Zolpidem

Indications

• FDA-approved for short-term treatment of insomnia characterized by difficulty with sleep initiation in adults, using the immediate-release tablet.
• Ambien CR is approved for insomnia characterized by difficulties with both sleep onset and sleep maintenance in adults.
• Intermezzo sublingual tablets are approved for middle-of-the-night awakening with difficulty returning to sleep, when 4 hours of bed time remain.
• Edluar sublingual tablets and Zolpimist oral spray are approved for sleep-onset insomnia and act somewhat faster than the swallowed tablet.
• Cognitive behavioral therapy for insomnia is first line per the American Academy of Sleep Medicine and the American College of Physicians.
• Off-label reports of transient responsiveness in disorders of consciousness and in catatonia exist but are anecdotal and not a practice standard.

Mechanism of action

• Non-benzodiazepine imidazopyridine that binds the benzodiazepine site of GABA-A receptors, enhancing chloride conductance in the presence of GABA.
• Preferential affinity for alpha-1 subunit-containing receptors gives sedation and amnesia with relatively less anxiolytic and muscle relaxant effect.
• Alpha-1 selectivity is only partial, so ataxia, falls and next-day impairment still occur, and the drug retains reinforcing properties.
• Sleep architecture is largely preserved compared with benzodiazepines, with modest suppression of stage 3 and REM sleep at higher doses.
• Partial arousal from non-REM sleep with intact motor output but absent memory encoding is the presumed basis for complex sleep behaviors.

Pharmacokinetics

• Rapid absorption with peak levels near 1.6 hours; a meal delays absorption and lowers peak concentration, so dose on an empty stomach.
• Elimination half-life is about 2.5-3 hours, short enough that residual next-day effects are usually modest at labeled doses.
• Metabolized by CYP3A4 with lesser contributions from CYP2C9 and CYP1A2 to three inactive metabolites cleared renally.
• Women clear zolpidem more slowly than men, producing roughly 45 percent higher morning blood levels and the sex-specific dose limits.
• Hepatic impairment markedly reduces clearance and prolongs half-life to about 10 hours in cirrhosis, requiring a lower dose or avoidance.

Dosing

• Immediate release: 5 mg for women and 5 or 10 mg for men, once nightly immediately before bed with at least 7-8 hours of sleep opportunity.
• Extended release: 6.25 mg for women and 6.25 or 12.5 mg for men, once nightly; swallow whole and do not divide, crush or chew.
• Intermezzo sublingual for middle-of-night awakening: 1.75 mg for women and 3.5 mg for men, only with at least 4 hours of bed time remaining.
• Older adults, debilitated patients and any hepatic impairment: 5 mg immediate release or 6.25 mg extended release regardless of sex; avoid in severe hepatic disease.
• Do not exceed 10 mg/day of immediate release or 12.5 mg/day of extended release, and give only one dose per night by any route.
• After nightly use for weeks, taper stepwise rather than stopping abruptly to limit rebound insomnia and withdrawal symptoms.

Adverse effects

• Drowsiness in about 8 percent, dizziness 5 percent and diarrhea 3 percent with immediate release; headache and nausea are also common.
• Complex sleep behaviors such as sleepwalking, sleep-driving, sleep-eating and sleep-sex with no memory of the event; these can be fatal.
• Next-morning psychomotor and driving impairment, worst with the extended-release form, with women and older adults most affected.
• Anterograde amnesia for events after dosing, hallucinations, and rarely confusional arousals or transient psychotic-like phenomena.
• Falls, fractures and delirium in older adults, plus a documented association between hypnotic use and motor vehicle crash risk.
• Angioedema and anaphylaxis after the first or subsequent doses, respiratory depression with opioids, and worsened depression or suicidality.

Monitoring

• Ask explicitly at every visit about sleepwalking, sleep-driving, nocturnal eating and any amnesia for nighttime events.
• Screen for and treat obstructive sleep apnea, restless legs, alcohol use, pain and mood disorder before or alongside hypnotic therapy.
• Reassess ongoing need at 2-4 weeks and periodically thereafter; the label supports short-term use, not indefinite nightly dosing.
• Assess next-morning alertness and counsel that driving may be impaired even when the patient feels fully awake.
• Check the prescription monitoring program and screen for substance use disorder before initiating this schedule IV hypnotic.

Interactions

• Contraindicated in patients who have previously experienced a complex sleep behavior on zolpidem, and in known hypersensitivity or angioedema.
• Additive respiratory depression and sedation with opioids, alcohol, benzodiazepines, gabapentinoids and sedating antihistamines.
• Strong CYP3A4 inhibitors such as ketoconazole and ritonavir raise exposure; avoid the combination or use the lowest dose available.
• Rifampin, carbamazepine and St. John's wort induce CYP3A4 and can substantially reduce efficacy of a given dose.
• Sertraline and fluvoxamine increase zolpidem concentrations modestly, and combined use raises the reported risk of complex sleep behaviors.

Special populations

• Pregnancy: associated with low birth weight and preterm birth in cohort studies; late exposure can cause neonatal sedation and respiratory depression.
• Lactation: small amounts appear in milk with a short half-life; monitor the infant for sedation and consider dosing after the last feed.
• Pediatrics: not approved under age 18 and a controlled trial in pediatric insomnia showed no benefit with more hallucinations and dizziness.
• Older adults: the AGS Beers Criteria advise avoiding Z-drugs entirely given delirium, falls, fractures and emergency department visits.
• Hepatic impairment: reduce to 5 mg and avoid in severe disease; no dose adjustment is needed for renal impairment.

Clinical pearls

• Women get half the dose of men because they clear zolpidem more slowly and wake more impaired.
• Any episode of sleep-driving or sleepwalking makes zolpidem permanently contraindicated.
• Give on an empty stomach with a full 7-8 hour sleep opportunity or expect a poor result.