What are prescription sleep medications proven to do?

Pharmaceutical sleep aids were created as a solution to improve sleep for those suffering from insomnia and other sleep disorders. If these sleep disorders could all be fixed with stress reduction exercises, patients wouldn’t need to take any medication. 

Prescription drugs specifically created to treat insomnia are known as hypnotics. Hypnotics are usually prescribed in cases where insomnia is causing serious impairment. 

The problem lies in the quality of sleep provided by these hypnotics. For those suffering from ongoing sleep problems, hypnotics provide sedation, however, this is not the same as healthy sleep. 

Considering that every prescription has risks and benefits, are hypnotics worth it? Let’s take a look at the research and risks of each of the popular medications in the main sleep medication classes.

The comparative effect of the drug against a control group

First, let’s discuss the importance of clinical trials (and how they are set up) in determining the effectiveness of these prescription sleep medications. Drug trials are organized so that the medication can be tested through a variety of trials. With this information, drug trials determine how successful medication is against a control group. A control group consists of patients not taking medication. 

For a medication to be deemed successful, the experiments have to prove that an isolated compound is able to provide a statistically significant improvement compared to placebo. A placebo is a pill given to a test group that has no medicinal properties — it’s basically a sugar pill. 

Drug trials are important because they offer a point of comparison between drugs and supplements against a placebo. These trials can even include alternative treatments. An example of this might be individuals that do guided meditation to address insomnia in sleep studies versus those who don’t do a guided meditation.

Having a control group and a placebo gives us the opportunity to look at the efficacy of different types of treatments.

The Non-Benzodiazepines Known as the ‘Z-Drugs’

Z drugs are now the most commonly prescribed hypnotic agents worldwide. However, there are some trials that show that Z drugs weren’t always more effective than placebos. Z drugs are the non-benzodiazepine hypnotic drugs (including eszopiclone [Lunesta], zaleplon [Sonata], and zolpidem [Ambien]). 

As benzodiazepine receptor agonists, these medications target the GABA (γ aminobutyric acid) receptor, which is known to help improve quality of sleep. Let’s take a look at each of the Z-drugs and see what the research says about their impact on sleep. 

Eszopiclone (Lunesta)

This prescription sleep medication is usually prescribed by a doctor for sleep onset and sleep maintenance insomnia. It’s available in 1mg, 2mg, and 3mg tablets.[4] 

Eszopiclone is the only hypnotic with FDA approval for use longer than 35 days.  It has demonstrated effectiveness for six months of therapy in one clinical trial although there is some decrease in benefit over time.[5]  

It has been shown to improve the time it takes to fall asleep by 14 minutes, improves total sleep time by 28-57 minutes, and decreases the number of nocturnal awakenings. Quality of life measures such as vitality and overall functioning was improved also in the 2 mg group of one clinical trial.[6,7,8]

The major side effect is a metallic taste in the mouth.[7] Compared to the other Z-drugs, it also has a higher potential for creating next-day drowsiness. According to a study conducted by McCrae, eszopiclone has not yet evaluated for transient insomnia in older adults, it has been shown to be safe and effective for short-term treatment (2 weeks) of insomnia in older adults (64–91 years). Clinical studies in younger adults (mean = 44 years) have shown eszopiclone can be used longer (6–12 months).[8]

Zolpidem (Ambien)

Zolpidem is a commonly-prescribed sleep medication that is used to treat sleep onset and sleep maintenance insomnia.[9][10] Zolpidem starts working within 10-30 minutes and has a long-acting formulation (controlled release) that may help individuals stay asleep longer.[11] 

Based on its clinical trials, zolpidem decreases the time it takes to fall asleep by five to 12 minutes, improves total sleep time by up to 29 minutes, improves sleep quality, and increases stage 2 sleep.[12][13] Unlike benzodiazepines that have a similar mechanism of action, Zolpidem does not appear to significantly reduce slow-wave sleep or REM sleep.[14]  

Zolpidem demonstrates tolerance or rebound even after five weeks of continuous use at recommended dosages. It also has a high incidence of causing drowsiness the next day. Other commonly reported side effects include dizziness, weakness, nausea, headache, upset stomach, feeling "drugged" or light-headed.[13]

Zaleplon (Sonata) 

Zaleplon is usually prescribed on a short-term basis and is intended to help you fall asleep faster and reduce the number of nighttime awakenings. [11][15] It is available in five and 10mg capsules. Zaleplon has the shortest circulation time of the three, with a half-life of about one hour, so repeated administration after nighttime awakenings is sometimes necessary. 

For this reason, zaleplon is best taken to help initiate sleep rather than maintain it. According to a review of its clinical trials, it improves the time to fall asleep by 10 minutes and increased total sleep duration by up to 40 minutes.[11][15] 

Some common side effects include dizziness, drowsiness, short-term memory impairment, and coordination problems. As a result of its short half-life, zaleplon is not associated with severe next-day side effects. After discontinuation, rebound effects can occur that can prolong the time it takes to fall asleep, reduce total sleep time, and increase the number of nighttime awakenings. 

The downsides of Z-drugs

There are also many studies that show the adverse effects of Z drugs. These negative side effects can include: cognitive effects (such as memory loss), psychomotor effects (such as falls, fractures, road traffic crashes), daytime fatigue, tolerance, and addiction. These are similar to the side effects you would find while taking benzodiazepines. [19, 20, 21, 22]

In 2019 the FDA began requiring a black box warning on these Z drugs due to the numerous risk factors. 

According to one study, Ambien, in particular, had a lot of negative side effects. Sleepers found that they suffered from movement-based parasomnias, hallucinations, and suicidality. These issues were reported more often by male subjects. Non-movement-based parasomnias and amnesias were more common in females.[11]

When taking these sleep aids, It is highly recommended not to drink alcohol. However, there are numerous cases where patients have disregarded this advice. This would affect the data gathered in these reports about adverse events. 

There is also a lack of clinical information about how other medical conditions interact with these drugs. Some of these conditions could include: depression, restless legs syndrome, epilepsy, and dementia, all of which are associated with some of the adverse drug reactions described.

A study published in 2009 demonstrated that hypnotics were associated with a 44% increased risk of infections compared to a placebo group. However, most of these infections were mild. The drugs eszopiclone and zolpidem individually were associated with increased instances of  infections, while zaleplon and ramelteon were not. Patients taking these two drugs saw esophageal reflux and aspiration into the lungs, as well as depressed immune function.[15]

Benzodiazepines

Benzodiazepines are a class of drugs prescribed for symptoms of insomnia, but also anxiety disorders, seizures, and drug withdrawals. They act on specific receptors in the brain called gamma-aminobutyric acid-A (GABAA) receptors. Benzodiazepines attach to these receptors and enhance the signaling of GABA, which produces its calming, muscle relaxing, and sleep-promoting effects. 

Benzodiazepines are prescribed for short-term sleep difficulties because their long-term use is associated with significant abuse potential. Most studies evaluating the use of benzodiazepines for insomnia have therefore been between two to four weeks in length. In general, these drugs, especially when used in the long term, may carry undesirable side effects such as memory impairment, dizziness, confusion, and impaired coordination. 

There are a wide variety of benzodiazepines with varying half-lives, but benzodiazepines used for treating insomnia on a short-term basis include quazepam (Doral), lorazepam (Ativan), temazepam (Restoril), flurazepam (Dalmane), estazolam (ProSom), and triazolam (Halcion). We will take a look at a few of the most commonly prescribed for insomnia. 

Temazepam (Restoril) 

Temazepam is prescribed for sleep onset and sleep maintenance insomnia. It is used in doses ranging from 7.5mg to 30mg for short-term insomnia (usually seven to 10 days). The average half-life of temazepam is about nine hours, so commonly reported side effects include next-day grogginess, drowsiness, headache, dizziness, lethargy, dry mouth, nausea, and more. 

In its clinical trials, temazepam has been shown to decrease the time it takes to fall asleep by 11.6 minutes and decrease wakefulness after sleep onset by 23.7 min. High doses (30mg) have been found to suppress slow-wave sleep with no effect on REM sleep.[18] 

Flurazepam (Dalmane)

Flurazepam (Dalmane) is usually used on a short-term basis to treat sleep onset and sleep maintenance insomnia. Doses between 15 and 30mg are commonly used. According to the available literature, flurazepam has been found to decrease the duration of stage 1 NREM sleep, increase time spent in stage 2 NREM sleep, and reduce total time in slow-wave sleep.

Flurazepam has been found to cause either slight reductions or no change in REM sleep percentage.[18] Common side effects of flurazepam include confusion, dizziness, daytime drowsiness, memory impairments, and trouble standing or walking.

Triazolam (Halcion)

Triazolam (brand name Halcion) is prescribed for short-term insomnia, as well as convulsions, seizures, and anxiety. It is mostly prescribed for sleep-onset insomnia because it is fast-acting and has a very short half life. For this reason, insomnia sufferers who wake up in the middle of the night or awaken early would not benefit from this benzodiazepine. 

Clinical trials have demonstrated that triazolam is effective in doses ranging from 0.5 to 1mg in reducing the time it takes to fall asleep by approximately nine minutes. In one study comparing CBT with triazolam, triazolam initially was more effective in decreasing sleep latency, but its efficacy decreased by the second week of treatment. Similar to the above benzodiazepines, triazolam decreases stage 1 NREM, increases stage 2 NREM, and suppresses slow-wave sleep.[20]

Halcion's side effects include depression, anxiety, confusion, dependency, rebound insomnia, dizziness, and drowsiness. Similar to the other benzodiazepines, abrupt cessation of use after repeated administration can cause rebound insomnia.

The risks associated with benzodiazepine use

While benzodiazepines can be effective in promoting and maintaining sleep, there are many risks to consider before trying them. All of the discussed benzodiazepines carry the potential for adverse side effects. Apart from a next-day hangover effect, dizziness, confusion, vision problems, impaired coordination, and memory problems are all common. 

The hypnotic properties of the drug have also been associated with reductions in memory consolidation, possibly by decreasing the quality and duration of slow-wave sleep.[21] Since benzodiazepines act on GABA signaling like alcohol, they should never be taken together or it could cause severe side effects like overdose, respiratory depression, and coma. 

Perhaps the most pressing problem in all of the benzodiazepines discussed is the serious potential for dependency. With dependency comes the need for increasingly higher doses of the drug, which can increase the chance of life-threatening withdrawal symptoms upon discontinuation or fatal overdoses.

For all ages, alprazolam and diazepam were listed as two of the top ten drugs causing overdose deaths from 2010-2014. Alprazolam was in the top five consistently.[21]

Benzodiazepine misuse is a growing problem in the older adult population in particular. Older adults are more likely to have insomnia and be in need of a sleep aid. They are also more susceptible to side effects and adverse reactions.

Memory and other cognitive functions might be affected. The risk of falls and hip fractures, as well as traffic accidents, increase with the use of these prescribed medications.[22]

Benzodiazepine and opioid prescription misuse has increased for those older than 65 years  since they are using these substances without medical indication (taking higher than the recommended dose, taking a drug prescribed for another person, drug-induced assault, or misuse or abuse).[31][32] Additionally, benzodiazepine use in older adults has been linked to activity limitations and a higher risk of dementia.[32]  

Antidepressants

Doxepin (Silenor)

Doxepin is a tricyclic antidepressant sometimes used as a sleep medication. Doxepin produces its drowsy effects primarily by blocking histamine in the body. Doxepin is often prescribed for sleep maintenance insomnia in low doses ranging from 3-6mg.

Clinical studies have shown the efficacy of low dose doxepin for alleviating symptoms of insomnia for up to four weeks. In particular, it has been shown to increase sleep efficiency and improve total sleep time by 26-32 minutes. It is available as a low strength brand name product, but generic alternatives with different strengths do exist. 

Given doxepin’s low dose in its use for insomnia, it isn’t associated with any concerning adverse side effects but may produce a hangover-like effect the next morning. Doxepin has the potential to cause urinary retention with higher doses or people with a history of urinary retention. [1][23]

Amitriptyline (Elavil)

Amitriptyline is another tricyclic antidepressant that is FDA-approved to treat depression but also commonly prescribed off-label for insomnia, migraines, and neuropathic pain. For sleep, it is typically prescribed in doses ranging from 50-100mg. 

Amitriptyline works by increasing levels of the neurotransmitters serotonin and epinephrine to help improve sleep, pain, and depression. Its drowsy effects may also be due to its histamine-blocking action. Amitripytiline’s long half-life of 12-24 hours is a helpful property for sleep, particularly sleep maintenance. 

Clinical trials have found that amitriptyline can promote sleep, especially in patients with depression and fibromyalgia. Long-term administration of amitriptyline in depressed patients has been found to increase total sleep time and slow-wave sleep while reducing the time it takes to fall asleep. However, amitriptyline is associated with REM sleep suppression.[24] 

Possible side effects of this drug include dry mouth, headache, weight gain, tremor, trouble urinating, dizziness, and blurry vision. Amitriptyline contains a black box warning from the FDA, which means it is associated with an increased risk of suicidal thoughts and behaviors. 

The downsides of tricyclic antidepressants for sleep

Tricyclic antidepressants such as doxepin and amitriptyline are associated with unpreferable changes in sleep architecture. specifically REM sleep suppression. As a consequence, these drugs tend to change both the intensity and frequency of dreaming, as well as a REM rebound effect that produces intense dreams upon discontinuation.[24] 

Additionally, all antidepressants have potentially significant adverse effects. Overall, there are not many studies that currently support their use for chronic insomnia. 

Melatonin Receptor Agonists

Ramelteon (Rozerem)

Ramelteon (Rozerem) is a melatonin receptor agonist, which means it binds to and activates melatonin receptors. Melatonin is a naturally-produced hormone that promotes tiredness and regulates our sleep-wake cycles. While melatonin can be supplemented in its synthetic form, its effectiveness appears to be minimal. It appears to slightly reduce the time it takes to fall asleep and therefore may be more useful for circadian rhythm dysfunctions stemming from things like jet lag or doing shift work.[26]

Ramelteon reduces the time to fall asleep by an average of nine minutes and increases sleep periods.[25] However, patient evaluations of improved sleep are inconsistent. Ramelteon has not been studied in patients with depression, anxiety, shift work, or jet lag.[26] Serious adverse effects from ramelteon are rare, affecting less than one percent of patients. 

Common side effects include daytime sleepiness, headache, fatigue, nausea, and dizziness. The metabolism of ramelteon is in the liver. This medication can also cause an increase in serum prolactin (best known as the hormone that creates breast milk) and can decrease testosterone levels. [1][25][26] Since Ramelteon has shown no evidence of abuse or dependence, it is the only non-restricted drug for insomnia per the Drug Enforcement Agency (DEA).

Orexin Receptor Antagonists

Belsomra (Suvorexant) 

Belsomra is one of the newest insomnia drugs approved by the FDA. It is an orexin receptor antagonist, which means it blocks the action of orexin. Orexin is a chemical that promotes wakefulness in the brain. Belsomra is prescribed for sleep onset and sleep maintenance insomnia and has been shown to improve the time to fall asleep by 10 minutes.

Belsomra is available as five, 10, 15, and 20 mg tablets. However, there is a potential for next-day drowsiness with higher doses, especially given its long half-life of 12.2 hours. Belsomra usually starts working within one hour and is well tolerated. Reported side effects include drowsiness, sedation, sleep paralysis, vivid dreams, muscle weakness, and headache. [27][30]

Why and how do doctors prescribe hypnotics?[1]

When doctors do prescribe medications for sleep, they follow this protocol to address specific behaviors, circumstances, and underlying disorders contributing to the symptoms of insomnia.

  • Prescribe the hypnotic at the lowest effective dose.
  • Prescribe the hypnotic for short durations (two to four weeks) and intermittently.
  • Avoid hypnotics or use caution if the person has a history of substance abuse, respiratory impairment, or stroke.
  • Monitor for requests for refills, increase in dose, unable or unwilling to taper or discontinuing the drug.
  • They should be discontinued gradual with a monitored taper and keep a lookout for adverse effects like worsening insomnia or withdrawal.

Generally, non-pharmacological approaches are considered first for treating insomnia or combined with pharmacological approaches in chronic and/or severe cases. 

Non-pharmacological treatments may include cognitive-behavioral therapy, which can help change incorrect beliefs and attitudes about sleep, exercise, relaxation therapy (biofeedback, hypnosis, meditation, yoga), sleep restriction, stimulus control therapy, and regularizing one’s sleep schedule.[37]

Would you rather take sleep aids or not?

When weighing the benefits of sleep medication it’s important to understand all the information. For example, would you rather forgo REM sleep, risking the many side effects of prescription sleep aids in exchange for falling asleep 10 minutes earlier? 

If you do decide the risk-benefit ratio for you deems them worth trying, keep in mind that most medical professionals generally advise their use on a short term basis only. Most of the studies on the drugs overviewed above have been in short-term trials. When the trials have assessed long-term use (as in eszopiclone), the treatment efficacy normally drops off with time. 

Besides this, long-term use is associated with the possibility of more severe side effects, including rebound side effects upon discontinuation. It’s worth mentioning again that in the case of benzodiazepines, there is a high potential for abuse in the long term, along with very severe withdrawal side effects if these drugs aren’t tapered correctly.

References

  1. Leopando ZE, Dela Cruz A, Limoso DD, Marcos JA, Alba ME. Clinical practice guidelines on the diagnosis and management of insomnia in family practice: part 2. Asia Pacific Fam Med. 2003;2:45–50.
  2. Buscemi N, Vandermeer B, Friesen C, Bialy L, Tubman M, Ospina M, et al. Manifestations and management of chronic insomnia in adults. Evid Rep Technol Assess (Summ). 2005;125:1–10.
  3. Glass J , Lanctot KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331:1169.
  4. Erman M, Rosenberg R, Caron J. Polysomnographic and patient-reported evaluation of the efficacy and safety of eszopiclone in elderly subjects with chronic insomnia. Sleep. 2004;27:A257–8.[Google Scholar] [Ref list]
  5. Krystal AD, Walsh JK, Laska E, Caron J, Amato DA, Wessel TC, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep. 2003;26:793–9.
  6. McCrae, C. S., Ross, A., Stripling, A., & Dautovich, N. D. (2007). Eszopiclone for late-life insomnia. Clinical interventions in aging, 2(3), 313–326. 
  7. Eszopiclone (Lunesta), a new hypnotic.Obstet Gynecol. 2005 Aug; 106(2):398-401.
  8. Zammit GK, McNabb LJ, Caron J, et al. Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia. Current Medical Research and Opinion. 2004;20:1979–91. [PubMed] [Google Scholar]
  9. Toner LC, Tsambiras BM, Catalano G, Catalano MC, Cooper DS. Central nervous system side effects associated with zolpidem treatment. Clin Neuropharmacol. 2000;23:54–8.
  10. Scharf MB, Roth T, Vogel GW, Walsh JK. A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry. 1994;55:192–9.
  11. Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet. 2004;43:227–38
  12. Monti JM. Effect of zolpidem on sleep in insomniac patients. Eur J Clin Pharmacol. 1989;36:461-466.
  13. Wong, C. K., Marshall, N. S., Grunstein, R. R., Ho, S. S., Fois, R. A., Hibbs, D. E.,  Saini, B. (2017). Spontaneous Adverse Event Reports Associated with Zolpidem in the United States 2003-2012. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 13(2), 223–234. doi:10.5664/jcsm.6452
  14. Blois R, Gaillard JM, Attali P, Coquelin JP. Effect of zolpidem on sleep in healthy subjects: a placebo-controlled trial with polysomnographic recordings. Clin Ther. 1993;15:797–809. 
  15. Joya, F. L., Kripke, D. F., Loving, R. T., Dawson, A., & Kline, L. E. (2009). Meta-analyses of hypnotics and infections: eszopiclone, ramelteon, zaleplon, and zolpidem. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 5(4), 377–383.
  16. Roth, T., Hartse, K. M., Saab, P. G., Piccione, P. M., & Kramer, M. (1980). The effects of flurazepam, lorazepam, and triazolam on sleep and memory. Psychopharmacology, 70(3), 231–237.
  17. Buscemi N, Vandermeer B, Friesen C, Biali L, Tubman M, Ospina M, et al. Manifestations and management of chronic insomnia in adults. Evidence report/technology assessment no. 125. AHRQ Publication no. 05-E021-2. Rockville, Md.: Agency for Healthcare Research and Quality, 2005.
  18.  Mitler MM, Carskadon MA, Phillips RL, et al: Hypnotic efficacy of temazepam: a long-term sleep laboratory evaluation. British Journal of Clinical Pharmacology 8:63S-68S, 1979
  19. Kales, J., Kales, A., Bixler, E., & Slye, E. S. (1971). Effects of placebo and flurazepam on sleep patterns in insomniac subjects. Clinical Pharmacology and Therapeutics, 12(4), 691-697.
  20. McClusky HY, Milby JB, Switzer PK, Williams V, Wooten V. Efficacy of behavioral versus triazolam treatment in persistent sleep-onset insomnia. Am J Psychiatry 1991;148:121-6.
  21. Nowell PD, Mazumdar S, Buysse DJ, Dew MA, Reynolds CF III, Kupfer DJ. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA. 1997;278:2170–7.
  22. Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ. 2000;162:225–33.
  23. Glass J, Lanctot KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ2005;331:1169.
  24. Riemann D, Velthaus S, Laubenthal S, Müller WE, Berger M. REM-suppressing effects of amitriptyline and amitriptyline-N-oxide after acute medication in healthy volunteers: results of two uncontrolled pilot trials. Pharmacopsychiatry. 1990;23:253–258
  25. Nguyen NN, Yu SS, Song JC. Ramelteon: a novel melatonin receptor agonist for the treatment of insomnia. Formulary. 2005;40:146–55.
  26.  Ward CR. Ramelteon (Rozerem) for insomnia. Am Fam Physician. 2006;73:1437–8
  27. Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open 2012;2:e000850.
  28. McCall WV, D’Agostino R Jr, Dunn A. A meta-analysis of sleep changes associated with placebo in hypnotic clinical trials.Sleep Med2003;4:57-62.
  29. Belanger L, Vallieres A, Ivers H, Moreau V, Lavigne G, Morin CM. Meta-analysis of sleep changes in control groups of insomnia treatment trials. J Sleep Res2007;16:77-84.
  30. Morin AK. Strategies for treating chronic insomnia. Am J Manag Care. 2006;12(8 suppl):S230–45.
  31. Koechl B, Unger A, Fischer G. Age-Related aspects of addiction. Gerontology. 2012;58(6):540–544. doi: 10.1159/000339095.Age-related. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  32. Mcinnes E, Powell J. Drug and alcohol referrals : are elderly substance abuse diagnoses and referrals being missed ? 1994;308(February):444–446. [PMC free article] [PubMed] [Google Scholar]
  33. Centers for Disease Control and Prevention. Emergency Department Visits Involving Nonmedical Use of Selected Prescription Drugs—United States, 2004–2008. Morb Mortal Wkly Rep. 2010;59(23):705–709.[PubMed] [Google Scholar]
  34. National Institutes of Health State of the Science Conference Statement. (2005). Sleep, 28(9), 1049–1057.
  35. Huedo-Medina, T. B., Kirsch, I., Middlemass, J., Klonizakis, M., & Siriwardena, A. N. (2012). Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ (Clinical research ed.), 345, e8343. doi:10.1136/bmj.e8343
  36. Maree, R. D., Marcum, Z. A., Saghafi, E., Weiner, D. K., & Karp, J. F. (2016). A Systematic Review of Opioid and Benzodiazepine Misuse in Older Adults. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 24(11), 949–963. doi:10.1016/j.jagp.2016.06.003
  37. D. Ramakrishnan, K,  Scheid, D. Treatment Options for Insomnia, Am Fam Physician. 2007 Aug 15;76(4):517-526.