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Research · Medication

Zolpidem

Pooled trials found zolpidem, eszopiclone and zaleplon shortened the time to fall asleep by about 22 minutes against placebo, with smaller and less consistent gains in total sleep. FDA's boxed warning covers sleepwalking and sleep-driving that have caused injuries and deaths. Next-morning impairment, fractures in older adults and withdrawal symptoms are also documented.

Add to Bio HackChecked 2026-11-13
Status
Prescription drugs in the US and Schedule IV controlled substances. Zolpidem is FDA-approved for the short-term treatment of insomnia marked by trouble falling asleep, zaleplon for the short-term treatment of insomnia, and eszopiclone for insomnia. All three labels carry a boxed warning for complex sleep behaviors.
Also called
zolpidem tartrate, Ambien, Ambien CR, Edluar, Zolpimist, Intermezzo, eszopiclone, Lunesta, zaleplon, Sonata, Z-drugs, nonbenzodiazepine hypnotics, sedative-hypnotics, sleeping pills
Taken for
sleep, insomnia, falling asleep faster, staying asleep

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help4

Reported risks20

What people take it for, and what was found

Shown to help4

Strong

Falling asleep faster

Shown to shorten the time to fall asleep by about 22 minutes on sleep-lab recordings in adults with insomnia, an effect the authors called small.

The numbers and sources
Effect
In 13 placebo-controlled trials submitted to FDA, eszopiclone, zaleplon and zolpidem together shortened sleep latency on polysomnography by 22 minutes (95% CI 11 to 33), with the 95% CI of the standardized mean difference running from -0.57 to -0.16. Self-rated sleep latency improved less (SMD -0.33, 95% CI -0.62 to -0.04). Latency fell more with larger doses, longer treatment, younger or female participants, and zolpidem [1]. A meta-analysis of 6 trials found one month of zolpidem reduced sleep latency against placebo [2]. In adults aged 60 and older, zaleplon reduced measured sleep onset latency by 21.63 minutes and self-rated latency by 15.86 minutes against control [3]. Across 75 sleep laboratory studies, zolpidem showed significant initial efficacy, with marginal tolerance over intermediate and long-term use [4].
Population
4,378 participants in 13 trials [1]; 1,068 patients with insomnia disorder in 6 trials [2]; 5,917 older adults in 24 articles [3]; 1,276 people in 75 studies, 804 of them with insomnia [4].
Sources
[1], [2], [3], [4]
Caveats
The authors of [1] described the drug effect as small and of questionable clinical importance, and noted that the placebo response accounted for much of the total improvement. The abstract of [2] gives no effect sizes. Most trials lasted days to weeks.
Moderate

Self-rated sleep quality

Shown to improve self-rated sleep quality over placebo in short trials of eszopiclone and zolpidem, by more than zaleplon, melatonin or ramelteon.

The numbers and sources
Effect
In a network meta-analysis of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem and zopiclone each improved self-rated sleep quality more than placebo (SMD range 0.36 to 0.83, certainty high to moderate). Benzodiazepines, eszopiclone, zolpidem and zopiclone improved it more than melatonin, ramelteon and zaleplon (SMD 0.27 to 0.71, certainty moderate to very low). Zolpidem caused more dropouts due to adverse events than placebo (OR 1.79, 95% CI 1.25 to 2.50) [8]. One month of zolpidem improved sleep quality against placebo in a second meta-analysis [2]. In people aged 60 and over, sedative hypnotics of all kinds improved sleep quality with an effect size of 0.14 [5].
Population
44,089 adults with insomnia disorder in 154 double-blind trials of 30 interventions [8]; 1,068 patients in 6 trials [2]; 2,417 participants aged 60 or over in 24 studies [5].
Sources
[8], [2], [5]
Caveats
The SMD ranges cover several drug classes, and the abstract does not give the figure for each Z-drug. Data on zaleplon were described as scarce [8]. The effect in older adults was small [5].
ModerateVery common

Insomnia treated for six months or longer

Shown to keep improving sleep against placebo across 6 to 8 months of use in four trials of eszopiclone and zolpidem in adults with chronic insomnia.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Over 6 months of nightly eszopiclone 3 mg, sleep latency, wake time after sleep onset, total sleep time and sleep quality all stayed better than placebo at every month (P 0.003 or lower), with no evidence of tolerance [9]. In a second 6-month trial, Insomnia Severity Index scores fell below clinically meaningful levels in 50% on eszopiclone and 19% on placebo [10]. Extended-release zolpidem 12.5 mg taken 3 to 7 nights a week was rated as helping sleep by 89.8% at week 12 against 51.4% on placebo, and by 92.3% against 59.7% at week 24 [11]. Over 8 months of nightly zolpidem, total sleep time and sleep efficiency rose and sleep latency and wake after sleep onset fell against placebo on sleep-lab recordings at months 1 and 8 [12]. In a network meta-analysis of long-term treatment, eszopiclone improved sleep quality more than placebo (SMD 0.63, 95% CI 0.36 to 0.90) and more than zolpidem (SMD 0.60, 95% CI 0.00 to 1.20), both rated very low certainty [8].
Population
788 adults aged 21 to 69 with primary insomnia, 593 on eszopiclone [9]; 830 adults with primary insomnia [10]; 1,018 adults aged 18 to 64, 669 on zolpidem [11]; 91 adults aged 23 to 70 with primary insomnia [12]; long-term trials within 154 pooled trials [8].
Sources
[9], [10], [11], [12], [8]
Caveats
In the 8-month trial, self-rated sleep did not differ between zolpidem and placebo [12]. In the 6-month eszopiclone trial, 12.8% on the drug and 7.2% on placebo left because of an adverse reaction [7]. The zolpidem label describes its supporting trials as 4 to 5 weeks long and its approved use as short-term [13].
Limited

Brain injury and movement disorders

Limited evidence: case reports and small trials described brief improvements, lasting 1 to 4 hours, in some people with disorders of consciousness or movement disorders.

The numbers and sources
Effect
A systematic review found 67 studies of zolpidem for neurologic conditions other than insomnia: 31 in movement disorders, 22 in disorders of consciousness and 14 in other conditions such as stroke and traumatic brain injury. Reported effects included gains on coma recovery, Parkinson disease and dystonia rating scales, and generally lasted 1 to 4 hours before the person returned to baseline. Sedation was the most common adverse effect [14].
Population
67 studies, of which 28 were case reports, 8 case series and 9 randomized trials. Only 11 studies had more than 10 participants [14].
Sources
[14]
Caveats
Mostly case reports and small trials, with no pooled effect size. Not an approved use.

Mixed results1

Moderate

Total sleep time and waking in the night

Mixed results: one meta-analysis found a month of zolpidem lengthened total sleep, while pooled FDA trial data found no significant change in sleep time or awakenings.

The numbers and sources
Effect
In the FDA trial data, waking after sleep onset, number of awakenings, total sleep time and sleep efficiency did not differ significantly from placebo, and the authors said too few studies reported these outcomes for firm conclusions [1]. One month of zolpidem increased total sleep time against placebo, with no significant difference in waking after sleep onset [2]. In adults aged 60 and older, eszopiclone added 26.69 minutes of measured total sleep time against placebo [3]. Across sedative hypnotics of all kinds in people aged 60 and over, total sleep time rose by a mean of 25.2 minutes and night awakenings fell by 0.63 [5]. The zaleplon label states it has not been shown to increase total sleep time or decrease the number of awakenings [6]. The eszopiclone label reports that 3 mg reduced waking after sleep onset against placebo in adults [7].
Population
4,378 participants in 13 trials [1]; 1,068 patients in 6 trials [2]; 5,917 older adults in 24 articles [3]; 2,417 participants aged 60 or over in 24 studies [5].
Sources
[1], [2], [3], [5], [6], [7]
Caveats
[5] pooled benzodiazepines with zaleplon, zolpidem and zopiclone and does not report the newer drugs alone. Results differ by drug: the evidence for longer sleep is for eszopiclone and zolpidem, not zaleplon.

Doses studied

The zolpidem label gives a starting dose of 5 mg for women and 5 or 10 mg for men, taken once immediately before bed with at least 7 to 8 hours before waking, a ceiling of 10 mg a day, and 5 mg for older adults and people with mild to moderate liver impairment [13]. For the extended-release form the label gives 6.25 mg for women and 6.25 or 12.5 mg for men [15]. In 2013 FDA required the labeled dose for women to be lowered from 10 mg to 5 mg for immediate-release products and from 12.5 mg to 6.25 mg for extended-release products [16]. The eszopiclone label gives a starting dose of 1 mg, raised to 2 or 3 mg, with a ceiling of 2 mg for older adults [7]. The zaleplon label gives 10 mg for most adults under 65 and 5 mg for older adults, and notes that doses above 20 mg were not adequately evaluated [6].

The long-term trials used eszopiclone 3 mg nightly for 6 months [9][10], extended-release zolpidem 12.5 mg on 3 to 7 nights a week for 24 weeks [11], and zolpidem 10 mg nightly, or 5 mg in people over 60, for 8 months [12].

Risks

Reported risks18

ModerateVery common

Next-morning impairment and driving

Shown to impair next-morning driving performance after 10 mg at bedtime in crossover trials, and linked to about twice the crash rate in new users.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In a network meta-analysis of on-road driving trials in healthy subjects, zolpidem 10 mg at bedtime produced significantly more lane weaving the next morning than placebo after a single dose. Repeated dosing caused fewer residual effects than a single dose [20]. In 3-week trials of extended-release zolpidem, next-day sleepiness was reported by 15% of adults on 12.5 mg against 2% on placebo, and by 6% of older adults on 6.25 mg against 5% [15]. The zolpidem label reports a small but statistically significant drop on a symbol substitution test in four of seven studies in people without insomnia [13]. Eszopiclone 3 mg impaired psychomotor function and memory at 7.5 hours after dosing and still at 11.5 hours, while people's own sense of sedation was not consistently different from placebo [7]. In a cohort linked to crash records, new users of zolpidem had a higher crash rate than non-users (HR 2.20, 95% CI 1.64 to 2.95) [21].
Population
22 crossover trials in healthy subjects [20]; 212 adults and 205 older adults with primary insomnia in 3-week trials [15]; 91 healthy adults aged 25 to 40 [7]; 409,171 licensed drivers aged 21 or older in one US health plan [21].
Sources
[20], [15], [13], [7], [21]
Caveats
The band above is the next-day sleepiness rate on extended-release 12.5 mg. Confidence in the driving evidence was rated low to very low [20]. The crash study is observational, and insomnia itself may affect driving [21]. Label studies in non-elderly people with insomnia did not detect next-day effects on the tests used [13].
ModerateVery common

Higher morning blood levels in women

FDA states women clear zolpidem more slowly than men, with about 15% of women and 3% of men above an impairing blood level 8 hours after 10 mg.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
FDA reported that driving simulation and laboratory studies indicate zolpidem blood levels above about 50 ng/mL appear capable of impairing driving. In pharmacokinetic trials of 10 mg in about 250 men and 250 women, about 15% of women and 3% of men were above that level roughly 8 hours after dosing. After extended-release 12.5 mg, about 33% of women and 25% of men were above it, and after 6.25 mg about 15% of women and 5% of men. On this basis FDA required the labeled dose for women to be halved [16]. The label reports peak level and total exposure about 45% higher in women than men at the same dose, and similar clearance in older men and women [13].
Population
About 500 adults in pharmacokinetic trials of immediate-release zolpidem, plus trials of the extended-release form [16].
Sources
[16], [13]
Caveats
These are blood levels, not counts of crashes or injuries. The threshold of 50 ng/mL is FDA's estimate from simulation and laboratory studies.
ModerateVery common

Unpleasant taste with eszopiclone

Shown to cause an unpleasant taste in 17% on eszopiclone 2 mg and 34% on 3 mg, against 3% on placebo, in a 6-week trial.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Unpleasant taste was reported by 34% on eszopiclone 3 mg, 17% on 2 mg and 3% on placebo. The label describes it as the adverse reaction with the clearest dose relationship [7]. Unpleasant taste and headache were the most common adverse events in the 6-month trial [9].
Population
104 adults on 2 mg, 105 on 3 mg and 99 on placebo for 44 days [7]; 788 adults over 6 months [9].
Sources
[7], [9]
Caveats
The evidence is for eszopiclone. The zolpidem label lists taste perversion as infrequent, between 1 in 100 and 1 in 1,000 [13].
ModerateCommon

Drowsiness, dizziness and other common side effects

Shown to cause drowsiness in 8% against 5% on placebo and dizziness in 5% against 1% in zolpidem trials lasting 28 to 35 nights.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In US trials of zolpidem up to 10 mg lasting 28 to 35 nights: drowsiness 8% vs 5% on placebo, dizziness 5% vs 1%, drugged feeling 3% vs 0, lethargy 3% vs 1%, dry mouth 3% vs 1% and palpitation 2% vs 0. In trials of up to 10 nights: headache 7% vs 6%, drowsiness 2% vs 0, dizziness 1% vs 0 and diarrhea 1% vs 0. About 4% of 1,701 people in US premarketing trials stopped because of an adverse reaction [13]. In a 6-week eszopiclone trial, somnolence was reported by 10% on 2 mg and 8% on 3 mg against 3% on placebo, dizziness by 5% and 7% against 4%, and headache by 21% and 17% against 13% [7].
Population
152 people on zolpidem and 161 on placebo in three trials of 28 to 35 nights, and 685 and 473 in 11 trials of up to 10 nights [13]; 308 adults in a 6-week eszopiclone trial [7].
Sources
[13], [7]
Caveats
The label notes a dose relationship for many of these reactions. Rates come from trials of people selected for insomnia without other major illness.
ModerateCommon

Memory loss, confusion and hallucinations

Shown to cause memory problems, confusion or hallucinations in about 1% to 3% of adults in trials, and hallucinations in 7% of children in one trial.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In zolpidem trials of 28 to 35 nights, amnesia was reported by 1% against 0 on placebo, and under 1% of adults on 10 mg reported hallucinations. In an 8-week trial in children aged 6 to 17 with ADHD, hallucinations were reported by 7% on zolpidem and none on placebo, and dizziness by 23.5% against 1.5% [13]. On eszopiclone 3 mg, confusion was reported by 3% and hallucinations by 3% against 0 on placebo over 6 weeks, and memory impairment by 1.3% (8 of 593) against 0 over 6 months [7]. The zolpidem label also describes out-of-character aggressiveness, bizarre behavior, agitation and depersonalization, and postmarketing reports of delirium [13]. In people aged 60 and over, adverse cognitive events were 4.78 times more common on sedative hypnotics than placebo (95% CI 1.47 to 15.47) [5].
Population
Adults in zolpidem and eszopiclone label trials [13][7]; children aged 6 to 17 with insomnia associated with ADHD [13]; 2,417 participants aged 60 or over in 24 studies [5].
Sources
[13], [7], [5]
Caveats
The label states that memory effects appeared mainly above 10 mg of zolpidem, and that zolpidem is not approved for children [13]. [5] pooled benzodiazepines with the newer drugs.
ModerateCommon

Falls and fractures in older adults

Linked to more fractures in older adults in three meta-analyses of observational studies, with hip fracture risk about 1.9 to 2.8 times higher.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Z-drugs were associated with more fractures (OR 1.63, 95% CI 1.42 to 1.87) and zolpidem with more injuries (OR 2.05, 95% CI 1.95 to 2.15). The odds of falls trended higher without reaching significance (OR 2.40, 95% CI 0.92 to 6.27) [22]. Z-drug use was associated with hip fracture (RR 1.90, 95% CI 1.68 to 2.13), about as strongly as benzodiazepines (RR 1.52, 95% CI 1.37 to 1.68), and most strongly in short-term use (RR 2.39, 95% CI 1.74 to 3.29) [23]. Zolpidem use was associated with fracture at any site (RR 1.84, 95% CI 1.67 to 2.03) and hip fracture (RR 2.80, 95% CI 2.19 to 3.58) [24]. In people with dementia, higher-dose Z-drugs were associated with fractures (HR 1.67, 95% CI 1.13 to 2.46) and falls (HR 1.33, 95% CI 1.06 to 1.66) against non-users with sleep disturbance [25]. In non-US zolpidem trials, 30 of 1,959 people (1.5%) reported falls, 28 of them aged 70 or older, and 23 of those 28 were on doses above 10 mg [13].
Population
14 observational studies, 830,877 people in the fracture analysis [22]; observational studies of hip fracture in older people [23]; 1,092,925 participants in 9 studies [24]; 3,532 people with dementia newly prescribed Z-drugs [25]; 1,959 people in non-US trials [13].
Sources
[22], [23], [24], [25], [13]
Caveats
Observational and open to confounding, with considerable heterogeneity in the fracture and falls analyses (I² 90% and 95%) [22]. The band above is the fall rate in trials, which had no placebo figure beside it. Minimal or inconsistent excess risk was seen at lower doses in people with dementia [25].
LimitedCommon

Use with opioids

Linked to higher mortality in older adults taking a Z-drug with an opioid, at 11.3 against 8.1 out-of-hospital deaths per 1,000 person-years on low-dose trazodone.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
The zolpidem label states that use with opioids may increase the risk of respiratory depression [13]. Among Medicare beneficiaries taking an opioid at the same time, out-of-hospital deaths occurred at 11.3 per 1,000 person-years on Z-drugs and 8.1 on low-dose trazodone (HR 1.98, 95% CI 1.14 to 3.44), and total mortality was also higher (HR 1.65, 95% CI 1.09 to 2.49). Without an opioid, out-of-hospital mortality on Z-drugs did not differ from trazodone (HR 0.96, 95% CI 0.76 to 1.23) [28].
Population
400,924 Medicare beneficiaries aged 65 or older starting a hypnotic, with 3,541 person-years of Z-drug use alongside an opioid [28].
Sources
[13], [28]
Caveats
Observational, with possible unmeasured confounding. The comparison is against another sleep medicine, not against no treatment, and the rates count deaths from any cause outside hospital.
LimitedRare

FDA boxed warning: complex sleep behaviors

FDA states sleepwalking, sleep-driving and other activities while not fully awake may occur after any dose, with 66 serious cases including 20 deaths identified through early 2018.

The numbers and sources
How common
Rare: fewer than 1 in 1,000 people.
Effect
The zolpidem, eszopiclone and zaleplon labels carry the boxed warning. The zolpidem label states that complex sleep behaviors may follow the first or any later use, at labeled doses, with or without alcohol or other central nervous system depressants, that people usually do not remember the events, and that the drug is contraindicated in anyone who has had such an episode [13][7][6]. An FDA review of adverse event reports from December 1992 through February 2018 and the medical literature identified 66 cases, 20 with death and 46 with serious injuries. Fatal cases involved carbon monoxide poisoning, drowning, falls, hypothermia, motor vehicle collisions and apparent suicide. Twenty-two cases reported an earlier episode on a Z-drug [17]. FDA stated these behaviors appear more common with these three drugs than with other prescription sleep medicines [18]. In the preapproval trial database of 3,660 people given zolpidem, somnambulism was listed as rare, meaning fewer than 1 in 1,000 [13].
Population
66 postmarketing cases in the FDA Adverse Event Reporting System and the literature [17]; 3,660 people in preapproval trials [13].
Sources
[13], [7], [6], [17], [18]
Caveats
Spontaneous reports have no denominator, and there was no placebo comparison. The band above is the label's trial-database frequency for sleepwalking. Clinic studies found higher rates, shown in the next block.
LimitedHow often is not known

Stroke in people with dementia

Linked to ischemic stroke or transient ischemic attack at higher Z-drug doses in one cohort of people with dementia, with minimal or inconsistent risk at lower doses.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Among people with dementia, those prescribed higher-dose Z-drugs had more ischemic stroke or transient ischemic attack than non-users with sleep disturbance over 2 years (HR 1.88, 95% CI 1.14 to 3.10). Mortality, infection and venous thromboembolism showed minimal or inconsistent excess risk [25].
Population
3,532 people with dementia newly prescribed Z-drugs and 1,833 non-users with sleep disturbance in England, mean age 83 [25].
Sources
[25]
Caveats
One observational cohort in England, with doses defined in zopiclone equivalents. The abstract gives no absolute rate.
LimitedHow often is not known

Dependence and misuse

The label warns zolpidem may lead to physical or psychological dependence, with risk rising with dose, duration and a history of alcohol or drug abuse.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Zolpidem, eszopiclone and zaleplon are Schedule IV controlled substances. The zolpidem label states that the risk of dependence increases with dose and duration, and that available data cannot provide a reliable estimate of the incidence of dependence at labeled doses. In people with a history of drug abuse, single doses of zolpidem 40 mg had effects similar to diazepam 20 mg, while 10 mg was difficult to tell from placebo [13]. In people with a history of benzodiazepine abuse, eszopiclone 6 and 12 mg produced euphoric effects similar to diazepam 20 mg [7]. A review of published case reports found 36 cases of zolpidem dependence, with doses in extreme cases 30 to 120 times the labeled dose. Most patients had a history of drug or alcohol abuse or another psychiatric condition [26].
Population
Abuse-liability studies in people with a history of drug abuse [13][7]; 36 published cases for zolpidem and 22 for zopiclone [26].
Sources
[13], [7], [26]
Caveats
Case reports have no denominator, and the label states no rate can be given. The case review judged the relative incidence of reported dependence to be lower than for benzodiazepines used for sleep [26].
LimitedHow often is not known

Alcohol and other sedating drugs

The label states alcohol and other central nervous system depressants add to zolpidem's effects, with additive impairment measured in single-dose studies. It gives no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The zolpidem label names benzodiazepines, opioids, tricyclic antidepressants and alcohol as adding to central nervous system depression. In single-dose studies in healthy volunteers, alcohol with zolpidem had an additive adverse effect on psychomotor performance, the tricyclic antidepressant imipramine had an additive effect of decreased alertness, and the antipsychotic chlorpromazine had an additive effect on alertness and psychomotor performance. Sertraline increased exposure to zolpidem, and fluoxetine lengthened its half-life by 17% with no additive psychomotor effect [13]. The eszopiclone label states the same additive effects for benzodiazepines, opioids, tricyclic antidepressants and alcohol [7].
Population
Healthy volunteers in single-dose interaction studies summarized in labeling [13].
Sources
[13], [7]
Caveats
The label gives no counts or rates, and notes that single-dose studies do not predict effects of long-term use together.
LimitedHow often is not known

Drugs that change zolpidem levels

The label states ketoconazole raised zolpidem exposure and effects, while rifampin lowered them and St. John's wort may lower blood levels. It gives no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label states that ketoconazole, a potent inhibitor of the liver enzyme CYP3A4, increased exposure to zolpidem and its effects. Rifampin, which induces the same enzyme, significantly reduced exposure and effects, and St. John's wort may decrease blood levels [13]. The eszopiclone label gives a ceiling of 2 mg for people taking potent CYP3A4 inhibitors [7].
Population
Drug interaction studies summarized in labeling [13].
Sources
[13], [7]
Caveats
Changes in drug levels, with no rate of harm. The label says the effect of drugs acting on other liver enzymes is not known.
LimitedHow often is not known

Breathing during sleep

The label reports lower oxygen levels during sleep on zolpidem than placebo in people with mild to moderate sleep apnea. It gives no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label states that 10 mg of zolpidem did not depress breathing in healthy subjects or in people with mild to moderate chronic obstructive pulmonary disease. In people with mild to moderate sleep apnea, the lowest oxygen saturation fell and time spent below 80% and 90% saturation rose against placebo. Postmarketing reports describe respiratory insufficiency, mostly in people with existing breathing impairment. Neonates exposed late in pregnancy have had respiratory depression [13].
Population
Studies in healthy subjects, people with chronic obstructive pulmonary disease and people with sleep apnea, summarized in labeling without counts [13].
Sources
[13]
Caveats
No numbers are given for the size of the oxygen changes.
LimitedHow often is not known

Worsening depression and suicidal thoughts

Linked to a higher rate of suicide or suicide attempt in zolpidem users than non-users across four observational studies, which cannot separate the drug from insomnia or depression.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label states that worsening of depression and suicidal thoughts and actions, including completed suicides, have been reported in primarily depressed people treated with sedative hypnotics. In long-term zolpidem trials, depression was reported by 2% against 1% on placebo [13]. A meta-analysis of four observational studies found more suicide or suicide attempts in zolpidem users than non-users (RR 1.88, 95% CI 1.54 to 2.30) and more suicide deaths (RR 1.82, 95% CI 1.43 to 2.30) [29].
Population
344,753 participants in four studies, 42,279 of them zolpidem users [29].
Sources
[13], [29]
Caveats
Observational. Insomnia and depression are themselves tied to suicide, so the association may reflect who is prescribed zolpidem. No absolute rate is given.
LimitedHow often is not known

Severe allergic reactions

The label warns of angioedema of the tongue, glottis or larynx after first or later doses of sedative hypnotics including zolpidem. It gives no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label reports cases of angioedema involving the tongue, glottis or larynx, some with shortness of breath, throat closing or nausea and vomiting suggesting anaphylaxis, and some needing emergency treatment. It states that airway obstruction may be fatal [13].
Population
Case reports summarized in labeling [13].
Sources
[13]
Caveats
Reports with no denominator. The trial database lists anaphylactic shock as rare, fewer than 1 in 1,000 [13].
LimitedHow often is not known

Liver disease and liver injury

The label warns that drugs acting on GABA receptors have been associated with hepatic encephalopathy in people with liver failure, and lists postmarketing reports of liver injury.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label states that people with liver impairment clear zolpidem more slowly, and that drugs affecting GABA receptors have been associated with precipitating hepatic encephalopathy in people with hepatic insufficiency. Postmarketing reports include acute hepatocellular, cholestatic or mixed liver injury with or without jaundice. In the trial database, abnormal liver function and raised ALT were listed as infrequent, between 1 in 100 and 1 in 1,000 [13].
Population
Postmarketing reports and 3,660 people in preapproval trials [13].
Sources
[13]
Caveats
The label states that events in the trial database were not necessarily caused by zolpidem, and gives no placebo rate.
LimitedHow often is not known

Pregnancy

The label reports breathing problems and sedation in newborns exposed late in pregnancy. One registry study linked zolpidem in pregnancy to low birth weight and preterm delivery.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The label states that neonates born to mothers using zolpidem late in the third trimester have had respiratory depression and sedation, in some reports needing ventilation, and that published observational studies, registries and case reports do not show a clear association with major birth defects [13]. In a Taiwan registry study, mothers who received zolpidem in pregnancy had higher odds of low birth weight (OR 1.39, 95% CI 1.17 to 1.64), preterm delivery (OR 1.49, 95% CI 1.28 to 1.74), small-for-gestational-age infants (OR 1.34, 95% CI 1.20 to 1.49) and cesarean delivery (OR 1.74, 95% CI 1.59 to 1.90) [32].
Population
2,497 mothers who received zolpidem during pregnancy and 12,485 who did not [32]; published reports summarized in labeling [13].
Sources
[13], [32]
Caveats
Observational, and insomnia or the conditions behind it may account for part of the association. The label gives no rate for neonatal effects.

Mixed results2

ModerateHow often is not known

Withdrawal symptoms and rebound insomnia

Mixed results: sleep worsened on the first night after stopping in some trials, while 12 months of nightly zolpidem did not produce rebound insomnia in one small trial.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In zolpidem trials, fatigue, nausea, flushing, lightheadedness, crying, vomiting, stomach cramps, panic attack and nervousness were each reported by 1% or less within 48 hours of switching to placebo. The label reports no measured rebound insomnia at labeled doses, and self-rated worse sleep on the first night in older adults above 5 mg [13]. With the extended-release form, a rebound effect was seen only on the first night after abrupt stopping [15]. After 44 nights of eszopiclone 2 mg, time to fall asleep and time awake in the night were worse than placebo on the first night off and not on the second. Withdrawal events such as anxiety, abnormal dreams and nausea were each reported by 2% or less [7]. In a meta-analysis of sleep laboratory studies, rebound insomnia on the first withdrawal night was mild with zolpidem and intense with triazolam [4]. Across 12 months of nightly zolpidem 10 mg with placebo substituted at months 1, 4 and 12, rebound insomnia was not observed. About 30% to 40% of participants met the definition of a rebounder, at the same rate in the placebo group [27]. The label also lists convulsions and delirium within the withdrawal syndrome reported for sedative hypnotics, and seizures were reported in two people in zaleplon trials [13][6].
Population
Adults in zolpidem and eszopiclone label trials [13][15][7]; 1,276 people in 75 sleep laboratory studies [4]; 33 adults with primary insomnia aged 32 to 65 [27].
Sources
[13], [15], [7], [4], [27], [6]
Caveats
The labels give only an upper bound for each withdrawal symptom and no placebo rate, so no band can be set. The 12-month trial had 17 people on zolpidem and excluded anyone with a psychiatric disorder or history of drug or alcohol abuse [27].
LimitedHow often is not known

Death rates in observational studies

Mixed results: one cohort linked hypnotic prescriptions to over three times the death rate, a Z-drug meta-analysis was not significant, and a Medicare cohort matched trazodone.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In a matched cohort, people prescribed any hypnotic had higher mortality than people prescribed none, with hazard ratios of 3.60 (95% CI 2.92 to 4.44) at 0.4 to 18 doses a year and 5.32 (95% CI 4.50 to 6.30) above 132 doses a year. Hazards were elevated in separate analyses of zolpidem, eszopiclone and zaleplon [30]. Pooling five studies, mortality with Z-drugs trended higher without reaching significance (HR 1.73, 95% CI 0.95 to 3.16) [31]. In older adults not taking opioids, total mortality on Z-drugs did not differ from low-dose trazodone (HR 0.87, 95% CI 0.72 to 1.05) [28].
Population
A matched cohort of people prescribed hypnotics and people prescribed none [30]; 2,350,093 patients in 25 studies [31]; 400,924 Medicare beneficiaries aged 65 or older [28].
Sources
[30], [31], [28]
Caveats
Observational. People prescribed sleep medicines differ from those who are not, and the meta-analysis found significant heterogeneity [31]. None of these studies shows the drug caused the deaths.

Claims tested and not found

  1. That Z-drugs add a large amount of sleep. In 13 trials submitted to FDA, sleep latency on polysomnography fell by 22 minutes, and total sleep time, awakenings and sleep efficiency did not differ significantly from placebo [1].
  2. That zolpidem helps children with ADHD fall asleep. In an 8-week trial in children aged 6 to 17, zolpidem 0.25 mg/kg at bedtime did not decrease sleep latency against placebo, and 7% reported hallucinations [13].
  3. That zaleplon lengthens sleep. The zaleplon label states it has not been shown to increase total sleep time or decrease the number of awakenings [6].
  4. That a sleeping pill outperforms cognitive behavioral therapy for trouble falling asleep. In a placebo-controlled trial in 63 adults with chronic sleep-onset insomnia, cognitive behavioral therapy produced the greatest changes in sleep-onset latency and sleep efficiency and kept them at long-term follow-up. Zolpidem produced moderate improvements that returned toward baseline after it was stopped, and adding it to therapy gave no advantage [33].
  5. That Z-drugs carry a lower hip fracture risk than benzodiazepines. Both were associated with hip fracture in a meta-analysis, with a relative risk of 1.90 for Z-drugs and 1.52 for benzodiazepines, and the authors found little difference between them [23].
  6. That long nightly use of zolpidem leads to worsening rebound insomnia. Over 12 months of nightly zolpidem 10 mg in 33 adults, the share of people with rebound insomnia on placebo substitution did not differ from the placebo group and did not rise over time [27].

Sources

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  2. Xiang T, Cai Y, Hong Z, Pan J. Efficacy and safety of Zolpidem in the treatment of insomnia disorder for one month: a meta-analysis of a randomized controlled trial. Sleep Medicine. 2021. https://doi.org/10.1016/j.sleep.2021.09.005
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