Alcohol Withdrawal Therapeutic Interventions The University of New Mexico Health Science Center Alcohol Withdrawal Therapeutic Interventions Lenka Hřebíčková, Pharm.D. ICU/ER Clinical Pharmacist III

The University of New Mexico Health Science Center Therapeutic Goals Over-treatment vs. under-treatment Control agitation Light somnolence Amount of medication required vary from patient to patient Taper to prevent the emergence of breakthrough symptoms and withdrawal seizures Prevent complications

The University of New Mexico Health Science Center Therapeutic Options Benzodiazepines Phenobarbital Propofol Dexmedetomidine Crit Care Med 2010 Vol. 38, No.9

The University of New Mexico Health Science Center Benzodiazepines 1st line agents Better efficacy, good margin of safety, lower potential of abuse No specific benzodiazepine is recommended for use Selection of agent based on kinetic parameters, potential for abuse, cost MCH: GABA agonist Increases the frequency of GABA chloride channel opening – alcohol replacement Crit Care Med 2010 Vol. 38, No.9 CMAJ. 1999;160:649-655

Benzodiazepines – Which One? The University of New Mexico Health Science Center Benzodiazepines – Which One? Duration of activity Long: prevent breakthrough Short: elderly, hepatic or renal disease Pharmacokinetics Absorption: Affects time to onset Distribution Lipophillicity Metabolism Oxidation (CYP P450 system) vs. conjugation, active metabolites Elimination

Benzodiazepines Comparison The University of New Mexico Health Science Center Benzodiazepines Comparison Medication (action) Onset of action Dose Equivalent (mg) Average Half Life (Hr) in Healthy patient Active Metabolite and Metabolism Chlordiazepoxide (long) Oral 1-2 hrs 25 6.6-25 Yes (Desmethyldiazepam) CYP3A4 Diazepam (long) Oral, IV, rectal Almost immediate 5 20-50 Yes (Desmethyldiazepam) Lorazapam (short) Oral, IV, IM 5-20 minutes 0.75-1 10.5 No Glucuronide conjugation Oxazepam (short) 15 2.8-8.6

Assessment Recommendation The University of New Mexico Health Science Center Assessment Recommendation Intubated and non-responsive: Sedation scale (Riker, etc.) Delirium assessment (CAM-ICU, ICDSC) Not intubated and responsive: CIWA-Ar

Benzodiazepines: Optimal Regimen The University of New Mexico Health Science Center Benzodiazepines: Optimal Regimen Dosing is variable (various protocols) Symptom-triggered vs. fixed-schedule Two studies in general population: Daeppen JB, et al: Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: A randomized treatment trial. Arch Intern Med 2002;162:1117-1121. Saitz R, et al: Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA 1994; 272:519-523 One study in ICU: Spies CD, et al: Alcohol withdrawal severity is decreased by symptom-oriented adjusted bolus therapy in the ICU. Intensive Care Med 2003; 29:2230-2238

Benzodiazepines: Symptom-Triggered Approach in Non-ICU Patients The University of New Mexico Health Science Center Benzodiazepines: Symptom-Triggered Approach in Non-ICU Patients Daeppen JB, et al: Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal: A randomized treatment trial. Arch Intern Med 2002;162:1117-1121 Prospective, randomized, double-blinded controlled trial 117 patients admitted to alcohol treatment inpatient program at Lausanne and Geneva university hospitals in Switzerland Fixed schedule: oxazepam 30 mg PO Q6H for 4 doses, then 15 mg PO Q6H for 8 doses and PRN oxazepam Symptom triggered: placebo 30 mg PO Q6H x 4 doses, then placebo 15 mg PO Q6H for 8 doses, CIWA-Ar score > 8 – 15 received 15 mg of oxazepam, CIWA-Ar score > 15 received 30 mg oxazepam; Q30min Results: Similar demographics between groups Only 22 (39%) patients in ST group were treated with oxazepam vs. 100% in FS group (p < 0.001) Mean oxazepam dose: 37.5 mg ST vs. 231.4 mg FS (p < 0.001) Mean duration of treatment: 20 hr ST vs. 62.7 hr FS (p < 0.001)

Benzodiazepines: Symptom-Triggered Approach in Non-ICU Patients The University of New Mexico Health Science Center Benzodiazepines: Symptom-Triggered Approach in Non-ICU Patients Saitz R, et al: Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA 1994; 272:519-523 Chlordiazepoxide QID with PRN medications (FS; Fixed-Schedule) vs. chlordiazepoxide PRN (ST; Symptom-Triggered) Randomized double-blind, controlled trial Inpatient detoxification unit in a Veterans Affairs 111 eligible patients Results: Similar demographics Total chlordiazepoxide doses: 100 mg ST vs. 425 mg FS (p < 0.001) Mean duration of treatment: 9 hr ST vs. 68 hr FS (p < 0.001)

Benzodiazepines: Symptom-Triggered Approach in ICU The University of New Mexico Health Science Center Benzodiazepines: Symptom-Triggered Approach in ICU Spies CD, et al. Intensive Care Med 2003:29;2230-2238. Flunitrazepam (infusion) + clonidine + haloperidol vs. flunitrazepam (PRN) + clonidine (PRN) + haloperidol (PRN) Prospective, randomized, controlled trial Surgical ICU patients Inclusion: non-intubated, CIWA-Ar > 20 Notable exclusion: concurrent acute medical illness (hypoxia, infection) Both groups titrated to CIWA-Ar score

Benzodiazepines: Symptom-Triggered Approach in ICU The University of New Mexico Health Science Center Benzodiazepines: Symptom-Triggered Approach in ICU Sample 44 patients No differences at baseline Mechanical Ventilation 34 of 44 patients (65%) ICU stays Bolus: 8 (5-10) days Infusion: 14 (7-24) days, p < 0.01 Pneumonia Bolus: 9/23 (39%) Infusion: 15/21 (71%), p < 0.01 Spies CD, et al. Intensive Care Med 2003;29: 2230-38.

The University of New Mexico Health Science Center Phenobarbital Used if benzodiazepine-resistance Doses of diazepam > 40 mg/1hr Down-regulation of GABA receptors Higher rates of intubation, longer ICU stay Phenobarbital augment benzodiazepines at GABA and inhibits stimulatory glutamate receptors Gold JA, et al: Crit Care Med 2007;35:724-30 Retrospective cohort study Subjects admitted to the medical ICU with severe alcohol withdrawal Symptom-triggered treatment: diazepam 10 mg IV up to 100-150 mg, then phenobarbital 65-260 mg IV + diazepam IV, then propofol Results: Need for mechanical ventilation: Pre 47% and Post 22% Among patients requiring MV, less DZP administered in first 24 hrs 120 mg vs. 280 mg, p = 0.01 High doses of benzodiazepines in some subjects is necessary

The University of New Mexico Health Science Center Propofol Recommended in patients uncontrolled with larger benzodiazepine doses Activates GABAa receptor and blocks stimulatory NMDA receptor Case reports and series Concerns: hypertriglyceridemia, pancreatitis, propofol-related infusion syndrome

The University of New Mexico Health Science Center Dexmedetomidine Centrally acting alpha-2 receptor agonist Mediate hyper-adrenergic response Only patient case reports Predominately severe alcohol withdrawal No phenobarbital or propofol used Alleviates ethanol withdrawal in rats (rigidity, tremor, and irritability) Adjunct therapy to benzodiazepines Neuroprotective? Role? Expensive Rovasalo A, et al. General Hospital Psychiatry 28 (2006) 362-363 Darrouj J, et al: Ann Pharmacother 2008; 42:1703-1705.

UNMH Alcohol Withdrawal Protocol The University of New Mexico Health Science Center UNMH Alcohol Withdrawal Protocol Based on and adapted from alcohol withdrawal protocol at Bayfront Medical Center CriticalCareNurse Vol 30, No. 3, June 2010