5 Drug Classes for Sleep Disorders

I recently consulted with a patient who approached the pharmacy counter to ask for something that could help her sleep. Her doctor made a few recommendations for prescription drug therapies, but she couldn’t remember the names.

My head started racing with all the different treatment options that could help this woman.

At first, I recommended some cognitive behavioral therapies, including removal of electronics from her room, avoidance of certain foods and drinks close to bedtime, and reduction of other stimuli. I could have listed 10 different drugs to try, but instead I told her to attempt the cognitive behavioral therapies and follow up in a week if they don’t work.

Upon follow up, I plan to provide her with the following types of medications that can be used for sleep disorders:

1. The “Z” Sedative-Hypnotics

Zolpidem (Ambien, Intermezzo), zaleplon (Sonata), and eszopiclone (Lunesta) work as facilitators/agonists of GABA_A receptors in the body’s central nervous system to inhibit brain activity. In clinical studies, these drugs have been shown to improve onset and duration of sleep. They are widely considered as part of first-line drug therapy for insomnia.

Zolpidem comes in a variety of formulations that are useful in many types of insomnia. Zaleplon has a quick onset and shorter duration of action, which makes it useful in midnight awakening. Eszopiclone has a longer half-life than the other “Z” sedative-hypnotics, so it should be used in patients who plan on sleeping for at least 7 hours.¹

These drugs do have their issues, though. For instance, there is related risk for abuse and dependence, so the drugs are listed as controlled substances.

The most common side effects involve the next-day hangover effect of residual somnolence/drowsiness, dizziness, and ataxia. Zolpidem, zaleplon, and eszopiclone also have some weird side effects like parasomnias and vivid dreams.²

In addition, the FDA has issued some safety alerts concerning the use of zolpidem and eszopiclone. In 2013, the recommended dosing for zolpidem in women was lowered to 5 mg for the immediate-release version and 6.25 mg for extended-release products.³ The FDA has also warned that eszopiclone and zolpidem can impair next-day operation of machinery and driving.^4,5

2. Benzodiazepines

There a lot of benzodiazepines on the market for various mental health conditions, but for insomnia, a shorter-acting agent in this class is generally better tolerated.² The longer-acting benzodiazepines are more strongly associated with increases in falls and included in the American Geriatrics Society’s Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.⁶

The acronym LOT (lorazepam, oxazepam, temazepam) will be help you remember the less harmful benzodiazepines. Of note, however, oxazepam is not approved for sleep disorders, but the others are.

Because benzodiazepines have shorter durations of action, the next-day hangover effect is not as prominent for benzodiazepines as it is for the “Z” sedative-hypnotics. However, the abuse potential of benzodiazepines is stronger because they have less-selective binding to the GABA_A receptors.¹

3. Dual Orexin Receptor Antagonists

Suvorexant (Belsomra), the newest drug to enter the dual orexin receptor antagonists party, was introduced to the market in the summer of 2014.

Belsomra works to inhibit/antagonize the orexin receptor, which normally promotes wakefulness. Unfortunately, there haven’t been any updated treatment guidelines for sleep disorders since Belsomra was made available, and there also haven’t been head-to-head studies with established therapies, so it is hard to tell its place in therapy. However, Belsomra has shown effectiveness compared with placebo, as patients fell asleep 10 minutes faster and slept for 23 minutes longer.⁷

Somnolence is common with Belsomra, and the potential for abuse is noted, although it may be lower than the “Z” sedative-hypnotics and benzodiazepines. As far as drug interactions go, there are dose caps and contraindications with Belsomra and cytochrome P450 3A4 inhibitors. Belsomra should also not be used in narcolepsy.²

Price is going to be an issue with this drug because it is new, but you can refer patients to the manufacturer’s website for a trial card.

Eisai and Purdue have partnered to develop lemborexan for insomnia, so an additional dual orexin receptor antagonist may hit the market in the next few years.⁸

4. Melatonin Receptor Agonists

With more than 30 million users, melatonin has become a crowd favorite for not only insomnia, but also jet lag.

Melatonin is naturally found in the body as a hormone created by the pineal gland.⁹ Its effectiveness has a questionable history, and as of the 2008 Clinical Guideline for the Evaluation and Management of Chronic Insomnia in Adults, it was not recommended for insomnia treatment.

The common theme of melatonin’s rejection from clinical guidelines is its lack of efficacy and safety studies.¹⁰ After conducting a brief PubMed search of the term “melatonin” with the phrase “sleep or insomnia,” I found some studies, but they all lacked generalizable populations.

Ramelteon (Rozerem) is a melatonin receptor agonist that has been approved for use in the United States since 2005. It has shown benefit in sleep-onset insomnia but not maintenance insomnia, due to its short duration of action.

Rozerem has a milder side effect profile than the “Z” sedative-hypnotics and may be beneficial in patients at higher risk for falls. Rozerem is also not controlled and may provide benefit in known drug abusers.

Nevertheless, Rozerem has terrible bioavailability (~2%), so instruct patients to avoid taking the drug with meals, especially those with high fat content.¹¹

Another melatonin receptor agonist, tasimelteon (Hetlioz), is not approved for insomnia, but it is approved for Non-24-Hour Sleep-Wake Disorder, a neurological sleep disorder that affects primarily blind patients.¹²

5. Antidepressants

Antidepressants generally work on either histamine or serotonin receptors to cause sedation in those with sleep disorders.

Silenor is a brand-name form of doxepin that is approved for insomnia. The 3-mg and 6-mg doses of Silenor are much lower than the parent drug and allow for milder side effects than when used for depression. Silenor isn’t great for sleep-onset insomnia, but it does show benefit for sleep maintenance.¹

Trazodone is frequently used off-label at lower doses for depressed patients. Using doses of 50 mg to 100 mg in insomnia avoids anticholinergic effects and curbs the risk for falls.¹ Beware of mix-ups with trazodone and the pain medicine tramadol, as they have similar names with overlapping doses and close storage locations.

Mirtazapine is used off-label in a similar manner as trazodone. A dose of 30 mg is most often used for insomnia, as higher doses may prove counteracting.¹

Tricyclic antidepressants like amitriptyline and imipramine have also been used for insomnia. Their side effect profiles are stronger than the other antidepressants’ and should thus be used with extreme caution, especially in the elderly.¹

Other Available Options

Herbals

A 2015 meta-analysis took a look at 4 different herbals and compared each of them with placebo. The researchers primarily examined valerian, but they also reviewed kava, chamomile, and wuling (Xylaria nigripes).

The researchers considered various insomnia endpoints and found poor evidence of the herbals providing benefit.¹³ The aforemented 2008 clinical guidelines do not recommend the use of herbals for chronic insomnia.¹⁰

Antihistamines

Antihistamines like diphenhydramine and doxylamine are main ingredients in OTC sleep products, but they are not recommended for sleep disorders.¹⁰ Antihistamines may be effective for a night or 2, but tolerance quickly occurs, which reduces their effects. These drugs are also associated with a large number of anticholinergic side effects, even at normal doses.¹

Barbiturates

Phenobarbital and some other barbiturates are actually approved for insomnia, but they are generally used for other indications like seizures and preoperative sedation.

Quetiapine

Quetiapine (Seroquel) is indicated for schizophrenia, bipolar, and major depressive disorder, but off-label use at a low dose (25 mg initially) has been beneficial for insomnia patients.

References

1. Lie JD, Tu KN, Shen DD, Wong BM. Pharmacological treatment of insomnia. P T. 2015 Nov;40(11):759-768, 771.

2. Bonnet MH, Arand DL. Treatment of insomnia. Up to Date. uptodate.com/contents/treatment-of-insomnia. Updated January 8, 2016. Accessed January 19, 2016.

3. FDA. FDA requiring lower recommended dose for certain sleep drugs containing zolpidem. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm334798.htm. Updated January 11, 2013. Accessed January 19, 2016.

4. FDA. FDA approves new label changes and dosing for zolpidem products and a recommendation to avoid driving the day after using Ambien CR. http://www.fda.gov/drugs/drugsafety/ucm352085.htm. Updated January 15, 2016. Accessed January 19, 2016.

5. FDA. FDA warns of next-day impairment with sleep aid Lunesta (eszopiclone) and lower recommended dose. www.fda.gov/Drugs/DrugSafety/ucm397260.htm. Updated October 22, 2015. Accessed January 19, 2016.

6. American Geriatrics Society. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of American Geriatrics Society. Nov 2015;63(11):2227-2246.

7. Michelson D, Snyder E, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurology. Mar 2014;13(5):461-471.

8. Eisai. Eisai Inc. and Purdue Pharma Enter Worldwide Collaboration to Develop and Commercialize Lemborexant. eisai.com/news/news201558.html. Published August 2015. Accessed January 20, 2016.

9. It’s 3 A.M. you’re wide awake. Here’s help. Consumer Reports. February 2016.

10. Schutte-Rodin S, Broch L, et al. Clinical guidelines for the evaluation and management of chronic insomnia in adults. Journal of Clinical Sleep Medicine. Oct 2008;4(5):487-504.

11. FDA. Rozerem (ramelteon) Package Labeling. www.accessdata.fda.gov/drugsatfda_docs/label/2010/021782s011lbl.prf. Updated November 2010. Accessed January 20, 2016.

12. FDA. Hetlioz (tasimelteon) Package Labeling. www.accessdata.fda.gov/drugsatfda_docs/label/2014/205677s000lbl.prg. Updated January 2014. Accessed January 20, 2016.

13. Leach ML, Page AT. Herbal medicine for insomnia: a systematic review and meta-analysis. Sleep Medicine Reviews. Dec 2015;24:1-12.