STOPPING THE SHAKES: Advanced Concepts in Alcohol Withdrawal Management. Michael Levine, MD 14 March, 2013

Transcription

1 STOPPING THE SHAKES: Advanced Concepts in Alcohol Withdrawal Management Michael Levine, MD 14 March, 2013

2 DISCLOSURES No financial, litigational, or other conflicts of interest to disclose

3 OBJECTIVES Briefly discuss receptor changes with chronic alcohol consumption Review various approaches for therapy with GABA agonists Discuss novel drugs/approaches

4 NEUROTRANSMITTER/RECEPTOR Excitatory NTs work on receptors to open calcium channels leading to excitatory postsynaptic potentials Primary excitatory: glutamate (NMDA) Inhibitory NT work on chloride channels to hyperpolarize cells Primary inhibitory: GABA

5 CHRONIC ETOH: RECEPTOR CHANGES Chronic EtOH produces several effects: NMDA 1) Increase number 2) Increase affinity and sensitivity for glutamate 3) Increase synaptic [glutamate] GABA: 1) Decrease number 2) Decrease function 3) Decrease synaptic [GABA]

6 GABA A RECEPTOR Heteromeric protein complex consisting of multiple subunits α (1-6), β (1-3), γ (1-3), δ, ε, θ, π Various sub-units responsible for different effects of EtOH α1 β1 Cl - Chronic EtOH α 1, α 2, and α 3 α 4, 1, 2, 3, 1, and 2

7 GABA A RECEPTOR Chronic EtOH causes decreased expression of α1 and increased expression of α4 Substitution of α4 for α1 receptor results in decreased efficacy and potency of various benzodiazepines.

8 NEUROTRANSMITTER CHANGES WITH CHRONIC ETHANOL FUNCTION GABA DA 5HT Adenosine FUNCTION Glutamate NE ACh Corticotropin-Releasing Factor (CRF)

9 AWS TREATMENT BACKGROUND Late 1950 s to early 1960s, AWS recognized to occur as a result of cessation of EtOH, not poor diet Various treatments proposed Reserpine Phenothiazines Meprobamate BZD Paraldehyde

10 Restraints for agitation Benzodiazepines Metoprolol for tachycardia Haloperidol and quetiapine for psychosis! possible NMS Propofol for sedation! intubated Magnesium sulfate and IV fluids

11 TREATMENT: GABA AGONISTS

12 537 patients randomized to: Chlordiazepoxide 50 mg IM q6h Chlorpromazine 100 mg PO q6h Hydroxyzine 100 mg IM q6h Thiamine 100 mg IM q6h Placebo Decreased dosages on subsequent days Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969: 125 (1640-6)

13 DRUG SZ DT DT + SZ Any AWS Chlordiazepoxide Chlorpromazine Hydroxyzine Placebo Thiamine BZD more effective than antihistamines or phenothiazines Antihistamines and phenothiazines equivalent to placebo Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969: 125 (1640-6)

14 BENZODIAZEPINES No single benzodiazepine proven to be more efficacious than others Some data short acting agents associated with higher incidence of seizure Long acting BZD with active metabolite preferred (e.g. diazepam or chlordiazepoxide)

15 FRONT-LOADING VS. SYMPTOM TRIGGERED Front loading rapid administration of longacting agent until there is a significant improvement in symptoms Can lead to over-sedation Permits self-tapering Typically titrated to the development of lid-lag

16 FRONT-LOADING VS. SYMPTOM TRIGGERED Symptom triggered is administration of agent in response to symptoms/aws score Example: 10 mg diazepam given each time CIWA-Ar > 8 Front-loading associated with More rapid resolution of symptoms Less need for additional medications Less reliance on withdrawal scales

17 SYMPTOM TRIGGERED VS. STANDING ORAL BZD Evaluated in both patients with alcohol dependence at risk for withdrawal, and in those in withdrawal Symptom triggered resulted in: Decreased amount of BZD Decreased duration of treatment Similar rate of withdrawal complications Daeppen JD, Gache P, Landry U, et. al. Symptom-triggered vs. fixed schedule dose of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med. 2012; 162: Saitz R, Mayo-Smith MF, Roberts MS, et. al. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA. 1994; 272:

18 Symptom triggered, titrating-bolus therapy decreases: Duration of AWS Medication requirements Fewer days of mechanical ventilation * Lower incidence of HCAP Shorter ICU stay

19 BARBITURATES Potentially attractive given sub-group of individuals that don t respond well to benzodiazepines Phenobarbital is most studied Primary complication is need for mechanical ventilation

20 Randomized to phenobarbital vs. placebo All subjects received lorazepam based on symptom-triggered protocol Continuous infusion used as part of protocol Phenobarb resulted in: Less ICU admits: (28% vs. 8%; 95% CI14-41%) Less overall lorazepam No change in outcome (LOS, intubation, Sz) Rosenson J, Clements C, Simon B, et. Al. Phenobarbital for acute alcohol withdrawal: A prospective randomized double-blind placebocontrolled study. J Emerg Med. 2012; e-publication. DOI: /j.jemergmed

21 BENZOS VS. BARBS Few studies exist directly comparing these agents: For mild withdrawal, no difference One study revealed barbiturates more efficacious in severe withdrawal than BZD, but not consistently observed

22 PROPOFOL GABA A agonist; NMDA antagonist Short functional half-life may result in return of AWS symptoms when infusion discontinued Tachyphylaxis occasionally reported

23 PROPOFOL Additional potential draw-backs not unique to AWS treatment Propofol infusion syndrome Hypertriglyceridemia

24 PROPOFOL Respiratory depression prompting intubation is common Propofol should not be used for treatment of AWS in non-intubated patients

25 PROPOFOL

26 BACLOFEN Stereo-selective agonist at GABA B Limited animal data suggest possible benefit 3 human studies Symptom triggered lorazepam + standing baclofen vs. placebo Standing dose baclofen vs. diazepam Prophylactic baclofen for patients at risk of developing AWS

27 BACLOFEN Baclofen better than placebo Single study comparing baclofen to diazepam had similar outcomes Relatively low overall amount of BZD given Cochrane review concluded insufficient data on outcome or safety

28 PROTOCOLS Associated with less over/under-dosing of BZD Numerous protocols exist Front-loading approach with increasing doses of BZD (e.g. diazepam) Addition of phenobarbital if agitation not significantly improved Use of such protocols associated with: Reduced mechanical ventilation Possibly reduced nosocomial infections Possibly shortened length of ICU stay

29 Gold JA, Rimal B, Nolan A, et. Al. A strategy of escalating doses of benzodiazepines and phenobarbital dministration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med. 2007; 35:

30 NON-GABA AGONIST THERAPY

31 SYMPATHOLYTICS AWS results in increased sympathetic output, including HTN and tachycardia Use of beta antagonists or centrally-acting α 2 agonists can ameliorate these signs, thereby masking the severity of withdrawal Limited data exist; their use may be associated with: Delayed diagnosis Under-treatment

32 DEXMEDETOMIDINE Centrally-acting α 2 agonist Similar to IV clonidine Can result in sedation, decrease HR/BP No anti-convulsant activity Most literature on dexmedetomidine (DEX) and AWS is uncontrolled case reports/series

33 60 Rats placed on 4 day binge of EtOH + vitamins 2 died during binge from intoxication Randomized to receive saline or dexmedetomidine (DEX) at 10, 16, 22, and 39 hours after last drink 3 mcg/kg, 10 mcg/kg, or 30 mcg/kg Assessed evidence of withdrawal

34 Withdrawal features noted in all rats DEX IN RATS U shaped response with regards to sum score Rigidity, tremor, irritability

35 DEX IN RATS GROUP SEIZURE Control 3 DEX 3 3 DEX 10 0 DEX 30 1 Riihioja P, Jaatinen P, Oksanen H, et al. Dexmedetomidine alleviates ethanol withdrawal symptoms in rat. Alcohol. 1997; 14:537-44

36 Non-randomized, retrospective review of patients receiving DEX for AWS Data collected 24 hours before/after DEX infusion began Lorazepam based on standardized AWS scoring system Haloperidol for agitation or hallucinations

37 DEXMEDETOMIDINE FOR AWS 20 subjects, mean age 45 Mean infusion: 49.1h (95% CI 37-61h) Mean dose was 0.53 mcg/kg/hr Bolus infusion given for 5 patients Post infusion: Mean in lorazepam: 32 mg/24h Mean in haloperidol: 5.6 mg/24h

38 DEXMEDETOMIDINE FOR AWS Complications: 9 second asystolic pause (n=1) Endotracheal intubation (n=1) in amount of drug administered should be expected during the second 24 hour period if good control achieved up front

39 DEXMEDETOMIDINE: SUMMARY Data at this point is primarily limited to a small, non-randomized study and rat data Animal data equivocal, and not compared with BZD May have some role in the future, but Dangerous for monotherapy Role in combination therapy not yet established

40 ANTICONVULSANTS

41 CARBAMAZEPINE Limited data for use in out-patient treatment of mild AWS Adverse events (nausea, ataxia, pruritus) commonly result in discontinuation (up to 50%) Meta-analysis of 7 studies vs. BZD Reduction in CIWA-Ar Not superior for preventing W/D seizures Possibly worse than BZD for preventing DT s

42 GABAPENTIN Theoretical benefit based on structure Minimal data to suggest decrease CIWA-Ar in mild withdrawal May be associated with probability of resuming EtOH early (but not late) during out-patient treatment No benefit in severe withdrawal

43 TOPIRAMATE Theoretical benefit due to: Suppress glutamatergic input Facilitate GABA mediated inhibitory impulse Rodent study demonstrated topiramate s ability to attenuate withdrawal signs Human studies failed to demonstrate benefit

44 VALPROIC ACID Theoretical benefit due to Increased GABA activity Little abuse potential Insignificant interaction with EtOH Beneficial for several concurrent psychiatric diseases Data limited to 2 small, RCTs and several unblinded studies with standing VPA

45 VALPROIC ACID VPA may have some small benefit in mild-moderate withdrawal Benefits are very minimal Unclear if any clinical significance No benefit in severe withdrawal Safety unknown as most studies had exclusionary criteria not representative of most AWS populations No role at present

46 ANTICONVULSANT VS. PLACEBO: META-ANALYSIS OUTCOME RELATIVE RISK (95% CI) Seizure 0.61 ( ) Adverse Event Severe, life-threatening 1.56 ( ) 2.98 ( ) Delirium 0.88 ( )

47 ANTIPSYCHOTICS Typical antipsychotics with D 2 receptor antagonism Hallucinations common with AWS D 2 receptor antagonism useful for hallucinations due to other etiologies Few objective data evaluating their use

48 49 patients, randomized to: Promazine (n=13) Paraldehyde + chloral hydrate (n=12) Ethanol (n=12) Chlordiazepoxide (n=12) 23 developed DT s, including 12/13 treated with promazine 2 deaths

49 Randomized patients with CIWA-Ar between to receive q1h PO drug Cyamemazine 50 mg (n=45) vs. diazepam 10 mg (n=44) with subsequent taper 26 subjects excluded 2 0 incomplete data Similar % of patients with CIWA-Ar < 5

50 CYAMEMAZINE (n=43) DIAZEPAM (n=44) Therapeutic failure 4 (9.1%) 1 (2.3%) Adverse events 19 subjects 34 events 15 subjects 24 events Serious withdrawal 4 (9.1%) 1 (2.3%)

51 GABA AGONISTS VS. ANTIPSYCHOTICS: META-ANALYSIS Relative risk of death with antipsychotics alone 6.6 (95% CI ) Comparing GABAergic drugs with antipsychotics, antipsychotics with: Prolonged times of delirium Longer time until adequately sedated No placebo-controlled RCTs evaluating antipsychotics with benzodiazepines

52 ANTIPSYCHOTICS Potential for adverse events: Lower seizure threshold Impair heat dissipation Under-treat with GABA agonists No role for routine management May have role in select patient with concurrent psychiatric illness (psychosis)

53 MISCELLANEOUS AGENTS

54 KETAMINE Non-competitive NMDA receptor antagonist Pain literature shows doses of mg/kg/hr welltolerated Rodent data demonstrating reduced severity of AWS

55 KETAMINE Small, non-randomized human case series with continuous infusion of lowdose ketamine demonstrating: Less BZD requirements than otherwise expected Shorter lengths of ICU stay Menke. Platform presentation at NACCT, Las Vegas.

56 SUMMARY GABA agonists remain first-line therapy for treatment of AWS Benzodiazepines first-line but some individuals may require barbiturates Aggressive front-loading, symptom triggered approach preferred over continuous infusions or standing doses

57 SUMMARY (CONT.) No role for routine use of antipsychotics, anticonvulsants, and clonidine, antagonists Ketamine appears to be a potential novel agent Further studies needed before routine administration

58 QUESTIONS THANK YOU!

59 REFERENCES Addolorato G, Leggio L, Abenavoli, et. al. Baclofen in the treatment of alcohol withdrawal syndrome: A comparative study vs. diazepam. Am J Med. 2006; 119:276.e Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the alcohol withdrawal syndrome. Cochrane Database Syst Rev. 2011; CD Barrons R, Roberts N. The role of carbamazepine and oxcarbazepine in alcohol withdrawal syndrome. J Clin Pharm Ther. 2010; 35: Bonnet U, Hamzavi-Abedi R, Specka M, et. al. An open trial of gabapentin in acute alcohol withdrawal using an oral loading protocol. Alcohol Alcohol. 2010; 45: Cagetti E, Baicy KJ, Olsen RW. Topiramate attenuates withdrawal signs after chronic intermittent ethanol in rats. Neuroreport. 2004; 15: Currier DS, Bevacgua BK. Acute tachyphylaxis to propfoll sedation during ethanol withdrawal. J Clin Anesth. 1997; 9: Daeppen JD, Gache P, Landry U, et. al. Symptom-triggered vs. fixed schedule dose of benzodiazepine for alcohol withdrawal: a randomized treatment trial. Arch Intern Med. 2012; 162:

60 REFERENCES (CONT.) Favre JD, Allain H, Aubin HJ, et. al. Double-blind study of cyamemazine and diazepam in the alcohol withdrawal syndrome. Hum Psychopharmcol Clin Exp. 2005; 30: Fodecla S. Langwinski R. Interaction between ketamine and ethanol in rats and mice. Pol J Pharmacol Pharm. 1989; 41: Golbert TM, Sanz CJ, Rose HD, et. al. Comparative evaluation of treatments of alcohol withdrawal syndromes. JAMA. 1967; 201: Gold JA, 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: Hjerm IH, Anderson JE, Fink-Jensen A. Phenobarbital versus diazepam for delirium tremens: a retrospective study. Dan Med Bull. 2010; 57:A4169 Hillbom M, Tokola R, Kuusela V, et. al. Prevention of alcohol withdrawal seizures with carbamazepine and valproic acid. Alcohol 1989; 6: Humeniuk RE, White JM, Ong J. The effects of GABAB ligands on alcohol withdrawal in mice. Pharmacol Biochem Behav. 1994; 49:561-6.

61 REFERENCES (CONT.) Kramp P, Rafaelsen OJ. Delirium tremens: A double-blind comparison of diazepam and barbital treatment. Acta psychiat Scand. 1978; 58: Kumar S, Porcu P, Werner DF. The role of GABA receptors in acute and chronic effects of ethanol: a decade of progress. Psychopharmacology (Berl). 2009; 205:529 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: Lum E, Gorman SK, Slavik RS. Valproic acid management of acute alcohol withdrawal. Ann Pharmacother. 2006; 40: Lyon JE, Khan RA, Gessert CE, et. al. Treating alcohol withdrawal with oral baclofen: a randomized, double-blind, placebo-controlled trial. J Hosp Med. 2011; 6: Mayo-Smith MF, Beecher LH, Fischer TL, et. al. Management of alcohol withdrawal delirium: An evidence-based practice guideline. Arch Intern Med. 2004; 164: Myrick H, Malcolm R, Randall PK. A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009; 33:

62 REFERENCES (CONT.) Minozzi S, Amato L, Vecchi S, et. al. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010; CD Reoux JP, Saxon AJ, Malte CA. Divalproex sodium in alcohol withdrawal: a randomized double-blind placebo-controlled clinical trial. Alcohol Clin Exp Res. 2011; 25: Saitz R, Mayo-Smith MF, Roberts MS, et. al. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA. 1994; 272: Spies CD, Otter HE, Huske B, et. al. Alcohol withdrawal severity is decreased by symptom-oriented adjusted bolus therapy in the ICU. Intensive Care Med. 2003; 29: Stehman CR, Mycyk MB. A rational approach to the treatment of alcohol withdrawal in the ED. Am J Emerg Med. 2013; in press Sullivan JT, Swift RM, Lewis DC. Benzodiazepine requirements during alcohol withdrawal syndrome: Clinical implications of using a standardized withdrawal scale. J Clin Psychopharmacol. 1991; 11:291-5.

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