatry and Sleep Research, University of Toronto, Toronto, Canada, Email:

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Description

Sleep disturbances are among the most widespread and underappreciated health problems faced globally. The inability to achieve restorative rest impairs physical and mental health, diminishes productivity, and increases the risk of long-term conditions such as cardiovascular disease, metabolic disorders, and mood disturbances. In the clinical setting, pharmacological sleep therapies remain a cornerstone for short-term and sometimes long-term management of insomnia and other sleep-related conditions. However, the comparative effectiveness of these therapies is a subject of intense debate, not only because of their pharmacodynamic differences but also due to variations in safety profiles, tolerability, patient adherence, and long-term impact.

Pharmacological agents for sleep can be broadly categorized into benzodiazepines, non-benzodiazepine hypnotics, melatonin receptor agonists, orexin receptor antagonists, antihistamines, and off-label drugs such as certain antidepressants and antipsychotics. Each of these therapeutic classes has been developed with a specific rationale, whether it be enhancing inhibitory neurotransmission, regulating circadian rhythm, or attenuating arousal pathways. Despite their mechanistic diversity, they converge on the same clinical goal: enabling the patient to fall asleep more easily, stay asleep for a reasonable duration, and awaken refreshed.

Benzodiazepines were among the first modern hypnotics to be widely used, providing effective short-term relief by potentiating the effects of Gamma-Aminobutyric Acid (GABA) at the GABAA receptor. Their sedative, anxiolytic, and muscle-relaxant properties made them particularly versatile, and in acute settings they were viewed as game-changing. Yet the long-term story of benzodiazepines is more complicated. Tolerance, dependence, and significant withdrawal phenomena limit their use to short courses. Concerns about cognitive impairment, risk of falls in the elderly, and potential associations with dementia have also tempered enthusiasm. Comparative studies frequently highlight that while benzodiazepines are highly effective in initiating sleep, their effectiveness diminishes over weeks due to tolerance, placing them at a disadvantage relative to newer agents when considering sustained therapy.

Antihistamines, such as diphenhydramine and doxylamine, remain among the most commonly used over-the-counter sleep aids. Their sedative properties derive from central histamine H1 receptor antagonism. While easily accessible and widely familiar to the public, they are generally less effective than prescription options, with benefits often diminishing after a few days due to rapid tolerance. Moreover, their anticholinergic burden raises particular concern in older adults, with risks of confusion, urinary retention, dry mouth, and falls. Comparative effectiveness analyses typically place antihistamines at the lowest end of the spectrum in terms of both efficacy and safety, yet their ubiquity reflects the ongoing demand for accessible solutions despite known limitations.

One of the greatest challenges in drawing comparative conclusions is the heterogeneity of patient populations. Age, comorbid conditions, concurrent medications, and personal sensitivity to side effects profoundly influence how effective or tolerable a drug may be. For instance, elderly patients may prioritize avoidance of falls and cognitive impairment, making melatonin agonists or low-dose doxepin more suitable despite lower efficacy. Patients with histories of substance misuse are at elevated risk for dependence, favoring therapies like orexin antagonists or melatonin receptor agonists.

The long-term perspective is equally important. Most pharmacological sleep therapies are recommended for short-term use, yet chronic insomnia often persists for years. Evidence on sustained use is limited, and concerns about tolerance, dependence, and subtle cognitive effects loom large. Cognitive Behavioral Therapy for Insomnia (CBT-I) is widely considered the gold standard for chronic management, yet its accessibility remains limited. Pharmacological options thus persist as frontline interventions despite imperfect evidence for long-term safety. From a comparative standpoint, this underscores the importance of integrating pharmacological and nonpharmacological strategies rather than relying on drugs in isolation.