Insomnia Treatment: Ambien, Lunesta and Sonata (Nonbenzodiazepines)
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on May 17, 2021.
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. The COVID pandemic has worsened sleep for many adults due to concern over viral status, anxiety, and social isolation.
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 take a deep dive into the 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) notes that lack of sleep has become a public health crisis. Daytime sleepiness has been linked with car accidents, industry disasters, and work-related errors.
How many are affected? 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.
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.
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, grief due to loss 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, increased errors or accidents.
- Worring about getting adequate sleep
- Having trouble concentrating.
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's sleep.
It is always important to first review your pre-bedtime routine, caffeine use, and other lifestyle issues.
- keep a regular bed and awake time
- avoid electronics use close to bedtime
- keep the room dark and at a comfortable temperature
- limit caffeine-containing drinks after lunch and heavy meals in the evening
- skip excessive alcohol at night, which can lead to middle-of-the-night awakenings
- engage in exercise earlier in the day, rather than late at night
- 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 Causes Insomnia?
Insomnia is not always just due to that extra cold brew late in the day. Health conditions can lead to trouble with a restful night, too. These include:
- obesity, diabetes or overactive thyroid
- sleep apnea or asthma
- overactive bladder
- chronic pain
- gastroesophageal reflux disease (GERD)
- depression, anxiety, PTSD
- restless leg syndrome
- Parkinson's disease, Alzheimer's disease or other dementias
- overactive thyroid
- chronic respiratory disorders such as asthma
Long-term insomnia can also be a result of: stress at work or in family life, travel schedule, shift changes or frequent jet lag, poor habits around bedtime (electronics, eating, drinking alcohol, uncomfortable environment), daytime naps, nicotine, and some medications.
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 and medications.
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. However, warnings for the nonbenzodiazepines were updated by the FDA in 2019 to warn of unusual, sleep-related side effects.
- Non-benzodiazepines or the "Z-drugs" (i.e., Lunesta, Ambien, and Sonata)
- Benzodiazepines (i.e, Ativan, Valium, Halcion)
- Melatonin agonist ramelteon (Rozerem)
- Low-dose doxepin (Sinequan) or trazodone (Desyrel), both classified as antidepressants.
Over-the-counter (OTC) antihistamines such as diphenhydramine (Benadryl) and doxylamine (Unisom) are included in many OTC treatments, but they may be associated with next-day side effects like sedation, impaired driving, dry mouth, and dizziness. It's best to avoid regular use of diphenhydramine for sleep. It has anticholinergic side effects that can pose a variety of risks, especially in the elderly. The Beers Criteria recommends against use of these drug in the elderly to promote sleep.
The American Academy of Sleep Medicine does not recommend the use of trazodone, diphenydramine or melatonin for treating ongoing (chronic) insomnia.
The Nonbenzodiazepines: Overview
Nonbenzodiazepines ("Z-drugs") for insomnia include:
These drugs are not benzodiazepines and are not structurally similar but can lead to a similar level of dependence. 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. They can differ in their length of action, available dosage forms, and costs.
All three drugs now have at least one generic formulation available and can save considerable money over their brand-name counterparts. See the Drugs.com Pricing Guide to review costs.
How Do The Nonbenzodiazepines Drugs Work?
Nonbenzodiazepines interact with benzodiazepine-like receptors, but are structurally different from the true benzodiazepines.
These sleep medicines work by slowing activity in the brain to allow sleep. 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 -- with no memory of the event -- have been documented.
Reported activities include:
- driving a car (“sleep-driving”)
- making and eating food
- talking on the phone
- having sex
These risks are greatly increased when the nonbenzodiazepines are combined with alcohol or other sedating drugs; their combined use should be strictly avoided.
Fatal events have been reported. In April 2019, the FDA updated the boxed warnings, their most prominent safety warning, on this medication class to warn of these complex sleep-related behaviors and associated injuries and death. Discontinue any non-benzodiazepine immediately if a patient experiences a complex sleep behavior.
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 the lower-dose generic form of Intermezzo. The brand name product Intermezzo has been discontinued.
The generic form of Intermezzo is a lower dose, sublingual (under-the-tongue) form of zolpidem tartrate (1.75 mg/tablet for women, 3.5 mg/tablet for men) and is specifically designed for middle-of-the-night awakenings when at least 4 hours can be devoted to sleep. The recommended doses for women and men differ as women clear zolpidem from the body more slowly than men.
All other forms of zolpidem 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 Label
In 2013, the FDA required the manufacturers of all zolpidem-containing products (except the brand Intermezzo, which is now discontinued) to lower the dose for women and to suggest lower doses for men in the labeling. The recommended initial doses for women and men are different because zolpidem clearance is lower in women.
- 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, those taking other CNS depressants, debilitated and those with liver impairment.
- For men under 65 years of age, providers should consider prescribing lower doses, as recommended by the FDA.
- Lower doses of CNS depressants may be necessary when combined with zolpidem.
- The patient should not take zolpidem if they drank alcohol that evening or before bed.
- Do not use zolpidem again in patients who report complex sleep behaviors.
Lower strengths of sublingual zolpidem tartrate are specifically for middle-of-the-night awakening. 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. Dosing should be followed closely.
- Sublingual 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. It is NOT used for middle-of-the-night 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). You should be able to devote 7-8 hours of sleep each night that you take it. Zolpimist works 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. As with other zolpidem products, the recommended initial doses for women and men are different because zolpidem clearance is lower in women. Administer Zolpimist on an empty stomach.
One 4.5 mL bottle of Zolpimist contains 30 sprays and is costly compared to generic zolpidem tablet formulations. Zolpimist runs about $340 per bottle (or more) for patients who do not have insurance. The manufacturer, Aytu BioSciences, 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). People must be able to devote 7 to 8 hours to sleep after taking Lunesta. Sleep onset is rapid in 15 to 30 minutes.
Eszopiclone is the S-isomer derivative of zopiclone. Zopiclone is not commercially available in the US.
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 (potent CYP3A4 inhibitors). Do not exceed 2 mg per dose in the elderly or debilitated patients.
Sleep-related behaviors are also a risk with Lunesta; this risk is increased if Lunesta is combined with alcohol or other sedating drugs. Do not take Lunesta if you drank alcohol that evening or before bed. Avoid taking Lunesta with a heavy, high-fat meal.
Generic Lunesta is now available in pharmacies. Look for discount coupons for the lowest prices.
- 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.
- Do not use zaleplon in patients with severe liver disease.
- 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.
- 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.
An initial dose of 5 mg should be used in patients taking cimetidine (Tagamet HB), 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 screen, and remember, do not combine drugs for sleep with alcohol, other sedating drugs or any illicit substance.
Orexin Antagonists: Belsomra and Dayvigo
Merck's orexin receptor antagonist 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. The maximum dose is 20 mg once per day at bedtime.
Metabolism by CYP3A is the major elimination pathway for suvorexant. Drug interactions may occur with certain CYP enzymes; do not use Belsomra with strong 3A4 inhibitors.
Belsomra can cause next-day drowsiness and impaired driving, especially at the highest 20 mg dose. Side effects may be more prominent in obese women at higher doses.
Although Belsomra was not included in the FDA's 2019 updated boxed warning about complex sleep-related behaviors, these behaviors are still outlined in the package insert for Belsomra, and prescribers should use caution and warn patients of these possible side effects.
In December 2019, Eisai's Dayvigo (lemborexant), also a C-IV controlled substance, was approved by the FDA. Dayvigo is another orexin receptor antagonist used to treat adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance (falling asleep and/or staying asleep).
Guidelines from AASM and Long-term Use
The American Academy of Sleep Medicine (AASM) has 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.
Of the nonbenzodiazepines, Ambien, Lunesta and Sonata are recommended for sleep onset insomnia, while Ambien and Lunesta are recommended for sleep maintenance insomnia in the guidelines.
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:
A 2021 observational study in JAMA Open also found that there was no difference in the effectiveness of long-term use of prescription sleep medications on sleep disturbances when compare to women who did not use such therapies. Many, if not all, of these women should have received CBT-I.
Finished: Insomnia Treatment: Ambien, Lunesta and Sonata (Nonbenzodiazepines)
Trouble falling or staying asleep is one of the most common medical complaints. Sometimes, just a few simple changes in lifestyle can make a big impact so you can get the shut-eye you need.
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- A Patient’s Guide to Understanding Treatment of Chronic Insomnia in Adults using Medications. American Academy of Sleep Medicine (AASM). Accessed May 17, 2021 at https://j2vjt3dnbra3ps7ll1clb4q2-wpengine.netdna-ssl.com/wp-content/uploads/2019/11/Pharma-Insomnia-Patient-Guide.pdf
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