References | Sedative-Hypnotic Withdrawal

<< Sedative-Hypnotic Drug Withdrawal Syndrome: Recognition and Treatment (Critical Care Topic and Pharmacology CME)


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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.

  1. Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings. Vol NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2013. (Government report)
  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: Accessed January 23, 2017. (Government website)
  4. McDonough M, Kennedy N, Glasper A, et al. Clinical features and management of gamma-hydroxybutyrate (GHB) withdrawal: a review. Drug Alcohol Depend. 2004;75(3). (Review)
  5. Rivas DA, Chancellor MB, Hill K, et al. Neurological manifestations of baclofen withdrawal. J Urol. 1993;150(6):1903- 1905. (Systematic review; 38 cases)
  6. Watve SV, Sivan M, Raza WA, et al. Management of acute overdose or withdrawal state in intrathecal baclofen therapy. Spinal Cord. 2012;50(2):107-111. (Systematic review; 36 studies)
  7. Leo R, Baer D. Delirium associated with baclofen withdrawal: a review of common presentations and management strategies. Psychosomatics. 2005;46(6):503-507. (Systematic review; 23 cases)
  8. Dang K, Bowery N, Urban L. Interaction of gamma-Aminobutyric acid receptor type B receptors and calcium channels in nociceptive transmission studied in the mouse hemisected spinal cord in vitro: withdrawal symptoms related to baclofen treatment. Neurosci Lett. 2004;361(1-3):72-75. (Experimental animal study)
  9. Agrawal V, Amos JD. The association between illicit drug use and infectious complications among trauma patients. Eur J Clin Microbiol Infect Dis. Epub ahead of print, 10/28/2016. (Databank study; 525,052 admissions)
  10. Casolla B, Dequatre-Ponchelle N, Rossi C, et al. Heavy alcohol intake and intracerebral hemorrhage: characteristics and effect on outcome. Neurology. 2012;79(11):1109-1115. (Prospective study; 540 patients)
  11. Tavel ME, Davidson W, Batterton TD. A critical analysis of mortality associated with delirium tremens. Review of 39 fatalities in a 9-year period. Am J Med Sci. 1961;242:18-29. (Case review)
  12. Khan A, Levy P, DeHorn S, et al. Predictors of mortality in patients with delirium tremens. Acad Emerg Med. 2008;15(8):788-790. (Case-control study; 35 patients)
  13. Poser W, Poser S, Eva-Condemarin P. Mortality in patients with dependence on prescription drugs. Drug Alcohol Depend. 1992;30(1):49-57. (Case follow-up study; 2082 cases)
  14. Brett J, Murnion B. Management of benzodiazepine misuse and dependence. Aust Prescr. 2015;38(5):152-155. (Commentary)
  15. Ashton H. The treatment of benzodiazepine dependence. Addiction. 1994;89(11):1535-1541. (Review)
  16. Mayo-Smith MF. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA. 1997;278(2):144-151. (Meta analysis; 134 articles including 65 prospective controlled trials)
  17. * Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med. 2004;164(13):1405-1412. (Metaanalysis; 9 prospective controlled trials)
  18. Gottlieb LD. The role of beta blockers in alcohol withdrawal syndrome. Postgrad Med. 1988;Spec No:169-174. (Randomized double-blind placebo-controlled trial; 120 patients)
  19. Muzyk AJ, Fowler JA, Norwood DK, et al. Role of alpha- 2-agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother. 2011;45(5):649-657. (Literature review)
  20. Muzyk AJ, Kerns S, Brudney S, et al. Dexmedetomidine for the treatment of alcohol withdrawal syndrome: rationale and current status of research. CNS Drugs. 2013;27(11):913-920. (Review article; 8 case series)
  21. * Mueller S, Preslaski C, Kiser T, et al. A randomized, doubleblind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal. Crit Care Med. 2014;42(5):1131-1139. (Randomized double-blind placebo-controlled trial; 24 patients)
  22. Tyrer P, Rutherford D, Huggett T. Benzodiazepine withdrawal symptoms and propranolol. Lancet. 1981;1(8219):520-522. (Controlled double-blind trial; 40 patients)
  23. Abernethy DR, Greenblatt DJ, Shader RI. Treatment of diazepam withdrawal syndrome with propranolol. Ann Intern Med. 1981;94(3):354-355. (Case report)
  24. Gauche WG. Propranolol for the treatment of diazepam withdrawal symptoms. S Afr Med J. 1984;66(23):870. (Case report)
  25. Seivewright N, Tyrer PJ. Use of beta-blocking drugs in withdrawal states. Postgrad Med J. 1984;60 Suppl 2:47-50. (Literature review)
  26. Turner P. Therapeutic uses of beta-adrenoceptor blocking drugs in the central nervous system in man. Postgrad Med J. 1989;65(759):1-6. (Review)
  27. Amato L, Minozzi S, Vecchi S, et al. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD005063. (Systematic review; 64 randomized controlled trials)
  28. Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs. 2014;28(5):401-410. (Review)
  29. Peppers MP. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. Pharmacotherapy. 1996;16(1):49-57. (Review)
  30. * Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012 366(7):591-600. (Double-blind randomized noninferiority trial; 893 patients)
  31. Wilson K, Reardon C, Theodore A, et al. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving IV benzodiazepines: a case series and prospective, observational pilot study. Chest. 2005;128(3):1674-1681. (Case series and prospective observational study; 44 patients)
  32. Daeppen J, Gache P, Landry U, et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med. 2002;162(10):1117-1121. (Prospective randomized doubleblind controlled trial; 117 patients)
  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)
  60. Likhitsathian S, Uttawichai K, Booncharoen H, et al. Topiramate treatment for alcoholic outpatients recently receiving residential treatment programs: a 12-week, randomized, placebo- controlled trial. Drug Alcohol Depend. 2013;133(2):440- 446. (Randomized double-blind placebo-controlled trial; 106 patients)
  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)
  71. Mariani JJ, Malcolm RJ, Mamczur AK, et al. Pilot trial of gabapentin for the treatment of benzodiazepine abuse or dependence in methadone maintenance patients. Am J Drug Alcohol Abuse. 2016;42(3):333-340. (Randomized doubleblind placebo-controlled outpatient pilot trial; 19 patients)
  72. Liu J, Wang LN. Baclofen for alcohol withdrawal. Cochrane Database Syst Rev. 2013 Feb 28;(2):CD008502. (Systematic review; 2 randomized clinical controlled trials)
  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)
  74. * Keating G. Sodium oxybate: a review of its use in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence. Clin Drug Investig. 2014;34(1):63-80. (Literature review)
  75. Kemp KM, Henderlight L, Neville M. Precedex: is it the future of cooperative sedation? Nursing. 2008;38 Suppl Critical: 7-8. (Review)
  76. Kaur M, Singh PM. Current role of dexmedetomidine in clinical anesthesia and intensive care. Anesth Essays Res. 2011;5(2):128-133. (Review)
  77. * Guinter JR, Kristeller JL. Prolonged infusions of dexmedetomidine in critically ill patients. Am J Health Syst Pharm. 2010;67(15):1246-1253. (Literature review; 6 adult trials, 5 pediatric trials)
  78. Frazee EN, Personett HA, Leung JG, et al. Influence of dexmedetomidine therapy on the management of severe alcohol withdrawal syndrome in critically ill patients. J Crit Care. 2014;29(2):298-302. (Retrospective case series; 33 patients)
  79. DeMuro JP, Botros DG, Wirkowski E, et al. Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: a retrospective case series. J Anesth. 2012;4:601-605. (Retrospective case series; 10 patients)
  80. Crispo AL, Daley MJ, Pepin JL, et al. Comparison of clinical outcomes in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: dexmedetomidine versus benzodiazepines. Pharmacotherapy. 2014;34(9):910-917. (Retrospective cohort study; 61 patients)
  81. Hantouche EG, Guelfi JD, Comet D. [alpha-beta L-aspartate magnesium in treatment of chronic benzodiazepine abuse: controlled and double-blind study versus placebo]. Encephale. 1998;24(5):469-479. (Randomized double-blind placebo controlled study; 144 patients)
  82. Wilson A, Vulcano B. A double-blind, placebo-controlled trial of magnesium sulfate in the ethanol withdrawal syndrome. Alcohol Clin Exp Res. 1984;8:542-545. (Randomized doubleblind placebo-controlled study; 100 patients)
  83. Sarai M, Tejani AM, Chan AH, et al. Magnesium for alcohol withdrawal. Cochrane Database Syst Rev. 2013 Jun 5;(6):CD008358. (Systematic review; 4 randomized or quasirandomized trials)
Publication Information

Cynthia Santos, MD; Ruben E. Olmedo, MD

Publication Date

March 1, 2017

CME Expiration Date

March 31, 2020

CME Credits

4 AMA PRA Category 1 Credits™, 4 ACEP Category I Credits, 4 AAFP Prescribed Credits, 4 AOA Category 2-A or 2-B Credits.
Specialty CME Credits: Included as part of the 4 credits, this CME activity is eligible for 4 Pharmacology CME credits

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