Insomnia Medications – Not All Are Created Equal

by Colonel Scott Williams, MD, FAASM

Insomnia and difficulty acclimating to oral appliance therapy (OAT) are two of the most significant barriers to initial adherence. Given that adherence is a big factor in selecting treatment for sleep disordered breathing, it is important for Dental Sleep Medicine (DSM) providers to be aware of the pharmacologic and behavioral treatments for insomnia. For CPAP (and likely OAT), the first few weeks of treatment are the most predictive of long-term success (Budhiraja 2007). While Cognitive Behavioral Treatment for Insomnia (CBT-I) is the first line treatment for chronic insomnia, medications are often helpful for short term treatment.

There are many different classes of sedative-hypnotic medications available to clinicians. The most widely prescribed medication for insomnia is the antidepressant trazodone despite lacking FDA approval for this indication (Wong 2020). Trazodone is a serotonin antagonist and re-uptake inhibitor (SARI) which has been available since the 1970s. Its profound antihistaminergic and anti-adrenergic effects can cause next-day somnolence as well as dizziness. Multiple organizations to include the American Academy of Sleep Medicine have suggested against the use of trazodone for insomnia (Sateia 2017, Martin 2020, Qaseem 2016).  Other off-label medications that have anti-histaminergic properties include tricyclic antidepressants, atypical antipsychotics, and the novel antidepressant mirtazapine.

In addition to blocking the wake promoting neurotransmitter histamine, the GABA system has long been a target for sedation.  One of the first classes of medications to enhance GABA were benzodiazepines (BZDs).  Of the many available BZDs, only five are FDA approved for insomnia (estazolam, flurazepam, quazepam, temazepam and triazolam). These medications are still used frequently although they have a variety of side effects to include dependence, tolerance, and risk of falls especially in the elderly (Holbrook 2000). Because of these concerns, there was pressure to develop additional options. Non-BZD GABA-A agonists, known as “Z-drugs”, surged in popularity during the first two decades of the 21st century. Zaleplon, zolpidem and eszopiclone are highly effective in reducing sleep latency and depending on their half-life, have differential effects on wake after sleep onset. Eszopiclone has a longer duration of action than zolpidem (6-7 hours vs. 2.5-3 hours), and as a result the manufacturer of zolpidem has developed novel delivery mechanisms to extend its effects throughout the second half of the sleep period. Concerns about complex sleep-related behaviors have gained significant attention in both scientific and lay press (FDA 2019, Carey 2019). While these medications remain effective and safe for the vast majority of patients, some clinicians and patients are hesitant to initiate even a brief course of treatment.

The type and duration of sedative medication to enhance OAT adherence is a topic that is vastly under-studied and an area ripe for exploration.

Melatonin is a regulatory hormone synthesized by the pineal gland in the absence of light. While melatonin is not in itself a sedative/hypnotic, it does enhance the release of sleep-promoting neurotransmitters and regulates the circadian rhythm. Melatonin is not regulated by the FDA and is considered a dietary supplement. Therefore, it is not approved for any indication and the potency of over-the-counter formulations can vary widely from the published label on the bottle (Cohen 2023, Erland 2017). Melatonin receptor agonists such as ramelteon are available and have shown some efficacy for sleep onset but do not appear helpful for sleep maintenance.

The newest class of insomnia medications are dual orexin receptor antagonists (DORAs). As opposed to GABA-ergic medications which enhance the sedative properties of this inhibitory neurotransmitter, DORAs block the wake-promoting effects of orexin.  Like GABA agonists, the DORAs have different half-lives. The three currently available DORAs, suvorexant (12 hours), lemborexant (17-19 hours), and daridorexant (8 hours) may have differential potential for next-day somnolence as a function of the markedly different half-lives, though the data for this is scant at the moment. DORAs appear to have a gentler onset of action and some patients who are expecting an immediate soporific effect can be disappointed unless appropriate expectation management and counseling is given at the time of prescription.

For dental sleep practitioners, it is important to discuss the risk-benefit ratio of medications for insomnia with patients who are being initiated on OAT. For most, the risk of untreated or under-treated OSA is far greater than the risk of a short course of sedative-hypnotic therapy. That being said, the type and duration of sedative medication to enhance OAT adherence is a topic that is vastly under-studied and an area ripe for exploration. In the absence of higher quality data, a standard practice of 2-3 weeks of an FDA-approved sedative with a medium-term (3-8 hour) half-life, is appropriate. As with all treatment decisions in DSM, a close working relationship between the dental clinic and the medical clinic is of paramount importance. A synchronized treatment paradigm for referrals, periodic follow-up and troubleshooting, is key to optimizing treatment outcomes.