Alprazolam

Alprazolam is a short-acting triazolobenzodiazepine used for generalised anxiety disorder and panic disorder. It acts quickly and wears off quickly, which makes it highly liable to misuse and to cause interdose anxiety and severe withdrawal. It is not first-line treatment, and its use is limited to short courses.

Classification. Benzodiazepine, short-acting, triazolobenzodiazepine.

Mechanism. Positive allosteric modulation of GABA-A receptors, which increases chloride channel opening and neuronal inhibition.

Pharmacokinetics. Well absorbed orally, peak in 1 to 2 hours. Metabolised by CYP3A4 to weakly active metabolites. Half-life about 11 hours (longer in older adults and liver disease). Smoking lowers levels by about 50%. Approximate equivalence for switching: alprazolam 0.5 mg is about diazepam 10 mg.

All regimens are oral with no loading dose.

Generalised anxiety disorder, adults (short-term only).

• Start 0.25 to 0.5 mg three times daily.
• Titration: increase by 0.25 to 0.5 mg every 3 to 4 days based on response.
• Usual 0.5 to 1.5 mg daily in divided doses. Maximum 3 mg daily (4 mg daily in some labels).
• Duration: no longer than 2 to 4 weeks.

Panic disorder, adults (specialist use).

• Start 0.5 mg three times daily.
• Titration: increase by no more than 1 mg daily at intervals of 3 to 4 days.
• Usual 3 to 6 mg daily; maximum 10 mg daily.
• Extended-release: start 0.5 to 1 mg once daily; usual 3 to 6 mg daily.

Dose limits. Older adults and debilitated patients: start 0.25 mg two to three times daily; maximum 3 mg daily. Liver impairment: start 0.25 mg two to three times daily. Strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir): avoid or reduce doses to the minimum.

Contraindications. Concurrent ketoconazole or itraconazole, acute narrow-angle glaucoma, myasthenia gravis, severe respiratory insufficiency, severe sleep apnoea, severe liver impairment, hypersensitivity. Major warning of profound sedation and death with opioids; abuse and misuse; dependence and withdrawal.

Serious adverse effects. Respiratory depression, dependence and severe withdrawal (seizures, delirium), rebound anxiety, paradoxical agitation, mania or hypomania in depression, falls, anterograde amnesia.

Common adverse effects. Drowsiness, light-headedness, memory impairment, ataxia, fatigue, increased salivation.

Interactions. Strong CYP3A4 inhibitors (azole antifungals, ritonavir, nefazodone, fluvoxamine, macrolides) raise levels sharply. Rifampicin, carbamazepine, phenytoin and St John’s wort lower levels. Opioids, alcohol and sedatives add respiratory depression. Smoking lowers levels.

Common prescribing errors. Prescribing for longer than 4 weeks; using it first-line for anxiety; abrupt stopping; combining with opioids or alcohol; not adjusting for CYP3A4 inhibitors.

Special groups.

• Pregnancy: avoid; floppy infant syndrome and neonatal withdrawal with late exposure.
• Breastfeeding: avoid; infant sedation and poor feeding reported.
• Children: not advised.
• Older adults: start 0.25 mg; high risk of falls, delirium and respiratory depression.
• Kidney impairment: start low.
• Liver impairment: start 0.25 mg two to three times daily.

Formulations. Tablets 0.25 mg, 0.5 mg, 1 mg and 2 mg; extended-release tablets 0.5 mg to 3 mg. Swallow extended-release tablets whole.

Baseline. History of substance misuse, alcohol and sedative use, respiratory status, liver function, mood history, pregnancy status, medicines list for CYP3A4 inhibitors and inducers.

Monitoring. Review at 2 weeks and then at the end of the planned course. Ask about escalating use, early refills and interdose symptoms. Monitor for sedation and falls.

Stopping. After more than 2 to 4 weeks of use, reduce the dose by 0.5 mg every 3 days or by 5 to 10% every 1 to 2 weeks, more slowly at the lowest doses; switching to a long-acting benzodiazepine (diazepam 10 mg for each 0.5 mg of alprazolam) can ease the taper.

Referral and escalation. Refer to addiction or psychiatric services for dependence or withdrawal. Seizures, delirium or respiratory depression needs emergency care.