Benzodiazepine Withdrawal Syndrome: Presentations and Emergency Department Management

Authors: Mounica Donepudi, MD (EM Resident Physician, Advocate Christ Medical Center) and Andrea Carlson, MD (EM Associate Program Director, Director of Toxicology, Advocate Christ Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Clinical Case:

A 56-year-old woman presents to the emergency department (ED) with chief complaint of “heart racing, chest pain, and shaking for the past 3-4 days”.  She has been unable to sleep for days and generally feels unwell with diffuse body aches. She does not have a regular doctor and frequents multiple EDs for her medical care. She tells you she has a history of anxiety, depression, chronic back pain, and sciatica but cannot recall the names of any of her medications that she takes for these conditions. She has 3-4 alcoholic drinks 1-2 times a week. She states she drank a glass of wine earlier today to “calm my nerves.” Upon further questioning, she states that she ran out of her prescription medications 1 week ago.

Vital signs show tachycardia (115 beats per minute), mildly elevated blood pressure (135/85), tachypnea (23 respirations per minute), with normal oxygenation saturation. She is afebrile.

Physical examination shows a very anxious, disheveled woman with a noticeable tremor, tachycardia, mild diaphoresis, and tachypnea. She is alert and oriented x 4 at the time of examination but keeps commenting that everything in the room “looks weird” to her. When pressed further about this, she states “nothing is straight, everything is wavy.” The remainder of the exam is normal.

Laboratory results are significant for mildly elevated transaminases, but otherwise unremarkable. Cardiac enzymes are normal. ECG reveals sinus tachycardia with no ischemic changes. Thyroid stimulating hormone (TSH) is within normal limits. Non-contrast CT scan of the head shows no acute intracranial pathology.

What is in your differential for this patient’s presentation?  What tests should be ordered to definitively diagnose this condition?

Background:

Prescription benzodiazepines continue to be commonly prescribed drugs for treatment of mood and anxiety disorders. In 2015, more than 32 million people over the age of 12 reported use of benzodiazepines in the previous year.  Of these, nearly 20% used benzodiazepines in a pattern of misuse (Figure 1).1 Benzodiazepines also ranked second among misused/abused drug related visits to the ED by patients aged 65 and older in 2011.2 The rates of long term benzodiazepine use have steadily increased over time. A retrospective study showed an age-related increase in the percentage of benzodiazepine use with higher rates of any benzodiazepine use in women at any age.3 Most of the patients with long term benzodiazepine use received their prescriptions from prescribers who were not psychiatrists. Benzodiazepine dependence can be seen within just 3-6 weeks of regular use at therapeutic doses.3

Benzodiazepine withdrawal classically presents in patients who have recent abrupt discontinuation of their medications in the setting of long-term use. The symptoms of withdrawal begin within 1-3 days of discontinuation and peak around 1-2 weeks.  Withdrawal syndrome tends to develop faster with shorter acting agents.3 The exact mechanism of withdrawal is unknown. However, benzodiazepines act via the GABA-A receptor, and long term use of benzodiazepines can cause aberrant expression of this receptor. It is theorized that when these dysfunctional receptors begin to function in the sudden absence of benzodiazepines, withdrawal syndrome occurs.4

Factors that predict increased severity of acute withdrawal include chronic high doses, use of multiple benzodiazepines, oral rather than injected use, longer duration of use, use of benzodiazepines with shorter half-lives, and rapid-tapering or abrupt discontinuation. At high dosage, long term use and rapid tapers can lead to convulsive status epilepticus. Withdrawal symptoms generally do not last longer than 1 month; however, 10%-25% of patients may experience symptoms for up to 12 months.3,5

Signs/Symptoms:

The patient described in the case above shows classic signs of benzodiazepine withdrawal, including anxiety, autonomic instability causing tachycardia, elevated blood pressure, diaphoresis, insomnia, and tremors. Other symptoms common in benzodiazepine withdrawal include sensory hypersensitivity and perceptual distortions of one’s body or surroundings.3,5,7

Testing:

Diagnosis is made by clinical suspicion combined with a focused history and physical exam.  It is very important to eliminate organic causes for the patient’s presenting symptoms. All patients should get a finger stick blood sugar level on arrival to the ED to evaluate for possible hypoglycemia. Basic labs including CBC, CMP, and magnesium should be ordered to evaluate for any signs of infection, anemia, or electrolyte imbalances. TSH should also be obtained to rule out thyroid dysfunction, as hyperthyroidism may manifest with symptoms of tachycardia and anxiety.3,5,7  ECG is recommended. If fever is present with neurologic alteration, a spinal fluid analysis to exclude CNS infection may be considered. If there is any concern for trauma, or the patient is too altered to provide adequate history, a non-contrast CT of the head should be obtained to evaluate for any acute intracranial pathology.

Differential Diagnosis:

It is crucial to consider all possible diagnoses in patients presenting with the symptoms described above.  A thorough past medical and medication history are particularly important in order to decipher whether the symptoms are indeed due to benzodiazepine withdrawal versus other substance withdrawal (e.g., gabapentin/pregabalin, alcohol) or organic causes. Of note, the prescription rates of gabapentin and pregabalin have increased rapidly in the last few years, and the withdrawal symptoms from these medications present identically to benzodiazepine withdrawal.  Both gabapentin and pregabalin function at a receptor other than GABA; therefore, withdrawal syndrome from these agents cannot be treated with long-acting benzodiazepines.9

Treatment:

The goal for management in the ED is to avoid progression to more severe withdrawal symptoms, such as delirium tremens or convulsive status epilepticus.  Use of the Clinical Institute Withdrawal Assessment (CIWA) scale protocol may allow for improved symptom-triggered treatment8. Phenobarbital can be considered as adjunctive therapy in recalcitrant cases, although routine use is not currently recommended. Alternative adjunctive therapies include the use of propranolol for treating tremors,8,10 haloperidol for treatment of hallucinations/delirium,2 and carbamazepine for mood stabilization.3 While there is no true gold standard for treatment, evidence favors a long-acting benzodiazepine, such as diazepam, if tolerated, with a slow taper over time. Use of a shorter-acting benzodiazepine instead, such as lorazepam, may be more appropriate in elderly patients, or in patients with hepatic impairment. The length of taper should be individually tailored based on severity of withdrawal symptoms and history of use with the overall consensus tapering over several weeks to months.3,4  Patients should be referred to an outpatient detoxification center or psychiatrist for close follow-up during this period of benzodiazepine taper to control withdrawal symptoms.

Key Points:

  1. Given the increase in benzodiazepine prescription rates in the last decade, it is important to recognize the signs and symptoms of benzodiazepine withdrawal syndrome to allow for prompt treatment and stabilization.
  2. While symptoms of benzodiazepine withdrawal typically peak by the second week after abrupt cessation, patients with history of chronic benzodiazepine use can present to the emergency department even months later.
  3. Pay careful attention to other causes for the patient’s acute presentation; eliminate organic causes before attributing symptoms solely to withdrawal.
  4. While withdrawal can and should be managed long term on an outpatient basis, patients presenting with acute withdrawal syndrome are best managed with hospitalization, especially if they have a history of high-dose benzodiazepine use. Patients manifesting severe withdrawal symptoms are best managed in an intensive care setting due to heightened risk of delirium tremens or convulsive status epilepticus.
  5. There is no consensus on a treatment protocol for benzodiazepine withdrawal but it is beneficial to place patients on a CIWA protocol to allow for symptom-triggered treatment with long-acting benzodiazepines as tolerated with slow tapers over time as well as other adjunctive therapies such as phenobarbital, propranolol, haloperidol, and carbamazepine

This post is sponsored by www.ERdocFinder.com, a supporter of FOAM and medical education, who with their sponsorship are making FOAM material more accessible to emergency physicians around the world.

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References/Further Reading:

  1. Hughes A, Williams MR, Lipari RN, et al. (2016, September). Prescription drug use and misuse in the United States: Results from the 2015 National Survey on Drug Use and Health. NSDUH Data Review. Retrieved from http://www.samhsa.gov/data/
  2. Mattson M, Lipari RN, Hays C, et al. “A day in the life of older adults: Substance use facts.” The CBHSQ Report: May 11, 2017. Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, Rockville, MD
  3. Puening SE, Wilson MP, Nordstrom K. “Psychiatric emergencies for clinicians: emergency department management of benzodiazepine withdrawal.” J Emerg Med52(1): 66-69. 2017.
  4. Olfson M, King M, Schoenbaum M. “Benzodiazepine use in the United States.” JAMA Psychiatry72(2): 136-142. 2015.
  5. Soyka M. “Treatment of Benzodiazepine Dependence.” NEJM376(12): 1147-1157. 2017.
  6. “How Long Do Benzo Withdrawal Symptoms Last?” American Addiction Centers. N.p., n.d. Web. 24 July 2017. (http://americanaddictioncenters.org)
  7. Gussow L, Carlson A. “Sedative Hypnotics.” Rosen’s Emergency Medicine: Concepts and Clinical Practice. 8th ed. Vol. 2. Philadelphia, PA: Elsevier Health Sciences, Saunders, 2014.
  8. Ashton H. “Benzodiazepine withdrawal: an unfinished story.” BMJ (Clinical research ed.) 288(6424): 1135. 1984.
  9. Mersfelder TL, Nichols WH. “Gabapentin: abuse, dependence, and withdrawal.” Annals of Pharmacotherapy50(3): 229-233. 2016.
  10. Tyrer P, Rutherford D, Huggett T. “Benzodiazepine withdrawal symptoms and propranolol.” The Lancet 317(8219): 520-522.

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