Addiction Medicine 2013

Addiction Medicine 2013 Pharmacotherapy for alcohol dependence Part I: alcohol withdrawal Roy M Stein, MD Durham Veterans Affairs Medical Center Duke University School of Medicine

Objectives Identify goals in treatment of alcohol withdrawal. Identify indications for ambulatory vs. inpatient detoxification. Compare symptom-triggered vs. fixed-taper treatment strategies. Identify first-line and alternative medication options. View detoxification in the broader context of personal recovery. Share experience with fellow clinicians.

Case 1 71y/o divorced, well-educated, retired male. Recently moved to the area.

primary care new patient appointment h/o alcohol abuse, sober x 22 months had alcohol counseling, attended AA h/o depression, on citalopram x 4 years hypertension; chronic pancreatitis; UGI bleed Alcohol Use Disorders Identification Test- Consumption Questions (AUDIT-C): negative Depression screen (PHQ-2): negative Continue citalopram, RTC 6 months.

5 months later: Emergency Department I need alcohol detox. Relapsed 3 weeks earlier. Consuming 8.5 drinks/day. Last drink eight hours ago. One prior inpatient detox for uncomplicated w/d. Mood anxious. P 110. No other withdrawal symptoms.

Clinical management Is medical detoxification warranted? If so, Setting: ambulatory vs. inpatient? Choice of medication? Dosing/monitoring strategy?

Goals of detoxification Patient Safety Prevent complicated withdrawal: seizures, delirium. Prevent medical complications, e.g., angina. Prevent adverse medication effects (e.g., falls, impaired cognition.) Patient comfort (suppress symptoms) Prepare for ongoing recovery. Enhance patient motivation. Establish concrete plan for next phase, which may include relapse prevention medication.

Pathophysiology of alcohol withdrawal Chronic alcohol exposure: depresses noradrenergic activity enhances GABAergic function Resultant compensatory changes. Alcohol cessation unopposed compensatory changes (rebound effects) Excess noradrenergic activity Depressed GABAergic inhibition Pharmacotherapy counteracts these rebound effects.

Initial evaluation Medical/psychiatric history Other substances, including nicotine Physical examination Mental status examination Suicidal ideation Hallucinations, delusions Cognitive status Labs Blood alcohol level, urine drug screen Electrolytes including Mg++ Liver function tests CIWA-Ar

Ambulatory alcohol detoxification Stable medically and psychiatrically No history of complicated withdrawal Able to return for daily visits without driving. Reliable friend or relative. Prescribe 24 hr med supply at each visit Safe and effective for appropriately selected patients.

Ambulatory alcohol detoxification Hayashida M et al. NEJM, 1989. 164 male veterans, low SES, mild-moderate withdrawal. No h/o seizures, delirium. Randomized to inpatient vs. outpatient detox Higher completion rate for IP (95 vs. 72%). No complications, much lower cost with OP. No difference in outcome at 6 months.

Medications for alcohol withdrawal Benzodiazepines* Thiamine* Anti-adrenergic agents Beta-adrenergic blockers Clonidine Anticonvulsants Carbamazepine Gabapentin Nicotine replacement if nicotine-dependent *first-line treatments

Advantages of benzodiazepines Suppress symptoms Prevent seizures Favorable safety profile Multiple routes of administration oral intravenous intramuscular

Risks of benzodiazepines Cognitive impairment Incoordination, falls Impaired driving accidents Euphoria, reinforcement Abuse and dependence Synergism with alcohol

Choose benzodiazepine based on pharmacokinetics Route of administration Rate of absorption Permeability across blood/brain barrier Mechanisms of metabolism, elimination Elimination half-life Active metabolites

Benzodiazepines Onset (po) half-life (h) metabolism admin lorazepam intermed 14 glucuron po, iv, sl oxazepam* slow 9 glucuron po diazepam* fast 40, 60 CYP450 po, iv, im chlordiazepoxide* intermed 20, 30, 60 CYP450 po clonazepam intermed 30-40 CYP450 po * FDA-approved for treatment of alcohol withdrawal.

Systematic review of benzodiazepine treatment of alcohol withdrawal syndrome. 64 studies, 4309 patients BZ s superior to placebo in preventing seizures. Non-significant trend favoring chlordiazepoxide over other BZ s. One study: symptom-triggered therapy with CIWA superior to fixed BZ schedule. Minozzi S et al. Cochrane Library. 2010.

In this case MD in ED initiated ambulatory detox. Chlordiazepoxide 25 mg q4h prn (#6, NR) Instructions to patient: No driving. Return for re-evaluation within 24 hours.

Pt did not return to complete ambulatory detox, but did return to ED 8 days later Continued to consume 8-10 drinks/day Last drink 8 hours ago. Anxious mood, anhedonia, nausea, anorexia, insomnia, no SI. Mild tremor. P 111. BP 150/95 Admitted for detox.

Benzodiazepine dosing strategies Fixed taper +/- prn s. Simple Monitor VS, sedation, withdrawal symptoms (?) Fine for the average patient; over- or under-medicates others. Symptom-triggered strategy. Titrate dose to standardized assessment of withdrawal severity, such as CIWA-Ar. Diazepam-loading is one form. Regardless of strategy, systematic monitoring of clinical response is essential.

Case 1: chlordiazepoxide fixed taper 250 200 150 100 Pulse SBP Librium 50 0 0 6 12 18 24 30 36 42 48 54 60 72 96 120

Mood and withdrawal symptoms resolved rapidly in the hospital. Patient endorsed goal of abstinence and agreed to outpatient treatment. Would you offer relapse prevention medications at this point?

7 days post discharge: SUD Clinic evaluation 2-3 glasses of wine daily since discharge. Considered himself in recovery for 2 years though drinking wine (not liquor) regularly throughout. Ambivalence: would like to be sober, i.e., drink less, to please daughter and not be encumbered by addiction. Recognizes negative effects on physical health and memory. I know I need to quit, it s just hard.

1 month post d/c: SUD Psychiatry evaluation 2-3 glasses of wine most days. Self-diagnosed dysthymic disorder Exercise 3x/week, attends adult ed classes. New relationship. Dx: alcohol dependence, dysthymic disorder, h/o major depressive disorder. Individual and group psychotherapy in SUD Clinic. Recommended AA. Continue citalopram. Naltrexone 25 50 mg daily.

During the next 12 months Multiple cycles of remission-relapse-detox. Admissions for alcohol-related cardiac arrhythmia and two medication overdoses. Inconsistent treatment adherence (naltrexone, acamprosate, therapy appointments). Residential rehab left early. The hospital instituted symptom-triggered detox protocol using CIWA-Ar.

Symptom-triggered treatment of alcohol withdrawal Saitz R, Mayo-Smith MF et al. Individualized treatment for alcohol withdrawal: a randomized double-blind controlled trial. JAMA. 1994;272:519-523. BZ dosing based on CIWA score. Protocol-driven order set. Requires nurse training, commitment. Results: Briefer detoxification. Lower average BZ administration. Avoid under-treatment of severe withdrawal.

Clinical Institute Withdrawal Assessment Alcohol, Revised (CIWA-Ar) Nausea/vomiting 0-7 Tremor 0-7 Paroxysmal Sweats 0-7 Anxiety 0-7 Agitation 0-7 Tactile Disturbances 0-7 Auditory Disturbances 0-7 Visual Disturbances 0-7 Headache, Fullness in Head 0-7 Orientation and Clouding of Sensorium 0-4

Clinical Institute Withdrawal Assessment of Alcohol, Revised (CIWA-Ar) Maximum score= 67 0-8 minimal or no withdrawal 9-15 mild 16-20 moderate >20 severe withdrawal

Nursing: Initial CIWA-Ar score 0-8 1. No chlordiazepoxide is needed now. 2. Repeat vital signs and CIWA-Ar q4 hours x 3; if all CIWA-Ar scores are 0-8, may go to daily assessments. 3. If CIWA score increases to 9 or above, go to protocol below. ACCEPT EDIT CANCEL

Nursing: Initial CIWA-Ar score 9-15 1. Nurse will call/notify MD of administration of loading dose of chlordiazepoxide 50 mg PO. 2. Administer chlordiazepoxide 50 mg PO and repeat vital signs in 2 hours; then go to every 4 hour schedule below. 3. If each CIWA-Ar score remains 9-15, give chlordiazepoxide 50 mg, not to exceed 300 mg in 24 hours. 4. If CIWA score increases to 16 or above, go to protocol below. 5. If CIWA score decreases to 0-8, return to lower protocol. 6. Hold chlordiazepoxide if patient is over-sedated or respiratory rate is < 10. ACCEPT EDIT CANCEL

Nursing: Initial CIWA-Ar score 16 or above 1. Give chlordiazepoxide 50 mg PO and call MD for individualized orders. 2. Continue vitals signs and CIWA-Ar every 4 hours while awaiting individualized orders. 3. Hold chlordiazepoxide if patient is over-sedated or respiratory rate is < 10. ACCEPT EDIT CANCEL

Thiamine

Case 1: symptom-triggered detox 180 16 160 14 140 12 120 100 80 60 10 8 6 Pulse SBP Librium CIWA 40 4 20 2 0 0 4 8 12 16 20 24 28 32 36 40 44 52 63 78 0

Psychiatry admissions treated for alcohol withdrawal pre- and post- initiation of CIWA protocol Fixed taper: 54 patients Symptom-triggered: 47 patients 14 12 10 8 6 4 Taper CIWA 2 0 Length of stay (days) Days of BZ administration BZ doses

Medicine admissions treated for alcohol withdrawal pre- and post-initiation of CIWA protocol Fixed taper: 15 patients Symptom-triggered: 21 patients 10 9 8 7 6 5 4 3 2 1 0 Length of Stay (days) BZ doses Taper CIWA

Turning point Pt. drove, intoxicated, to convenience store, where he fell. Brought to ED by ambulance. Consuming up to 16 drinks daily x 3 weeks. Tremulous, weak, nausea, anorexia Mood depressed. Affect dysphoric, reactive. Admitted, completed uneventful detox with symptom-triggered protocol.

Prior to discharge a family conference was held in which the patient agreed, as conditions of continued family contact, to: Sell his car and give up driving. Resume consistent AA Resume outpatient therapy. Resume naltrexone.

14 months present Sustained abstinence. Daily AA. Gradual restoration of family relationships. Resumed driving after 9 months sobriety. Completed courses of group cognitive-behavioral therapy for alcohol relapse prevention and depression. Mirtazapine, naltrexone

Alternative medications for alcohol withdrawal Antiadrenergic agents β-blockers α 2 -agonists Anticonvulsants

Antiadrenergic agents β-blockers Atenolol Metoprolol Propranolol α 2 -agonists Presynaptic inhibition of NE release. Clonidine (oral, transdermal) Dexmedetomidine (IV for use in ICU) Less respiratory depression than propofol Endotracheal intubation is not required.

Antiadrenergic agents Both classes reduce sympathetic overdrive. Both may reduce other symptoms: Anxiety Craving Neither class prevents seizures. May be useful as adjuncts to conventional treatment, but never as monotherapy.

Anticonvulsants: Carbamazepine 88 men with severe alcohol withdrawal. 66 completed the study. CBZ 800 mg/day vs. OXZP 120 mg/day Comparable outcomes overall. CBZ group had lower psychological distress on days 3-7. Malcolm R, Ballenger JC, Sturgis ET, Anton R. (1989). Double-blind, controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal. Am J Psychiatry 146(5):617-621.

Systematic review of anticonvulsant treatment of AWS. 56 studies, 4076 participants CBZ superior to oxazepam or lorazepam with more favorable side effect profile Otherwise, no evidence of advantage of anticonvulsants over placebo or other drugs. Minozzi S et al. Cochrane Library. 2010.

Anticonvulsants: Gabapentin 100 subjects seeking OP detox, CIWA>10. Treated x 4 days with: Gabapentin 1200 -> 800 Gabapentin 900 -> 600 Lorazepam 6 -> 4 Assessed days 1-4, 5,7,12 Relative to lorazepam, GB was well-tolerated, effective in relieving withdrawal symptoms, lower probability of drinking Myrick H, Malcolm R et al. (2009). A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res 33(9): 1582-1588.

Gabapentin for alcohol detox in clinical practice Local pockets of active use. Extent of use in real-world clinical practice? One clinical approach for ambulatory detox: Standard ambulatory detox criteria. 9-day taper, staring at 400 mg tid. Follow-up at 24 hours, then as needed. Gabapentin may be maintained for relapse prevention in some cases. J. Gochnour, MD. Personal communication.

Alternative strategy to assess and manage withdrawal Type Process NT Pharmacotherapy A CNS excitation GABA GLUT benzodiazepines anticonvulsants B Adrenergic hyperactivity NE β-blockers α 2 -agonists C Delirium/psychosis DA DA antagonists Paolo B. DePetrillo & Mark K. McDonough, PO Box 530, Glen Echo, MD USA 20812; (800 728 6799;http://www.sagetalk.com Stanley KM et al. Pharmacotherapy 2005;25(8):1073 1083. Nejad SH et al. Case 39-2012: A 55-Year-Old Man with Alcoholism, Recurrent Seizures, and Agitation. N Engl J Med 367;25 December 20, 2012.

Protracted abstinence syndrome negative emotionality + sensitivity to stress + sleep disturbance return to drinking Are the processes in acute withdrawal mechanistically linked to those that persist during protracted abstinence? Heilig M, Egli M, Crabbe JC, Becker HC. Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addict Biol. 2010 Apr;15(2):169-84

And this just in Walker B et al. Ethanol for alcohol withdrawal: the end of an era. J Trauma Acute Care Surg. 2013;74:926-931.

Summary Benzodiazepines remain first-line treatment. Supplement thiamine (oral vs. parenteral). Symptom-triggered therapy with CIWA is safe and reduces average BZ exposure and length of stay. Ambulatory detoxification is safe and effective for selected patients. Anticonvulsants may be a safe, effective alternative, but their role is not fully established. Anti-adrenergics useful as adjuncts, not as monotherapy. Considering protracted abstinence syndrome, treatment of withdrawal may merge into relapse prevention.