Introduction
Benzodiazepines (BZDs) are a class of medications that enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. They are widely prescribed for their anxiolytic, muscle relaxant, anticonvulsant, and sedative properties, commonly used to treat anxiety and insomnia. However, abrupt cessation of benzodiazepine therapy can lead to a severe withdrawal syndrome characterized by anxiety, tremors, insomnia, agitation, hypertension, tachycardia, altered sensation, diaphoresis, and seizures. Managing severe benzodiazepine withdrawal typically involves readministration of benzodiazepines with a gradual taper or symptom-triggered treatment, often supplemented with adjuvant anxiolytics and anticonvulsants. High doses of benzodiazepines required in severe cases carry the risk of respiratory depression.
Ketamine, an anesthetic agent increasingly recognized for its diverse applications, including in the management of alcohol withdrawal, presents a potential alternative or adjunct in benzodiazepine withdrawal treatment. Ketamine differs significantly from benzodiazepines in its mechanism of action and is not a benzodiazepine. While benzodiazepines act as GABA-A receptor agonists, ketamine primarily functions as an NMDA receptor antagonist. However, it also exhibits some GABA-A receptor agonism and has a low risk of respiratory depression, making it a potentially valuable tool in managing severe withdrawal scenarios. This article explores the potential role of ketamine, based on a compelling case study, as an adjunct medication in managing benzodiazepine withdrawal, particularly when conventional treatments prove insufficient.
Case Presentation
A 27-year-old male with a history of both benzodiazepine and opioid abuse was admitted to our emergency department due to drug withdrawal symptoms. The patient reported significant daily polysubstance use, including 30mg of alprazolam and 10 bags of fentanyl. Upon arrival, his symptoms were indicative of combined opioid and benzodiazepine withdrawal, including palpitations, tremors, agitation, nausea, and diarrhea. Physical examination revealed tachycardia, resting tremor, and mydriasis, further confirming withdrawal.
Initial treatment focused on symptomatic control, starting with 4mg of lorazepam and 4mg of buprenorphine for opioid withdrawal. Despite these measures, the patient’s agitation, tremors, and nausea persisted, necessitating increased doses of both benzodiazepines and buprenorphine. The buprenorphine dosage was escalated by an additional 12mg, and diazepam was administered at 45mg. To manage the ongoing symptoms, a multimodal approach was implemented, including 10mg olanzapine, 300mg gabapentin, 260mg phenobarbital, and 4mg ondansetron. While the patient’s opioid withdrawal symptoms seemed to stabilize with buprenorphine, the benzodiazepine withdrawal symptoms—tremor, agitation, tachycardia, and hypertension—remained prominent, requiring further diazepam administration, escalating to a total of 105mg.
Concerned about potential respiratory depression from escalating benzodiazepine doses combined with buprenorphine, and aiming for better symptom control, a ketamine infusion (0.5mg/kg over 30 minutes) was initiated. The patient exhibited a remarkable improvement following ketamine administration, with subjective and objective reductions in tremor and agitation, and resolution of tachycardia and hypertension. Subsequently, the patient was transferred to the intensive care unit for continued management and monitoring. An inpatient benzodiazepine taper protocol was initiated, and the patient was successfully discharged several days later without requiring further escalation of withdrawal management therapies.
Discussion
The escalating rates of benzodiazepine prescriptions and related healthcare visits are a growing public health concern. Between 2003 and 2008, ambulatory care visits related to benzodiazepine use doubled, with a significant portion of the US population receiving benzodiazepine prescriptions. This increase highlights the potential for abuse and dependence associated with these medications. While benzodiazepine overdose risk is amplified when combined with opioids or alcohol, fatal outcomes from benzodiazepine withdrawal alone have also been reported. Benzodiazepine withdrawal syndrome encompasses a spectrum of symptoms, from irritability and insomnia to severe manifestations like seizures, particularly in individuals with long-term, high-dose prescriptions or those using short-acting formulations. Dependence can develop rapidly, with sensitivity to benzodiazepines potentially declining within just one week of regular use.
The established treatment for benzodiazepine withdrawal primarily involves long-acting benzodiazepines. While alternative or adjunctive therapies such as beta-blockers, GABA-B agonists, NMDA antagonists, and neuroleptics have been explored, robust evidence supporting their use as first-line treatments remains limited. The increasing prevalence of benzodiazepine prescriptions underscores the critical need for effective withdrawal management strategies, especially for patients with high tolerance due to chronic use, who often require substantial benzodiazepine doses for symptom control. High benzodiazepine dosages raise concerns about central nervous system depression and respiratory compromise, particularly in conjunction with opioids or alcohol. While the risk of respiratory depression solely from benzodiazepines might be debated, ketamine emerges as a promising supplementary therapy for benzodiazepine withdrawal.
Ketamine, a phencyclidine derivative, initially known for its anesthetic properties, is increasingly recognized for its analgesic, antidepressant, and anxiolytic effects. Its applications have expanded to include non-opioid pain management, sedation of agitated patients, and procedural analgesia and anesthesia. Despite potential side effects like nausea, vomiting, and hallucinations at subanesthetic doses, ketamine is generally considered safe due to its wide therapeutic index.
Ketamine’s mechanism of action is multifaceted, involving NMDA receptor antagonism and agonism of both GABA-A and GABA-B receptors. NMDA receptor antagonism has demonstrated efficacy in alleviating benzodiazepine withdrawal symptoms in animal models, and GABA-B agonists have shown promise in clinical trials. However, the direct application of ketamine for benzodiazepine withdrawal in human cases remains under-reported. A prior case report indicated that low-dose ketamine reduced medication requirements for delirium and agitation management in a patient with opioid and benzodiazepine dependence, suggesting its potential in managing withdrawal-related agitation.
The presented case is subject to limitations. The polysubstance nature of the patient’s withdrawal makes it challenging to isolate the specific effect of ketamine on benzodiazepine withdrawal, given the symptom overlap between opioid and benzodiazepine withdrawal. Additionally, the patient might have improved with further benzodiazepine administration alone. Furthermore, it is not definitively proven whether the patient’s improvement was solely attributable to ketamine or a delayed effect of previously administered medications. Despite these limitations, this case highlights the potential of ketamine as an adjunct in managing benzodiazepine withdrawal, especially in complex clinical scenarios.
Conclusions
With benzodiazepine prescriptions on the rise, emergency departments are increasingly encountering patients presenting with benzodiazepine withdrawal symptoms. Standard treatment protocols emphasize long-acting benzodiazepines, often with adjunctive medications to manage residual withdrawal symptoms. Ketamine’s pharmacological profile, encompassing NMDA receptor antagonism and GABA-A and GABA-B receptor agonism, positions it as a rationally appealing adjunct for benzodiazepine withdrawal management. In this specific case of combined benzodiazepine and opioid withdrawal, where escalating benzodiazepine doses were needed, subanesthetic ketamine administration as an adjunct led to a notable improvement in the patient’s withdrawal symptoms, mitigating concerns about respiratory depression associated with high-dose benzodiazepines and buprenorphine co-administration. Future research should focus on evaluating ketamine’s efficacy in patient populations experiencing isolated benzodiazepine withdrawal to definitively assess its role as an effective adjunct medication in benzodiazepine withdrawal treatment protocols.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
