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Management of Abstinence Bradley J. Phillips, MD Substance Abuse • Alcohol Abuse • 76 million people in the US • MVC leading cause of death • 50% of MVC involve alcohol • 2/5 Americans involved • 67% of home, fire, and job injuries • Illicit Drug Abuse • cocaine > 50% of trauma • cocaine > 80% of violent crime Pitfalls of Intoxication • Increased incidence of diagnostic errors • • • • desire to “treat and street” assuming just a “repeater” failure to recognize serious neurologic lesions decreased pain perception Acute/Chronic EtOH Effects on Physiology • Respiratory • “snoring” = partial airway obstruction • prone to aspirate • Cardiovascular • decreased compensatory response to hemorrhage • increased arrhythmias • increased cardiomyopathy Acute/Chronic EtOH Effects on Physiology • Neurologic • Korsakoff’s syndrome • Wernicke’s syndrome • peripherial neuropathy • GI • cirrhosis • GI bleeds • varices • peptic ulcers Acute/Chronic EtOH Effects on Physiology • Metabolism • alcohol ketoacidosis • hypoglycemia • Hematology • coagulopathies • anemia • poor resistance to infection Illicit Drugs Effects on Physiology • Cocaine/amphetamines/hallucinogens • respiratory difficulty • tachycardia • hypertension • Narcotics/barbiturates/tranquilizers • hypoventilation • bradycardia • hypotension Cocaine • • • • • • • • • Local anesthetic and sympathomimetic Hyperdynamic cardiovascular response CVA (hypertensive crisis) Myocardial infarcts Aortic dissection Pulmonary edema/bronchospasm Rhabdomyolysis GI ischemia/perforations Mental status (judgement, paranoia) Opiates • • • • • Decreased mental status Hypotension Hypovolemia Pulmonary congestion Infectious (heroin) Historical Withdrawal • Victor and Adams, 1953 • • • • Ist comprehensive account 4 “states” occur separately or in combinations mortality = 15% (delirium state) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 tremulous hallucinatory epileptic delirious “Modern” EtOH Withdrawal • Acute Withdrawal • hours to days • irritability, tremulous, tachycardia • Delirium tremens (DT’s) • usually > 48 hrs tremors confusion delusions tachycardia hypertension hyperreflexia hallucinations seizures “Modern” Time Course Foy, Kay, Taylor. QJM, 1997 Diagnosis • Symptoms • • • • • • • • • drug craving restlessness irritability dec. pain tolerance nausea cramps anxiety myoclonus delirium • Signs • • • • • • • • tachycardia sweating vomiting diarrhea hypertension fever seizure tachypnea Evaluation • History • • • • timing of last usage amount previous withdrawal/seizures family member informant • Labs • EtOH/toxicology screen (blood/urine) • CBC/coags • electrolytes/bun/cr/mg/phos/LFT’s Differential Dx • • • • • • Hypoxia Shock/hypovolemia Head trauma Sepsis Hypoglycemia Electrolyte abnormalities • Withdrawal DT’s Complications • Significant co-morbidity • Cardiac collapse • CI 36% • O2 consumption 25% • Seizures • Renal failure • Mortality • 1 to 15% Onset/Duration of Complications Duration (hrs.) Time to Onset (hrs.) Foy, Kay, Taylor. QJM, 1997 Pharmacological Management • Shown beneficial • benzodiazepines • alpha-adrenergic agonist • anti-seizures • Propofol • barbiturates • neuroleptics • clomethiazole • No efficacy (humans) • beta-adrenergic antagonist • Ca-channel blockers • ethyl alcohol • magnesium • thiamine Benzodiazepines • Moskowitz et al, Alcohol Clin Exp Res, 1983 - 81 studies • Only proven efficacious drug • Drugs of choice • Safer than other drugs if taken in excess Benzodiazepines • Pharmacological characteristics • CNS and peripherial interaction with GABA receptors • no particular one better at preventing withdrawal symptoms • ? longer-acting better at preventing seizures • no data on reducing delirium • duration of action dependent on lipophilicity, volume of distribution and half-life • hepatic metabolism only Benzodiazepines • Long-acting • Chlordiazepoxide (Librium) • • • • active metabolites t1/2 = 1-8 days po/IV/IM avoid IM • Diazepam (Valium) • • • • active metabolites t1/2 = 25-100 hrs po/IV/IM avoid IM • Short-acting • Lorazepam (Ativan) • no active metabolites • t1/2 = 10-20 hrs. • slower onset of action • po/IV/IM • Midazolam (Versed) • active metabolites • t1/2 = < 12 hrs • IV/IM Benzodiazepines • Method of Dosing • scheduled vs. prn • Sellers et al, Clin Phar Ther, 1983 − valium 20 mg q 1-2 hrs prn − successful = 72% (valium) vs 56% (placebo) − 90% improved in 30 hrs. • Saitz et al, JAMA, 1994 − po Librium scheduled vs prn − scheduled = 68 hrs. vs prn = 9 hrs. − scheduled = 425 mg vs. prn = 100 mg Benzodiazepines Foy, Kay, Taylor. QJM, 1997 Benzodiazepines • Adverse effects • • • • respiratory depression cardiovascular depression iatrogenic withdrawal metabolic acidosis • propylene glycol • carrier in diazepam IV • converted to lactic acid • also found in silver sulfadiazene, IV nitro, and etomidate Barbiturates • Used by 10% of detoxification programs • No controlled studies for effectiveness • Advantages • low abuse potential • cheap • well-documented anti-seizure • Disadvantages • greater respiratory depression • cardiovascular depression • lower safety profile than benzodiazepines Clonidine • Alpha1-adrenergic agonist • Controlling withdrawal symptoms/signs • superior to placebo • equivalent to carbazepine + neuroleptic • superior to clomethiazole • Controlling delirium/seizures • no adequate sized studies • Clonidine vs benzodiazepine • only one randomized study • no significant difference • seizure patients excluded Neuroleptics • No controlled studies • Early studies less effective than benzos • Advantages • effective for psychosis • safe respiratory/cardiovascular profile • Disadvantages • increased seizures (thorazine,promazine) • extra-pyramidal side-effects Carbamazepine • Used in Europe • Efficacious vs clomethiazole/placebo • Advantages • lower abuse potential • less CNS depression • Disadvantages • side-effects = N/V, vertigo, rash • 50% stop therapy secondary SE • IV not available in US Propofol • Activates GABA-A receptor • Effectiveness • no controlled studies • ? benefit in refractory withdrawal • adjunct to primary therapy • Advantage • short-acting • easily titratable • Disadvantage • tolerance • cost Alternative Agents • Beta-adrenergic antagonists • IV/po differential effectiveness • studies support effective for tremors • Advantages • ? may be effective for mild withdrawal • no addiction potential • Disadvantages • cardiovascular effects • cause hallucinations • no role for mod-severe withdrawal Alternative Agents • Clomethiazole (Used in Europe) • effective as benzos and barbiturates • severe adverse effects • Ethyl alcohol • no trials on safety/efficacy • numerous adverse effects • Magnesium • no reduction in delirium/seizures • Thiamine • no reduction in delirium/seizures • prevention of Wernicke-Korsakoff Recommendations • Benzodiazepines • ativan/valium prn • Clonidine • adjunctive agent • excellent control of hyperadrenergic state • po preferred over patch • Neuroleptics • excellent control of psychosis • possible side-effects (less likely with Haldol) • Propofol/barbiturates • 2nd line adjuncts Recommendations • Dosing • Closely monitored setting • prn dosing • IV for acute withdrawal/inability to tolerate po • Untrained monitoring setting • fixed-scheduled po dosing Outcomes • Increased mortality • Luna et al, J Trauma, 1984 • double mortality vs sober with similar injuries • Waller et al, JAMA, 1986 • 1.7 to 2.1x mortality vs. matched sober MVC • Tinkoff, Ann Surg, 1990 • 30-40% mortality in cirrhotic trauma • sepsis and MSOF • predictors - ascites, PT, bilirubin, laparotomy Delay in Treatment Foy, Kay, Taylor. QJM, 1997 Length of Stay Foy, Kay, Taylor. QJM, 1997 Risk Factors Foy, Kay, Taylor. QJM, 1997 ICU Withdrawal Syndrome • • • • • Cammarano, Crit Care Med, 1998 Retrospective study Trauma/surgical ICU 28 mechanically ventilated patients > 7 day ICU stay ICU Drug Potencies Cammarano et al, Crit Care Med, 1998 ICU Withdrawal vs Drug Non-withdrawal Withdrawal Cammarano et al, Crit Care Med, 1998 Duration Non-withdrawal Withdrawal Cammarano et al, Crit Care Med, 1998 Mean Doses Non-withdrawal Withdrawal Cammarano et al, Crit Care Med, 1998 ICU Withdrawal Syndrome • Results • 32 % acute withdrawal • opiates/benzodiazepines • ICU stay > 7 days • withdrawal group • higher daily doses of fentanyl and ativan • received neuromuscular blockade • received propofol • longer duration of agents ICU Withdrawal Syndrome • Prevention • adequate monitoring of level of sedation • avoid neuromuscular blockade if possible • realization of predisposition • ARDS • younger patients • wean opiates/benzo in pts at risk • 5-10% / day • ? change to longer acting agent po • use bolus method over continuous Questions…?
