Alcohol withdrawal: Difference between revisions

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'''Alcohol withdrawal''' is a group of syndromes that may occur after cessation of drinking ethanol alcohol.<ref name="pmid15249349">{{cite journal |author=Mayo-Smith MF, Beecher LH, Fischer TL, ''et al'' |title=Management of alcohol withdrawal delirium. An evidence-based practice guideline |journal=Arch. Intern. Med. |volume=164 |issue=13 |pages=1405-12 |year=2004 |pmid=15249349 |doi=10.1001/archinte.164.13.1405}}</ref><ref name="titleManagement of alcohol withdrawal delirium. An evidence-based practice guideline.">{{cite web |url=http://www.guideline.gov/summary/summary.aspx?ss=15&doc_id=6543&nbr=4109 |title=Management of alcohol withdrawal delirium. An evidence-based practice guideline. |accessdate=2008-04-03 |author=Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, Jara G, Kasser C, Melbourne J. |authorlink= |coauthors= |date=2004 |format= |work= |publisher=National Guidelines Clearinghouse |pages= |language=English |archiveurl= |archivedate= |quote=}}</ref><ref name="pmid9214531">{{cite journal |author=Mayo-Smith MF |title=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 |journal=JAMA |volume=278 |issue=2 |pages=144-51 |year=1997 |pmid=9214531 |doi=}} [http://gateway.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=9214531.ui Full text] at OVID</ref>
'''Alcohol withdrawal''' is a group of syndromes that may occur after cessation of drinking [[ethanol]] alcohol.<ref name="pmid15249349">{{cite journal |author=Mayo-Smith MF, Beecher LH, Fischer TL, ''et al'' |title=Management of alcohol withdrawal delirium. An evidence-based practice guideline |journal=Arch. Intern. Med. |volume=164 |issue=13 |pages=1405-12 |year=2004 |pmid=15249349 |doi=10.1001/archinte.164.13.1405}}</ref><ref name="titleManagement of alcohol withdrawal delirium. An evidence-based practice guideline.">{{cite web |url=http://www.guideline.gov/summary/summary.aspx?ss=15&doc_id=6543&nbr=4109 |title=Management of alcohol withdrawal delirium. An evidence-based practice guideline. |accessdate=2008-04-03 |author=Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, Jara G, Kasser C, Melbourne J. |authorlink= |coauthors= |date=2004 |format= |work= |publisher=National Guidelines Clearinghouse |pages= |language=English |archiveurl= |archivedate= |quote=}}</ref><ref name="pmid9214531">{{cite journal |author=Mayo-Smith MF |title=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 |journal=JAMA |volume=278 |issue=2 |pages=144-51 |year=1997 |pmid=9214531 |doi=}} [http://gateway.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=9214531.ui Full text] at OVID</ref>


==Classification==
==Classification==
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===Seizures===
===Seizures===
Alcohol withdrawal seizures is a "condition where [[seizure]]s occur in association with ethanol abuse (alcoholism) without other identifiable causes. Seizures usually occur within the first 6-48 hours after the cessation of alcohol intake, but may occur during periods of alcohol intoxication. Single generalized tonic-clonic motor seizures are the most common subtype, however, [[status epilepticus]] may occur".<ref>{{MeSH|Alcohol withdrawal seizures}}</ref><ref name="isbn0-07-067439-6p1174">{{cite book |author=Ropper, Allan H.; Adams, Raymond Delacy; Victor, Maurice |title=Principles of Neurology |publisher=McGraw-Hill, Health Professions Division |location=New York |year=1997 |pages=1174 |isbn=0-07-067439-6 |oclc= |doi=}}</ref>
Alcohol withdrawal seizures is a "condition where [[seizure]]s occur in association with ethanol abuse (alcoholism) without other identifiable causes. Seizures usually occur within the first 6-48 hours after the cessation of alcohol intake, but may occur during periods of alcohol intoxication. Single generalized tonic-clonic motor seizures are the most common subtype, however, [[status epilepticus]] may occur".<ref>{{MeSH|Alcohol withdrawal seizures}}</ref><ref name="isbn0-07-067439-6-p1174">{{cite book |author=Ropper, Allan H.; Adams, Raymond Delacy; Victor, Maurice |authorlink= |editor= |others= |title=Principles of Neurology |edition=6th |language=English |publisher=McGraw-Hill, Health Professions Division |location=New York |year=1997 |origyear= |pages=1174 |quote= |isbn=0-07-067439-6 |oclc= |doi= |url= |accessdate=}}</ref>


===Delirium===
===Delirium===
Alcohol withdrawal delirium,formerly called delerium tremens, is an "acute organic mental disorder induced by cessation or reduction in chronic alcohol consumption. Clinical characteristics include confusion; delusions; vivid hallucinations; [[tremor]]; agitation; insomnia; and signs of autonomic hyperactivity (e.g., elevated blood pressure and heart rate, dilated pupils, and diaphoresis). This condition may occasionally be fatal."<ref>{{MeSH|Alcohol withdrawal delirium}}</ref><ref name="isbn0-07-067439-6p1175">{{cite book |author=Ropper, Allan H.; Adams, Raymond Delacy; Victor, Maurice |title=Principles of Neurology |publisher=McGraw-Hill, Health Professions Division |location=New York |year=1997 |pages=1175 |isbn=0-07-067439-6 |oclc= |doi=}}</ref>
Alcohol withdrawal delirium,formerly called delerium tremens, is an "acute organic mental disorder induced by cessation or reduction in chronic alcohol consumption. Clinical characteristics include confusion; delusions; vivid hallucinations; [[tremor]]; agitation; insomnia; and signs of autonomic hyperactivity (e.g., elevated blood pressure and heart rate, dilated pupils, and diaphoresis). This condition may occasionally be fatal."<ref>{{MeSH|Alcohol withdrawal delirium}}</ref><ref name="isbn0-07-067439-6p1175">{{cite book |author=Ropper, Allan H.; Adams, Raymond Delacy; Victor, Maurice |title=Principles of Neurology |publisher=McGraw-Hill, Health Professions Division |location=New York |year=1997 |pages=1175 |isbn=0-07-067439-6 |oclc= |doi=}}</ref>
==Diagnosis==
The revised clinical institute withdrawal assessment (CIWA-AR) can help diagnose and assess severity.<ref name="pmid2597811">{{cite journal |author=Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM |title=Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) |journal=Br J Addict |volume=84 |issue=11 |pages=1353–7 |year=1989 |month=November |pmid=2597811 |doi= |url= |issn=}}</ref> The CIWA-AR is available online at the links below. The CIWA-AR is a 10 item scale. The CIWA-AR was derived from the earlir CIWA-A that had 15 items.<ref name="pmid7334148">{{cite journal |author=Shaw JM, Kolesar GS, Sellers EM, Kaplan HL, Sandor P |title=Development of optimal treatment tactics for alcohol withdrawal. I. Assessment and effectiveness of supportive care |journal=J Clin Psychopharmacol |volume=1 |issue=6 |pages=382–7 |year=1981 |month=November |pmid=7334148 |doi= |url= |issn=}}</ref> The CIWA-AD is an 8 item scale and tends to score about one-half point higher than the CIWA-AR.<ref name="pmid16449097">{{cite journal |author=Reoux JP, Oreskovich MR |title=A comparison of two versions of the clinical institute withdrawal assessment for alcohol: the CIWA-Ar and CIWA-AD |journal=Am J Addict |volume=15 |issue=1 |pages=85–93 |year=2006 |pmid=16449097 |doi=10.1080/10550490500419136 |url=http://www.informaworld.com/openurl?genre=article&doi=10.1080/10550490500419136&magic=pubmed&#124;&#124;1B69BA326FFE69C3F0A8F227DF8201D0 |issn=}}</ref>


==Treatment==
==Treatment==
{| class="wikitable" align="right"
|+ [[Systematic review]]s of the treatment of alcohol withdrawal by the [[Cochrane Collaboration]]
! Intervention!! [[Relative risk ratio]]
|-
| [[Benzodiazepine]]s<ref name="pmid16034964">{{cite journal |author=Ntais C, Pakos E, Kyzas P, Ioannidis JP |title=Benzodiazepines for alcohol withdrawal |journal=Cochrane Database Syst Rev |volume= |issue=3 |pages=CD005063 |year=2005 |pmid=16034964 |doi=10.1002/14651858.CD005063.pub2 |url=http://dx.doi.org/10.1002/14651858.CD005063.pub2 |issn=}}</ref> || 0.16
|-
| [[Anticonvulsant]]s<ref name="pmid16034965">{{cite journal |author=Polycarpou A, Papanikolaou P, Ioannidis JP, Contopoulos-Ioannidis DG |title=Anticonvulsants for alcohol withdrawal |journal=Cochrane Database Syst Rev |volume= |issue=3 |pages=CD005064 |year=2005 |pmid=16034965 |doi=10.1002/14651858.CD005064.pub2 |url=http://dx.doi.org/10.1002/14651858.CD005064.pub2 |issn=}}</ref>||  0.57
|}
===Benzodiazepines===
===Benzodiazepines===
[[Benzodiazepine]]s such as diazepam (Valium), lorazepam (Ativan) or oxazepam (Serax) are the most commonly used drugs used to reduce alcohol withdrawal symptoms.  There are several treatment patterns in which it is used.
{| class="wikitable" align="right"
|+ Sample symptom triggered protocol.<ref name="pmid12020181">{{cite journal |author=Daeppen JB, Gache P, Landry U, ''et al'' |title=Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial |journal=Arch. Intern. Med. |volume=162 |issue=10 |pages=1117-21 |year=2002 |pmid=12020181|url=http://archinte.ama-assn.org/cgi/content/full/162/10/1117|doi=}}</ref>
! CIWA-Ar score!! [[Oxazepam]] dose
|-
|  8 to 15  || 15 mg of oxazepam
|-
|  > 15  || 30 mg of oxazepam
|}
[[Benzodiazepine]]s such as diazepam (Valium), lorazepam (Ativan) or oxazepam (Serax) are the most commonly used drugs used to reduce alcohol withdrawal symptoms.  There are several approaches:
# One option takes into consideration the varying degrees of tolerance. In it, a standard dose of the benzodiazepine is given every half hour until light sedation is reached. Once a baseline dose is determined, the medication is tapered over the ensuing 3-10 days.
# Another option is to defer treatment until symptoms occur.<ref name="pmid8046805">{{cite journal |author=Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR |title=Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial |journal=JAMA |volume=272 |issue=7 |pages=519-23 |year=1994 |pmid=8046805 |doi=}}</ref><ref name="pmid12020181">{{cite journal |author=Daeppen JB, Gache P, Landry U, ''et al'' |title=Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial |journal=Arch. Intern. Med. |volume=162 |issue=10 |pages=1117-21 |year=2002 |pmid=12020181|url=http://archinte.ama-assn.org/cgi/content/full/162/10/1117|doi=}}</ref> A non-randomized, before and after, observational study found that symptom triggered therapy was advantageous.<ref name="pmid11444401">{{cite journal |author=Jaeger TM, Lohr RH, Pankratz VS |title=Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients |journal=Mayo Clin. Proc. |volume=76 |issue=7 |pages=695-701 |year=2001 |pmid=11444401 |doi=}}</ref>


# One option takes into consideration the varying degrees of tolerance. In it, a standard dose of the benzodiazepine is given every half hour until light sedation is reached. Once a baseline dose is determined, the medication is tapered over the ensuing 3-10 days.
Dosing of the benzodiazepines can be guided by the CIWA-Ar scale.<ref name="pmid2597811" /> The scale is available online (see external links below). However, using the CIWA-Ar for patients who cannot answer questions is associated with increased complications of withdrawal.<ref name="pmid18315992">{{cite journal |author=Hecksel KA, Bostwick JM, Jaeger TM, Cha SS |title=Inappropriate use of symptom-triggered therapy for alcohol withdrawal in the general hospital |journal=Mayo Clin. Proc. |volume=83 |issue=3 |pages=274–9 |year=2008 |month=March |pmid=18315992 |doi= |url=http://www.mayoclinicproceedings.com/Abstract.asp?AID=4611&Abst=Abstract&UID= |issn=}}</ref>
# Another option is to defer treatment until symptoms occur.<ref name="pmid8046805">{{cite journal |author=Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR |title=Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial |journal=JAMA |volume=272 |issue=7 |pages=519-23 |year=1994 |pmid=8046805 |doi=}}</ref><ref name="pmid12020181">{{cite journal |author=Daeppen JB, Gache P, Landry U, ''et al'' |title=Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial |journal=Arch. Intern. Med. |volume=162 |issue=10 |pages=1117-21 |year=2002 |pmid=12020181 |doi=}}</ref> A non-randomized, before and after, observational study found that symptom triggered therapy was advantageous.<ref name="pmid11444401">{{cite journal |author=Jaeger TM, Lohr RH, Pankratz VS |title=Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients |journal=Mayo Clin. Proc. |volume=76 |issue=7 |pages=695-701 |year=2001 |pmid=11444401 |doi=}}</ref>


Dosing of the benzodiazepines can be guided by the CIWA-Ar scale.<ref name="pmid2597811">{{cite journal |author=Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM |title=Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) |journal=British journal of addiction |volume=84 |issue=11 |pages=1353-7 |year=1989 |pmid=2597811 |doi=}}</ref> The scale is available online (see external links below).
For patients who have a [[seizure]] related to alcohol withdrawal, a single dose of 2 mg [[lorazepam]] intravenously can reduce the chance of a second seizure from 24% to 3%.<ref name="pmid10094637">{{cite journal |author=D'Onofrio G, Rathlev NK, Ulrich AS, Fish SS, Freedland ES |title=Lorazepam for the prevention of recurrent seizures related to alcohol |journal=N. Engl. J. Med. |volume=340 |issue=12 |pages=915–9 |year=1999 |month=March |pmid=10094637 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=10094637 |issn=}}</ref>


Regarding the choice of benzodiazepine:
Regarding the choice of benzodiazepine:
* [[Chlordiazepoxide]] (Librium®) is the benzodiazepine of choice in uncomplicated alcohol withdrawal. <ref> Raistrick, D, Heather N & Godfrey C (2006) "Review of the Effectiveness of Treatment for Alcohol Problems" National Treatment Agency for Substance Misuse, London http://www.nta.nhs.uk/publications/documents/nta_review_of_the_effectiveness_of_treatment_for_alcohol_problems_fullreport_2006_alcohol2.pdf</ref>
* [[Chlordiazepoxide]] (Librium®) is the benzodiazepine of choice in uncomplicated alcohol withdrawal. <ref> Raistrick, D, Heather N & Godfrey C (2006) "[http://www.nta.nhs.uk/publications/documents/nta_review_of_the_effectiveness_of_treatment_for_alcohol_problems_fullreport_2006_alcohol2.pdf Review of the Effectiveness of Treatment for Alcohol Problems]" National Treatment Agency for Substance Misuse, London</ref>
* [[Lorazepam]] or [[diazepam]] are available parenterally for patients who cannot safely take medications by mouth.
* [[Lorazepam]] or [[diazepam]] are available parenterally for patients who cannot safely take medications by mouth.
* [[Lorazepam]] and [[oxazepam]] may be best in patients with cirrhosis (shorter half life).
* [[Lorazepam]] and [[oxazepam]] may be best in patients with cirrhosis (shorter half life).
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===Adrenergic antagonists===
===Adrenergic antagonists===
{| class="wikitable" align="right"
{| class="wikitable" align="right"
|+ Number of treatment failures due to severe hallucinations or alcohol withdrawal.
|+ Factorial randomized controlled trial: number of treatment failures due to severe hallucinations or alcohol withdrawal.<ref name="pmid7004240">{{cite journal |author=Zilm DH, Jacob MS, MacLeod SM, Sellers EM, Ti TY |title=Propranolol and chlordiazepoxide effects on cardiac arrhythmias during alcohol withdrawal |journal=Alcohol. Clin. Exp. Res. |volume=4 |issue=4 |pages=400-5 |year=1980 |pmid=7004240 |doi= |issn=}}</ref>
!colspan="2" rowspan="2"| || colspan="2"| Chlordiazepoxide
!colspan="2" rowspan="2"| || colspan="2"| Chlordiazepoxide
|-
|-
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| colspan="4" |Notes:<br>1. There were 15 patients in each group.<br>
| colspan="4" |Notes:<br>1. There were 15 patients in each group.<br>
2. Not shown is the arrhythmia scores,<br>
2. Not shown is the arrhythmia scores,<br>
which were best in the groups receiving propanolol.
which were best in the groups receiving [[propranolol]].
|}
|}


[[Randomized controlled trial]]s have found benefit from [[adrenergic beta-receptor blockader]]s such as [[atenolol]]<ref name="pmid2863754">{{cite journal |author=Kraus ML, Gottlieb LD, Horwitz RI, Anscher M |title=Randomized clinical trial of atenolol in patients with alcohol withdrawal |journal=N. Engl. J. Med. |volume=313 |issue=15 |pages=905-9 |year=1985 |pmid=2863754 |doi=}}</ref> and [[clonidine]].<ref name="pmid3300587">{{cite journal |author=Baumgartner GR, Rowen RC |title=Clonidine vs chlordiazepoxide in the management of acute alcohol withdrawal syndrome |journal=Arch. Intern. Med. |volume=147 |issue=7 |pages=1223-6 |year=1987 |pmid=3300587 |doi=}}</ref>
[[Randomized controlled trial]]s have found benefit from [[adrenergic beta-antagonist]]s such as [[atenolol]]<ref name="pmid2863754">{{cite journal |author=Kraus ML, Gottlieb LD, Horwitz RI, Anscher M |title=Randomized clinical trial of atenolol in patients with alcohol withdrawal |journal=N. Engl. J. Med. |volume=313 |issue=15 |pages=905-9 |year=1985 |pmid=2863754 |doi=}}</ref> and [[propranolol]]<ref name="pmid7004240">{{cite journal |author=Zilm DH, Jacob MS, MacLeod SM, Sellers EM, Ti TY |title=Propranolol and chlordiazepoxide effects on cardiac arrhythmias during alcohol withdrawal |journal=Alcohol. Clin. Exp. Res. |volume=4 |issue=4 |pages=400-5 |year=1980 |pmid=7004240 |doi= |issn=}}</ref><ref name="pmid592834">{{cite journal |author=Sellers EM, Zilm DH, Degani NC |title=Comparative efficacy of propranolol and chlordiazepoxide in alcohol withdrawal |journal=J. Stud. Alcohol |volume=38 |issue=11 |pages=2096–108 |year=1977 |month=November |pmid=592834 |doi= |url= |issn=}}</ref> In the major trial, [[atenolol]] was given to patients without contraindications at a dose of 50 mg if the pulse was 50-79 and 100 mg if the pulse was 80 or more.<ref name="pmid2863754"/>  Deciding which patients are appropriate for atenolol based on this trial is difficult because it was conducted prior to the developement of the CIWA-Ar; however, the authors describe their patients as mild to moderate.


A factorial [[randomized controlled trial]]<ref name="pmid7004240">{{cite journal |author=Zilm DH, Jacob MS, MacLeod SM, Sellers EM, Ti TY |title=Propranolol and chlordiazepoxide effects on cardiac arrhythmias during alcohol withdrawal |journal=Alcohol. Clin. Exp. Res. |volume=4 |issue=4 |pages=400-5 |year=1980 |pmid=7004240 |doi= |issn=}}</ref> has been misinterpreted leading to concerns that beta-blockers are associated with hallucinations.<ref name="pmid15249349">{{cite journal |author=Mayo-Smith MF, Beecher LH, Fischer TL, ''et al'' |title=Management of alcohol withdrawal delirium. An evidence-based practice guideline |journal=Arch. Intern. Med. |volume=164 |issue=13 |pages=1405-12 |year=2004 |pmid=15249349 |doi=10.1001/archinte.164.13.1405}}</ref> However, the table at right shows that in the factorial study, the hallucinations were associated with the absence of chlordiazepoxide and not the presence of propanolol. The combination of both propanolol and chlordiazepoxide gave the best combination of reduction in withdrawal symptoms and arrhythmias.<ref name="pmid7004240"/>
A factorial [[randomized controlled trial]]<ref name="pmid7004240">{{cite journal |author=Zilm DH, Jacob MS, MacLeod SM, Sellers EM, Ti TY |title=Propranolol and chlordiazepoxide effects on cardiac arrhythmias during alcohol withdrawal |journal=Alcohol. Clin. Exp. Res. |volume=4 |issue=4 |pages=400-5 |year=1980 |pmid=7004240 |doi= |issn=}}</ref> has been misinterpreted leading to concerns that beta-blockers are associated with hallucinations.<ref name="pmid15249349">{{cite journal |author=Mayo-Smith MF, Beecher LH, Fischer TL, ''et al'' |title=Management of alcohol withdrawal delirium. An evidence-based practice guideline |journal=Arch. Intern. Med. |volume=164 |issue=13 |pages=1405-12 |year=2004 |pmid=15249349 |doi=10.1001/archinte.164.13.1405}}</ref> However, the table at right shows that in the factorial study, the hallucinations were associated with the absence of chlordiazepoxide and not the presence of propranolol. The combination of both propranolol and chlordiazepoxide gave the best combination of reduction in withdrawal symptoms and arrhythmias.<ref name="pmid7004240"/>


A case report shows that beta-blockers may remove signs of hyperactivity of the [[sympathetic nervous system]] thus leading to overlooking a diagnosis of delirium tremens in a chronic alcholic with hallucinations after stopping alcohol.<ref name="pmid6122874">{{cite journal |author=Zechnich RJ |title=Beta blockers can obscure diagnosis of delirium tremens |journal=Lancet |volume=1 |issue=8280 |pages=1071-2 |year=1982 |pmid=6122874 |doi= |issn=}}</ref> Thus clinicians should not require the presence of [[sympathetic nervous system|sympathetic]] hyperactivity in diagnosing delirium tremens in a patient receiving beta-blockers.
A case report shows that [[adrenergic beta-antagonist]]s may remove signs of hyperactivity of the [[sympathetic nervous system]] thus leading to overlooking a diagnosis of [[delirium tremens]] in a chronic alcoholic with hallucinations after stopping alcohol.<ref name="pmid6122874">{{cite journal |author=Zechnich RJ |title=Beta blockers can obscure diagnosis of delirium tremens |journal=Lancet |volume=1 |issue=8280 |pages=1071-2 |year=1982 |pmid=6122874 |doi= |issn=}}</ref> Thus clinicians should not require the presence of [[sympathetic nervous system|sympathetic]] hyperactivity in diagnosing delirium tremens in a patient receiving beta-blockers.
 
The central alpha-2 adrenergic agonist [[clonidine]] has also been studied.<ref name="pmid3300587">{{cite journal |author=Baumgartner GR, Rowen RC |title=Clonidine vs chlordiazepoxide in the management of acute alcohol withdrawal syndrome |journal=Arch. Intern. Med. |volume=147 |issue=7 |pages=1223-6 |year=1987 |pmid=3300587 |doi=}}</ref><ref name="pmid8625628">{{cite journal |author=Spies CD, Dubisz N, Neumann T, ''et al'' |title=Therapy of alcohol withdrawal syndrome in intensive care unit patients following trauma: results of a prospective, randomized trial |journal=Crit. Care Med. |volume=24 |issue=3 |pages=414–22 |year=1996 |month=March |pmid=8625628 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=24&issue=3&spage=414 |issn=}}</ref> Oral clonidine at 0.2 mg three times a day (day 1 at 9 p.m.; day 2 at 9 a.m., 1 p.m., and 6 p.m.; day 3 at 9 a.m. and 6 p.m.; and day 4 at 9 a.m.) showed benefit<ref name="pmid3300587">{{cite journal |author=Baumgartner GR, Rowen RC |title=Clonidine vs chlordiazepoxide in the management of acute alcohol withdrawal syndrome |journal=Arch. Intern. Med. |volume=147 |issue=7 |pages=1223-6 |year=1987 |pmid=3300587 |doi=}}</ref>, whereas a trial of intravenous clonidine titrated to stop [[sympathetic nervous system|sympathetic]] symptoms in patients with an average CIWA-Ar of 39 had cases of hallucinations and bradycardia after an average total dose of clonidine of 8.2 mg spread over 4 days.<ref name="pmid8625628">{{cite journal |author=Spies CD, Dubisz N, Neumann T, ''et al'' |title=Therapy of alcohol withdrawal syndrome in intensive care unit patients following trauma: results of a prospective, randomized trial |journal=Crit. Care Med. |volume=24 |issue=3 |pages=414–22 |year=1996 |month=March |pmid=8625628 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=24&issue=3&spage=414 |issn=}}</ref>.
 
Adrenergic antagonists should not be used alone.<ref name="pmid7978098">{{cite journal |author=Adinoff B |title=Double-blind study of alprazolam, diazepam, clonidine, and placebo in the alcohol withdrawal syndrome: preliminary findings |journal=Alcohol. Clin. Exp. Res. |volume=18 |issue=4 |pages=873–8 |year=1994 |month=August |pmid=7978098 |doi= |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0145-6008&date=1994&volume=18&issue=4&spage=873 |issn=}}</ref><ref name="pmid7004240">{{cite journal |author=Zilm DH, Jacob MS, MacLeod SM, Sellers EM, Ti TY |title=Propranolol and chlordiazepoxide effects on cardiac arrhythmias during alcohol withdrawal |journal=Alcohol. Clin. Exp. Res. |volume=4 |issue=4 |pages=400-5 |year=1980 |pmid=7004240 |doi= |issn=}}</ref>


===Carbamazepine===
===Carbamazepine===
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===Other drugs===
===Other drugs===
'''[[Sodium oxybate]]''' is the sodium salt of [[gamma-hydroxybutyric acid]] (GHB).  It has been studied for both acute alcohol withdrawal<ref name="pmid17613965">{{cite journal |author=Nava F, Premi S, Manzato E, Campagnola W, Lucchini A, Gessa GL |title=Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolism in severe abstinent alcoholics: an open study vs. diazepam |journal=Am J Drug Alcohol Abuse |volume=33 |issue=3 |pages=379-92 |year=2007 |pmid=17613965 |doi=10.1080/00952990701315046 |url=http://www.informaworld.com/openurl?genre=article&doi=10.1080/00952990701315046&magic=pubmed||1B69BA326FFE69C3F0A8F227DF8201D0 |issn=}}</ref> and medium to long-term detoxification<ref name="pmid17611081">{{cite journal |author=Caputo F, Addolorato G, Stoppo M, ''et al'' |title=Comparing and combining gamma-hydroxybutyric acid (GHB) and naltrexone in maintaining abstinence from alcohol: an open randomised comparative study |journal=Eur Neuropsychopharmacol |volume=17 |issue=12 |pages=781-9 |year=2007 |pmid=17611081 |doi=10.1016/j.euroneuro.2007.04.008 |url=http://linkinghub.elsevier.com/retrieve/pii/S0924-977X(07)00100-9 |issn=}}</ref>. This drug enhances [[Gamma aminobutyric acid]] (GABA) neurotransmission and reduces glutamate levels.
'''[[Sodium oxybate]]''' is the sodium salt of [[gamma-hydroxybutyric acid]] (GHB).  It has been studied for both acute alcohol withdrawal<ref name="pmid17613965">{{cite journal |author=Nava F, Premi S, Manzato E, Campagnola W, Lucchini A, Gessa GL |title=Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolism in severe abstinent alcoholics: an open study vs. diazepam |journal=Am J Drug Alcohol Abuse |volume=33 |issue=3 |pages=379-92 |year=2007 |pmid=17613965 |doi=10.1080/00952990701315046 |url=http://www.informaworld.com/openurl?genre=article&doi=10.1080/00952990701315046&magic=pubmed||1B69BA326FFE69C3F0A8F227DF8201D0 |issn=}}</ref> and medium to long-term detoxification<ref name="pmid17611081">{{cite journal |author=Caputo F, Addolorato G, Stoppo M, ''et al'' |title=Comparing and combining gamma-hydroxybutyric acid (GHB) and naltrexone in maintaining abstinence from alcohol: an open randomised comparative study |journal=Eur Neuropsychopharmacol |volume=17 |issue=12 |pages=781-9 |year=2007 |pmid=17611081 |doi=10.1016/j.euroneuro.2007.04.008 |url=http://linkinghub.elsevier.com/retrieve/pii/S0924-977X(07)00100-9 |issn=}}</ref>. This drug enhances neurotransmission by the inhibitory [[neurotransmitter]] [[gamma aminobutyric acid]] (GABA) and reduces levels of the excitatory [[neurotransmitter]] [[glutamate]].


'''[[Baclofen]]''' has been shown in animal studies and in small human studies to enhance detoxification<ref name="pmid11893350">{{cite journal |author=Addolorato G, Caputo F, Capristo E, ''et al'' |title=Rapid suppression of alcohol withdrawal syndrome by baclofen |journal=Am. J. Med. |volume=112 |issue=3 |pages=226-9 |year=2002 |pmid=11893350 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0002934301010889 |issn=}}</ref> and maybe reduce craving<ref name="pmid12217947">{{cite journal |author=Addolorato G, Caputo F, Capristo E, ''et al'' |title=Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study |journal=Alcohol Alcohol. |volume=37 |issue=5 |pages=504-8 |year=2002 |pmid=12217947 |doi= |url=http://alcalc.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12217947 |issn=}}</ref>. This drug acts as a [[gamma aminobutyric acid|GABA]] B receptor agonist and this may be beneficial.
'''[[Baclofen]]''' has been shown in animal studies and in small human studies to enhance detoxification<ref name="pmid11893350">{{cite journal |author=Addolorato G, Caputo F, Capristo E, ''et al'' |title=Rapid suppression of alcohol withdrawal syndrome by baclofen |journal=Am. J. Med. |volume=112 |issue=3 |pages=226-9 |year=2002 |pmid=11893350 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0002934301010889 |issn=}}</ref> and maybe reduce craving<ref name="pmid12217947">{{cite journal |author=Addolorato G, Caputo F, Capristo E, ''et al'' |title=Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study |journal=Alcohol Alcohol. |volume=37 |issue=5 |pages=504-8 |year=2002 |pmid=12217947 |doi= |url=http://alcalc.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12217947 |issn=}}</ref>. This drug acts as a [[gamma aminobutyric acid|GABA]] B receptor agonist.


Some hospitals administer alcohol to prevent alcohol withdrawal although there are potential problems with this practice.<ref name="pmid12578486">{{cite journal |author=Blondell RD, Dodds HN, Blondell MN, ''et al'' |title=Ethanol in formularies of US teaching hospitals |journal=JAMA |volume=289 |issue=5 |pages=552 |year=2003 |pmid=12578486 |doi=}}</ref>
Some hospitals administer alcohol<ref name="pmid12578486">{{cite journal |author=Blondell RD, Dodds HN, Blondell MN, ''et al'' |title=Ethanol in formularies of US teaching hospitals |journal=JAMA |volume=289 |issue=5 |pages=552 |year=2003 |pmid=12578486 |doi=}}</ref> to prevent alcohol withdrawal although this may<ref name="pmid16864031">{{cite journal |author=Dissanaike S, Halldorsson A, Frezza EE, Griswold J |title=An ethanol protocol to prevent alcohol withdrawal syndrome |journal=J. Am. Coll. Surg. |volume=203 |issue=2 |pages=186–91 |year=2006 |month=August |pmid=16864031 |doi=10.1016/j.jamcollsurg.2006.04.025 |url=http://linkinghub.elsevier.com/retrieve/pii/S1072-7515(06)00446-7 |issn=}}</ref> or may not<ref name="pmid18188105">{{cite journal |author=Weinberg JA, Magnotti LJ, Fischer PE, ''et al'' |title=Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: results of a randomized trial |journal=J Trauma |volume=64 |issue=1 |pages=99–104 |year=2008 |month=January |pmid=18188105 |doi=10.1097/TA.0b013e31815eb12a |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00005373-200801000-00015 |issn=}}</ref> help.


==References==
==References==
<references/>
{{reflist|2}}[[Category:Suggestion Bot Tag]]
 
==External links==
* CIWA-AR - this is freely available without copyright restrictions from
** [http://www.chce.research.va.gov/apps/PAWS/content/quiz.htm Department of Veterans Affairs]
** [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat5.section.45979#46038 AHRQ]

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https://en.citizendium.org/wiki/index.php?title=Alcohol_withdrawal&printable=yes
This editable Main Article is under development and subject to a disclaimer.

Alcohol withdrawal is a group of syndromes that may occur after cessation of drinking ethanol alcohol.[1][2][3]

Classification

Autonomic hyperactivity

Withdrawal may cause hyperactivity of the sympathetic nervous system.

Seizures

Alcohol withdrawal seizures is a "condition where seizures occur in association with ethanol abuse (alcoholism) without other identifiable causes. Seizures usually occur within the first 6-48 hours after the cessation of alcohol intake, but may occur during periods of alcohol intoxication. Single generalized tonic-clonic motor seizures are the most common subtype, however, status epilepticus may occur".[4][5]

Delirium

Alcohol withdrawal delirium,formerly called delerium tremens, is an "acute organic mental disorder induced by cessation or reduction in chronic alcohol consumption. Clinical characteristics include confusion; delusions; vivid hallucinations; tremor; agitation; insomnia; and signs of autonomic hyperactivity (e.g., elevated blood pressure and heart rate, dilated pupils, and diaphoresis). This condition may occasionally be fatal."[6][7]

Diagnosis

The revised clinical institute withdrawal assessment (CIWA-AR) can help diagnose and assess severity.[8] The CIWA-AR is available online at the links below. The CIWA-AR is a 10 item scale. The CIWA-AR was derived from the earlir CIWA-A that had 15 items.[9] The CIWA-AD is an 8 item scale and tends to score about one-half point higher than the CIWA-AR.[10]

Treatment

Systematic reviews of the treatment of alcohol withdrawal by the Cochrane Collaboration
Intervention Relative risk ratio
Benzodiazepines[11] 0.16
Anticonvulsants[12] 0.57

Benzodiazepines

Sample symptom triggered protocol.[13]
CIWA-Ar score Oxazepam dose
8 to 15 15 mg of oxazepam
> 15 30 mg of oxazepam

Benzodiazepines such as diazepam (Valium), lorazepam (Ativan) or oxazepam (Serax) are the most commonly used drugs used to reduce alcohol withdrawal symptoms. There are several approaches:

  1. One option takes into consideration the varying degrees of tolerance. In it, a standard dose of the benzodiazepine is given every half hour until light sedation is reached. Once a baseline dose is determined, the medication is tapered over the ensuing 3-10 days.
  2. Another option is to defer treatment until symptoms occur.[14][13] A non-randomized, before and after, observational study found that symptom triggered therapy was advantageous.[15]

Dosing of the benzodiazepines can be guided by the CIWA-Ar scale.[8] The scale is available online (see external links below). However, using the CIWA-Ar for patients who cannot answer questions is associated with increased complications of withdrawal.[16]

For patients who have a seizure related to alcohol withdrawal, a single dose of 2 mg lorazepam intravenously can reduce the chance of a second seizure from 24% to 3%.[17]

Regarding the choice of benzodiazepine:

  • Chlordiazepoxide (Librium®) is the benzodiazepine of choice in uncomplicated alcohol withdrawal. [18]
  • Lorazepam or diazepam are available parenterally for patients who cannot safely take medications by mouth.
  • Lorazepam and oxazepam may be best in patients with cirrhosis (shorter half life).

Adrenergic antagonists

Factorial randomized controlled trial: number of treatment failures due to severe hallucinations or alcohol withdrawal.[19]
Chlordiazepoxide
Given Not given
Propranolol Given 1 4
Not given 0 4
Notes:
1. There were 15 patients in each group.

2. Not shown is the arrhythmia scores,
which were best in the groups receiving propranolol.

Randomized controlled trials have found benefit from adrenergic beta-antagonists such as atenolol[20] and propranolol[19][21] In the major trial, atenolol was given to patients without contraindications at a dose of 50 mg if the pulse was 50-79 and 100 mg if the pulse was 80 or more.[20] Deciding which patients are appropriate for atenolol based on this trial is difficult because it was conducted prior to the developement of the CIWA-Ar; however, the authors describe their patients as mild to moderate.

A factorial randomized controlled trial[19] has been misinterpreted leading to concerns that beta-blockers are associated with hallucinations.[1] However, the table at right shows that in the factorial study, the hallucinations were associated with the absence of chlordiazepoxide and not the presence of propranolol. The combination of both propranolol and chlordiazepoxide gave the best combination of reduction in withdrawal symptoms and arrhythmias.[19]

A case report shows that adrenergic beta-antagonists may remove signs of hyperactivity of the sympathetic nervous system thus leading to overlooking a diagnosis of delirium tremens in a chronic alcoholic with hallucinations after stopping alcohol.[22] Thus clinicians should not require the presence of sympathetic hyperactivity in diagnosing delirium tremens in a patient receiving beta-blockers.

The central alpha-2 adrenergic agonist clonidine has also been studied.[23][24] Oral clonidine at 0.2 mg three times a day (day 1 at 9 p.m.; day 2 at 9 a.m., 1 p.m., and 6 p.m.; day 3 at 9 a.m. and 6 p.m.; and day 4 at 9 a.m.) showed benefit[23], whereas a trial of intravenous clonidine titrated to stop sympathetic symptoms in patients with an average CIWA-Ar of 39 had cases of hallucinations and bradycardia after an average total dose of clonidine of 8.2 mg spread over 4 days.[24].

Adrenergic antagonists should not be used alone.[25][19]

Carbamazepine

A randomized controlled trial has found benefit from carbamazepine.[26]

Other drugs

Sodium oxybate is the sodium salt of gamma-hydroxybutyric acid (GHB). It has been studied for both acute alcohol withdrawal[27] and medium to long-term detoxification[28]. This drug enhances neurotransmission by the inhibitory neurotransmitter gamma aminobutyric acid (GABA) and reduces levels of the excitatory neurotransmitter glutamate.

Baclofen has been shown in animal studies and in small human studies to enhance detoxification[29] and maybe reduce craving[30]. This drug acts as a GABA B receptor agonist.

Some hospitals administer alcohol[31] to prevent alcohol withdrawal although this may[32] or may not[33] help.

References

  1. ↑ 1.0 1.1 Mayo-Smith MF, Beecher LH, Fischer TL, et al (2004). "Management of alcohol withdrawal delirium. An evidence-based practice guideline". Arch. Intern. Med. 164 (13): 1405-12. DOI:10.1001/archinte.164.13.1405. PMID 15249349. Research Blogging.
  2. ↑ Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, Jara G, Kasser C, Melbourne J. (2004). Management of alcohol withdrawal delirium. An evidence-based practice guideline. (English). National Guidelines Clearinghouse. Retrieved on 2008-04-03.
  3. ↑ Mayo-Smith MF (1997). "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 278 (2): 144-51. PMID 9214531. [e] Full text at OVID
  4. ↑ Anonymous (2024), Alcohol withdrawal seizures (English). Medical Subject Headings. U.S. National Library of Medicine.
  5. ↑ Ropper, Allan H.; Adams, Raymond Delacy; Victor, Maurice (1997). Principles of Neurology (in English), 6th. New York: McGraw-Hill, Health Professions Division, 1174. ISBN 0-07-067439-6. 
  6. ↑ Anonymous (2024), Alcohol withdrawal delirium (English). Medical Subject Headings. U.S. National Library of Medicine.
  7. ↑ Ropper, Allan H.; Adams, Raymond Delacy; Victor, Maurice (1997). Principles of Neurology. New York: McGraw-Hill, Health Professions Division, 1175. ISBN 0-07-067439-6. 
  8. ↑ 8.0 8.1 Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM (November 1989). "Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar)". Br J Addict 84 (11): 1353–7. PMID 2597811. [e]
  9. ↑ Shaw JM, Kolesar GS, Sellers EM, Kaplan HL, Sandor P (November 1981). "Development of optimal treatment tactics for alcohol withdrawal. I. Assessment and effectiveness of supportive care". J Clin Psychopharmacol 1 (6): 382–7. PMID 7334148. [e]
  10. ↑ Reoux JP, Oreskovich MR (2006). "A comparison of two versions of the clinical institute withdrawal assessment for alcohol: the CIWA-Ar and CIWA-AD". Am J Addict 15 (1): 85–93. DOI:10.1080/10550490500419136. PMID 16449097. Research Blogging.
  11. ↑ Ntais C, Pakos E, Kyzas P, Ioannidis JP (2005). "Benzodiazepines for alcohol withdrawal". Cochrane Database Syst Rev (3): CD005063. DOI:10.1002/14651858.CD005063.pub2. PMID 16034964. Research Blogging.
  12. ↑ Polycarpou A, Papanikolaou P, Ioannidis JP, Contopoulos-Ioannidis DG (2005). "Anticonvulsants for alcohol withdrawal". Cochrane Database Syst Rev (3): CD005064. DOI:10.1002/14651858.CD005064.pub2. PMID 16034965. Research Blogging.
  13. ↑ 13.0 13.1 Daeppen JB, Gache P, Landry U, et al (2002). "Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial". Arch. Intern. Med. 162 (10): 1117-21. PMID 12020181. [e]
  14. ↑ Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR (1994). "Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial". JAMA 272 (7): 519-23. PMID 8046805. [e]
  15. ↑ Jaeger TM, Lohr RH, Pankratz VS (2001). "Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients". Mayo Clin. Proc. 76 (7): 695-701. PMID 11444401. [e]
  16. ↑ Hecksel KA, Bostwick JM, Jaeger TM, Cha SS (March 2008). "Inappropriate use of symptom-triggered therapy for alcohol withdrawal in the general hospital". Mayo Clin. Proc. 83 (3): 274–9. PMID 18315992. [e]
  17. ↑ D'Onofrio G, Rathlev NK, Ulrich AS, Fish SS, Freedland ES (March 1999). "Lorazepam for the prevention of recurrent seizures related to alcohol". N. Engl. J. Med. 340 (12): 915–9. PMID 10094637. [e]
  18. ↑ Raistrick, D, Heather N & Godfrey C (2006) "Review of the Effectiveness of Treatment for Alcohol Problems" National Treatment Agency for Substance Misuse, London
  19. ↑ 19.0 19.1 19.2 19.3 19.4 Zilm DH, Jacob MS, MacLeod SM, Sellers EM, Ti TY (1980). "Propranolol and chlordiazepoxide effects on cardiac arrhythmias during alcohol withdrawal". Alcohol. Clin. Exp. Res. 4 (4): 400-5. PMID 7004240. [e]
  20. ↑ 20.0 20.1 Kraus ML, Gottlieb LD, Horwitz RI, Anscher M (1985). "Randomized clinical trial of atenolol in patients with alcohol withdrawal". N. Engl. J. Med. 313 (15): 905-9. PMID 2863754. [e]
  21. ↑ Sellers EM, Zilm DH, Degani NC (November 1977). "Comparative efficacy of propranolol and chlordiazepoxide in alcohol withdrawal". J. Stud. Alcohol 38 (11): 2096–108. PMID 592834. [e]
  22. ↑ Zechnich RJ (1982). "Beta blockers can obscure diagnosis of delirium tremens". Lancet 1 (8280): 1071-2. PMID 6122874. [e]
  23. ↑ 23.0 23.1 Baumgartner GR, Rowen RC (1987). "Clonidine vs chlordiazepoxide in the management of acute alcohol withdrawal syndrome". Arch. Intern. Med. 147 (7): 1223-6. PMID 3300587. [e]
  24. ↑ 24.0 24.1 Spies CD, Dubisz N, Neumann T, et al (March 1996). "Therapy of alcohol withdrawal syndrome in intensive care unit patients following trauma: results of a prospective, randomized trial". Crit. Care Med. 24 (3): 414–22. PMID 8625628. [e]
  25. ↑ Adinoff B (August 1994). "Double-blind study of alprazolam, diazepam, clonidine, and placebo in the alcohol withdrawal syndrome: preliminary findings". Alcohol. Clin. Exp. Res. 18 (4): 873–8. PMID 7978098. [e]
  26. ↑ Malcolm R, Ballenger JC, Sturgis ET, Anton R (1989). "Double-blind controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal". The American journal of psychiatry 146 (5): 617-21. PMID 2653057. [e]
  27. ↑ Nava F, Premi S, Manzato E, Campagnola W, Lucchini A, Gessa GL (2007). "Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolism in severe abstinent alcoholics: an open study vs. diazepam". Am J Drug Alcohol Abuse 33 (3): 379-92. DOI:10.1080/00952990701315046. PMID 17613965. Research Blogging.
  28. ↑ Caputo F, Addolorato G, Stoppo M, et al (2007). "Comparing and combining gamma-hydroxybutyric acid (GHB) and naltrexone in maintaining abstinence from alcohol: an open randomised comparative study". Eur Neuropsychopharmacol 17 (12): 781-9. DOI:10.1016/j.euroneuro.2007.04.008. PMID 17611081. Research Blogging.
  29. ↑ Addolorato G, Caputo F, Capristo E, et al (2002). "Rapid suppression of alcohol withdrawal syndrome by baclofen". Am. J. Med. 112 (3): 226-9. PMID 11893350. [e]
  30. ↑ Addolorato G, Caputo F, Capristo E, et al (2002). "Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study". Alcohol Alcohol. 37 (5): 504-8. PMID 12217947. [e]
  31. ↑ Blondell RD, Dodds HN, Blondell MN, et al (2003). "Ethanol in formularies of US teaching hospitals". JAMA 289 (5): 552. PMID 12578486. [e]
  32. ↑ Dissanaike S, Halldorsson A, Frezza EE, Griswold J (August 2006). "An ethanol protocol to prevent alcohol withdrawal syndrome". J. Am. Coll. Surg. 203 (2): 186–91. DOI:10.1016/j.jamcollsurg.2006.04.025. PMID 16864031. Research Blogging.
  33. ↑ Weinberg JA, Magnotti LJ, Fischer PE, et al (January 2008). "Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: results of a randomized trial". J Trauma 64 (1): 99–104. DOI:10.1097/TA.0b013e31815eb12a. PMID 18188105. Research Blogging.
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