Alcohol Dependence and Alcohol Withdrawal Syndrome

1 Alcohol Dependence and Alcohol Withdrawal Syndrome Tina C. Lee, PharmD, MSCR Assistant Professor, Pharmacy Practice University of the Incarnate Word April 25, 2015 Objectives 2 Identify how much alcohol is in a standard drink. Differentiate betw een alcohol use disorder, intoxication, and w ithdraw al. Review the pathophysiology of alcohol w ithdraw al. Triage a patient appropriately for outpatient or inpatient management for alcohol w ithdraw al. Identify the standard of therapy for alcohol w ithdraw al syndrome Identify agents w ith limited evidence in its role for alcohol w ithdraw al syndrome. Recognize FDA approved agents for the treatment of alcohol dependence. 3 Background 1

What is One Drink? 4 In the United States, a standard drink contains fluid ounces of pure alcohol. A) 0.6 (14 grams or 1.2 Tablespoons) B) 1 ( 23.3 grams or 2 Tablespoons) C) 1.5 (35 grams or 3 Tablespoons) D) 5 (116.7 grams or 10 Tablespoons) Alcohol and Public Health. Centers for Disease Control and Prevention website http://www.c dc.go v/alc o ho l/fac t-s he e ts /alc o ho l-us e.htm. Update d Nove mbe r 7, 2014. Ac c e s s e d Marc h 26, 2015 Alcohol Use Disorder 5 Alcohol often taken in larger amounts or over a longer period than was intended Persistent desire or unsuccessful attempts to cut down or control alcohol use Great deal of time spent in activities to obtain alcohol, use alcohol, or recover from its effects Craving or a strong desire/urge to use alcohol Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol Important social, occupational, or recreational activities are given up or reduced because of alcohol use Recurrent alcohol use in situations in which it is physically hazardous Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol Tolerance: need for markedly increased amounts of alcohol to achieve intoxication or desired effect or markedly diminished effect with continued use of the same amount of alcohol Withdrawal: benzodiazepine or alcohol is taken to relieve or avoid withdrawal symptoms American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric As s oc iation; 2013 More Definitions 6 Alcohol Intoxication A. Recent ingestion of alcohol B. Clinically significant problematic or psychological changes that developed during or shortly after alcohol ingestion C. 1 of the following signs/or symptoms developing during or shortly after alcohol use Slurred speech Incoordination Unsteady gait Nystagmus Impairment in attention or memory Stupor or coma Alcohol Withdrawal A. Cessation or reduction in alcohol use that has been heavy and prolonged B. 2 of the following developing within several hours to days after cessation or reduction in alcohol use Autonomic hyperactivity Increased hand tremor Insomnia Nausea/vomiting Transient visual, tactile, or auditory hallucinations or illusions Psychomotor agitation Anxiety Generalized tonic-clonic seizures C. Signs/symptoms in B that cause significant distress or impairment in American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric social, As s occupational, iation; 2013 or other important areas of functioning 2

Statistics 7 In 2012, 17 million adults in the US had an alcohol use disorder In the United States, excessive alcohol use... Led to 88,000 deaths and 2.5 million years potential life lost (YPLL) each year in from 2006-2010 Was responsible for 1 in 10 deaths among working-age adults 20-64 years In 2006, economically cost: $223.5 billion= $1.90 per drink National Institute of Health: National Institute on Alcohol Abuse and Alcoholism website http://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-use-disorders. Last Ac c e s s e d: Marc h 26, 2015 Alcohol and Public Health. Centers for Disease Control and Prevention website http://www.c dc.go v/alc o ho l/fac t-s he e ts /alc o ho l-us e.htm. Update d Nove mbe r 7, 2014. Ac c e s s e d Marc h 26, 2015 Bouchery EE, Harwood HJ, Sacks JJ, Simon CJ, Brewer RD. Ec onomic c os ts of e xc e s s ive alcohol c ons umption in the Unite d State s, 2006. Am J Prev Med 2011;41:516 24. 8 Adult Prev alence Of Alcohol Use Disorder 14 12.1 12 Prevalence Percentage 10 8 6 4 2 8.9 7.9 6.9 4.5 0 Native Americans /Alaskan Natives Caucasians Hispanics African Americans Asians/Pacific Islanders American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric As s oc iation; 2013 In Texas 9 In 2006, ~14,500 admissions into a state-funded treatment program for alcohol use In 2000, 16% of all Tex as adults had a problem w ith alcohol Per capita, the Austin area has the highest rate of alcohol use problems in Texas Substance Abuse Statistics Texas Statewide Totals. Texas Department of State and Health Services website https ://www.ds hs.s tate.tx.us /s a/re s e arc h/s tate wide -to tals /. Update d Se pte mbe r 3, 2010. Last Ac c e s s e d: Marc h 29, 2015 Drug and Alcohol Abuse Statistics. Aus tin Recovery website http://www.aus tinrecovery.org/research/drug andalcoholabusesta tistics.aspx#txsubstance. Updated 2015. Accessed March 30, 2015 3

10 Pathophysiology and Signs/Symptoms of Alcohol Withdrawal Pathophysiology of Alcohol Withdrawal 11 GABA Glutamate Non-Alcoholic W ithdraw al GABA+ Alcohol Glutamate Chronic Alcohol Use Adapted from: Kattimani S, Bharadwaj B.Clinical management of alcohol withdrawal: a systematic review. Ind Psychiatry J. 2013 Jul-De c ; 22(2): 100 108 Signs and Symptoms of Alcohol Withdrawal Syndrome 12 Insomnia Tremor Mild anx iety GI upset/anorexia Headache Diaphoresis/Elevated body temperature Palpitations/Tachycardia Increased respiratory rate Tactile disturbances Visual hallucinat ions Seizures Schuckit, MA. Recognition and management of withdrawal delirium (delirium tremens). N Eng J Med. 2014; 371: 2109-13 4

13 Timeline of Alcohol Withdrawal Symptoms Alcoholic Hallucinations Delirium Tremens Seizures Minor W ithdraw al Last Drink 24 hours 48 hours 72 hours 96 hours Onset after Last Drink 14 Triaging the Patient Tool To Assess Sev erity of Symptoms: Short Alcohol Withdrawal Scale (SAWS) 15 Self-Scored Max Score: 30 points M ild: <12 points Moderate to severe: 12 point s Gossop M, Keaney F, Stewart D, Marshall EJ, Strang J. A short alcohol withdrawal scale (SAWS) development and psychometric properties. Addict Biol. 2002; 7(1): 37-43 5

16 Anx ious Sleep Disturbance Problems w ith Memory Nausea Restless Tremor (Shakes) Feeling Confused Sw eating Miserable Heart Pounding None (0) Mild (1) Moderate (2) Severe (3) Gossop M, Keaney F, Stewart D, Marshall EJ, Strang J. A short alcohol withdrawal scale (SAWS) development and psychometric properties. Addict Biol. 2002; 7(1): 37-43 Tool To Assess Severity of Symptoms: Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar) 17 10 questions/observations rated from 0-7 points Max possible score: 67 Absent or very mild: <8 M ild: 9-14 M oderat e: 15-20 Severe: >20 Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict. 1989 Nov;84(11):1353-7 18 6

Triage: Outpatient or Inpatient Management 19 Cont raindicat ions t o Out pat ient Management Treatment of Alcohol Withdraw al Syndrome Abnormal lab results Absence of support netw ork Acute illness High risk of delirium tremens History of w ithdraw al seizure Long-term intake of large amounts of alcohol Poorly controlled chronic conditions Serious psy chiat ric condit ions Severe alcohol w ithdraw al sy mptoms Urine drug screen positive for other substances M unc ie Jr, HL, Yas inian, Y, Og e L. Outpatie nt manag e me nt o f alc o ho l withdrawal s yndro me. Am Fam Physician. 2013; 88: 589-595 20 Pharmacotherapy Benzodiazepines Anticonvulsants Agents with Limited Evidence Benzodiazepines 21 Long Acting Shorter Acting M unc ie Jr, HL, Yas inian, Y, Og e L. Outpatie nt manag e me nt o f alc o ho l withdrawal s yndro me. Am Fam Physician. 2013; 88: 589-595 7

Benzodiazepines 22 Chlordiazepoxide Diazepam Lorazepam Oxazepam Half-Life Parent Drug: 5-30 hours Metabolite: 14-95 hours Parent: 20-80 hours Metabolite: 50-100 hours 10-20 hours 5-20 hours Active Metabolite Yes Yes No No Formulations PO PO, IV, rectal gel PO, IV PO Potential Adverse Effects Sedation, dizziness, hypotension Consideration: Caution in: Elderly and hepatic Impairment Caution in: Elderly and hepatic Impairment IV formulation contains propylene glycol Slower onset of action Psychotropic Drug Information Handbook. 5 th edition. Benzodiazepines 23 Fixed ScheduleTherapy Fix ed dosing of benzodiazepines ev en w hen symptoms are absent Additional medication may be needed depending on severity of sy mpt oms Symptom-Triggered Therapy Medication only given w hen patient ex periences symptoms More popular in the inpatient setting Associated w ith more rapid detoxification and low er total doses of medicat ions Anticonvulsants 24 Alternative to benzodiazepines No evidence anticonvulsants are superior to benzodiazepines in preventing seizures M unc ie Jr, HL, Yas inian, Y, Og e L. Outpatie nt manag e me nt o f alc o ho l withdrawal s yndro me. Am Fam Physician. 2013; 88: 589-595 8

Anticonvulsants 25 Carbamazepine Valproic Acid Gabapentin M unc ie Jr, HL, Yas inian, Y, Og e L. Outpatie nt manag e me nt o f alc o ho l withdrawal s yndro me. Am Fam Physician. 2013; 88: 589-595 Anticonvulsants 26 Limited Evidence: Oxcarbazepine Tiagabine M unc ie Jr, HL, Yas inian, Y, Og e L. Outpatie nt manag e me nt o f alc o ho l withdrawal s yndro me. Am Fam Physician. 2013; 88: 589-595 Agents with Limited Evidence 27 Beta Blockers Alpha-adrenergic agonist Baclofen Anti-glutamatergic medications M unc ie Jr, HL, Yas inian, Y, Og e L. Outpatie nt manag e me nt o f alc o ho l withdrawal s yndro me. Am Fam Physician. 2013; 88: 589-595 9

Empiric Treatment 28 Multivitamin Indication: Malnutrition Thiamine Indication: Potential Thiamine Deficiency 29 Complications of Alcohol Withdrawal Delirium Tremens Wernicke-Korsakoff Syndrome Delirium 30 A. Disturbance in attention and aw areness B. Disturbance develops over short period or time and tends to fluctuate in severity during the course of the day C. Additional disturbance in cognition D. Disturbances in Crit erion A and C are not ex plained by anot her preex isting, established, or evolving neurocognitive disorder and do not occur in the contex t of a severely reduced level of arousal, such as coma E. There is evidence that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or w ithdrawal, or exposure to a toxin, or is due to multiple etiology American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric As s oc iation; 2013 10

Delirium Tremens (DT) 31 Mortality: 1%-4% of hospitalized patients w ith DT w ill due Predicted by : CIW A-Ar Scores >15 Recent w it hdraw al s eizures Prior withdrawal delirium or seizures Older age Misuse of other depressant agents Concomitant medical problems Schuckit, MA. Recognition and management of withdrawal delirium (delirium tremens). N Eng J Med. 2014; 371: 2109-13 Kim DW et al. Clincal predictors for delirium tremens in patients with alcohol withdrawal seizures. Am J Emerg Med. 2015; http://dx.doi.org/10.1016/j.ajem.2015.01.0 30 Delirium Tremens 32 Treatment Goals: Control agitation Decrease risk of seizures Decrease risk of injury or death ICU Setting Schuckit, MA. Recognition and management of withdrawal delirium (delirium tremens). N Eng J Med. 2014; 371: 2109-13 Delirium Tremens 33 Limited Evidence for Treatment Phenobarbit al- 1 s t udy vs diazepam Clomet hiazole- 1 s t udy vs clonazepam for uncomplicat ed w it hdraw al Midazolam Oxacarbaze pine Schuckit, MA. Recognition and management of withdrawal delirium (delirium tremens). N Eng J Med. 2014; 371: 2109-13 11

Wernicke-Korsakoff Syndrome 34 Brain disorder due to thiamine deficiency Tw o separate conditions: W ernicke Encephalopat hy K ors akoff Syndrome National Institute of Health website http://www.nlm.nih.go v/me dline plus /e nc y/artic le /000771. htm. Update d: Fe bruary 24, 2014. Last Ac c e s s e d: Marc h 26, 2015 Wernicke Encephalopathy 35 Damage to thalamus and hy pothalamus Signs and Sy mpt oms Confusion or loss of ment al act ivit y t hat can progress t o coma or deat h At axia Vis ion changes National Institute of Health website http://www.nlm.nih.go v/me dline plus /e nc y/artic le /000771. htm. Update d: Fe bruary 24, 2014. Last Ac c e s s e d: Marc h 26, 2015 Wernicke Encephalopathy 36 Treatment: thiamine 200 mg I M or I V TI D 500 mg I V TI D for 3 days if res pond t o t reat ment t hen 250 mg I M or I V for addit ional 5 days or clinical improvement Resolution of symptoms: Ocular abnormalit ies : days -w eeks Ataxia: response within first week1-2 mont hs t o res olve Acute Confusion/Delirium: 1-2 days Gavin R et al. EFNS guidelines for diagnosis, therapy, and prevention of Wernicke s encephalopathy. Eur J Neurol. 2010; 18:1408-1418 Royal College of Physicians. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke's encephalopathy in the ac c ide nt and Eme rg e nc y De partme nt. Alcohol Alcohol. 2002;37(6):513-21 KopelmanMD, Thomson AD, Guerrini I, Marshall EJ. The Korsakoff Syndrome: clinical aspects, psychology, and treatment. Alcohol Alcohol. 2009; 44: 148-154 12

Korsakoff s Syndrome 37 Permanent damage to areas of the brain involved w ith memory Signs/Sy mpt oms Inability to form new memories Memory loss Making up stories Hallucinations National Institute of Health website http://www.nlm.nih.go v/me dline plus /e nc y/artic le /000771. htm. Update d: Fe bruary 24, 2014. Last Ac c e s s e d: Marc h 26, 2015 KopelmanMD, Thomson AD, Guerrini I, Marshall EJ. The Korsakoff Syndrome: clinical aspects, psychology, and treatment. Alcohol Alcohol. 2009; 44: 148-154 38 After Alcohol Withdrawal Syndrome Now What? Medications for Alcohol Dependence 39 Medication Action CI Precautions AE Evidence Adult Dose Disulfiram Inhibits intermediate metabolism of alcohol Use of alcohol Treatment with metronidazole CAD Hypersensitivity to rubber Monitor LFTs Cirrhosis Renal impairment Cerebrovascular disease Pregnancy C Metallic taste Hepatotoxic effects (rare) Optic neuritis Drowsiness Headache Improved shortterm abstinence by a factor of almost 4 when daily dosing was supervised 250 mg PO daily [range 125 to 500 mg] Acamprosate Stabilizes glutamate and GABA systems CrCl <30 ml/min Renally dose Diarrhea Caution if patient has Somnolence or history of depression insomnia or suicide Anorexia Pregnancy C Dizziness Increased the number of days of abstinence by 10% and doubled rate of abstinence Largest US trial was negative 666 mg PO TID 333 mg PO TID if CrCl 30-50 ml/min Oral Naltrexone Blocks opioid Current use of Needs to be opioid Nausea receptors opioids free for 7-10 days Vomiting Acute hepatitis or Monitor LFTs Anorexia liver failure Pregnancy C Fatigue Extended-Release Same as oral but Rash or infection at Use with caution with Injection site Injectable Naltrexone effects lasts 30 days injection site bleeding disorder reaction Joint pain Muscle aches Adapted from: Friedmann PD. Alcohol use in adults. N Eng J Med. 2013; 368: 365-73 Jonas DE et al. Pharmacotherapy for adults with alcohol us e disorder in outpatient settings: A systematic review and meta-analys is. JAMA. 2014; 311:1889-1900 Reduced short term 50 mg PO daily heavy drinking by 83% but did not increase abstinence Reduced heavy 380 mg gluteal IM drinking by 25% monthly 13

Treatment Options in the Pipeline? 40 DOES NOT HAVE FDA APPROVED INDICATION Gabapentin I nt ervent ion: Placebo or gabapent in 900 mg PO daily or 1800 mg PO daily Conclus ion: Gabapent in ( part icularly 1800 mg PO daily) w as effect ive in t reat ing alcohol dependence Varenicline Intervention: Placebo vs varenicline 2mg/day Conclusion: Varenicline significantly reduced alcohol consumption and craving Zonisamide Study completed- results pending compared to placebo M as o n e t al. Gabape ntin tre atme nt fo r alc o ho l de pe nde nc e. JAMA Intern Med. 2014; 174: 70-77 Litten et al. A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. J Addict Med. 2013 ; 7(4): 277 286 ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=alcohol+dependence&search=search. Last Ac c e s s e d: Marc h 31, 2015 Resources of Assistance in Long-Term Abstinence 41 Substance Abuse and Mental Health Services Administration www.samhsa.gov National Institute on Alcohol Abuse an Alcoholism www.niaaa. nih. gov Alcoholics Anonymous www.alcoholics-anonymous.org American Council on Alcoholism www.aca-usa.com Summary 42 Alcohol use disorder is increasing in prevalence and costs the US billions of dollars Alcohol w ithdraw al can lead to serious consequences such as death Triage the patient appropriately using the SAWS or CIWA-Ar tools Benzodiazepines are first line agents for treatment Alcohol w ithdraw al can progress to delirium tremens Alcohol abuse can lead to W ernicke-korsakoff Syndrome Pharmacological agents are approved for alcohol dependence w ith many studies being conducted on ex isting medications for different indications 14

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