Continuing Education Activity

Oxazepam is a short-acting benzodiazepine used to treat alcohol withdrawal, management of anxiety disorders, and tension. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of patients with anxiety and alcohol withdrawal.

Objectives:

• Identify the indications for oxazepam use.
• Describe the contraindications for using oxazepam.
• Summarize the potential adverse effects associated with oxazepam use.
• Outline the importance of improving care coordination amongst the interprofessional team to improve outcomes for patients receiving oxazepam.

Indications

Oxazepam is an FDA-approved benzodiazepine used for the treatment of alcohol withdrawal and the management of anxiety disorders. Oxazepam has a variety of uses, including several outside of its approved indications such as confusional arousals, sleep terrors, social phobia, PTSD, insomnia, PMDD, and catatonia. Currently, oxazepam is not FDA-approved for use in children under the age of six due to the risk of respiratory arrest. Oxazepam can also be a recommended agent in patients who have difficulties remaining asleep in contrast to drugs helping to initiate sleep.[1][2]

Oxazepam classifies, as a short-intermediate-acting benzodiazepine; its efficacy in long-term use has undergone evaluation in clinical studies. The Convention of Psychotropic Substances classifies oxazepam as a Schedule IV substance, meaning that oxazepam has a lower potential for abuse than substances in Schedule III substances (e.g., ketamine).[3]

Mechanism of Action

Benzodiazepines are among the most prescribed medications for the treatment of insomnia and anxiety. Unlike long-acting benzodiazepines (over 24 hours), short (0 to 6 hours), and intermediate (6 to 24 hours), benzodiazepines do not undergo oxidation by the cytochrome P450 system. Therefore, short-intermediate-acting benzodiazepines like oxazepam are in an active form and undergo direct glucuronidation to produce inactive metabolites.[4]

Benzodiazepines bind to GABA-A receptors, which consist of ligand-gated chloride ion channels that mediate inhibition of the synapses in the CNS. Benzodiazepines bind as allosteric modulators and increase the number of chloride ions crossing the cell membrane. Once benzodiazepines bind to the receptor, the GABA receptor changes conformation and has an increased affinity for GABA. This conformational change causes an increased frequency in opening chloride ion channels and, subsequently, hyperpolarization of the neuronal cell membrane occurs, resulting in a decreased rate of firing of the synapse.[3]

Oxazepam is a short-acting benzodiazepine metabolized via glucuronidation out the liver into its inactive metabolites; hence it is a preferred drug in patients with hepatic impairment. It does not have any active metabolites. The drug has a rapid onset of action and an elimination half-life of between 3 to 21 hours. Elimination is via the renal pathway. Oxazepam is not subject to CYP interaction and does not accumulate upon CYP inhibition.[5]

Administration

Oxazepam is administered orally as a capsule of 10 mg, 15 mg, or 30 mg or tablet of 15 mg. Dosing is without regard to meals. No dose adjustments are needed for patients with hepatic or renal impairments, though caution is advised in renally impaired patients.[6]

For anxiety:

• In adults with mild to moderate anxiety: administer 10 to 15 mg orally every 6 to 8 hours, do not exceed 120 mg daily.
• In adults with severe anxiety or agitation: administer 15 to 30 mg orally every 6 to 8 hours.
• In children age 6 to 12: there are no clear guidelines, but clinicians may administer 1mg/kg/day by mouth; dose divided to 3 times a day.  
• In the geriatric population: administer 10 to 15 mg orally three or four times daily initially and increase the dose cautiously if needed - it is recommended not to exceed 60 mg per day. 

For alcohol withdrawal:  

• In adults; administer 15 mg orally three times daily

Oxazepam has no indications in children under the age of six. 

It is generally not necessary to titrate oxazepam. The recommendation is to use the lowest effective dose possible for the shortest reasonable timeframe.

Adverse Effects

Common adverse effects associated with benzodiazepines such as oxazepam may include sedation, fatigue, depression, confusion, memory impairment, dizziness, ataxia, slurred speech, hyper-excitability, nervousness, and weakness. Less frequently encountered adverse effects may involve hypotension, hallucinations, mania, dry mouth, hypersalivation, edema, leukopenia, decreased libido, incontinence, rash, menstrual irregularities, jaundice, and diplopia. Severe adverse effects of oxazepam include respiratory depression and neonatal abstinence syndrome. Anterograde amnesia also has correlations with benzodiazepine use.[7]

Several cases of fixed drug eruptions, which clinically present as demarcated ovular macules, have been noted in patients taking oxazepam. In these select cases, however, urticaria and diffuse exanthems have not been observed.[8]

Contraindications

Patients taking oxazepam for insomnia should avoid caffeine-containing products as they may decrease the efficacy of the drug. Coadministering oxazepam with other CNS depressants such as diphenhydramine or hydrocodone may result in enhancement of CNS effects (e.g., severe sedation and respiratory depression). It is also not recommended for those who suffer from sleep apnea.[9]

Concurrent use of opioid agonists such as methadone, morphine, and naltrexone may result in respiratory depression, severe hypotension, and sedation. 

Oxazepam may also cross the placenta and be excreted into breastmilk; thus, it is not a recommended pharmaceutical therapy in pregnant or nursing women. According to the prior system of FDA categorization of the safety of medications during pregnancy, there is evidence of risk to the fetus when using benzodiazepines during pregnancy. In some instances, potential benefits may still justify use. In mothers receiving benzodiazepines during pregnancy, neonatal flaccidity, as well as withdrawal symptoms, may be present.[10]

Oxazepam use is not recommended for geriatric patients due to increased risk of dependence and cognitive impairment as well as falls. Several studies have indicated that long-term use of benzodiazepines such as oxazepam may potentiate the development of dementia in the elderly; clinicians should exercise caution when prescribing oxazepam in the geriatric population.[11]

Patients who have demonstrated hypersensitivity to previous oxazepam use or other benzodiazepines should not take oxazepam. Also, patients with substance misuse disorders should not be prescribed oxazepam. 

Monitoring

For patients using oxazepam, it is critical to monitor cardiovascular and respiratory status. Hemodynamic stability and vital signs also require frequent monitoring. Benzodiazepine adverse effects, overdose, toxicity can present as other conditions—especially in long-term oxazepam use—so it is crucial to collect appropriate labs such as CBC, BUN/creatinine, and other serum values when deemed necessary. 

Toxicity

A patient with oxazepam overdose typically presents with normal vital signs with severe CNS depression. Clinical symptoms may include ataxia, slurred speech, confusion, drowsiness, and lethargy. Comatose patients are also commonly seen with severe toxicity. Respiratory compromise most commonly occurs when patients intentionally ingest benzodiazepine with another sedative agent such as an opioid. Oxazepam is the least sedating among all benzodiazepines due to slower absorption.[12][13][14]

If toxicity is suspected, maintenance of airway, breathing, and circulation must be rapid and immediate. Intubation may be necessary if there is a severe compromise.

If the clinician suspects an isolated oxazepam overdose with a patient having stable hemodynamics and a relatively normal physical examination, monitoring of vital signs and clinical observation are appropriate. 

Patients who exhibit respiratory compromise due to oxazepam toxicity may have also taken another drug such as an opioid. Therefore, it may be appropriate to administer naloxone. Clinicians can administer flumazenil, a competitive benzodiazepine receptor antagonist, to reverse an overdose. However, the administration may precipitate withdrawal seizures in patients who chronically use benzodiazepines and have developed tolerance.[15][16]

Enhancing Healthcare Team Outcomes

Oxazepam is a commonly prescribed benzodiazepine and can potentially be subject to misuse. Managing patients on oxazepam requires an interprofessional team of healthcare professionals, including nurses, laboratory technicians, pharmacists, and different specialty physicians. The healthcare team must vigilantly monitor patients on oxazepam by observing any changes in hemodynamic stability (respiratory compromise) or patient demeanor (e.g., stupor, somnolence, or altered mental status). Careful consideration of adverse effects and signs of toxicity by the interprofessional team is necessary to ensure effective treatment and care for patients who exhibit signs of oxazepam use toxicity. Nursing should be well-versed in recognizing toxicity to promptly report any signs to the prescriber or consult with the pharmacist. Additionally, prescribers and pharmacists collaborate in improving patient safety outcomes through the CURES report and could help decrease the likelihood of drug-drug interaction by prescribing oxazepam to a patient receiving an opioid therapy through another provider.

In summary, oxazepam therapy requires an interprofessional team approach, including clinicians (including mid-level practitioners such as NPs and PAs), specialists, specialty-trained nurses, and pharmacists, all collaborating across individual disciplines to achieve optimal patient results. [Level 5]