The sleep-medication families: what the research says about each

All sleep articles

By Small Hours · Last reviewed

Gloved hands sorting several different kinds of tablets and capsules into separate small trays on a bright white counter

Sleep medicines fall into a handful of families, and the research on each is different. The major guidelines agree on the frame: CBT-I first, and medication as a short-term, shared decision when CBT-I alone is not enough. [1][3] Within that frame, the prescription sleeping pills do help people fall asleep sooner, by about 22 minutes on average in the trial data, at the cost of dependence, next-day effects and changed sleep structure. [5][11][15] Several of the medicines most often used for sleep in Canada, including trazodone, quetiapine, mirtazapine and the drowsy antihistamine in Gravol, have never been approved for insomnia and have thin or negative trial evidence. [19][20][23][33] In adults over 65, every one of these families appears on a list of medicines to avoid. [7] Please do not stop or change any medicine on your own. Talk with your doctor or pharmacist first.

This article gives no doses, no products to choose and no schedules for stopping, because those belong to your prescriber and your situation. It is a field guide to what the research says about each family, so that a conversation with your prescriber starts from the same facts. For how the pills compare with CBT-I, see CBT-I versus sleeping pills; for what happens when people reduce them with supervision, see coming off sleeping pills.

What the research says

The guidelines put medication second and short. The American College of Physicians recommends CBT-I as the initial treatment for all adults with chronic insomnia (a strong recommendation) and, if that alone is not enough, a decision made together with the patient that weighs what a short course of medication offers against its harms and cost (a weak one). [1] The 2023 European guideline says the same, allowing benzodiazepines, Z-drugs, daridorexant and low-dose sedating antidepressants for four weeks or less, orexin antagonists for up to three months or longer in some cases, and stating that antihistamines and antipsychotics are not recommended. [3] The largest comparison of sleep medicines, a 2022 network meta-analysis of 154 trials and 44,089 people, found that benzodiazepines, zolpidem, zopiclone, eszopiclone, lemborexant and doxylamine beat placebo for short-term treatment, that zopiclone and zolpidem caused about twice as many dropouts for side effects as placebo, and that long-term data exist for only two drugs and are of very low certainty. [5] In adults aged 60 and over, pooling 24 trials, sleeping pills added about 25 minutes of sleep over placebo while adverse cognitive events were 4.78 times and daytime fatigue 3.82 times as common; the authors concluded the benefits may not justify the risks in that age group. [6] In plain terms, the medicines work modestly in the short term, nobody has good long-term data, and the older you are the worse the trade.

The studies behind this
  • American College of Physicians guideline (Qaseem, 2016): recommendation 1, CBT-I as the initial treatment for all adults with chronic insomnia disorder (strong recommendation, moderate-quality evidence). Recommendation 2, when CBT-I alone has not worked, decide together with the patient whether to add a drug, after talking through what short-term medication offers, what it risks and what it costs (weak recommendation, low-quality evidence). [1]
  • American Academy of Sleep Medicine guideline (Sateia, 2017): reviews individual drugs rather than families. Every drug-specific recommendation is weak: "suggest use" (versus no treatment) for suvorexant, eszopiclone, zaleplon, zolpidem, triazolam, temazepam, ramelteon and doxepin; "suggest not use" for trazodone, diphenhydramine, melatonin, tiagabine, tryptophan and valerian. It states that a weak recommendation "should not be construed as an indication of ineffectiveness", and explains that the evidence is downgraded because most drug trials are industry-funded, few, and inconsistent. Zopiclone was not among the drugs reviewed. [2]
  • European Insomnia Guideline (Riemann, 2023): CBT-I first-line for adults of any age (grade A). When it is not sufficiently effective, benzodiazepines, Z-drugs, daridorexant and low-dose sedating antidepressants can be used for short-term treatment (four weeks or less); orexin receptor antagonists for up to three months or longer in some cases; prolonged-release melatonin for up to three months in people 55 and over. Antihistamines, antipsychotics, fast-release melatonin, ramelteon and herbal products are not recommended (grade A). [3]
  • Canadian deprescribing guideline (Pottie, 2018): groups benzodiazepines and Z-drugs together as benzodiazepine receptor agonists, says they are associated with harms and that their therapeutic effect might be short term, and recommends offering a slow, supervised taper to adults 65 and over regardless of duration of use, and to adults 18 to 64 who have used them for more than four weeks. [4]
  • Network meta-analysis (De Crescenzo, 2022): 154 double-blind randomised trials, 30 interventions, 44,089 participants. For short-term treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem and zopiclone were more effective than placebo with high-to-moderate certainty. Zopiclone and zolpidem caused more dropouts due to adverse events than placebo. For long-term treatment only eszopiclone and lemborexant had data, both very low certainty, and lemborexant's safety data were inconclusive. Trazodone, daridorexant and suvorexant "can be effective" short term but with poor tolerability or missing long-term data. [5]
  • Older adults (Glass, 2005): 24 randomised trials, 2,417 people aged 60 and over, benzodiazepines and Z-drugs pooled. Total sleep time rose by 25.2 minutes over placebo and night-time awakenings fell. Adverse cognitive events were 4.78 times as common (95% CI 1.47 to 15.47), adverse psychomotor events 2.61 times, and daytime fatigue 3.82 times (1.88 to 7.80). The authors wrote that in people over 60 "the benefits of these drugs may not justify the increased risk". [6]
  • Beers Criteria (American Geriatrics Society, 2023): the standard list of medicines to avoid in adults 65 and over. It says "Avoid" (moderate evidence, strong recommendation) for benzodiazepines, for the Z-drugs eszopiclone, zaleplon and zolpidem, for first-generation antihistamines (naming diphenhydramine, dimenhydrinate and doxylamine), and for antipsychotics outside their approved uses. The Z-drug entry reads "minimal improvement in sleep latency and duration". Designed for the United States; zopiclone, which is not sold there, is not named. [7]

Benzodiazepines

Temazepam, lorazepam, clonazepam, triazolam and their relatives. Some are approved for sleep and others for anxiety or seizures but prescribed for sleep anyway. They work in the short term: the network meta-analysis ranks them among the drugs that beat placebo for acute insomnia with high-to-moderate certainty, and the American guideline gives weak "suggest use" recommendations for temazepam and triazolam. [2][5]

The costs are the reason every guideline limits them. Since 2020 every benzodiazepine sold in the United States carries a boxed warning for abuse, addiction, physical dependence and withdrawal; the FDA states that physical dependence can develop within days to weeks even when taken as prescribed, that stopping abruptly or reducing too quickly can cause withdrawal reactions including life-threatening seizures, and that combining them with opioids, alcohol or other sedatives has caused severe breathing suppression and death. [13] Among people prescribed opioids, a current benzodiazepine prescription was associated with 3.86 times the risk of overdose death, rising with the amount taken. [14] In a sleep-laboratory meta-analysis, tolerance with continued use and intense first-night rebound insomnia were clear for triazolam. [16] In adults over 60, benzodiazepines carried 1.57 times the odds of a fall. [9] Canada's deprescribing guideline recommends that adults 65 and over be offered a slow, supervised taper regardless of how long they have taken one. [4]

Z-drugs

Zopiclone, zolpidem, eszopiclone and zaleplon are approved for insomnia and are the most-studied sleep medicines. In the trials submitted to the US regulator for zolpidem, eszopiclone and zaleplon, the drugs shortened measured time to fall asleep by about 22 minutes compared with placebo; the authors called the drug effect "of questionable clinical importance" on its own, with much of the total response coming from the placebo effect. [15] The network meta-analysis confirms that zolpidem, zopiclone and eszopiclone beat placebo short term, and that zopiclone and zolpidem had roughly twice the dropouts for side effects. [5]

Canada is a zopiclone country, and that matters. In Manitoba, Z-drug prescribing was about 99% zopiclone, and the share of adults receiving one more than doubled from 2.0% to 4.8% between 2001 and 2016 while the share receiving a benzodiazepine edged down from 9.3% to 8.1%. [18] Yet zopiclone is the Z-drug with the least evidence: the American guideline did not assess it, the sleep-laboratory meta-analysis found its tolerance and rebound data "insufficient" and "inadequate", it was not in the regulator trial data above, and the Beers list does not name it. [2][7][15][16] The best-studied Z-drugs are not the one most Canadians take.

Three harms are specific enough to name. Complex sleep behaviours, meaning sleepwalking, sleep-driving and similar acts with no memory of them, led the US regulator in 2019 to add its strongest warning to zolpidem, eszopiclone and zaleplon after reviewing 66 serious cases including 20 deaths, and to rule that a prior episode means the drug must not be used again; a third of the cases had had an earlier episode on a Z-drug. [17] New users of zolpidem had 2.20 times the crash risk of non-users in a study of 409,171 drivers, a risk the authors equate to a blood alcohol level between 0.06% and 0.11%. [10] And in adults 65 and over, the Beers Criteria say to avoid them, with adverse effects similar to benzodiazepines (delirium, falls, fractures, crashes) and "minimal improvement in sleep latency and duration". [7] Canada's guideline treats them exactly as it treats benzodiazepines. [4]

Trazodone

Trazodone is an antidepressant. Its use for insomnia is off-label and, by one review's account, now exceeds its use for depression. [21] The American guideline suggests against it for insomnia (a weak recommendation). [2] A meta-analysis of seven placebo-controlled trials (429 people) found better perceived sleep quality and fewer awakenings, but no significant improvement in sleep efficiency, time to fall asleep, total sleep time or time awake during the night. [19] The Cochrane review reached the same place: a small subjective benefit from three trials, little or no difference on sleep recordings, and low-quality evidence of more morning grogginess, dry mouth and thirst than placebo. It also notes that no antidepressant is licensed for insomnia. [20] The network meta-analysis puts it among drugs that "can be effective" short term but with poor tolerability or missing long-term data. [5]

Its adverse effects are listed as drowsiness, headache, dizziness and dry mouth, with less common orthostatic hypotension (a blood-pressure drop on standing, particularly in older people or those with heart disease), QT prolongation on the heart tracing, and rare priapism. [22] New trazodone users had 1.91 times the crash risk of non-users in the driving study above. [10] It does not appear on the Beers list. [7]

Quetiapine and other antipsychotics

Quetiapine is approved for schizophrenia, bipolar disorder and depression, and is sedating, which is why it is prescribed for sleep. In Canada, quetiapine prescriptions written by family doctors rose 300% between 2005 and 2012, and recommendations of it for sleep disturbances rose ten-fold, almost all from family physicians. [25]

The trial evidence for insomnia on its own is close to empty. The entire randomised evidence is one two-week trial of 13 people, rated very low quality, which found no significant benefit over placebo; a second review counts two trials totalling 31 patients and concludes that its benefit "has not been proven to outweigh potential risks", even in people who have a psychiatric reason to take it. [23] At the low amounts used for sleep, follow-up data showed significant weight gain, and case reports include fatal liver toxicity, restless legs and akathisia (an inner restlessness). [24] In older adults, antipsychotics carried 1.59 times the odds of a fall. [9] The European guideline says antipsychotics are not recommended for insomnia; the Beers Criteria say to avoid them outside their approved uses; and Choosing Wisely Canada's psychiatry list says not to use them routinely for primary insomnia in any age group, because of weight gain and metabolic harm even at the amounts used for sleep. [3][7][26]

Mirtazapine

Mirtazapine is an antidepressant whose strong antihistamine action makes it sedating. Until 2025 there was essentially no placebo-controlled evidence for it in insomnia without depression: the Cochrane review found no eligible trial. [20] Two trials have since been published. In 60 adults aged 65 and over, four weeks of mirtazapine lowered insomnia severity more than placebo, but 6 of 30 people on the drug stopped because of side effects against 1 of 30 on placebo. [27] In 80 adults in general practice, low-dose mirtazapine beat placebo at six weeks, with 52% improved against 14%, but from 12 weeks on there was no difference, and the authors do not support prescribing it for months. [28]

Two harms are well documented. Among antidepressants, mirtazapine and the tricyclics are linked to the greatest weight gain, and the strength of a drug's antihistamine action, the same property that makes it sedating, is the best predictor of that weight gain. [29] In a prospective series of people starting antidepressants, mirtazapine provoked or worsened restless legs in 28% of them, the highest of the drugs studied, usually in the first days. [30] Restless legs is itself a cause of poor sleep, so a sleep aid that triggers it can worsen the problem it was prescribed for.

Antihistamines, including Gravol

Diphenhydramine (Benadryl, Nytol, and the "PM" in many night-time pain and cold products), doxylamine, and dimenhydrinate, which is sold in Canada as Gravol, are first-generation antihistamines whose drowsiness side effect is used as a sleep aid without a prescription. Gravol is diphenhydramine combined, roughly half and half, with 8-chlorotheophylline, a caffeine-like compound that blocks adenosine receptors and is included to partly offset the drowsiness; a Gravol taken for sleep is, in effect, Benadryl with a mild counter-sedative built in. [34][36]

The benefit is small and short-lived. In 184 adults with mild insomnia, diphenhydramine gave a modest subjective improvement over 14 days with no measurable change on sleep recordings. [32] In a crossover study of healthy men, its sedating effect was indistinguishable from placebo by the fourth day of twice-daily use: tolerance was complete within about three days. [31] A systematic review of over-the-counter sleep aids found only three qualifying diphenhydramine trials, no doxylamine trial, and concluded that diphenhydramine lacks robust evidence of efficacy and safety. [33] The American guideline suggests against diphenhydramine; the European guideline says antihistamines are not recommended. [2][3] One nuance: the network meta-analysis did find doxylamine beat placebo for short-term use. [5]

The concern in older adults is anticholinergic load. The Beers Criteria name diphenhydramine, dimenhydrinate and doxylamine as medicines to avoid in people 65 and over, because they are highly anticholinergic, clearance falls with age, tolerance develops when they are used as a sleep aid, and cumulative anticholinergic exposure is associated with falls, delirium and dementia. [7] In a study of 3,434 older adults in which first-generation antihistamines were among the most-used anticholinergic medicines, about three years of daily anticholinergic use was associated with a 54% higher dementia rate; the lowest level of use showed no increase. [35] That finding is for the whole anticholinergic family, not for the sleep aids alone; the dementia question for sleeping pills as a whole is in sleeping pills, insomnia and dementia.

The newer prescription options

Dual orexin receptor antagonists block the brain's wake-promoting signal rather than sedating it. In Canada, lemborexant (Dayvigo) has been marketed since November 2020 and daridorexant (Quviviq) since July 2023; suvorexant (Belsomra) was on the Canadian market only briefly in 2019 and 2020 and its listings are cancelled. Low-dose doxepin (Silenor), a tricyclic antidepressant at a tiny fraction of its antidepressant amount, has been marketed since 2013. Ramelteon has no Canadian listing. [36]

The evidence is promising and incomplete. Lemborexant beat placebo short term with moderate-to-high certainty and was one of only two drugs with any long-term data, but its safety data were inconclusive; daridorexant and suvorexant "can be effective" short term but with poor tolerability or missing long-term data; doxepin was well tolerated but its efficacy data were scarce. [5] The Cochrane review found moderate-quality evidence that low-dose doxepin modestly improves sleep quality and adds about 23 minutes of sleep. [20] The American guideline gives weak "suggest use" recommendations for suvorexant and doxepin for staying asleep, and the European guideline allows orexin antagonists for up to three months or longer in some cases. [2][3] Whether the orexin drugs avoid the dependence and sleep-structure costs of the older families over years of use is not something any study we found can answer.

Sedation is not the same as sleep

The claim that sedation is not the same as sleep can be checked on sleep recordings, and it holds. A systematic review of benzodiazepines found they increase stage-2 (light) sleep and reduce stages 3 and 4 (deep sleep) and REM sleep, and the authors note the extra light sleep "may lead to a subjective improvement of sleep quality with no awakenings". [11] In a 2025 Montreal study of 101 older adults, long-term users of benzodiazepines or Z-drugs had less deep sleep and more of the lightest sleep on recordings than people with untreated insomnia and than good sleepers. [12] So a medicated night can feel more solid while containing less of the deep sleep that restores. That study compared groups at one point in time and cannot show that the drugs caused the difference.

Older adults

Every family above appears on the Beers list for people 65 and over: benzodiazepines, Z-drugs, first-generation antihistamines and antipsychotics outside approved uses, each "Avoid" on moderate evidence with a strong recommendation. [7] Choosing Wisely Canada's geriatrics list says not to use benzodiazepines or other sedative-hypnotics as first choice for insomnia in older adults, citing large studies in which crashes, falls and hip fractures leading to hospital or death more than doubled, and summarising the trial evidence as a number needed to treat of 13 against a number needed to harm of 6. [8] The pooled trials behind that summary are the ones above: 25 minutes more sleep, cognitive side effects 4.78 times as common. [6] In the falls meta-analysis, sedatives and hypnotics (1.47), benzodiazepines (1.57), antidepressants (1.68) and antipsychotics (1.59) each raised the odds of falling. [9]

For clinicians

The guideline frame is consistent across the ACP, AASM and the 2023 European guideline: CBT-I first, pharmacotherapy as a time-limited shared decision, and every drug-specific AASM recommendation weak, which the guideline says reflects industry funding, few trials and heterogeneity rather than proof of ineffectiveness. [1][2][3] The Canadian specifics worth having at hand: zopiclone dominates Z-drug prescribing (about 99% in Manitoba) and is the least-studied Z-drug, absent from the AASM review, the FDA trial dataset and the Beers list; [2][7][15][18] family-physician quetiapine prescribing rose 300% between 2005 and 2012 with a ten-fold rise for sleep, against a randomised evidence base of 13 people; [23][25] the two 2025 mirtazapine trials show benefit at four to six weeks that is gone by twelve, with a 6-of-30 discontinuation rate for adverse effects in the older-adult trial. [27][28] The Canadian deprescribing guideline (Pottie and colleagues, 2018) is the starting point for benzodiazepines and Z-drugs; it covers no other family. [4] Choosing Wisely Canada's geriatrics and psychiatry lists are the Canadian statements on sedative-hypnotics in older adults and on antipsychotics for primary insomnia. [8][26] Health Canada's Drug Product Database is the authority on what is marketed here; as of this article's review date, lemborexant and daridorexant are, suvorexant is not, and ramelteon has no listing. [36] Small Hours has a page for clinicians whose patients use the program.

Where the evidence is thin

  • Long-term trial data exist for two drugs only, and are of very low certainty. Every family's long-term picture rests on observational studies. [5]
  • Zopiclone, the Z-drug most Canadians take, has the least trial evidence of any Z-drug. [2][15][16][18]
  • The quetiapine evidence in primary insomnia is one 13-person trial. [23]
  • The mirtazapine trials are two, recent, small, and run four to twelve weeks. [27][28]
  • The antihistamine tolerance study was in healthy men taking the drug twice a day for four days; once-nightly use in people with insomnia may differ. [31]
  • The anticholinergic-dementia finding is for a family of drugs, not for over-the-counter sleep aids on their own. [35]
  • The older-adult trial figures pool benzodiazepines and Z-drugs, and the Beers Criteria were designed for the United States. [6][7]
  • The orexin antagonists are too new for anyone to know their long-term profile. [5]

Where does this leave you?

If you take one of these medicines, nothing here is a reason to stop it tonight. Stopping some of them suddenly can be dangerous, and the research on reducing them is about supervised, gradual change. [4][13] What this article gives you is the vocabulary for the conversation: which family yours belongs to, what the trials found, and what the guidelines say about how long it was meant to be used. If sleep problems have lasted months, the first-line treatment in every major guideline is CBT-I. Small Hours turns a nightly sleep diary into a six-week CBT-I program built around your own sleep. It gives no medication advice and works alongside the care you already have. You can sign up at trysmallhours.com.

When should you talk to a doctor?

  • Before changing any sleep medicine, and especially before stopping a benzodiazepine or Z-drug, because abrupt withdrawal can cause seizures. [13]
  • If you take a sleep medicine with an opioid, alcohol or another sedative. [13][14]
  • If you have sleepwalked, eaten, driven or done anything else with no memory of it after taking a sleeping pill. [17]
  • If you are 65 or over and taking any medicine in this article, to ask whether it is still the right choice. [7][8]
  • If a sleep aid has started restless, crawling feelings in your legs at night. [30]
  • Low mood or anxiety that comes with the poor sleep. If you are in distress in Canada, call or text 9-8-8 at any hour.

General education, not medical advice.

References

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This article is general education, not medical advice. It cannot diagnose anything or replace a conversation with your doctor. Read how we choose and check sources on the how we write page.

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