What are the potential side effects of Ambien (zolpidem) in older adults or those with certain medical conditions?

Ambien (Zolpidem) Side Effects

Zolpidem carries significant risks including complex sleep behaviors, next-day cognitive impairment, falls, fractures, and increased mortality, with elderly patients and women at particularly high risk due to slower drug clearance. 1, 2

Most Serious and Life-Threatening Side Effects

Complex Sleep Behaviors

• Sleep-walking, sleep-driving, and engaging in activities while not fully awake can occur after the first or any subsequent dose, potentially resulting in serious injury or death. 2
• Patients may prepare food, make phone calls, have sex, or drive vehicles with no memory of these events. 2
• These behaviors can occur at recommended doses, even without alcohol or other CNS depressants. 2
• Zolpidem must be discontinued immediately if complex sleep behaviors occur. 2

Severe Allergic Reactions

• Angioedema involving the tongue, glottis, or larynx has been reported after first or subsequent doses, which can cause fatal airway obstruction. 2
• Additional symptoms may include dyspnea, throat closing, nausea, and vomiting suggesting anaphylaxis. 2

Psychiatric and Behavioral Changes

• Hallucinations occurred in 7% of pediatric patients and <1% of adults in controlled trials. 2
• Abnormal behaviors include decreased inhibition, aggressiveness, bizarre behavior, agitation, and depersonalization. 2
• Suicide attempts and completion are significantly associated with zolpidem use (OR 2.08; 95% CI 1.83-2.63), regardless of psychiatric comorbidity. 3
• Worsening depression and suicidal ideation have been reported in depressed patients. 2

Common and Clinically Significant Side Effects

Next-Day Cognitive and Motor Impairment

• Women experience slower drug clearance with plasma concentrations 45% higher than men at the same dose, resulting in greater next-day impairment. 2
• After 8 hours, mean plasma concentrations in women versus men were 28 vs. 20 ng/mL for 10mg IR and 33 vs. 28 ng/mL for 12.5mg extended-release. 3
• Impaired driving, drowsiness, prolonged reaction time, dizziness, blurred/double vision, and reduced alertness occur the morning after use. 2
• Risk increases substantially if taken with less than 7-8 hours of sleep remaining, at higher than recommended doses, or with other CNS depressants. 2

Falls and Fractures

• Zolpidem is associated with a 4.28-fold increased risk of falls in hospitalized patients (P <0.001). 3
• Hip fractures occur with a relative risk of 1.92 (95% CI 1.65-2.24; P<0.001). 3
• In non-U.S. trials, 1.5% of patients reported falls, with 93% being ≥70 years old and 82% taking doses >10mg. 2

Central Nervous System Effects

• Most common adverse reactions include dizziness (23.5% in pediatric patients, 3% in elderly), drowsiness (5% in elderly), and headache (12.5% in pediatric patients). 2
• In older adults using sedative-hypnotics, there is a 5-fold increase in memory loss, confusion, and disorientation; 3-fold increase in dizziness, loss of balance, or falls; and 4-fold increase in residual morning sedation. 1
• Confusion was reported in 1.2% of non-U.S. patients, with 75% being ≥70 years old and 78% taking doses >10mg. 2
• A case series of 119 inpatients aged ≥50 showed 80.8% of adverse reactions were CNS-related (confusion, dizziness, daytime sleepiness). 3

Gastrointestinal Effects

• Nausea is among the most common adverse events. 4
• Diarrhea occurred in 3% of elderly patients versus 1% with placebo. 2

Long-Term and Withdrawal Effects

Mortality Risk

• Anxiolytic and hypnotic drugs including zolpidem are associated with increased all-cause mortality according to UK observational data. 5
• Observational studies and FDA data suggest associations with dementia, major injuries, and possibly cancer. 1

Dependence and Withdrawal

• Withdrawal seizures have been reported, most commonly at daily dosages of 450-600mg/day, but documented as low as 160mg/day. 3
• Tolerance can develop in patients taking high dosages for prolonged periods (several years). 4
• Rebound insomnia occurs after discontinuation, with sleep onset latency significantly increased by 13.0 minutes on the first night (95% CI 4.3-21.7; P<0.01). 3

Loss of Efficacy

• With continued use, zolpidem shows no statistically significant difference from placebo for sleep onset latency, total sleep time, or wake after sleep onset. 5
• Memory impairment, psychiatric adverse effects, depression, and anxiety occur at higher rates with long-term use. 5

High-Risk Populations

Elderly Patients (≥65 years)

• The American Geriatrics Society recommends avoiding benzodiazepine-like GABA receptor hypnotics including zolpidem in older adults due to sedation, cognitive impairment, and unsafe mobility with injurious falls. 5
• Elderly patients are at specific high risk for falls, headaches, nausea, medication interactions, and drug dependence. 1
• Demented older adults face even greater risks due to cognitive and other vulnerabilities, yet high-quality data for this population are nonexistent. 1

Women

• The FDA recommends 5mg initial dose for women (versus 5-10mg for men) due to 45% higher drug exposure. 2
• Women require lower doses to minimize next-day impairment and complex sleep behaviors. 6

Patients with Hepatic Impairment

• Recommended dose is 5mg in mild to moderate hepatic impairment; avoid entirely in severe hepatic impairment as it may contribute to encephalopathy. 2

Pregnancy and Lactation

• FDA classifies zolpidem as Category C based on adverse fetal outcomes in animal studies. 3
• Maternal use is associated with increased incidence of low birth weight (OR 1.39; P<0.001), preterm delivery (OR 1.49; P<0.001), small for gestational age babies (OR 1.34; P<0.001), and cesarean deliveries (OR 1.74; P<0.001). 3
• Severe to moderate respiratory depression requiring artificial ventilation or intubation has been reported in neonates after birth. 2
• Infants exposed through breastmilk should be monitored for excess sedation, hypotonia, and respiratory depression. 2

Critical Prescribing Warnings

Dosing Restrictions

• Maximum dose is 5mg in women, elderly patients, and those with hepatic impairment. 6, 2
• Never exceed 10mg in men or 5mg in women due to increased risk of next-day impairment and complex sleep behaviors. 6
• Zolpidem should only be used for short-term treatment (≤4 weeks) to minimize dependency and adverse effects. 6

Drug Interactions

• Coadministration with other CNS depressants (benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases CNS depression risk and requires dosage adjustments. 2
• Use with other sedative-hypnotics at bedtime or middle of the night is not recommended. 2

Discontinuation Strategy

• If discontinuing after prolonged use, taper gradually rather than abrupt cessation to minimize withdrawal symptoms. 6

Common Clinical Pitfalls

• Prescribing standard 10mg doses to women or elderly patients instead of the recommended 5mg dose. 6, 2
• Failing to ensure patients have a full 7-8 hours available for sleep before activities requiring alertness. 2
• Continuing therapy beyond 4 weeks without reassessing for primary psychiatric or medical disorders. 6, 2
• Not warning patients about the risk of complex sleep behaviors and impaired morning driving. 2
• Combining with alcohol or other CNS depressants without dose adjustment. 2