Alprazolam

Indications

• FDA-approved for anxiety disorder and short-term relief of anxiety symptoms in adults; safety and efficacy are not established below age 18.
• FDA-approved for panic disorder with or without agoraphobia in adults, using either the immediate-release tablet or the extended-release formulation.
• Guidelines place SSRIs and SNRIs first line for panic and generalized anxiety, with alprazolam reserved as short-term adjunct during antidepressant onset.
• Off-label for procedural and situational anxiety such as MRI claustrophobia or aviophobia, given as a single dose rather than standing therapy.
• Off-label as brief adjunct for catatonia or severe agitation, though lorazepam is the better studied and more practical benzodiazepine for both.
• Not indicated for PTSD; benzodiazepines show no benefit and are associated with worse outcomes and impaired extinction learning in that population.

Mechanism of action

• Positive allosteric modulator at the benzodiazepine site of the GABA-A receptor, increasing chloride channel opening frequency when endogenous GABA is present.
• Non-selective across alpha-1, alpha-2, alpha-3 and alpha-5 subunits, so sedation and amnesia arrive together with anxiolysis and muscle relaxation.
• High receptor potency and rapid CNS penetration give a fast, perceptible effect that also drives the reinforcing subjective high and misuse liability.
• Tolerance to sedative and anticonvulsant effects develops faster than to anxiolytic effect; receptor adaptation underlies dependence and rebound anxiety.
• Suppresses limbic and brainstem arousal circuits without touching monoamine systems, which is why benzodiazepines treat anxiety but not depression.

Pharmacokinetics

• Rapidly and near completely absorbed orally with peak levels at 1-2 hours; the XR tablet peaks near 9 hours and gives a flatter once-daily profile.
• Mean elimination half-life is about 11 hours, far shorter than clonazepam or diazepam, producing interdose rebound and three-times-daily dosing.
• Metabolized almost entirely by CYP3A4 to alpha-hydroxyalprazolam and an inactive benzophenone; no clinically meaningful active metabolite accumulates.
• Clearance falls in hepatic cirrhosis, obesity, older age and Asian ancestry, with half-life roughly doubling in alcoholic liver disease.
• Unlike lorazepam, oxazepam and temazepam, alprazolam requires hepatic oxidation, so it is a poor choice when liver function is compromised.

Dosing

• Anxiety: start 0.25-0.5 mg PO three times daily, raise at intervals of 3-4 days as tolerated, to a labeled maximum of 4 mg/day in divided doses.
• Panic disorder: start 0.5 mg three times daily, increase by no more than 1 mg/day every 3-4 days; mean effective dose 5-6 mg/day, maximum 10 mg/day.
• Extended-release: start 0.5-1 mg once daily in the morning, titrate to a usual 3-6 mg/day, maximum 10 mg/day; swallow whole and do not crush.
• Older adults, debilitated patients and hepatic impairment start at 0.25 mg two or three times daily and titrate only if clearly tolerated.
• Taper by no more than 0.5 mg every three days after short courses; after months of use reduce 5-10 percent every 2-4 weeks with holds as needed.
• Abrupt discontinuation can cause seizures, delirium and death, so never stop this drug outright and never let a prescription lapse unplanned.

Adverse effects

• Somnolence in roughly 40 percent, fatigue 14 percent, impaired coordination 15 percent, memory impairment 15 percent, dizziness and slurred speech.
• Anterograde amnesia and psychomotor slowing that patients underreport; measurable driving impairment persists into the day after a bedtime dose.
• Falls and hip fracture in older adults, plus delirium, making this a high-yield deprescribing target on any geriatric medication review.
• Paradoxical disinhibition with irritability, agitation or aggression, most common in children, older adults, traumatic brain injury and personality disorder.
• Respiratory depression and death when combined with opioids or alcohol; benzodiazepines appear in a large share of US opioid overdose fatalities.
• Withdrawal produces rebound anxiety, insomnia, tremor, autonomic hyperactivity, psychosis and grand mal seizures, and can be fatal if unmanaged.

Monitoring

• Take a substance use history and check the state prescription monitoring program before the first prescription and periodically during therapy.
• At each visit assess sedation, cognition, falls, driving safety, dose escalation and whether the original indication still justifies continued use.
• No routine laboratory monitoring is required; obtain LFTs when liver disease is suspected and a urine drug screen if diversion or misuse is a concern.
• Set an explicit exit plan at initiation, reassess at 2-4 weeks, then at least every three months, since the label supports short-term use only.
• Co-prescribe naloxone and document the risk discussion whenever an opioid is used concurrently and the combination cannot be avoided.

Interactions

• Contraindicated with ketoconazole and itraconazole; strong CYP3A4 inhibition can more than double alprazolam exposure and precipitate oversedation.
• Ritonavir, clarithromycin, nefazodone, fluvoxamine and grapefruit juice raise levels; start lower and monitor for sedation and confusion.
• Carbamazepine, rifampin, phenytoin and St. John's wort induce CYP3A4 and can drop levels enough to trigger breakthrough panic or withdrawal.
• Additive CNS and respiratory depression with opioids, alcohol, gabapentinoids, sedating antihistamines, muscle relaxants and other hypnotics.
• Also contraindicated in acute narrow-angle glaucoma and in known hypersensitivity to alprazolam or other benzodiazepines.

Special populations

• Pregnancy: associated with neonatal sedation, floppy infant syndrome and neonatal withdrawal after third-trimester exposure; avoid or use lowest effective dose.
• Lactation: small amounts enter breast milk and infant sedation and poor feeding are reported; if a benzodiazepine is needed, lorazepam is preferred.
• Pediatrics: not FDA-approved under age 18, and paradoxical disinhibition plus diversion risk make routine outpatient use hard to justify.
• Older adults: the AGS Beers Criteria advise avoiding benzodiazepines in this group entirely because of delirium, falls, fractures and motor vehicle crashes.
• Hepatic impairment: reduce the dose substantially; lorazepam, oxazepam and temazepam bypass oxidation via glucuronidation and are safer choices.

Clinical pearls

• Short half-life makes alprazolam the hardest benzodiazepine to taper; cross to clonazepam first.
• Interdose rebound anxiety mimics worsening illness and drives escalation, not true disease progression.
• Never stop abruptly after chronic use: withdrawal seizures and delirium can be fatal.