What are the long-term side effects of zolpidem (Ambien)?

Long-Term Side Effects of Zolpidem (Ambien)

Zolpidem can cause serious long-term side effects including dependency, cognitive impairment, complex sleep behaviors, increased risk of falls and fractures, and potential mortality risk, requiring careful monitoring and limited duration of use. 1, 2

Neurological and Cognitive Effects

• Zolpidem may cause significant next-day cognitive impairment and psychomotor performance issues, particularly at higher doses or with extended use 1
• Long-term use can lead to memory loss, confusion, disorientation, and impaired driving ability 1, 3
• Sex differences exist in zolpidem metabolism, with women experiencing slower drug clearance and greater next-day impairment compared to men, leading to FDA recommendations for lower dosing in women 1

Complex Sleep Behaviors

• Long-term use increases risk of complex sleep behaviors that can cause serious injury or death, including sleep-driving, sleep-eating, sleep-walking, and engaging in other activities while not fully awake 2
• These behaviors can occur without any memory of the events the next morning 2
• Complex sleep behaviors have been reported regardless of age, dose, or prior medical history 4

Dependency and Withdrawal

• Despite initial claims of lower dependency risk compared to benzodiazepines, zolpidem can lead to tolerance, dependence, and withdrawal symptoms with long-term use 3, 5
• Withdrawal symptoms may include rebound insomnia, anxiety, irritability, and in severe cases, seizures 5, 4
• Withdrawal seizures have been reported with doses as low as 160mg/day, though most commonly at higher doses 4
• Approximately half of patients prescribed Z-drugs (including zolpidem) in some studies have been treated continuously for at least 12 months, despite recommendations against long-term use 3

Physical Health Risks

• Long-term zolpidem use is associated with increased risk of falls and fractures, particularly hip fractures (relative risk 1.92) 4, 1
• Observational studies have found associations between zolpidem and increased risk of infections 1
• Some studies suggest an association between hypnotic use and increased all-cause mortality, though these findings must be interpreted cautiously due to potential confounding factors 1

Psychiatric Effects

• Long-term use may be associated with abnormal thinking, behavioral changes, confusion, agitation, and hallucinations 2
• Studies have linked zolpidem use with increased risk of suicide attempts (odds ratio 2.08), even in patients without pre-existing psychiatric illness 4
• Worsening of depression has been reported in some patients 2

Special Populations Considerations

• Elderly patients are at higher risk for adverse effects due to slower drug metabolism and should receive lower doses 3, 2
• Women metabolize zolpidem more slowly than men, leading to higher blood levels and greater risk of next-day impairment 1
• Pregnant women using zolpidem have shown increased risk of low birth weight, preterm delivery, and small for gestational age babies 4

Clinical Management Recommendations

• Zolpidem should only be used for short-term treatment of insomnia (≤4 weeks) to minimize risk of dependency and adverse effects 6, 3
• Careful monitoring for signs of tolerance, dependency, or adverse effects is essential during treatment 2
• If discontinuing after long-term use, gradual tapering is recommended to minimize withdrawal symptoms 3, 5
• Patients should be warned about the risk of complex sleep behaviors and advised to report any unusual sleep-related events 2, 4
• Lower doses should be used in women, elderly patients, and those with hepatic impairment 3, 6