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Comparison of Sleeping Pills: Which is The Best and The Worst?

Types of Sleeping pills
Non-Benzodiazepines
Zolpidem (Ambien)
Sonata (Zaleplon)
Lunesta (Eszopiclone)
Rozerem (Ramelteon)
Sedative Antidepressants
Comparison Chart
Head-to-Head Comparisons
Ambien vs Lunesta
Rozerem vs Non-Benzodiazepines
Trazodone vs Ambien

Based on "Sleep Disorders Medicine"
written by Dr. Sudhansu Chokroverty, MD

The best sleeping pills are the ones that work for you. Every person ambien, lunesta is different. So you may need to experiment to figure out which medication works best for you. When considering treatment for insomnia, the relative benefits and drawbacks of sleeping pills should be taken into account.

The purpose of this review is to help you choose the right medication. Here we compare the effectiveness and safety of sedative hypnotics.

Our analysis is based on the results of an examination of treatments for chronic insomnia by a group of medical experts from Oregon Evidence-based Practice Center3, clinical studies, and the medical literature.

Types of Sleeping pills

The following medications are discussed:

Non-Benzodiazepines (Z-Drugs):

Zolpidem (Ambien®)
Eszopiclone (Lunesta®)
Zaleplon (Sonata®)

Melatonin receptor agonists:

Ramelteon (Rozerem®)

Sedative antidepressants:

Check full list of sleep medications

Non-Benzodiazepines (Z-Drugs)

Non-benzodiazepine hypnotics currently approved in the United States: zolpidem (Ambien®, Ambien® CR), zaleplon (Sonata®), and eszopiclone (Lunesta®).
They are commonly called the "Z" drugs.
"Z" drugs work act in a similar way to benzodiazepines.
"Z" drugs have similar problems with long-term use as benzodiazepines: tolerance, rebound effects, and dependence.

Zolpidem (Ambien®)

Zolpidem (Ambien®), an imidazopyridine, is one of the most commonly prescribed drugs for insomnia. Zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines.

Zolpidem Efficacy & Benefits

Very effective. Good short term sleep aid that works for most people: hastens sleep onset, increases total sleep time and decreases the number of awakenings during the nights6. It works quickly within 15-30 min.

Many physicians consider zolpidem the best available hypnotic for short-term use when early awakening and cost are not problems.

Relatively mild next-day hangover. Zolpidem does not have that bad hangover effect that many other sleep aids have. It is less likely to cause marked residual daytime sedation than benzodiazepines4. However, zolpidem may cause grogginess if you sleep less than eight hours.

No active metabolite. Zolpidem does not accumulate in the body during repeated use. Therefore it is less likely to cause rebound insomnia7.

Less disruption of normal sleep architecture. Unlike the benzodiazepines, zolpidem has less or no disruption of sleep architecture. It does not interfere with sleep stages 3 and 4, nor does it decrease rapid-eye-movement (REM) sleep4-6.

Approved version for long-term use. Ambien CR, a time-release pill, is approved for long-term use. The medicine is delivered in two steps. The first layer dissolves quickly, allowing to fall asleep. The second layer helps stay asleep.

Regular Ambien is not approved for long-term use. According to the research, it may be used on an as-needed basis, with up to 5 times a week8. After 3 weeks, most people taking Ambien this way are able to reduce the intake by more than 25% without losing improvements in sleep.

Controlled-release version Ambien CR may theoretically be more effective for sleep maintenance than regular Ambien, but might also lead to more pronounced next day hangover.

Generic availability. Zolpidem is now available as a generic.

Zolpidem Drawbacks & Side effects

Abuse and Dependence. Is zolpidem addictive? Undoubtedly. Zolpidem main drawback is that it is habit-forming. But it is less addictive then benzodiazepines. The research provides strong evidence that zolpidem abuse and dependence potential is much lower than that of benzodiazepines9.

Rebound insomnia. You may have difficulty sleeping (rebound insomnia) after you stop taking the drug.

Withdrawal symptoms. Zolpidem is known to cause withdrawal symptoms in people who quickly stop the medicine after taking it regularly for a long time.

Tolerance problems. Zolpidem has a tendency to gradually lose its efficacy when taken nightly for longer than two weeks17.

Bizarre behaviours. Zolpidem can cause bizarre behavior (parasomnia) that goes beyond traditional sleep-walking, such as memory loss, sleep-cooking, night time snacking, making phone calls while asleep.

Increased risk of depression. Modern hypnotics zolpidem, zaleplon, eszopiclone, and ramelteon are found to increase the risk of developing depression12.

Driving impairment. On May 2013 U.S. FDA approved new, lower-dose labeling for zolpidem in an effort to decrease the likelihood of daytime drowsiness that could be a hazard while performing certain tasks such as driving37.

Parkinson's disease. Prolonged zolpidem use increases the risk of Parkinson's disease38.

Side effects: headache (19%); somnolence (15%); dizziness (12%); drowsiness (8%); nausea (7%); myalgia (7%); dyspepsia (5%); arthralgia, back pain (4%); hallucinations (4%); anxiety, disorientation, drugged feeling, fatigue, lethargy, memory disorders (3%).

Controlled substance. Zolpidem is classified as a schedule IV controlled substance (like benzodiazepines).

Zaleplon (Sonata®)

Zaleplon (Sonata®) is the weakest of the sedative pills with ultra-short half-life of about 1 hour. The drug may be taken at bedtime or later as long as the patient can sleep for at least 4 hours. Because zaleplon is rapidly eliminated from the body it may be best for people who have difficulty falling asleep, but not for those who wake up often throughout the night.

Zaleplon Efficacy & Benefits

Helps get to sleep. Sonata decreases the amount of time it takes to get to sleep. Sonata is removed from the body too quickly. So the drug neither increases total sleep time nor does it decrease the number of awakenings.

It works very quickly (within 10-20 minutes) and should be taken right before going to bed. Sonata has more rapid onset of hypnotic effect than zolpidem (Ambien).

Possible middle-of-the-night dosing. Zaleplon can be taken during the night if you have problems staying asleep11. The drug wears off in about four hours.

Low risk of next day hangover. It's one of the sleeping pills that supposedly does not triggers hangover or next day grogginess, even when taken in the middle of the night11. Zaleplon is metabolized much more quickly than other sleep aids, so is far less likely to leave you feeling sleepy in the morning.

Minimal-to-absent rebound insomnia. Another potential benefit is minimal rebound insomnia after discontinuation10.

Zaleplon Risks & Drawbacks

Side effects: headache, pain, and dizziness10, 16. If you have less than six hours to sleep, it is much more likely that you will still feel sedated or lethargic when you get up.

Food interaction. Zaleplon may not work well if it is taken after heavy or high fat foods.

Memory loss. There is a chance that you may experience a certain type of memory loss (amnesia). Memory impairment can usually be avoided by taking Sonata only when you are able to get 4 or more hours of sleep before you need to be active again.

Dependence. Zaleplon may cause dependence, especially if it has been used regularly for an extended time (more than a few weeks) or in high doses.

Withdrawal. Withdrawal symptoms may occur when the medication is stopped suddenly after being used daily for a long time. Such reactions can include unusual depressed or anxious mood, stomach cramps, vomiting, sweating, fatigue, irritability.

Tolerance. Sonata can lose its effectiveness if used for long periods of time.

Rebound insomnia. You may have more trouble falling asleep the first few nights after you stop taking Sonata than before starting this hypnotic.

Bizarre behaviours. Rarely Sonata can cause bizarre behavior (parasomnia), such as sleepwalking, sleep-eating, making phone calls, or having sex while not fully awake. Often, people do not remember these events.

Controlled substance. Sonata is classified as a Schedule IV controlled substance by federal regulation.

Increased risk of depression. May increase the risks of developing depression12.

Eszopiclone (Lunesta®)

Eszopiclone (Lunesta®) is a short acting non-benzodiazepine sedative hypnotic and belongs to the class of drugs known as cyclopyrrolones. Eszopiclone is the active stereoisomer of zopiclone.

Eszopiclone Efficacy & Benefits

Lunesta helps you to fall asleep and stay asleep. But it should only be used when you expect to get eight hours of rest. Lunesta takes effect within an hour and keeps working for about six hours.

Approved for long-term use. Unlike other sleep aids, eszopiclone can be taken on a long-term basis. It has the distinction of being approved for long-term use by the U.S. FDA. In clinical trials, patients used eszopiclone for up to 6 months15.

Mild next day hangover. At recommended doses, eszopiclone (despite its relatively long half-life) appear to cause less day-after grogginess than Ambien (zolpidem) or benzodiazepines.

Low risk of tolerance. Does not lose its effectiveness over time. Important advantage of Lunesta is that studies found that no tolerance to the drug develops13, 15.

Rebound insomnia. Relatively low risk of rebound insomnia31.

Eszopiclone is less likely than the benzodiazepines to change sleep patterns.

Eszopiclone has fewer anticholinergic side effects than racemic zopiclone.

Eszopiclone Risks & Drawbacks

Withdrawal. Although Lunesta is not a highly addictive substance stopping it abruptly can lead to withdrawal symptoms that include anxiety, unusual dreams, sweating, shakiness, fatigue.

Bizarre behaviours. There have been lots of documented cases of sleep walking, sleep driving, sleep-cooking, sleep-eating, and other bizarre behaviours after taking Lunesta.

Increased risk of depression. May increase the risks of developing depression12.

Bad taste. Leaves a unpleasant metallic taste (unrelated to the taste of the pill itself) in the mouth that is hard to get rid of.

Side effects: peculiar or bitter taste (17-34%), dizziness (5-7%), dry mouth (5-7%), drowsiness (4-9%)14.

Controlled substance. Lunesta (Eszopiclone) is classified as a Schedule IV controlled substance by federal regulation.

Ramelteon (Rozerem®)

Ramelteon (Rozerem®) is a melatonin receptor agonist. Rozerem works by interacting with melatonin receptors in the brain. It is specifically indicated for insomnia characterized by difficulty in falling asleep.

Ramelteon Efficacy & Benefits

Rozerem helps with sleep-onset problems but is not recommended for restarting sleep if you wake up during the night.

Ramelteon has a different mechanism of action from its competitors. While hypnotics work to slow down the central nervous system (act as a generalized CNS depressants at the GABA receptors), ramelteon instead mimics melatonin, a chemical that helps regulate the body's natural sleep-wake cycle.

However, as with the other sleeping pills, Rozerem will not address any underlying medical problem causing the insomnia.

Lack of abuse potential is the major benefit of Rozerem. Unlike many other hypnotics, ramelteon is not addictive -- clinical trials did not yield the evidence of physical dependence or abuse potential. This is good choice for people who have trouble falling asleep but do not want to risk having a dependence on a sleep aid.

Not a controlled substance. Rozerem is the only FDA-approved hypnotic that is not a controlled substance.

No withdrawal and rebound insomnia. Another good thing about Rozerem is lack of withdrawal symptoms and rebound insomnia after its discontinuation. In all clinical studies, no regimens of Rozerem produced evidence of rebound insomnia at any time point following treatment.

Rozerem is unlikely to cause the bizarre sleep-related behavior.

Ramelteon Risks & Drawbacks

Relatively weak sleeping aid. The main drawback of Rozerem is that it may not work sufficiently. Simply it is not as effective as sedatives in helping with insomnia. Other causes may be involved in insomnia that Rozerem doesn't address.

Sexual side effects. Rozerem can cause changes in certain hormone levels, including testosterone and prolactin18. These changes could lead to sexual side effects, including decreased libido, milk-like nipple discharge, fertility problems.

Expensive. Rozerem is not yet available as a generic.

Next-day drowsiness. Despite its claims, there are risks of drowsiness and lack of concentration after taking Rozerem.

Side effects: headache, fatigue, and somnolence.

Sedative Antidepressants

The sedating antidepressants most commonly used to help with sleep include trazodone (Desyrel®), amitriptyline (Elavil®), and doxepin (Sinequan®). They have been used for many years to promote sleep.

A major benefit of antidepressants is that these medicines are not potentially addictive and are not a controlled substances. And if you suffer from depression in addition to insomnia, the right antidepressant might effectively treat both conditions.

All of the low-dose sedating antidepressants have half-lives greater than the usual sleep period.

Trazodone Efficacy & Benefits

Trazodone is widely used for insomnia in the United States1.

Trazodone is good choice for those who suffer from mild depression and insomnia. It is especially effective for the treatment of insomnia caused by other antidepressants19.

Studies of people with various kinds of insomnia have found that main effect of trazodone on sleep architecture is an increase in slow-wave (stages 3 and 4) sleep20.

Unscheduled status. Unlike hypnotics, antidepressants have a lower potential for abuse or dependency35.

Perceived safety. Trazodone has a long safety record.

Inexpensive. Available as a generic formulation.

Low risk of daytime grogginess. Unlike benzodiazepine hypnotics, trazodone causes less performance-impairing effects21.

Trazodone Risks & Drawbacks

Day-time sedation. Even trazodone, the shortest-acting of sedating antidepressants and the least sedating, at a dose of 50 mg is associated with reports of daytime somnolence in 23% of patients compared with 8% for placebo.

Rebound insomnia. Trazodone has also been associated with rebound insomnia after withdrawal.

Side effects include drowsiness, dry mouth, nausea, vomiting, constipation, headache and blurred vision.

Drug-induced priapism can rarely occur in men.

Amitriptyline Efficacy & Benefits

Amitriptyline is commonly prescribed in low doses for insomnia.

In clinical trials amitriptyline increased total sleep time and decreased the number of awakenings during the night in depressed people24.
Additional benefit of providing some analgesic effect as compared to the hypnotics.
Very inexpensive.
Low rate of side effects when used in low doses.
Suitable for long-term treatment.

Amitriptyline Risks & Drawbacks

Strong anticholinergic properties and as a result severe anticholinergic side effects.
Tend to suppress REM sleep.
Cardiotoxicity.
Potentially lethal overdose.
Risk of weight gain.

Doxepin (Sinequan®)

Doxepin has long been known to have significant sleep promoting effects. Low dose doxepin is effective treatment for insomnia due to its sedating effects22. This antidepressant currently is being evaluated by the FDA for use as a possible insomnia treatment.

Doxepin Efficacy & Benefits

Doxepin 1 mg, 3 mg, and 6 mg is effective for people suffering from chronic insomnia23. All three doses improved wake time during sleep, total sleep time, and sleep efficiency relative to placebo.

Suitable for long-term treatment.

Doxepin Risks & Drawbacks

Cardiovascular side effects.
Potentially lethal overdose.
Substantial anticholinergic and sedative effects.

Key Points: Non-benzodiazepines vs Benzodiazepines

Newer-generation non-benzodiazepine hypnotics offer multiple advantages over traditional benzodiazepines, including:

Effectiveness. Ambien (zolpidem), Lunesta (eszopiclone), and Sonata (zaleplon) have efficacies similar to those of the hypnotic benzodiazepines in the management of insomnia33. For some people Rozerem (ramelteon) seems to be less effective than benzos and the Z drugs.
Addiction, abuse and dependence potential. All four of the newer medicines are less likely to cause dependence and abuse problems - and that may be their principal advantage over the older drugs25.
Withdrawal and rebound Insomnia. The risk for withdrawal symptoms, rebound insomnia, and tolerance is lower with non-benzodiazepine hypnotics than with benzodiazepines.
Next-day impairment. Another favorable feature of newer hypnotics is modest day-after psychomotor depression.
Sleep architecture. Unlike the benzodiazepines, non-benzodiazepines cause minimal disruption of sleep architecture.

Easy-to-understand comparison chart that covers important points to consider:

	Ambien (Zolpidem)	Ambien CR (Zolpidem CR)	Lunesta (Eszopiclone)	Sonata (Zaleplon)	Rozerem (Ramelteon)
Company	Sanofi-Aventis	Sanofi-Aventis	Sepracor	King	Takeda
FDA approval date	1992	2005	2004	1999	2005
How it works	Binds to a specific type of GABA receptor in the brain.	Binds to a specific type of GABA receptor in the brain.	Binds to a specific type of GABA receptor in the brain.	Binds to a specific type of GABA receptor in the brain.	Stimulates melatonin receptors in the brain area that controls the sleep-wake cycle.
Half-life	2.5	2.8	6	1	1-2.6
Helps You Fall Asleep?	Yes	Yes	Yes	Yes	Yes
Average Time to Fall Asleep	30 to 45 minutes	30 minutes	50 minutes	15-20 minutes	75 minutes
Helps You Stay Asleep?	Yes	Yes	Yes	No	No
Risk of Rebound Insomnia?	Yes	Yes	Yes	Low	No
Risk of Dependency	Yes	Yes	Yes	Yes	No
Generic	Yes	No	No	No	No

Head-to Head Comparisons

While Sonata (zaleplon) may be best indicated for the delayed onset of sleep, Ambien (zolpidem) and Lunesta (eszopiclone) may be better indicated for maintaining a complete night's sleep26.

Of the three, zaleplon has the shortest half-life, so it may be best when the main problem is getting to sleep, or when you don’t want to sleep for more than four or five hours (for example, on a cross-country airplane trip).

Ambien (zolpidem) vs Sonata (zaleplon)

Effectiveness: There is evidence that zaleplon is more efficacious than zolpidem for sleep latency (time to sleep onset)36, but zolpidem is more efficacious than zaleplon for sleep duration and sleep quality26.
Zaleplon has a more rapid onset of action and a shorter elimination half-life.
Ambien may be a better choice for those with difficulty falling and staying asleep.
Next-day effects: Zaleplon at recommended doses is free of residual hypnotic or sedative effects when taken as little as 2 h before waking. In contrast, residual effects of zolpidem are still apparent when the drug is taken 5 h before waking27.
Patient's preference: In general, most insomniacs are likely to prefer zolpidem to zaleplon28.

Ambien (zolpidem) vs Lunesta (eszopiclone)

Effectiveness: Indirect comparisons based on placebo-controlled trials29,30 provide evidence that the drugs are similar for sleep onset and sleep maintenance insomnia. However, eszopiclone may be more effective for increasing sleep duration.
Next-day effects: Some people find that Ambien causes more the next-day hangover effects32. Lunesta is much better in that aspect.
Rebound insomnia: The rebound insomnia is more common with Ambien than Lunesta31.
Tolerance: A significantly higher number of Ambien users report developing a tolerance to the drug than is the case with Lunesta15,17. Developing tolerance means that with regular use the drug loses its effectiveness and that increasing the dosage is required to maintain its effectiveness.
Bad taste: The most common side effect with Lunesta is an unpleasant metallic taste in the mouth.

Rozerem (ramelteon) vs Non-benzodiazepines

Effectiveness: Rozerem tends to be less effective than sedatives in helping with insomnia.
Mode of action: Rozerem works differently than other sleeping pills. While hypnotics work to slow down the central nervous system, Rozerem instead mimics melatonin.
Potential for abuse, addiction or dependency: Unlike many other hypnotics, clinical trials of Rozerem did not yield evidence of physical dependence or abuse potential.
Rozerem is not a controlled substance and is the first, and only, non-scheduled hypnotic that is FDA approved for insomnia.
Effect on reproductive hormones: Rozerem may affect the reproductive hormones by increasing prolactin and potentially decreasing testosterone levels. This may cause missed menstrual periods, nipple drainage, decreased sex drive, or problems getting pregnant.

Trazodone vs Ambien (zolpidem)

Effectiveness: Compared to trazodone, Ambien is somewhat more effective in treating insomnia34. However, as an antidepressant, trazodone has the advantage of treating insomnia while treating concurrent conditions like depression or psychological disorders. Ambien actually may increase the risk of developing depression.
Potential for abuse, addiction and dependency: Trazodone offers a lower potential for abuse or dependency in comparison with Ambien35.
Side effects: Ambien may cause memory loss (amnesia), parasomnias (such as sleepwalking, nocturnal eating), whereas trazodone can produce hypotension, constipation, and priapism.