Sedative-Hypnotic Drug Withdrawal Syndrome: Recognition and Treatment

Table of Contents

 

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Pathophysiology
   1. GABAergic Agent Withdrawal
      1. Benzodiazepine And Barbiturate Withdrawal
      2. GHB, GBL, And Baclofen Withdrawal
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. Initial Management
   2. History
   3. Physical Examination
9. Diagnostic Studies
   1. Laboratory Studies 
   2. Imaging Studies
10. Treatment
    1. Benzodiazepines
       1. Patients With Liver Disease 
       2. Onset And Duration Of Action 
       3. Administration 
       4. Symptom-Triggered Versus Fixed-Schedule Dosing 
    2. Phenobarbital And Propofol 
    3. Alpha-2 Agonists
    4. Beta Blockers 
    5. Anticonvulsants 
    6. Antidepressants 
    7. Antihistamines
    8. Antipsychotics 
11. Special Circumstances
    1. Managing Critically Ill Patients
       1. Refractory Symptoms
    2. Managing Elderly Patients
12. Controversies And Cutting Edge
    1.  Anticonvulsants 
    2. GABAB Receptor Agonists
    3. Dexmedetomidine
    4. Magnesium
13. Disposition
14. Key Points
15. Summary
16. Risk Management Pitfalls For Sedative-Hypnotic Drug Withdrawal
17. Time- And Cost-Effective Strategies
18. Case Conclusions
19. Clinical Pathway For Managing Sedative-Hypnotic Drug Withdrawal In The Emergency Department
20. Tables and Figures
    1. Table 1. Common Generic or Brand Name Drugs In Sedative-Hypnotic Withdrawal
    2. Table 2. Differential Diagnosis For Sympathomimetic Toxidrome
    3. Table 3. Causes Of Sympathomimetic Toxidrome
    4. Table 4. Signs And Symptoms Of Toxidromes
    5. Table 5. Comparison Of Commonly Used Benzodiazepines
21. References

Abstract

Sedative-hypnotic drugs include gamma-Aminobutyric acid (GABA)ergic agents such as benzodiazepines, barbiturates, gamma-Hydroxybutyric acid [GHB], gamma-Butyrolactone [GBL], baclofen, and ethanol. Chronic use of these substances can cause tolerance, and abrupt cessation or a reduction in the quantity of the drug can precipitate a life-threatening withdrawal syndrome. Benzodiazepines, phenobarbital, propofol, and other GABA agonists or analogues can effectively control symptoms of withdrawal from GABAergic agents. Managing withdrawal symptoms requires a patient-specific approach that takes into account the physiological pathways of the particular drugs used, as well as the patient's age and comorbidities. Adjunctive therapies include alpha-2 agonists, beta blockers, anticonvulsants, and antipsychotics. Newer pharmacological therapies offer promise in managing withdrawal symptoms.

Case Presentations

A 23-year-old male weight-lifter with no significant past medical history is brought to the ED after having a seizure at the gym. Upon ED arrival, you note the patient is agitated and is demanding to be released. On examination, he is a well-developed man who appears diaphoretic, restless, and hyper-vigilant. His vital signs are: blood pressure, 180/80 mm Hg; respiratory rate, 16 breaths/ min; pulse, 125 beats/min; room-air pulse oximetry, 100%; and temperature 39.2°C (102.5°F). He is alert and oriented to person, place, and time. His pupils are 5 mm and equally reactive to light, and he has a resting tremor. He has normal breath sounds on auscultation of his chest wall, and his skin is diaphoretic. A friend arrives shortly after the patient’s arrival to the ED and states that the patient had been drinking "blue something" over the course of the past year and had run out of it earlier that morning. You wonder if the drink and the seizure could be related...

A 40-year-old obese woman is brought to the ED by EMS after being found wandering on the street on a warm day. She has a past medical history significant for anxiety and takes alprazolam chronically. On examination, she is soiled in her own feces and vomit, is diaphoretic, combative, altered, groaning incoherently, and unable to follow commands. You administer haloperidol for her agitation. Her vital signs are: blood pressure, 210/105 mm Hg; respiratory rate, 32 breaths/min; room-air pulse oximetry, 84%; and temperature, 40°C (104.1°F). Shortly after she arrives, she has a generalized tonic-clonic seizure. You wonder whether the haloperidol might have made her symptoms worse and what other agents you should use...

A 25-year-old intubated patient diagnosed with clonazepam withdrawal is boarding in your ED, awaiting an ICU bed. He is receiving fentanyl and propofol infusions. The nurse alerts you that his heart rate is in the 130s and his blood pressure is 190/100 mm Hg. You are worried about his vital signs, but you are not sure what to do about it...

Introduction

As the prescription drug abuse crisis reaches epidemic proportions in the United States,^1,2 so are the numbers of emergency department (ED) patients suffering from sedative-hypnotic drug withdrawal.³ According to 2011 data from the Drug Abuse Warning Network (DAWN), sedative-hypnotic agents were the second most frequently reported drug class to cause an ED visit. (Opioids were the most frequent cause.) Of drug-related ED visits, benzodiazepines accounted for 28.7%, and sedative-hypnotics in general accounted for 34%. (See Table 1 for a partial listing of sedative-hypnotic and related drugs by class, with chemical and common brand names.) From 2004 to 2011, ED visits due to use of oxycodone and alprazolam increased 263% and 166%, respectively.³ Many of these ED visits also involved co-ingestions with other drugs, concurrent illnesses, motor vehicle crashes, or other types of trauma.

There is a growing body of literature on sedative- hypnotic withdrawal that attempts to identify the best management strategies. Benzodiazepines are, classically, the first-line agents in managing withdrawal syndromes; however, there are other adjunct medications available that have good supporting evidence. Treating these patients can be improved by following a step-wise, patient-specific approach that requires an understanding of the particular pathophysiology of sedative-hypnotic withdrawal. This issue of Emergency Medicine Practice reviews the pathophysiology, general approach, diagnostic decision-making tools, pharmaceutical treatment options, and disposition criteria to help emergency clinicians create a patient-tailored approach to sedative-hypnotic withdrawal.

Critical Appraisal Of The Literature

A PubMed and Cochrane Database of Systematic Reviews search was performed for articles published between 1980 and 2016 using the search terms sedativehypnotic withdrawal, GABA, benzodiazepine, barbiturate, baclofen, GHB, GBL, ethanol, and emergency department. A total of 2873 articles were identified, of which, 83 were used for this review. The majority of the guidelines and recommendations regarding the treatment of withdrawal symptoms from gamma-Aminobutyric acid (GABA)ergic agents have come from literature on ethanol withdrawal. By contrast, the majority of the literature regarding withdrawal symptoms from GABAergic agents such as benzodiazepines, barbiturates, baclofen, gamma-Hydroxybutyric acid [GHB], and gamma-Butyrolactone (GBL) are case reports and retrospective studies. There is a paucity of randomized prospective studies or clinical trials for these individual GABAergic agents, and the majority of the guidelines are derived from expert consensus opinion and literature reviews.

Risk Management Pitfalls For Sedative-Hypnotic Drug Withdrawal

1.  “His ECG showed sinus tachycardia and nonspecific T-wave changes. I thought it was due to his withdrawal.”
   Withdrawal from GABAergic agents can cause nonspecific ECG changes due to strain placed on the heart from the secondary tachycardia. In these situations, serial ECGs should be done to evaluate for the presence of dynamic changes and possible development of acute coronary syndromes caused by the withdrawal syndrome.
    
2. “His rectal temperature was 39.4°C (103°F), so I ordered acetaminophen for his fever and started him on antibiotics.”
   Fever secondary to sedative-hypnotic withdrawal will not respond to antipyretics since it is centrally mediated and not immune-mediated. Patients who are hypothermic should have their core temperatures monitored (rectal, bladder, esophageal) and given cool fluids, cold blankets, or more invasive cooling methods if severely hypothermic.
    
3. “I thought the fever and tachycardia were due to his pneumonia.”
   Vital sign abnormalities in the setting of withdrawal should be a diagnosis of exclusion. Do not neglect to ask patients their substance abuse history. A delay in recognizing sedativehypnotic drug withdrawal may result in insufficient quantities of benzodiazepines to control symptoms and the progression of minor withdrawal symptoms to severe withdrawal.
    
4. “EMS just brought in a patient with altered mental status, slurred speech, ophthalmoplegia, and ataxia. Activate the stroke team.”
   Withdrawal symptoms can be mistaken for other serious conditions, such as hypoglycemia, hypoxia, sepsis, stroke, delirium, or adverse drug reactions. Another common pitfall is the misunderstanding of the relationship between withdrawal syndromes and comorbid medical illnesses.
    
5. “I discharged him after serial neurological checks, but he was brought back 15 minutes later by EMS after having seized a few blocks away.”
   Inappropriate disposition for patients suffering from withdrawal syndromes can occur if a patient is discharged prematurely from the ED, the emergency physician fails to recognize withdrawal at the time of admission, or if the emergency clinician fails to recognize a critically ill patient and fails to admit the patient to an ICU.
    
6. “I thought the fever and tachycardia in my quadriplegic patient with spasticity was from sepsis.”
   Withdrawal from intrathecal baclofen can be life-threatening and very difficult to manage. Baclofen withdrawal can start early, usually within 12 to 24 hours of cessation. These patients may be resistant to even high-dose benzodiazepines. The intrathecal pump should be interrogated for malfunction, and the patient should be restarted on intrathecal baclofen as soon as possible.
    
7. “After giving him lorazepam, he was still agitated and pulling at lines. I switched to propofol, and then I had to prepare for intubation, since he had respiratory depression.”
   Inadequate treatment for withdrawal syndromes can occur by using inappropriate medications (eg, haloperidol alone), insufficient dosing of medications, or inappropriate route of medication administration (eg, use of oral or intramuscular medications with erratic or delayed absorption in a patient with moderateto- severe withdrawal symptoms). Patients with withdrawal symptoms may require large doses of benzodiazepines.
    
8. “The patient with sedative-hypnotic withdrawal was persistently tachycardic and hypertensive, so I started him on a propranolol drip since I didn’t want to give him any more benzodiazepines. His vital signs improved, but later, on he seized.”
   The use of beta blockers as adjunct therapy may reduce some symptoms of withdrawal, but it does not prevent the development of seizures. These agents should not be considered standard therapy and, if used at all, administered only after giving appropriate quantities of benzodiazepines, barbiturates, and pain medications.
    
9. “I didn’t start benzodiazepines in my benzodiazepine- dependent patient who was altered because he didn’t have tremors or tachycardia.”
   Withdrawal from GABAergic agents does not always follow the linear progression of abnormal vital signs > tremors > altered mental status > seizures. Altered mental status and seizures can sometimes occur prior to vital sign abnormalities.
    
10. “I thought his altered mental status was due to his benzodiazepine abuse, so I didn't order a head CT.”
    Altered mental status due to drug ingestion or withdrawal should be a diagnosis of exclusion after ruling out metabolic, infectious, or traumarelated causes. A full neurological and physical examination should be done with patients who have altered mental status to detect possible occult trauma. Patients with a sedative-hypnotic clinical picture (slured speech, sedated, ataxic, etc) should have a head CT if there is a history of fall and if they have an abnormal neurological examination. If a patient is too altered to comply with a neurological examination and there are physical examination findings of head trauma, imaging should be done to rule out occult head trauma.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study is included in bold type following the reference, where available. The most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.

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2. United States Department of Justice National Drug Intelligence Center. The economic impact of illicit drug use on American society. In: US Department of Justice, ed. Washington D.C: United States Department of Justice; 2011. (Government report)
3. Substance Abuse and Mental Health Services Administration Center for Behavioral Health Statistics and Quality. The DAWN Report: highlights of the 2011 Drug Abuse Warning Network (DAWN) findings on drug-related emergency department visits. 2013; Available at: https://www.samhsa.gov/data/sites/default/files/DAWN127/DAWN127/sr127-DAWN-highlights.htm. Accessed January 23, 2017. (Government website)
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33. Sachdeva A, Chandra M, Deshpande S. A comparative study of fixed tapering dose regimen versus symptom-triggered regimen of lorazepam for alcohol detoxification. Alcohol Alcohol. 2014;49(3):287-291. (Prospective randomized doubleblind controlled trial; 63 patients)
34. Cassidy E, O’Sullivan I, Bradshaw P, et al. Symptomtriggered benzodiazepine therapy for alcohol withdrawal syndrome in the emergency department: a comparison with the standard fixed dose benzodiazepine regimen. Emerg Med J. 2012;29(10):802-804. (Retrospective review; 100 patients)
35. * Jaeger T, Lohr R, Pankratz V. Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients. Mayo Clin Proc. 2001;76(7):695-701. (Retrospective review; 216 admissions)
36. * Ungur LA, Neuner B, John S, et al. Prevention and therapy of alcohol withdrawal on intensive care units: systematic review of controlled trials. Alcohol Clin Exp Res. 2013;37(4):675- 686. (Systematic review and meta-analyses; 6 clinical trials, 4 cohort studies)
37. * Saitz R, Mayo-Smith M, Roberts M, et al. Individualized treatment for alcohol withdrawal. A randomized doubleblind controlled trial. JAMA. 1994;272(7):519-523. (Randomized double-blind controlled trial; 101 patients)
38. Busto UE, Sykora K, Sellers EM. A clinical scale to assess benzodiazepine withdrawal. J Clin Psychopharmacol. 1989;9(6):412-416. (Retrospective study; 63 patients)
39. Corbett SM, Montoya ID, Moore FA. Propofol-related infusion syndrome in intensive care patients. Pharmacotherapy. 2008;28:250-258. (Literature review)
40. Sohraby R, Attridge R, Hughes D. Use of propofol-containing versus benzodiazepine regimens for alcohol withdrawal requiring mechanical ventilation. Ann Pharmacother. 2014;48(4):456-461. (Retrospective cohort study; 64 cases)
41. Albertson TE, Chenoweth J, Ford J, et al. Is it prime time for alpha2-adrenocepter agonists in the treatment of withdrawal syndromes? J Med Toxicol. 2014;10(4):369-381. (Review)
42. Morr S, Heard CM, Li V, et al. Dexmedetomidine for acute baclofen withdrawal. Neurocrit Care. 2015;22(2):288-292. (Case report)
43. Oschman A, McCabe T, Kuhn RJ. Dexmedetomidine for opioid and benzodiazepine withdrawal in pediatric patients. Am J Health Syst Pharm. 2011;68(13):1233-1238. (Review)
44. Phan H, Nahata MC. Clinical uses of dexmedetomidine in pediatric patients. Paediatr Drugs. 2008;10(1):49-69. (Review)
45. da Silva PS, Passos RM, Waisberg DR. Withdrawal treatment with clonidine after prolonged use of chloral hydrate in a pediatric intensive care patient. Paediatr Anaesth. 2011;21(10):1082-1083. (Case report)
46. Joshi D, Naidu PS, Singh A, et al. Reversal of triazolam tolerance and withdrawal-induced hyperlocomotor activity and anxiety by bupropion in mice. Pharmacology. 2005;75(2):93-97. (Experimental animal study)
47. Chandrasekaran PK. Employing mirtazapine to aid benzodiazepine withdrawal. Singapore Med J. 2008;49(6):e166-e167. (Case report)
48. Lemoine P, Touchon J, Billardon M. [Comparison of 6 different methods for lorazepam withdrawal. A controlled study, hydroxyzine versus placebo]. Encephale. 1997;23(4):290-299. (Multicenter randomized placebo-controlled study; 154 patients)
49. Avedisova AS, Iastrebov DV. [Use of anxiolytic atarax as a substitutive drug for benzodiazepine tranquilizers]. Zh Nevrol Psikhiatr Im S S Korsakova. 2007;107(3):37-41. (Prospective placebo-controlled study; 59 patients)
50. Blum K, Eubanks JD, Wallace JE, et al. Enhancement of alcohol withdrawal convulsions in mice by haloperidol. Clin Toxicol. 1976;9:427-434. (Experimental animal study)
51. Golbert TM, Sanz CJ, Rose HD, et al. Comparative evaluation of treatments of alcohol withdrawal syndromes. JAMA. 1967;201:99-102. (Clinical comparative study; 49 patients)
52. Greenblatt DJ, Gross PL, Harris J, et al. Fatal hyperthermia following haloperidol theapy of sedative hypnotic withdrawal. J Clinic Psychiatry. 1978;39:673-675. (Case report)
53. Greenland P, Southwick W. Hyperthermia associated with chlorpromazine and full sheet restraint. Am J Psychiatry. 1978;135:1234-1235. (Case report)
54. Oldham A, Bott M. The management of excitement in a general psychiatric ward by high dosage of haloperidol. Acta Psychiatr Scand. 1971;47:369-376. (Retrospective review; 67 cases)
55. Hedges D, Jepsson K, Whitehead P. Antipsychotic medication and seizures: a review. Drugs Today. 2003;39:551–557. (Review)
56. Attard A, Ranjith G, Taylor D. Delirium and its treatment. CNS Drugs. 2008;22(8):631-644. (Review)
57. * Gold J, Rimal B, Nolan A, et al. A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med. 2007;35(3):724-730. (Retrospective cohort study; 54 patients)
58. Leggio L, Kenna GA, Swift RM. New developments for the pharmacological treatment of alcohol withdrawal syndrome. A focus on non-benzodiazepine GABAergic medications. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32:1106-1117. (Literature review)
59. Krupitsky EM, Rudenko AA, Burakov AM, et al. Antiglutamatergic strategies for ethanol detoxification: comparison with placebo and diazepam. Alcohol Clin Exp Res. 2007;4:604- 611. (Placebo-controlled randomized single-blinded; 127 patients)
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61. Djokić G, Lazić D, Nenadović M, et al. Lamotrigine augmentation in delirium tremens. Srp Arh Celok Lek. 2011;139(1):41- 45. (Prospective clinical study; 240 patients)
62. Voris J, Smith NL, Rao SM, et al. Gabapentin for the treatment of ethanol withdrawal. Subst Abus. 2003;24(2):129-132. (Retrospective study; 40 patients)
63. Stock CJ, Carpenter L, Ying J, et al. Gabapentin versus chlordiazepoxide for outpatient alcohol detoxification treatment. Ann Pharmacother. 2013;47(7-8):961-969. (Retrospective study; 49 patients)
64. Oulis P, Konstantakopoulos G. Efficacy and safety of pregabalin in the treatment of alcohol and benzodiazepine dependence. Expert Opin Investig Drugs. 2012;21(7):1019- 1029. (Systematic review; 4 randomized controlled trials)
65. Biermann T, Bleich S, Kornhuber J, et al. Pregabalin in benzodiazepine withdrawal. Pharmacopsychiatry. 2007;40(6):292- 293. (Commentary)
66. Hadley SJ, Mandel FS, Schweizer E. Switching from longterm benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial. J Psychopharmacol. 2012;26(4):461-470. (Randomized double-blind placebo controlled trial; 106 patients)
67. Cheseaux M, Monnat M, Zullino DF. Topiramate in benzodiazepine withdrawal. Hum Psychopharmacol. 2003;18(5):375- 377. (Case report)
68. Croissant B, Grosshans M, Diehl A, et al. Oxcarbazepine in rapid benzodiazepine detoxification. Am J Drug Alcohol Abuse. 2008;34(5):534-540. (Case study; 10 patients)
69. Oulis P, Nakkas G, Masdrakis VG. Pregabalin in zolpidem dependence and withdrawal. Clin Neuropharmacol. 2011;34(2):90-91. (Case series; 10 patients)
70. Rubio G, Bobes J, Cervera G, et al. Effects of pregabalin on subjective sleep disturbance symptoms during withdrawal from long-term benzodiazepine use. Eur Addict Res. 2011;17(5):262-270. (Prospective open noncontrolled study; 282 patients)
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73. Maitre M, Humbert J, Kemmel V, et al. A mechanism for gamma-Hydroxybutyrate (GHB) as a drug and a substance of abuse. Med Sci. 2005;21(3):284-289. (Review)
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Shownotes

Welcome back to another episode of EMplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. This month, we’ll be talking about sedative-hypnotics. Specifically, we’ll be talking about sedative-hypnotic drug withdrawal syndromes, both the recognition of such syndromes and their appropriate treatment. 

This episode’s content was curated by Cynthia Santos, MD, of Emory University Hospital and Ruben Olmedo, MD, who is director of the division of toxicology at Mount Sinai Hospital. Don’t miss it! 

Topics: 

• Why EB Medicine chose this topic 
• Pathophysiology of sedative-hypnotic drug withdrawal syndromes 
• Specific sedative hypnotic classes 
• Toxicologic syndromes’ differential subcategories 
• Prehospital care 
• Initial ED management 
• Emergency department diagnostic studies 
• Treatment 
• Different classes of medications 
• Controversies 
• Quick rundown of the key take-home points 
• Bonus: Interview with Dr. Cynthia Santos 

Links and Resources: 

Sedative-Hypnotic Drug Withdrawal Syndrome: Recognition And Treatment – http://bit.ly/2mp4mAR 

Alcohol Withdrawal Syndrome: Improving Outcomes Through Early Identification And Aggressive Treatment Strategies (Critical Care Issue) – http://bit.ly/2mWN8hp 

Current Guidelines For The Management Of Acute Alcohol Withdrawal In The Emergency Department – http://bit.ly/2nkBM7H 

Emory University Hospital - https://www.emoryhealthcare.org/locations/hospitals/emory-university-hospital/ 

Mount Sinai Hospital - http://www.mountsinai.org/locations/mount-sinai 

16th Annual Clinical Decision Making in Emergency Medicine - http://clinicaldecisionmaking.com/ 

Hosts: Nachi Gupta, MD, PhD; Jeff Nusbaum, MD