Insomnia Treatment: Non-Benzodiazepines Ambien, Lunesta & Sonata
Medically reviewed on Mar 13, 2018 by L. Anderson, PharmD.
Why Can't I Get a Good Night's Sleep?
If you can't get a good night's rest, you are not alone. Insomnia - trouble getting to sleep and/or staying asleep long enough to get adequate rest - is one of the most common medical complaints by patients.
Roughly 10 to 30 percent of adults experience trouble sleeping. There are many options to help you get a good night's rest, but first you should look at your sleep routine and habits and identify any needed changes.
Before you dive into use of sleep medications, it's important to review your options and special safety concerns with these drugs. You and your doctor can work together to come up with a long-term plan to restore a restful sleep.
Is Insomnia a Common Condition?
The Centers for Disease Control and Prevention (CDC) noted that insufficient sleep has become a public health epidemic. Lack of sleep has been linked with car accidents, industry disasters, and work-related errors.
More than one-quarter of the U.S. population report occasionally not getting enough sleep, while nearly 10% experience chronic insomnia. In general, most adults need 7 to 9 hours of sleep per night.
In 2018, the University of Pennsylvania published research in the journal Sleep that found Americans were getting 17 minutes more sleep every night, or a full four days more sleep per year. However, despite these modest gains, a third of Americans are still sleep-deprived, which can have serious consequences for their health. Sleep-deprived patients are more likely to be obese, have high blood pressure, diabetes, heart disease and declines in mental function, or can lead to serious accidents.
Is It Just a Restless Night or Is it True Insomnia?
Everyone can experience a disruptful night of sleep from time to time. Stress, caffeine use, death of a loved one, or illnesses can block restful sleep.
However, true insomnia is classified as a chronic condition when it happens almost every night for at least one month.
Symptoms of insomnia can include:
- Difficulty falling asleep.
- Waking up periodically during the night.
- Waking up in the early morning, but not feeling rested.
- Feeling tired and irritable during the day; unable to complete tasks due to drowsiness.
- Having trouble concentrating.
What Causes Insomnia?
Health conditions can cause insomnia:
- sleep apnea
- overactive bladder
- chronic pain
- chronic respiratory disorders such as asthma are all possibilities.
If you are not sure what's causing you to toss and turn, your physician can diagnose your cause of insomnia by learning about your sleep habits and patterns, doing a physical exam, and reviewing your symptoms.
You may need additional tests, such as an overnight sleep study where your brain waves, breathing pattern and oxygen levels are monitored, and your body movements can be observed. Sleep apnea is often diagnosed by this method.
Is There Any Way to Prevent Insomnia?
Adjusting your sleep routine may be all that's needed to lull yourself back to a restful night.
It is important to review your pre-bedtime routine, caffeine use, and other lifestyle issues.
Keep a regular bed and awake time, avoid electronics use close to bedtime, and keep the room dark and at a comfortable temperature. Avoid caffeine-containing drinks after lunch and heavy meals in the evening.
Also, avoid excessive alcohol at night, which can lead to middle-of-the-night awakenings.
Engage in exercise early in the day, rather than later.
Avoid daytime naps. Read or watch TV in a room other than your bedroom. If your partner keeps you awake, consider sleeping in another bed or room.
What Medications Are Prescribed For Sleep Problems?
Sometimes insomnia can still persist, even after adjusting your sleep habits.
Several types of drugs are prescribed for the short-term treatment of insomnia. These agents are the most common treatments for insomnia, and are considered to be relatively safe when used for short periods of time.
- Non-benzodiazepines (i.e., Lunesta, Ambien, and Sonata)
- Benzodiazepines (i.e, Ativan, Valium, Halcion)
- Melatonin agonist ramelteon (Rozerem)
- Low dose doxepin (Sinequan), an antidepressant
Over-the-counter (OTC) antihistamines, such as diphenhydramine (Benadryl), are included in many OTC treatments, but they may be associated with next-day side effects like sedation, impairment at work and with driving, dry mouth, and dizziness - especially in the elderly. It's best to avoid avoid regular use of diphenhydramine for sleep.
The Nonbenzodiazepines: Overview
Nonbenzodiazepines for insomnia include:
- zolpidem (Ambien, Ambien CR, Edluar, Zolpimist, Intermezzo)
- eszopiclone (Lunesta)
- zaleplon (Sonata).
These drugs should be taken only if needed for insomnia; they do not need to be taken every night if you can get to sleep without them.
All of these drugs act quickly to decrease the amount of time it takes to fall asleep; however, they can differ in their length of action, available dosage forms, and costs.
All three drugs are now available in generic formulations and cost from $10 to $20 per 30 tablets or capsules.
How Do The Nonbenzodiazepines Drugs Work?
Nonbenzodiazepines interact with benzodiazepine-like receptors, but are structurally different from the true benzodiazepines.
Nonbenzodiazepines raise the levels of the amino acid Gamma-Aminobutyric Acid (GABA). Their mechanism is thought to be selective attachment to the GABA-BZ receptors found in close proximity to the benzodiazepine receptors.
The nonbenzodiazepines are NOT indicated for use in seizures. GABA slows down brain activity, allowing the mind and body to relax and promotes sleep. Short-term treatment of insomnia with nonbenzodiazepines is preferred, using the lowest effective dose of these drugs.
The Nonbenzodiazepines: Adverse Effects
Patients should be aware of the serious side effects that may occur with the nonbenzodiazepines, including next day drowsiness that may impair driving, work performance, and decision-making; not all patients will be aware they are impaired.
In fact, several years ago the FDA required lower doses for zolpidem and eszopiclone to help prevent morning impairment.
Anterograde amnesia (memory loss) and unusual sleep-related behaviors, like sleep driving or walking, making phone calls, having "sleep sex", or preparing and eating food -- with no memory of the event -- have been documented.
These risks are greatly increased when the nonbenzodiazepines are combined with alcohol or other sedating drugs; their combined use should be strictly avoided.
The Nonbenzodiazepines: Zolpidem
Zolpidem is one of the most prescribed hypnotics in the U.S.
The various brands include:
- immediate-release and extended-release forms (Ambien, Ambien CR)
- oral spray Zolpimist
- dissolvable tablet forms such as Edluar and Intermezzo.
Intermezzo is a lower dose of zolpidem that is specially designed for middle-of-the-night awakenings when at least 4 hours can be devoted to sleep; all other forms are to be used before bed when there is at least 7 to 8 hours to devote to sleep.
The onset of action of nonbenzodiazepines is very rapid, ranging from 15 to 30 minutes. Zolpidem should not be taken with or immediately after a meal as this may slow the effect of the drug.
Zolpidem Dosing: Follow the Guidelines
The FDA required that doses for women be reduced to 5 mg for immediate-release products (Ambien, Edluar, Zolpimist, generics) and to 6.25 mg for extended-release products (Ambien CR, generics).
Lower doses should also be used for the elderly, debilitated and those with liver impairment. For men under 65 years of age, providers should consider prescribing lower doses, as recommended by the FDA. Do not drink alcohol or use any sedating drug while taking any form of zolpidem.
Intermezzo and Edluar: Sublingual Zolpidem
Sublingual Intermezzo is specifically for middle-of-the-night awakening. Dosing is specific: It comes in a 1.75 mg strength for women, the elderly, and patients with liver impairment, and a 3.5 mg strength for men 65 years of age or younger.
Intermezzo tablets should be dissolved under the tongue; do not swallow the tablets whole or take with water.
Only one tablet should be used per night if needed, and only when there is at least 4 hours to devote to sleeping before awakening and engaging in activities or driving.
Edluar is also a sublingual tablet of zolpidem, but is a higher dose and is used at bedtime when there are at least 7 to 8 hours to devote to sleep before awakening.
Zolpimist: An Oral Zolpidem Spray
Zolpimist is an oral spray form of zolpidem to be used in people who have trouble falling asleep (NOT for middle-of-the-night-awakening). Zolpimist leads to sedation in about 15 to 20 minutes.
The dose in women, elderly, debilitated, and patients with liver impairment is one spray (5 mg) at bedtime. Men 65 years and younger may receive 5 to 10 mg at bedtime. The recommended initial doses for women and men are different because zolpidem clearance is lower in women. Take Zolpimist on an empty stomach.
One 7.7 mL bottle of Zolpimist contains 60 sprays and is expensive compared to generic tablet formulations - running about $80 per bottle or more for patients who do not have insurance. The 4.4 mL bottle has 30 sprays and costs roughly $50.The manufacturer, Magna Pharmaceuticals, may be able to offer cost assistance for the medicine.
As with all nonbenzodiazepines, these drugs should be slowly discontinued with prolonged use.
Lunesta (eszopiclone) is used in those who have trouble falling asleep or staying asleep (sleep maintenance). Eszopiclone is a derivative (the S-isomer) of zopiclone.
People must be able to devote 7 to 8 hours to sleep after taking Lunesta. Sleep onset is rapid in 15 to 30 minutes.
In May 2014, FDA required lower doses of eszopiclone in both men and women. Starting doses are 1 mg at bedtime, but doses may be adjusted upwards with doctor approval, if needed. The total dose of eszopiclone should not exceed 3 mg once daily immediately before bedtime. Lower doses are needed in the elderly, those with liver impairment, and with certain medications.
Sleep-related behaviors are also a risk with Lunesta; this risk is increased if Lunesta is combined with alcohol or other sedating drugs. Avoid taking Lunesta with a heavy, high-fat meal.
Generic Lunesta is now available in pharmacies.
Sonata comes in capsules; the normal dose is 5 to 10 mg at bedtime; use lower doses in the elderly and those with mild to moderate liver impairment.
A dose of 20 mg at bedtime may be used in the occasional patient who does not respond to lower doses; however, the risk of sleep-related behaviors may be a risk at this higher dose.
Do not use zaleplon in patients with severe liver disease. Doses above 20 mg have not been adequately evaluated and are not recommended.
Like the other nonbenzodiazepines, complex sleep behaviors like sleep driving or sleep walking may occur; especially if Sonata is combined with alcohol. Next-day drowsiness may impair driving and is a risk without a full 7 to 8 hours of sleep. However, FDA has not yet required post-approval label changes for lower doses with Sonata.
An initial dose of 5 mg should be used in patients taking cimetidine (Tagamet), as clearance is reduced.
Sonata is available generically for cost-savings.
Non-Benzodiazepines: Drug Interactions
Drug interactions with nonbenzodiazepines are a concern, particularly because some interactions can lead to higher blood levels of these drugs which can raise the side effect risks.
Many of these drugs are broken down for elimination from the body via liver enzymes. If these enzymes are blocked by other drugs, such as the antibiotic clarithromycin, nonbenzodiazepine blood levels may rise. On the flip-side, drugs that boost the breakdown of this class may reduce their sleep effectiveness.
Always have your pharmacist run a drug interaction check, and remember, do not combine drugs for sleep with alcohol, other sedating drugs or any illicit substance.
First-in-Class Orexin Antagonist: Belsomra
Merck's first-in-class orexin receptor antagonist orexin Belsomra (suvorexant) was FDA-approved in August 2014 for insomnia. Belsomra alters the signaling (action) of orexin, a chemical involved in the sleep-wake cycle in the brain.
Merck's sleep agent is a controlled substance (C-IV) and is available in 5, 10, 15, and 20 milligrams strengths. The 10 mg dose is recommended initially, taken within 30 minutes of bed and no more than once per night. At least seven hours should remain before the planned time of awakening after taking Belsomra. Cash prices can run over $300 for 30 tablets. The maximum dose is 20 mg once per day at bedtime.
Belsomra can cause next-day drowsiness and impaired driving, especially at the highest 20 mg dose.
AASM Clinical Practice Guidelines: 2017
In 2017 The American Academy of Sleep Medicine (AASM) issued evidence-based clinical practice guidelines on the drug treatment of chronic insomnia in adults. The group recommends cognitive behavioral therapy for insomnia (CBT-I) for patients as a first line therapy for sleep disorders, before pharmacologic treatment.
Drug therapy can also be used as an adjunct to CBT-I or for those who do not have adequate response to CBT-I. CBT-I teaches the patient how to alter thoughts that may be interfering with sleep. This type of therapy can help the patient to learn to eliminate poor sleep habits, adjust lifestyle habits, and control worrisome thoughts that prevent a restful sleep.
Ambien, Lunesta and Sonata are used for sleep onset insomnia, while Ambien and Lunesta are recommended for sleep maintenance insomnia.
Clinicians can use the guidelines to determine the need for treatment, drug choices, as well as how to target therapy for sleep onset or sleep maintenance.
Several recommendations are also made of drugs to AVOID for sleep onset insomnia or maintenance including:
Finished: Insomnia Treatment: Non-Benzodiazepines Ambien, Lunesta & Sonata
- Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of Clinical Sleep Medicine. Vol. 13, No. 2, 2017. Accessed March 14, 2018 at http://www.aasmnet.org/Resources/pdf/PharmacologicTreatmentofInsomnia.pdf
- Skimp on Sleep and You Just May Wind Up Sick. Drugs.com. Consumer News. Accessed March 14, 2018 at https://www.drugs.com/news/skimp-sleep-you-just-may-wind-up-sick-64422.html
- Centers for Disease Control and Prevention (CDC). Data and Statistics. Getting Enough Sleep? Accessed March 14, 2018 at https://www.cdc.gov/features/dssleep/
- Institute of Medicine. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Washington, DC: The National Academies Press; Accessed March 14, 2018 at https://www.ncbi.nlm.nih.gov/pubmed/20669438
- Centers for Disease Control and Prevention MMWR. Accessed March 14, 2018 at http://www.cdc.gov/mmwr/PDF/wk/mm6008.pdf