Best Practice Tom Shiffler, MD 7/23/10 Alcohol Withdrawal Best Practice Tom Shiffler, MD 7/23/10 UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Goals Understand the pathophysiology of alcohol withdrawal Recognize why we use symptom triggered therapy (CAGE or CIWA) Discuss the role of “prophylaxis” (oral benzodiazepine) Discuss when/where to use benzodiazepine drips Become familiar with evidence on other agents (haldol, clonidine, barbiturates, baclofen, precedex) Substance abuse resources for patients UNM Hospitalist Best Practices- Alcohol Withdrawal

Epidemiology of Alcohol Withdrawal 500,000 cases per year requiring pharmacologic treatment Delirium tremens mortality 5% (down from 37% in the early 1900s) Arrhythmia Complication Pneumonia Pancreatitis Hepatitis UNM Hospitalist Best Practices- Alcohol Withdrawal

Course of Alcohol Withdrawal Minor symptoms 6 hours after cessation Resolve in 24-48 hours Insomnia Tremulousness Mild anxiety GI upset HA Diaphoresis palpitations UNM Hospitalist Best Practices- Alcohol Withdrawal

Course of Alcohol Withdrawal Withdrawal Seizures 12-48 hours after cessation Generalized tonic-clonic More common in those with chronic alcoholism Progress to delirium tremens in 1/3 if untreated UNM Hospitalist Best Practices- Alcohol Withdrawal

Course of Alcohol Withdrawal Alcoholic Hallucinosis NOT DT’s Develop within 12-24 hours of cessation Resolve within 24-48 hours of cessation Visual, auditory and tactile are possible NOT associated with global sensorial clouding, rather specific hallucinations Vital signs usually normal UNM Hospitalist Best Practices- Alcohol Withdrawal

Course of Alcohol Withdrawal Delirium Tremens 48-96 hours after cessation Hallucinations, disorientation, tachycardia, hypertension, fever, agitation and diaphoresis Generally last 5-7 days Risk factors Sustained drinking Previous DT Age >30 Concurrent illness Withdrawal with elevated alcohol level UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Goals Understand the pathophysiology of alcohol withdrawal Recognize why we use symptom triggered therapy (CAGE OR CIWA) Discuss the role of “prophylaxis” (oral benzodiazepine) Discuss when/where to use benzodiazepine drips Become familiar with evidence on other agents (haldol, clonidine, barbiturates, baclofen, precedex) Substance abuse resources for patients UNM Hospitalist Best Practices- Alcohol Withdrawal

Pathophysiology-general considerations Apparent genetic predisposition Longer period of continual use associated with more severe withdrawal UNM Hospitalist Best Practices- Alcohol Withdrawal

Pathophysiology-Molecular Alcohol increases inhibitory tone via enhancement of GABA activity (an inhibitory neurotransmitter) Chronic alcohol reduces functional GABA receptors Cellular internalization Gene expression Removal of alcohol leads to functional loss of GABA and unchecked excitatory neurotransmitters Dopamine Glutamate norepinephrine UNM Hospitalist Best Practices- Alcohol Withdrawal

Pathophysiology-acute Alcohol www.niaaa.nih.gov/.../31_4_acute_gaba.htm UNM Hospitalist Best Practices- Alcohol Withdrawal

Pathophysiology-absence of alcohol after chronic use www.niaaa.nih.gov/.../31_4_acute_gaba.htm UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Goals Understand the pathophysiology of alcohol withdrawal Recognize why we use symptom triggered therapy (CAGE OR CIWA) Discuss the role of “prophylaxis” (oral benzodiazepine) Discuss when/where to use benzodiazepine drips Become familiar with evidence on other agents (haldol, clonidine, barbiturates, baclofen, precedex) Substance abuse resources for patients UNM Hospitalist Best Practices- Alcohol Withdrawal

Symptom Triggered Therapy (CIWA or CAGE) Benzodiazepine given in RESPONSE to signs or symptoms Why is this standard of care? UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Individualized Treatment for Alcohol Withdrawal. Saitz et al. JAMA Aug 17, 1994 Clinical question: Is symptom triggered superior to fixed schedule in reducing quantity and duration of treatment of alcohol withdrawal? Methods Randomized Double-Blind Controlled Trial 101 patients admitted to VA alcohol withdrawal unit Control Chlordiazepoxide q6h SCHEDULED 50mg x4 25mg x8 25-100mg q 1hour per CIWA-Ar scale Not administered if somnolent or refused UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Individualized Treatment for Alcohol Withdrawal. Saitz et al. JAMA Aug 17, 1994 Symptom triggered group 25-100mg chlordiazepoxide at CIWA-Ar >7 See hand out UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Individualized Treatment for Alcohol Withdrawal. Saitz et al. JAMA Aug 17, 1994 Outcomes Duration of medication treatment from admission to last dose of benzodiazepine Fixed schedule group: 68 hours mean Symptom triggered group: 9 hours mean (p<0.001) Amount of chlordiazepoxide administered Fixed schedule group: 425mg mean Symptom triggered group: 100mg mean (p<0.001) UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Individualized Treatment for Alcohol Withdrawal. Saitz et al. JAMA Aug 17, 1994 Conclusions “Symptom-triggered therapy individualizes treatment, decreases both treatment duration and the amount of benzodiazepine used, and is as efficacious as standard fixed-schedule therapy for alcohol withdrawal.” UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Individualized Treatment for Alcohol Withdrawal. Saitz et al. JAMA Aug 17, 1994 Limitations/concerns Results expected 66 hours 400 mg chlordiazepoxide morbidity/mortality differences? (n too small) Take home Symptom-triggered was better than standard of care (American Society for Addiction Medicine guidelines) for alcohol withdrawal Weaning built into symptom-triggered treatment Thank these authors for any alcohol withdrawal patient discharged in < 3 days UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal Daeppen et al. Arch Intern Med May 27 2002 Clinical question: Is symptom triggered superior to fixed schedule in reducing quantity and duration of treatment in patients AT RISK of withdrawal? Methods Prospective RCT 117 patients entering alcohol TREATMENT program UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal Daeppen et al. Arch Intern Med May 27 2002 Methods (cont) Control (n=61) 30mg oxazepam q6h for 4 doses scheduled 15mg oxazepam q6h for 8 doses scheduled Plus 15-30mg oxazepam q30 minutes for CIWA-Ar score >7 and >14 respectively Experimental (n=56) Received placebo, then q 30 minutes evaluated CIWA-Ar >7 received 15mg oxazepam CIWA-Ar >14 received 30mg oxazepam Patients observed for 48 hours after study UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal Daeppen et al. Arch Intern Med May 27 2002 Results 22 of 56 (39%) in symptom-triggered received oxazepam Dosage 37.5mg mean symptom triggered group 231.4mg mean fixed schedule group (p<0.001) Duration 20 hours mean symptom triggered group 62.7 hours mean fixed schedule group (p<0.001) UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal Daeppen et al. Arch Intern Med May 27 2002 Conclusion “Symptom-triggered benzodiazepine treatment for alcohol withdrawal is safe, comfortable, and associated with a decrease in the quantity of medication and duration treatment.” UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Goals Understand the pathophysiology of alcohol withdrawal Recognize why we use symptom triggered therapy (CAGE OR CIWA) Discuss the role of “prophylaxis” (oral benzodiazepine) Discuss when/where to use benzodiazepine drips Become familiar with evidence on other agents (haldol, clonidine, barbiturates, baclofen, precedex) Substance abuse resources for patients UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal Daeppen et al. Arch Intern Med May 27 2002 Limitations/concerns Results expected 66 hours 240mg oxazepam Patients were NOT in alcohol withdrawal Safety not addressed (1 seizure in symptom-triggered group) Take home Used to support symptom-triggered management Sort of addresses “prophylaxis” Only 39% of “heavy” drinkers needed oxazepam per CIWA-Ar When do we use “prophylactic” oral benzodiazepine? UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal CIWA-Ar vs CAGE NO STUDIES COMPARING CIWA-Ar vs CAGE Thank you Sarah Morley CIWA-Ar (see handout) Used at VA (in ER, all inpatient wards and Psych) “Gold standard” in studies, review articles Symptom based evaluation (8 categories with 0-7 point scale) Vital signs taken but not part of the scoring mechanism Starts treatment much earlier in withdrawal UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal CIWA-Ar vs CAGE CAGE (see handout) Used at UNMH More objective measures Pulse Temperature Blood pressure Respiratory rate Tremor Visible mild/marked palpable UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal CIWA-Ar vs CAGE Take Home Anyone looking for a research project? Neither group should feel superior UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Goals Understand the pathophysiology of alcohol withdrawal Recognize why we use symptom triggered therapy (CAGE OR CIWA) Discuss the role of “prophylaxis” (oral benzodiazepine) Discuss when/where to use benzodiazepine drips Become familiar with evidence on other agents (haldol, clonidine, barbiturates, baclofen, precedex) Substance abuse resources for patients UNM Hospitalist Best Practices- Alcohol Withdrawal

How about a benzodiazepine drip? Alcohol withdrawal severity is decreased by symptom-oriented adjusted bolus therapy in the ICU. Spies et al. Intensive Care Med 2003 29:2230-38 Clinical Question: Does bolus vs continuous infusion adjustment affect severity and duration of alcohol withdrawal syndrome, medication requirements and effect on ICU stay? Confounded by use of clonidine and haloperidol in addition to flunitrazepam (Rohypnol-yes that Rohypnol) Summarized conclusion: Bolus titrated therapy decreased severity, medication requirements and ICU stay Limitations: In ICU setting Flunitrazepam is illegal in the US Again, use of clonidine and haloperidol confounds the study UNM Hospitalist Best Practices- Alcohol Withdrawal

How about a lorazepam drip? Where can this be used at UNMH? 5 West No cage or lorazepam drip allowed Q4h IV lorazepam and/or chlordiazepoxide No written protocol-d/w Aiko (charge nurse) 4 West (All SAC floors the same, 4 E, 7S and ED the same) Yes (on cardiac monitor and o2 sat monitor) Close monitoring by physician >10mg/hour room close to RN station, 3:1 >25 mg/hour must be transferred to ICU Weaned by 1mg/hour UNM Hospitalist Best Practices- Alcohol Withdrawal

How about a lorazepam drip? Where can this be used at the VA? Emergency Room, Ward 7 Have individual protocols for treatment 3A, 5A, 5D telemetry Low intensity CIWA Protocol Q4 hour oral or iv bolus therapy Nursing driven protocol, can be initiated by Physician or Nursing based on patient history 5D Step-Down Low or High intensity protocols Q2 hour evaluation Close monitoring by physician <20mg/hour IV drip 5C MICU High intensity Protocol Q1-2 hour monitoring >20mg/hour IV drip +/- additional medications So, when do you use a benzodiazepine drip? UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Goals Understand the pathophysiology of alcohol withdrawal Recognize why we use symptom triggered therapy (CAGE OR CIWA) Discuss the role of “prophylaxis” (oral benzodiazepine) Discuss when/where to use benzodiazepine drips Become familiar with evidence on other agents (haldol, clonidine, barbiturates, baclofen, precedex) Substance abuse resources for patients UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Ethanol (Enhances GABA activity) IV Ethanol for the Treatment of Alcohol Withdrawal Syndrome in Critically Ill Patients Hodges et al. Pharmacotherapy 2004:24 (11): 1578-1585. Review article (looked at 9 studies) Ethanol NOT recommended for alcohol withdrawal syndrome Few well designed clinical trials ? Efficacy of IV ethanol Inconsistent pharmacokinetic profile (absorption, distribution, etc) Narrow therapeutic index (difference between minimum therapeutic and minimum toxic concentration) UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Ethanol (Enhances GABA activity) Take home Avoid as adjuvant or first line UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Baclofen (GABA receptor agonist) Baclofen in the Treatment of Alcohol Withdrawal Syndrome: A comparative study vs diazepam. Addolorato et al. American Journal of Medicine (2006) 119, 276.e13-e18. Clinical question: In patients with alcohol withdrawal does baclofen compared to diazepam provide efficacious, tolerable and safe treatment of alcohol withdrawal? UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Baclofen Methods 37 patients in alcohol withdrawal (CIWA-Ar >9) Control 19 patients 0.5-0.75mg/kg 6 times per day for 10 days Tapered 25% days 7-10 Experiment 18 patients 10mg Baclofen TID for 10 days UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Baclofen Results Both baclofen and diazepam significantly decreased CIWA-Ar score (p<0.0001) UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Baclofen Conclusion “The efficacy of baclofen in treatment of uncomplicated AWS is comparable to that of the “gold standard” diazepam. These results suggest that baclofen may be considered as a new drug for treatment of uncomplicated AWS.” Limits Excluded DT or hallucinations Small n Outpatient Not clearly placebo controlled UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Baclofen Take home points Consider baclofen as ADJUVANT to benzodiazepine Makes sense molecularly Thin data to support 1st line inpatient use Potential outpatient use “higher quality” studies needed UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Haloperidol (Dopamine 2 antagonist) “Frequently” used at UNMH Recommend against per Up To Date Lower the seizure threshold based on study from 1976 on mice Noted in JAMA review article from 1997 also Take home Absolutely not to be used as single agent Would avoid ADJUVANT use Medical-legal reasons UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Anticonvulsants (Phenobarbital, carbamazepine) No role for seizures in alcohol withdrawal Recommended as a first ADJUVANT by UTD BUT combination associated with respiratory depression Pt. should be in ICU setting Take home Adjuvant use is dangerous Withdrawal seizures self limited UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Clonidine (alpha 2 agonist) May prevent minor symptoms Not shown to prevent seizures/DT Take home Not to be used as monotherapy ? Adjuvant if indicated Opioid withdrawal On as outpatient (rebound hypertension) May mask worsening withdrawal (CAGE) Antihypertensive Reduced heart rate UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Beta-Blockers (Metoprolol, atenolol, etc) May prevent minor symptoms Not shown to prevent seizures/DT Take home Not to be used as monotherapy ? Adjuvant if indicated CAD On as outpatient May mask worsening withdrawal (CAGE) Antihypertensive Reduced heart rate UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal ADJUVANT Agents Precedex (Dexmedetomidine) Central alpha(2)-receptor agonist that induces a state of cooperative sedation and does not overly suppress respiratory drive Few (but very promising) case reports of primary treatment for alcohol withdrawal which does not respond to benzodiazepine Currently used for difficult cases at VA and UNM ICU Does not mask neurologic-exams Major side effect are hypotension, bradycardia and respiratory depression UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Goals Understand the pathophysiology of alcohol withdrawal Recognize why we use symptom triggered therapy (CAGE OR CIWA) Discuss the role of “prophylaxis” (oral benzodiazepine) Discuss when/where to use benzodiazepine drips Become familiar with evidence on other agents (haldol, clonidine, barbiturates, baclofen, precedex) Substance abuse resources for patients UNM Hospitalist Best Practices- Alcohol Withdrawal

Substance Abuse Resources Detox is only the first step UNMH Social worker RN Case Manager Included in handout VA SUD walk in clinic M-F 1-4pm SARRTP (residential program) Inpatient Substance Abuse consultation 4 available Addiction boarded attendings UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Conclusion Alcohol withdrawal occurs when GABA mediated neuro inhibition is lost Symptom triggered therapy (CAGE OR CIWA-Ar) with a benzodiazepine is standard of care Consider low dose cage (or equivalent) instead of oral benzodiazepine prophylaxis Clear evidence does not exist supporting the use of benzodiazepine drip vs bolus therapy Adjuvant therapies have limited evidence supporting their use and may be contraindicated. Substance abuse resources for patients are readily available from your social worker UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal References Addolorate, G et al. Baclofen in the Treatment of Alcohol Withdrawal Syndrome: a comparative study vs diazepam. Amer J Med 2006 119, 276.e13-276.e18. Daeppen JB et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med. 2002 May 27;162(10):1117-21. Hodges B et al. Intravenous Ethanol for the Treatment of Alcohol Withdrawal Syndrome in Critically Ill Patients. Pharmacotherapy 2004: 24 (11): 1578-85. Hoffman RS et al. Management of moderate and severe alcohol withdrawal syndromes. UpToDate. Jaeger, TM et al. Symptom-Triggered Therapy for Alcohol Withdrawal Syndrome in Medical Inpatients. Mayo Clinic Proceedings vol 76 (7), July 2001. pp 695-701. Mayo-Smith MF. Pharmacological Management of Alcohol Withdrawal: a Meta-analysis and Evidence-Based Practice Guideline. JAMA vol 278 (2), 9 July 1997, p144-151. Saitz R et al. Individualized Treatment for Alcohol Withdrawal. JAMA, Aug 17, 1994. Vol 272 no. 7. Spies CD et al. Alcohol withdrawal severity is decreased by symptom-oriented adjusted bolus therapy in the ICU. Intensive Care Med 2003 29:2230-38. Dave Olson, MD UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Thank you, no really. UNM Hospitalist Best Practices- Alcohol Withdrawal

UNM Hospitalist Best Practices- Alcohol Withdrawal Comments/questions UNM Hospitalist Best Practices- Alcohol Withdrawal