Introduction
Diazepam is a benzodiazepine medication first synthesized in 1959 and approved for medical use in 1963. It remains one of the most widely prescribed medications in its class, serving as a cornerstone therapy for anxiety disorders, muscle spasm, and seizure emergencies. As a Schedule IV controlled substance, diazepam requires careful prescribing practices due to its potential for dependence and abuse.
Mechanism of Action
Diazepam exerts its therapeutic effects through potentiation of gamma-aminobutyric acid (GABA) neurotransmission. It binds to specific sites on GABA-A receptors, which are ligand-gated chloride channels. This binding increases the frequency of chloride channel opening events in response to GABA, resulting in enhanced inhibitory effects throughout the central nervous system. The net effect is neuronal hyperpolarization and reduced neuronal excitability, producing anxiolytic, sedative, hypnotic, anticonvulsant, and muscle relaxant properties.
Indications
FDA-approved indications include:
- Anxiety disorders
- Acute alcohol withdrawal symptoms
- Adjunctive therapy for skeletal muscle spasm
- Adjunctive therapy for convulsive disorders
- Preoperative anxiety relief
Off-label uses include:
- Agitation treatment
- Panic disorders
- Restless legs syndrome
- Insomnia (short-term management)
Dosage and Administration
Adults:- Anxiety: 2-10 mg PO 2-4 times daily
- Alcohol withdrawal: 10 mg PO 3-4 times first 24 hours, then 5 mg 3-4 times daily
- Muscle spasm: 2-10 mg PO 3-4 times daily
- Seizures: 2-10 mg PO 2-4 times daily
- Hepatic impairment: Reduce dose by 50% or avoid
- Renal impairment: Use with caution
- Pediatrics: 0.2-0.5 mg/kg/day divided every 6-8 hours (not first-line)
Pharmacokinetics
Absorption: Well absorbed orally with bioavailability of 93%; peak concentrations reached in 1-1.5 hours Distribution: Highly lipid-soluble; rapidly crosses blood-brain barrier; volume of distribution 0.8-1.0 L/kg; 98% protein-bound Metabolism: Extensive hepatic metabolism via CYP2C19 and CYP3A4 to active metabolites (desmethyldiazepam, temazepam, oxazepam) Elimination: Terminal half-life 20-50 hours (up to 100 hours for active metabolites); primarily renal excretionContraindications
- Hypersensitivity to diazepam or other benzodiazepines
- Acute narrow-angle glaucoma
- Severe respiratory depression
- Severe hepatic impairment
- Myasthenia gravis
- Sleep apnea syndrome
- Pregnancy (first trimester)
Warnings and Precautions
Boxed Warning:- Risk of concomitant use with opioids: Profound sedation, respiratory depression, coma, death
- Abuse, misuse, and addiction: Can lead to overdose or death
- Dependence and withdrawal reactions: May be life-threatening
- Elderly patients: Increased sensitivity to CNS effects; fall risk
- Depression: May worsen or unmask depression
- Hepatic impairment: Reduced clearance requiring dose adjustment
- Respiratory disease: Use with extreme caution in COPD, sleep apnea
- Pregnancy: Avoid in first trimester; third trimester use may cause neonatal withdrawal
- Breastfeeding: Excreted in human milk; not recommended
Drug Interactions
Major interactions:- Opioids: Additive CNS and respiratory depression (contraindicated)
- Alcohol: Enhanced sedation and impairment
- CYP3A4 inhibitors (ketoconazole, clarithromycin): Increased diazepam levels
- CYP3A4 inducers (rifampin, carbamazepine): Decreased diazepam levels
- Other CNS depressants: Antipsychotics, antidepressants, anticonvulsants
- Oral contraceptives: May decrease diazepam clearance
- Proton pump inhibitors: Potential interaction via CYP2C19 inhibition
- Valproic acid: Displacement from protein binding sites
Adverse Effects
Common (≥10%):- Sedation
- Fatigue
- Ataxia
- Dizziness
- Confusion
- Depression
- Diplopia
- Hypotension
- Constipation
- Nausea
- Respiratory depression
- Dependence and withdrawal syndrome
- Paradoxical reactions (agitation, aggression)
- Suicidal ideation
- Blood dyscrasias
- Hepatitis
Monitoring Parameters
Baseline:- Comprehensive metabolic panel
- Respiratory assessment
- Mental status examination
- Fall risk assessment (especially elderly)
- Efficacy assessment (anxiety scales, seizure frequency)
- Sedation level and cognitive function
- Signs of misuse or dependence
- Respiratory function in at-risk patients
- Withdrawal symptoms during taper
- Liver function tests (long-term therapy)
- Complete blood count
- Reassessment of continued need for therapy
Patient Education
- Take exactly as prescribed; do not increase dose without consultation
- Avoid alcohol and other CNS depressants
- Do not abruptly stop medication due to withdrawal risk
- May cause drowsiness; avoid driving or operating machinery until effects known
- Use caution with activities requiring mental alertness
- Report any thoughts of self-harm or worsening depression
- Inform all healthcare providers of diazepam use
- Store securely to prevent misuse by others
- Use reliable contraception during treatment
- Not recommended during breastfeeding
References
1. FDA Prescribing Information: Valium (diazepam) tablets 2. Lexicomp Online, Lexi-Drugs. Hudson, OH: Wolters Kluwer Clinical Drug Information, Inc. 3. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Diazepam monograph 4. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders 5. WHO Model List of Essential Medicines, 22nd List (2021) 6. Griffin CE 3rd, et al. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013 7. Brett J, et al. Management of benzodiazepine misuse and dependence. Aust Prescr. 2015
Note: This monograph provides general information and does not replace professional medical advice. Always consult with a healthcare provider for personalized medical guidance.