What are the long-term effects of zolpidem (Ambien) in older adults or those with a history of substance abuse?

Long-Term Effects of Zolpidem

Long-term zolpidem use beyond 4-5 weeks carries significant risks including tolerance requiring dose escalation, dependence with withdrawal symptoms, cognitive impairment, falls with fractures, and complex sleep behaviors, with evidence showing efficacy diminishes over time while adverse effects accumulate, particularly in older adults and those with substance abuse history.

Evidence on Long-Term Efficacy

The longest-term trial available (32 weeks) demonstrated that zolpidem was not statistically significantly different from placebo for sleep onset latency, total sleep time, or wake after sleep onset, indicating loss of efficacy with continued use 1. The FDA has approved zolpidem only for short-term use of 4-5 weeks 2. This limited duration reflects the reality that tolerance develops, necessitating dose escalation rather than sustained benefit 2.

Serious Long-Term Adverse Effects

Cognitive and Psychiatric Effects

• Memory impairment, psychiatric adverse effects, depression, and anxiety occur at higher rates with long-term use according to FDA medical reviews 1
• Observational studies show a 5-fold increase in memory loss, confusion, and disorientation in older patients using sedative-hypnotics compared to placebo 1
• Amnesia, confusion, and hallucinations are documented serious adverse effects, with 7% of pediatric patients reporting hallucinations 2

Falls and Fractures

• Zolpidem is associated with adjusted odds ratio of 1.72 for fractures and major head injuries requiring hospitalization 3
• A 3-fold increase in dizziness, loss of balance, or falls occurs in older patients 1
• Elderly patients show particular vulnerability, with 93% of fall reports occurring in those ≥70 years of age, and 82% of these were receiving doses >10 mg 2

Complex Sleep Behaviors

• Sleep-walking, sleep-driving, preparing food, making phone calls, or having sex while not fully awake can occur at any time during treatment, even at recommended doses 2
• These behaviors may result in serious injury or fatal outcomes 2
• Patients typically have no memory of these events 2

Mortality Risk

• Observational data from the UK General Practice Research Database showed that anxiolytic and hypnotic drugs were associated with increased all-cause mortality 1

Dependence and Withdrawal

Abuse Potential

• Studies in former drug abusers found zolpidem 40 mg produced effects similar to diazepam 20 mg, indicating significant abuse potential 2
• Persons with history of substance abuse are at increased risk for misuse, abuse and addiction and require careful monitoring 2
• One case report documented severe chronic abuse reaching 6,000 mg per day for over a decade, resulting in seizure-like withdrawal symptoms 4

Withdrawal Syndrome

• Abrupt discontinuation produces withdrawal symptoms including fatigue, nausea, stomach cramps, panic attacks, nervousness, tremors, and rarely convulsions 2
• Withdrawal symptoms meeting DSM criteria occurred in ≥1% of patients within 48 hours of discontinuation 2
• Chronic high-dose use leads to extreme cravings and physical dependence requiring medically supervised detoxification 4

Prevalence of Long-Term Use

• In a Veterans Health Administration study, 20% of new zolpidem users continued for at least 180 days, despite recommendations for short-term use only 5
• 41% of women used doses higher than FDA-recommended within 180 days of initiation 5
• Prior use of other sleep medications predicted both high-dose and long-term use 5

Special Populations at Higher Risk

Older Adults (≥65 years)

• The Beers Criteria and STOPP criteria recommend avoiding benzodiazepine-like GABA receptor hypnotics including zolpidem in older adults 1
• Elderly patients require maximum dose of 5 mg to minimize adverse effects related to impaired motor and cognitive performance 2
• Sedation, cognitive impairment, unsafe mobility with injurious falls, and motor skill impairment are particular concerns 1
• However, one Japanese study in subjects ≥80 years without cognitive/mental complications found lower risk of adverse symptoms (OR 0.39) when prescribed appropriate low doses 6

Women

• Women clear zolpidem 45% slower than men, resulting in higher blood levels at the same dose 2
• The recommended initial dose for women is 5 mg versus 5-10 mg for men due to this pharmacokinetic difference 2

Patients with Substance Abuse History

• These patients show increased risk for misuse, abuse and addiction and require careful monitoring 2
• Substance abuse/dependence was associated with high-dose use in women (OR 1.20) 5

Patients with Depression

• Worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported in depressed patients treated with sedative-hypnotics 2
• Protective measures may be required in patients with suicidal tendencies 2

Common Pitfalls to Avoid

• Do not prescribe beyond 4-5 weeks without re-evaluation for underlying psychiatric or medical illness 2
• Do not combine with other CNS depressants or alcohol due to additive psychomotor impairment and increased risk of complex sleep behaviors 2
• Do not use doses >5 mg in elderly patients or women without compelling justification 2
• Do not ignore failure of insomnia to remit after 7-10 days, as this indicates need for evaluation of primary sleep disorders like sleep apnea 2
• Avoid use in patients with severe hepatic impairment as it may contribute to encephalopathy 2

Safer Long-Term Alternatives

When insomnia persists beyond the appropriate short-term use of zolpidem:

• Cognitive behavioral therapy for insomnia (CBT-I) should be the initial and ongoing treatment, with moderate-quality evidence for improving sleep onset latency, wake after sleep onset, and sleep efficiency 7, 8
• Sedating antidepressants (trazodone 25-100 mg, mirtazapine 7.5-15 mg, or doxepin 3-6 mg) are recommended as first-line alternatives for patients requiring ongoing pharmacotherapy 7, 8
• These alternatives avoid the tolerance, dependence, and serious adverse effects associated with long-term zolpidem use 7, 8