Diazepam

Indications

• FDA-approved for anxiety disorders and short-term relief of anxiety symptoms in adults, and for symptomatic relief in acute alcohol withdrawal.
• FDA-approved as an adjunct for skeletal muscle spasm from local pathology, cerebral palsy, athetosis, stiff-person syndrome and upper motor neuron disorders.
• FDA-approved as an adjunct in convulsive disorders; the injection is used for status epilepticus when lorazepam is unavailable.
• Rectal gel is approved for acute repetitive seizures from age 2, and nasal spray for seizure clusters from age 6, both as rescue therapy.
• Off-label for benzodiazepine cross-tapering, where its long half-life and small dose increments make gradual withdrawal more tolerable.
• Off-label for vertigo, tetanus-related spasm and procedural sedation; anxiety maintenance still belongs to SSRIs and SNRIs by guideline.

Mechanism of action

• Positive allosteric modulator at the GABA-A benzodiazepine site, raising chloride channel opening frequency and suppressing neuronal firing.
• Very high lipophilicity produces the fastest brain entry in the class, but rapid redistribution out of brain shortens the effect of a single dose.
• Spinal and supraspinal GABA-A facilitation reduces polysynaptic reflex transmission, which is the basis of its skeletal muscle relaxant effect.
• Long-lived active metabolites give sustained receptor occupancy, self-tapering the drug and smoothing alcohol withdrawal symptom control.
• Chronic exposure downregulates GABA-A receptors and produces cross-tolerance with alcohol, the reason it substitutes so well in withdrawal.

Pharmacokinetics

• Oral bioavailability approaches 100 percent with peak levels in 1-1.5 hours; intramuscular absorption is erratic and should be avoided.
• Parent half-life is 43-48 hours and the active metabolite nordiazepam runs to about 100 hours, so accumulation over days is expected.
• Oxidized by CYP2C19 and CYP3A4 to nordiazepam, then to temazepam and oxazepam, all pharmacologically active before glucuronidation.
• CYP2C19 poor metabolizers, common in East Asian populations, show roughly four-fold higher exposure and need lower starting doses.
• Clearance falls sharply in cirrhosis and in older adults, where half-life can exceed 100 hours, making accumulation and delirium likely.

Dosing

• Anxiety: 2-10 mg PO two to four times daily depending on severity; most adults need no more than 40 mg/day, and less is usually enough.
• Alcohol withdrawal: 10 mg three or four times in the first 24 hours, then 5 mg three or four times daily; symptom-triggered dosing is preferred.
• Muscle spasm 2-10 mg three or four times daily; adjunctive seizure use 2-10 mg two to four times daily added to the primary anticonvulsant.
• Rectal gel is dosed 0.2-0.5 mg/kg by age band, and nasal spray 5-20 mg by weight, with one repeat dose allowed and no more than five episodes monthly.
• Older adults, debilitated patients and hepatic impairment start at 2-2.5 mg once or twice daily; avoid entirely in advanced cirrhosis.
• Taper by about 10 percent of the current dose every 2-4 weeks after chronic use; abrupt discontinuation can cause seizures, delirium and death.

Adverse effects

• Drowsiness, fatigue, ataxia and muscle weakness are the most common effects and are dose-related; slurred speech and diplopia occur at higher doses.
• Anterograde amnesia and impaired psychomotor performance that carry into the following day because of the long parent and metabolite half-lives.
• Accumulation in older adults produces confusion, gait instability, falls, hip fracture and delirium, often days after the dose looked tolerated.
• Paradoxical excitation, hostility and rage reactions, described most often in children, older adults and patients with brain injury.
• Respiratory depression, hypotension and death when combined with opioids or alcohol; intravenous use adds apnea and thrombophlebitis risk.
• Withdrawal is delayed by days because of long half-life and includes rebound anxiety, psychosis and seizures that can prove fatal.

Monitoring

• Assess sedation, gait and cognition at each visit, remembering that steady state is not reached for 5-10 days after any dose change.
• Screen for substance use disorder and check the prescription drug monitoring program before starting and periodically thereafter.
• Use CIWA-Ar or a similar validated scale to drive symptom-triggered dosing in alcohol withdrawal rather than fixed tapering schedules.
• Check LFTs when liver disease is suspected, and switch to lorazepam or oxazepam if hepatic synthetic function is impaired.
• For rescue formulations, document seizure cluster frequency and confirm caregivers can recognize when emergency care is still required.

Interactions

• Additive respiratory depression and overdose death with opioids; also with alcohol, gabapentinoids, sedating antihistamines and other hypnotics.
• Strong CYP2C19 or CYP3A4 inhibitors such as omeprazole, fluvoxamine, fluconazole, ketoconazole and ritonavir raise levels substantially.
• Rifampin, carbamazepine, phenytoin and St. John's wort induce clearance and may cause breakthrough seizures or withdrawal symptoms.
• Contraindicated in acute narrow-angle glaucoma, myasthenia gravis, severe respiratory insufficiency, sleep apnea and severe hepatic insufficiency.
• Concurrent clozapine has been associated with collapse and respiratory arrest; introduce one drug at a time and monitor closely.

Special populations

• Pregnancy: crosses the placenta freely; third-trimester use causes floppy infant syndrome and neonatal withdrawal lasting days to weeks.
• Lactation: diazepam and nordiazepam accumulate in the nursing infant because of immature clearance; prefer lorazepam if a benzodiazepine is required.
• Pediatrics: oral use is not recommended under 6 months; rescue rectal gel is approved from age 2 and nasal spray from age 6.
• Older adults: the AGS Beers Criteria advise avoiding benzodiazepines, and diazepam is among the worst choices given metabolite accumulation.
• Hepatic impairment: contraindicated in severe disease; lorazepam, oxazepam and temazepam avoid oxidation and are the appropriate substitutes.

Clinical pearls

• Fast in, fast out of brain: a single IV dose wears off quickly despite a 48-hour half-life.
• Long half-life self-tapers, which is why it suits alcohol withdrawal but not older adults.
• CYP2C19 poor metabolizers, common in East Asian patients, reach roughly four-fold higher levels.