Section Free - Video Lectures

06. Other Pharmacologic Interventions for Insomnia

Published on December 1, 2023 Certification expiration date: December 1, 2026

Amit Chopra, M.D.

Psychiatrist and sleep specialist at Massachusetts General Hospital. - Harvard Medical School

Key Points

Approved medication for the treatment of insomnia includes:
° Melatonin agonists.
° Histamine receptor antagonists.
° DORAs.
Ramelteon is indicated for sleep-initiation insomnia.
Doxepin is indicated for sleep-maintenance insomnia.
DORAs have shown efficacy for sleep-onset and sleep-maintenance insomnia.

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Slides and Transcript

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Welcome to video number 6, Other Pharmacological Interventions for Insomnia Disorder.

Other Pharmacologic Interventions for Insomnia Slide 1 of 22

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The neuropeptide orexin plays an important role in the stabilization and maintenance of wakefulness by reinforcing wake-promoting signaling in the brain via G protein-coupled orexin receptors, namely orexin-1 and orexin-2 receptors. Orexins are key to the vigilance state control as shown dramatically by the profound sleep-wake state instability in patients with narcolepsy who develop near complete loss of orexin neurons.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 2 of 22

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Slide 3 of 22

Dual orexin receptor antagonists or DORAs including suvorexant, lemborexant and daridorexant have been FDA approved for the treatment of insomnia disorder. DORAs have been shown to improve sleep latency, sleep efficiency and wake after sleep onset time. DORAs also increase total sleep time primarily by promoting REM sleep.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

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DORAs have been recommended for sleep-onset and sleep maintenance insomnia with more prominent effects on the latter. Currently, suvorexant at the dosages of 10 to 20 mg nightly, lemborexant at the dosages between 5 to 10 mg nightly and daridorexant 25 to 50 mg dosage range nightly have been recommended for treatment of insomnia disorder.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 4 of 22

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Slide 5 of 22

On a good note, DORAs are not associated with tolerance, rebound insomnia and withdrawal upon abrupt discontinuation. DORAs have been shown to have absent respiratory effects during sleep which could be of value in patients with comorbid insomnia and obstructive sleep apnea. DORAs may have some abuse potential and therefore these medications are DEA Schedule IV medications. DORAs are contraindicated in patients with narcolepsy, a condition characterized by deficiency of orexin.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

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Common side effects include somnolence, abnormal dreams, fatigue and dry mouth.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 6 of 22

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Slide 7 of 22

Ramelteon at the dose of 8 mg acts as melatonin-1 and melatonin-2 receptor agonists. Ramelteon has been shown to decrease sleep onset latency in patients with insomnia disorder and therefore it has been recommended for sleep initiation insomnia. Ramelteon has no addiction potential and it has not been associated with tolerance, rebound insomnia and withdrawal symptoms.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 7 of 22

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The side effects of this medication include nausea, dizziness, tiredness and drowsiness.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 8 of 22

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Slide 9 of 22

Doxepin, a tricyclic antidepressant with selective affinity for histamine receptor at low dosages, is FDA approved for insomnia disorder at dosages of 3 to 6 mg nightly. Its safety and efficacy for insomnia treatment has been demonstrated in the elderly patients at dosages of 1 to 3 mg nightly. Use of doxepin has been associated with reduced wake after sleep onset time, increased sleep efficiency and total sleep time for up to five weeks with little effect on sleep latency in clinical trials. Due to its effect on wake after sleep onset time, it is indicated for sleep maintenance insomnia complaints.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

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Doxepin is not associated with rebound insomnia and withdrawal effects upon discontinuation and it has not been shown to have any addiction potential.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 10 of 22

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Slide 11 of 22

Side effects of doxepin use include nausea, vomiting, dizziness and dry mouth.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 11 of 22

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All patients with insomnia disorder should be recommended cognitive behavioral therapy for insomnia or CBT-I as a primary intervention as it carries significantly favorable benefit-risk ratio.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 12 of 22

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Medications should be recommended for patients who are unable to participate in CBT-I, who still have symptoms despite participation in such treatments or in select cases as a temporary adjunct to CBT-I.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

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Clinicians should perform a comprehensive initial evaluation including a detailed history of sleep complaints, medical and psychiatric history, medication use and substance use. These factors together with patient preferences and treatment availability should be used to select specific treatments for specific patients.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 14 of 22

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American Academy of Sleep Medicine recommends the use of ramelteon, zaleplon, eszopiclone, triazolam and temazepam for sleep-onset insomnia. For treatment of sleep maintenance insomnia, American Academy of Sleep Medicine recommends use of doxepin, suvorexant, eszopiclone, zolpidem extended release and temazepam.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

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It is preferable to use lowest effective dosages in adults and even lower dosages in elderly and in women for certain compounds. The FDA mandated a lower starting dose for zolpidem, zolpidem ER and eszopiclone in women as compared to men. The patients should be advised to take the medication 30 to 45 minutes before the desired bedtime and the patient should be allowed seven to eight hours in bed or at least four hours when using a zolpidem sublingual formulation or zaleplon for middle of the night insomnia.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 16 of 22

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Slide 17 of 22

Caution should be exercised in patients with respiratory and hepatic impairments, those with substance use disorders and those already taking sedatives or using alcohol. Gradual dose reduction is recommended when discontinuing hypnotic agents.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

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Continued long-term efficacy and safety studies including both placebo-controlled, double-blind studies and open-label studies ranging from 3 to 12 months have demonstrated that zolpidem, zaleplon, eszopiclone, ramelteon, doxepin and suvorexant retain their efficacy without tolerance, abuse or withdrawal effects.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 18 of 22

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Slide 19 of 22

Thus, clinicians may use hypnotics long term if necessary. The need for continued use should be reassessed periodically. Periodic follow-up visits are recommended for patients with chronic use and patients should be advised to consider cognitive behavioral therapy for insomnia or CBT-I which can help them successfully wean off the hypnotic agents.

References:

Perlis, M. L., Posner, D., Riemann, D., Bastien, C. H., Teel, J., & Thase, M. (2022). Insomnia. The Lancet, 400(10357), 1047-1060.

Other Pharmacologic Interventions for Insomnia Slide 19 of 22

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Key points. Medications including melatonin agonists, histamine receptor antagonists and dual orexin receptor antagonists have been approved for treatment of insomnia disorder.

Other Pharmacologic Interventions for Insomnia Slide 20 of 22

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Slide 21 of 22

Ramelteon, a melatonin agonist, is indicated for sleep initiation insomnia; doxepin, a histamine receptor antagonist at low dosages, is indicated for sleep maintenance insomnia; and DORAs including suvorexant, lemborexant and daridorexant have shown efficacy for sleep-onset and sleep maintenance insomnia.

Other Pharmacologic Interventions for Insomnia Slide 21 of 22

Slide 22 of 22

Other Pharmacologic Interventions for Insomnia Slide 22 of 22

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Next Section

07. Treatment Strategies for Managing Insomnia in MDD

Learning Objectives:

After completing this activity, the learner will be able to:

Gain insights into the sleep–wake cycle and its correlation with depression.
Diagnose and assess insomnia.
Implement effective pharmacologic and nonpharmacologic interventions for insomnia and depression.

Original Release Date: December 1, 2023

Review and Re-release Date: March 1, 2024

Expiration Date: December 1, 2026

Expert: Amit Chopra, M.D.

Medical Editor: Andrea Quintás, M.D.

Relevant Financial Disclosures:

Amit Chopra declares the following interests:

- Oxford University Press: Royalty

All of the relevant financial relationships listed above have been mitigated by Medical Academy and the Psychopharmacology Institute.

None of the others faculty, planners, and reviewers for this educational activity have relevant financial relationships to disclose during the last 24 months with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

Contact Information: For questions regarding the content or access to this activity, contact us at support@psychopharmacologyinstitute.com

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Participants must complete the activity online during the valid credit period that is noted above.

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This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Medical Academy LLC and the Psychopharmacology Institute. Medical Academy is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Statement

Medical Academy designates this enduring activity for a maximum of 1.25 AMA PRA Category 1 credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.