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Diazepam is a benzodiazepine medication that is FDA approved for the management of anxiety disorders, short-term relief of anxiety symptoms, spasticity associated with upper motor neuron disorders, adjunct therapy for muscle spasms, preoperative anxiety relief, management of certain refractory epilepsy patients, and adjunct in severe recurrent convulsive seizures, and an adjunct in status epilepticus. Off-label (non-FDA approved) use for diazepam includes sedation in the ICU and short-term treatment of spasticity in children with cerebral palsy. This activity will highlight the mechanism of action, adverse event profile, approved and off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions of diazepam, pertinent for interprofessional team members using diazepam for any of its intended indications. Objectives: Identify the indications for using diazepam. Summarize the adverse effects of diazepam. Review the mechanism of action of diazepam. Outline the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients when using diazepam. Access free multiple choice questions on this topic.

Diazepam Overdose The toxic-to-therapeutic ratio of benzodiazepines is very high, making them relatively safe medications. However, the potential of overdose from diverted diazepam always exists when combined with opioids, alcohol, or other centrally acting agents. Overdose in adults frequently involves the co-ingestion of other CNS depressants, which work synergistically to increase toxicity. In the case of single-agent diazepam overdose, symptoms manifest as CNS depression and are very rarely fatal. In mild cases, lethargy, drowsiness, and confusion are common symptoms. In cases of severe overdose, symptoms manifest as ataxia, diminished reflexes, hypotonia, hypotension, respiratory depression, coma (rarely), and death (rarely).[14] Treatment of benzodiazepine overdose involves protecting the airway, fluid resuscitation, and the use of flumazenil if indicated. Flumazenil works via competitive antagonism at the benzodiazepine receptor and can rapidly reverse coma. However, in patients with benzodiazepine tolerance, flumazenil can precipitate acute withdrawal symptoms, autonomic instability, and seizures.[3] Potential for Diazepam Abuse and Dependence Diazepam is a Schedule IV controlled substance with the potential for abuse. Development of dependence and tolerance can occur in addiction-prone, long-term treatment or those patients taking high doses. Thus, these individuals should be under careful supervision; once an individual develops dependence, the risk of developing withdrawal symptoms increases. Signs of benzodiazepine withdrawal include tremors, rebound anxiety, perceptual disturbances, dysphoria, psychosis, agitation, irritability, restlessness, sweating, headache, confusion, myalgias, abdominal pain, and vomiting. In long-term use and abrupt cessation, there is potential for hallucinations and epileptic seizures to occur.[29][25] Propylene Glycol Toxicity

Diazepam is a Schedule IV controlled substance with the potential for abuse. Development of dependence and tolerance can occur in addiction-prone, long-term treatment or those patients taking high doses. Thus, these individuals should be under careful supervision; once an individual develops dependence, the risk of developing withdrawal symptoms increases. Signs of benzodiazepine withdrawal include tremors, rebound anxiety, perceptual disturbances, dysphoria, psychosis, agitation, irritability, restlessness, sweating, headache, confusion, myalgias, abdominal pain, and vomiting. In long-term use and abrupt cessation, there is potential for hallucinations and epileptic seizures to occur.[29][25] Propylene Glycol Toxicity Propylene glycol toxicity is a rare toxidrome associated with the parenteral use of diazepam. Propylene glycol is a common diluent used in the suspension of IV diazepam. Large doses or long-term infusions of IV diazepam can cause accumulation of propylene glycol and subsequent anion gap metabolic acidosis. Signs of propylene glycol poisoning include the development of serum hyperosmolality, hemolysis, cardiac dysrhythmias, hypotension, lactic acidosis, seizure, acute kidney injury, and multisystem organ failure.[30]

Diazepam is a fast-acting potent anxiolytic popular due to its broad therapeutic index, low toxicity, and improved safety profile. Nonetheless, diazepam is still a drug with a high potential for use disorder associated with severe adverse/toxic effects. Therefore, clinicians should identify the proper indication for the prescription of diazepam. Psychiatrist consultation is necessary in the cases of anxiety disorders. Neurologists should prescribe diazepam in spasticity and status epilepticus, considering the risk vs. benefit ratio for the individual patients. The pharmacists are responsible for the proper dosing of diazepam, medication reconciliation, and patient counseling. The pharmacist should report to the clinician or nurse if there are significant interactions.[31][32] In acute overdose of diazepam, triage nurses and emergency department physicians are responsible for rapid diagnosis and stabilization of the patient. Critical care physicians should manage respiratory depression, which can be life-threatening if not treated promptly. In ICU, regular assessment of RASS(Richmond agitation-sedation scale) and CAM-ICU (confusion assessment method for the ICU) scoring should guide the proper use of sedatives. Consulting the psychiatrist is especially important if the diazepam overdose is intentional.[33] A randomized controlled trial, EMPOWER (Eliminating Medications Through Patient Ownership of End Results), for reducing inappropriate benzodiazepine prescriptions for older adults through direct patient education was conducted to compare the result of a direct-to-consumer educational intervention against usual care on benzodiazepine discontinuation in older adults. At the end of six months, 27% of the intervention group discontinued benzodiazepine compared to 5% in the control group using the stepwise tapering protocol.[34] [Level 1]

A randomized controlled trial, EMPOWER (Eliminating Medications Through Patient Ownership of End Results), for reducing inappropriate benzodiazepine prescriptions for older adults through direct patient education was conducted to compare the result of a direct-to-consumer educational intervention against usual care on benzodiazepine discontinuation in older adults. At the end of six months, 27% of the intervention group discontinued benzodiazepine compared to 5% in the control group using the stepwise tapering protocol.[34] [Level 1] As illustrated above, managing patients on diazepam requires an interprofessional team approach consisting of clinicians (MDs, DOs, NPs, PAs), specialists, nurses, pharmacists, and other healthcare providers. As stated previously, prescribing clinicians should be responsible for checking state and federal controlled substance databases to detect benzodiazepine use disorder, diversion, and prevent improper drug use.[28] An interprofessional team approach would achieve maximum efficacy and minimize potential adverse drug reactions for the patients requiring diazepam, which can translate to better patient outcomes. [Level 5]