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Sleeping Pills - Sedative Hypnotics Overview

What is insomnia?

Insomnia is an experience of inadequate or poor quality sleep as characterized by one or more of the following sleep complaints:

  • difficulty falling asleep
  • difficulty maintaining sleep
  • waking too early in the morning.

Insomnia is not a serious medical condition but it can greatly affect the person's work and social life.

What are Sleep medications

Sleep (sedative-hypnotic) medications are medicines that have been shown to reduce the length of time it takes to fall asleep or increase sleep duration. These medicines are usually taken at bedtime to relieve the symptoms of insomnia, although some newer medications may be appropriate for use on an "as needed" basis, whenever symptoms occur.

There are different classes of sedative-hypnotic medications. The most effective sleeping pills are benzodiazepines and a newer class of drugs known as non-benzodiazepine, benzodiazepine receptor agonists.

Sleep medication guidelines

Sleep medications may be taken when:

  • The cause of insomnia is determined and the medication is the best treatment option.
  • Sleep problems seriously affect daily activities.
  • Behavioral approaches have proven ineffective and the person is reluctant to try them.
  • Insomnia is transient or short-term (e.g. traveling across time zones).
  • Insomnia is associated with a known medical condition.

Treatment with medications should:

  • begin with the lowest effective dose
  • be short-term, if used nightly
  • be intermittent, if used long-term
  • be used only in combination with good sleep practices and behavioral approaches

Disadvantages of sleep medications

  • Sleep medications don't treat the causes of insomnia, therefore insomnia often returns after discontinuation of medication therapy
  • development of drug tolerance or dependence
  • reduced effectiveness of drug - most hypnotics lose effectiveness after 4-6 weeks of nightly use
  • physical side effects
  • potential interactions with alcohol or other medications
  • withdrawal symptoms
  • rebound insomnia

Advantages of sleep medications

  • appropriate and effective for transient or acute insomnia
  • work fast in improving sleep in the short-term
  • for chronic insomnia, sleep medications may be the preferred treatment for people who do not respond to CBT (cognitive-behavioral therapy) or for whom CBT is not available
  • easy to use, widely available, and cost effective
  • may prevent transient or acute insomnia form developing into chronic form

Benzodiazepines

Benzodiazepines, also referred to as benzodiazepine receptor agonists, were once the most commonly prescribed sedative hypnotics. These drugs were originally developed in the 1960s to treat anxiety. They have since proven effective and safe.

The main difference among benzodiazepines is length of effect, which depends on drug half-life. Long-acting benzodiazepines cause a lot of next morning sedation. Short-acting benzodiazepines cause a higher rate of rebound insomnia after discontinuation. Short-acting benzodiazepines are particularly useful for travelers who want to reduce the effects of jet lag. Long-term use (sometimes even after a few weeks) is associated with dependence and withdrawal syndrome.

Long acting benzodiazepines include: flurazepam (Dalmane), clonazepam (Klonopin), quazepam (Doral).

Medium- to short-acting benzodiazepines include triazolam (Halcion), lorazepam (Ativan), alprazolam (Xanax), temazepam (Restoril), oxazepam (Serax), prazepam (Centrax), estazolam (ProSom), and flunitrazepam (Rohypnol).

Benzodiazepines are potentially dangerous when used in combination with alcohol, and have potential to interact with other medications.

Rebound insomnia, the most common withdrawal symptom, usually occurs on the first night and sometimes the second night after stoping benzodiazepine. In some cases people may experience the return of original severe insomnia. Rebound insomnia is less common with long-acting medications.

Non-Benzodiazepines - Short-acting sedative-hypnotics

In the late 1980s a newer class of medications, known as non-benzodiazepine, benzodiazepine receptor agonists were introduced for the treatment of insomnia. The drugs in this class are as effective as the benzodiazepines in promoting sleep. Both benzodiazepine (BZD) and non-benzodiazepine (non-BZD) hypnotics act on GABA-A receptor sites in the brain. However, non-benzodiazepines are believed to have very low risk of abuse or dependence and fewer side effects.

From an efficacy standpoint, there are no clinical trials that show non-BZDs are more effective than the BZDs.

These drugs are very effective for preventing jet lag, however zolpidem (Ambien) should not be used on flights less than 7 - 8 hours. They also may be helpful for people with concomitant mood disorders, such as depression.

The risk for dependence, tolerance, withdrawal symptoms, and rebound insomnia is lower with non-benzodiazepines than with benzodiazepine hypnotics. Also, non-benzodiazepines generally cause less disruption of sleep architecture than benzodiazepines.

As with any hypnotics, alcohol increases the sedative effect of these drugs. These sleep medications also interact with other drugs, including rifampin, ketoconazole, erythromycin, and cimetidine.

Ramelteon (Rozerem)

Ramelteon (Rozerem) was approved by the FDA in July 2005. Rozerem is a novel non-benzodiazepine hypnotic. Rozerem is the first insomnia medication in a new drug class known as the melatonin receptor agonists.

Unlike other sleep medications, Rozerem works by mimicking the actions of melatonin in the body. Melatonin is a hormone released by the brain that is believed to be important in the sleep-wake cycle. Rozerem also differs from other sleep medications because in clinical studies, it has demonstrated no abuse potential, no withdrawal syndrome and no rebound insomnia. These findings led to Rozerem's market approval without a controlled designation. All other sleep aids have a Schedule IV designation, indicating a low, yet recognizable risk of abuse/addiction.

Rozerem may be particularly suitable for adolescents, who don't usually do well on benzodiazepines. It may be the medication of choice for elderly people who have reduced melatonin and trouble falling asleep.

Rozerem is not the best choice for severe insomnia or insomnia associated with depression or anxiety. Development of tolerance hasn't been seen but there are no very long studies. It may be helpful if added on to other sleeping pills when they are not fully effective.

Rozerem has the following advantages over the other benzodiazepines and non-benzodiazepines:

  • specifically targets brain structures responsible for the sleep-wake cycle.
  • the first and only prescription sleep medication that has shown no evidence of abuse, dependence or withdrawal, and unlike other sleep medications is not a controlled substance
  • is approved by the FDA for long-term treatment in adults
  • has been shown to be safe in older adults, as well as those with mild-to-moderate chronic obstructive pulmonary disease (COPD) and mild-to-moderate sleep apnea.

Because of its specific mechanism of action, Rozerem may not be the best medication for persons who need sleep promptly because it takes time for the drug to begin working.

Zolpidem (Ambien)

Zolpidem (Ambien) is one of the most commonly prescribed drugs for insomnia.

Large study demonstrated that the drug may be used on an as-needed basis, with up to 5 tablets taken a week1. After 3 weeks, two-thirds of the patients taking zolpidem this way were able to reduce their tablet intake by more than 25% without losing improvements in sleep.

Zolpidem (Ambien) has a rapid onset of action and a half-life of only 1.5- 2.5 hours. This means that it may be taken later in the night when having trouble falling asleep without worrying about residual cognitive impairment the next morning. Ambien decreases sleep latency and increases total sleep time. Unlike nonselective -benzodiazepines, Ambien does not decrease REM or sleep.

Ambien could be less useful if you tend to wake up frequently in the middle of the night.

Zaleplon (Sonata)

Zaleplon (Sonata) is the shortest-acting non-benzodiazepine. Its half-life is just one hour. That means you can try to fall asleep on your own. Then, if you're still staring at the clock at 2 a.m., you can take it without feeling drowsy in the morning. The drug takes effect within 30 minutes and may be taken at bedtime or later as long as you can sleep for at least 4 hours. However, if you tend to wake during the night, this might not be the best choice for you.

Sonata appears to have a better safety record than other hypnotics and may be particularly useful for patients in the younger and older age groups.

Eszopiclone (Lunesta)

Eszopiclone (Lunesta) is a new, non-benzodiazepine hypnotic approved by the FDA in December 2004. It may help persons who have trouble falling asleep, wake frequently during the night, or wake up too early in the morning. Eszopiclone is related to zopiclone (Imovane), which has been used for many years in Europe.

Unlike other sleep medications, Lunesta can be taken on a long-term basis. In clinical trials, patients used Lunesta for up to 6 months.

Of all the new sleeping pills approved so far, Lunesta has the longest half-life (about 6 hours) and is FDA approved for sleep maintenance.

Comparison of Non-Benzodiazepines

Ambien
(Zolpidem)
Sonata
(Zaleplon)
Lunesta
(Eszopiclone)
Rozerem
(Ramelteon)
Indications short-term treatment of insomnia short-term treatment of insomnia short-term treatment of insomnia (difficulty falling asleep and sleep maintenance) treatment of insomnia characterized by sleep onset difficulty
Half life 2.8 hours 1 - 2 hours 6 hours 1 - 2.5 hours
Pregnancy category B C C C
Legal status Schedule IV Schedule IV Schedule IV Non-Scheduled
Risk of dependency Yes Yes Yes No
Percent
with next-day
drowsines
2-3%
5%
8-10%
5-6%
Risk of
rebound
insomnia?
Yes No Yes No
Average time to fall asleep 33 to 46 minutes 36 to 55 minutes 50 minute 75 minutes
Duration short ultra-short intermediate short
Sleep Maintenance +/- No +++ No

Sedating Antidepressants

Sedating antidepressants are medications that have been developed for the treatment of depression, but that are known to have sedative side effects. These medications have been used for many years to promote sleep. The sedating antidepressants most commonly used include trazodone (Desyrel), nefazodone (Serzone), amitriptyline (Elavil), nortriptyline (Pamelor), and doxepin (Sinequan).

Benefits of these antidepressants include:

  • they are non-addictive
  • provide some analgesic benefit as compared to the hypnotic class of medications (which have no pain relieving properties)
  • do not produce physical dependence or tolerance
  • generally have a low incidence of side effects, especially when used in low doses.

Trazodone

During last few years there have been a remarkable rise in the off-label use of trazodone for sleep problems in non-depressed patients, to a degree that it is prescribed for this purpose as commonly as the popular hypnotics. Trazodone also decreases the insomnia caused by selective serotonin reuptake inhibitors and is a good choice for depressed patients with difficulty sleeping.

Trazodone is not associated with tolerance or dependence. Trazodone does not affect sleep latency but does decrease REM sleep and may be associated with significant rebound insomnia. It has an advantage over benzodiazepines in that it does not cause respiratory depression and anticholinergic effects. Priapism is a rare, but potentially serious side effect of trazodone and may limit its use in men. Trazodone may induce arrhythmias, primarily in persons with histories of cardiac disease.

References

  • 1. Hajak G, Cluydts R, Declerck A, Estivill SE, Middleton A, Sonka K, Unden M. Continuous versus non-nightly use of zolpidem in chronic insomnia: results of a large-scale, double-blind, randomized, outpatient study. Int Clin Psychopharmacol. 2002 Jan;17(1):9-17.

Last updated: March 2010

Interesting Facts

sleep medications facts
  • Approximately 70 million people in the United States are affected by a sleep problem. About 40 million Americans suffer from a chronic sleep disorders, and an additional 20-30 million are affected by intermittent sleep-related problems. However, an overwhelming majority of sleep disorders remain undiagnosed and untreated (National Commission on Sleep Disorders Research, 1992).
  • According to the National Sleep Foundation's 2001 Sleep in America poll, nearly seven out of 10 Americans said they experience frequent sleep problems, although most have not been diagnosed.
  • Motherhood seems to lead most women to develop a high sensitivity to the sounds of their children, which causes them to wake easily. Women who have had children sleep less efficiently than women who have not had children. Some researchers believe that many women never unlearn this sensitivity and continue to wake easily long after the children have grown.
  • Sleep medications can be habit forming and often do not treat the specific cause of the insomnia.