Treatment of Alcohol Withdrawal Pam Lyons PharmD Candidate 2014 Pharmacotherapy Scholars Program University of Pittsburgh School of Pharmacy

Explain the pathophysiology of alcohol withdrawal Objectives Explain the pathophysiology of alcohol withdrawal Design a treatment algorithm for a patient in alcohol withdrawal Describe the role of alcohol in the treatment of alcohol withdrawal

The Impact of Alcohol Abuse Prevalence: 7% of the US population 24% of all emergency room visits 80,000 alcohol-related deaths each year 500,000 episodes of alcohol withdrawal requiring treatment per year Estimated cost per year: 223.5 billion dollars 7% of the US population abuses or is dependent on alcohol - CDC. Fact sheets – Alcohol use and health http://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm Stehman CR. Am J Emerg Med. 2013;31:734-42 . Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11. Walker B. J Trauma Acute Care Surg. 2013;74(3):926-31.

Criteria for Alcohol Withdrawal – DSM V A. Cessation of (reduction in) alcohol use that has been heavy and prolonged B. Two or more of the following that develop w/in several hours of cessation of use: Autonomic hyperactivity Increased hand tremor Insomnia N/V Transient visual , tactile, or auditory hallucinations Psychomotor agitation Anxiety Generalized tonic-clonic seizures Autonomic: sweating or pulse rate greater than 100 bpm). American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013. Web. [access date: 1 June 2013]. dsm.psychiatryonline.org

Criteria for Alcohol Withdrawal – DSM V (continued) C. Symptoms cause distress or impairment D. Signs and symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal form another substance. C. The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013. Web. [access date: 1 June 2013]. dsm.psychiatryonline.org

Pathophysiology of Alcohol Withdrawal

Vs. Inhibitory Excitatory Normal Physiology NMDA receptor Ca+2 Ca+2 80% of neurons in the brain use Gaba and glutamine as neurotransmitters. GABA acts as an inhibitory molecule on the GABA receptor  open chloride channels to stabilize the cell membrane and prevent depolarization Glutamate acts on NMDA (n-methyl-d-aspate) receptor acts as an excitatory neurotransmitter.  works to open calcium channels to cause action potentials http://www.med.unc.edu, commons.wikimedia.org Ca+2 Inhibitory Excitatory Stehman CR. Am J Emerg Med. 2013;31:734-42 Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Physiology in the Presence of Alcohol – Acute Setting NMDA receptor Ca+2 Vs. Alcohol is a depressant  it increases the inhibitory effect of Gaba and decreases the excitatory effect of glutamate on the NMDA receptor In the acute setting, this is what leads to the depressant effects of alcohol: depressed consciousness, slowed cognition, impaired sensory and motor function, slowed reaction times The body doesn’t like this, so it tries to compensate http://www.med.unc.edu, Ca+2 Inhibitory Excitatory Stehman CR. Am J Emerg Med. 2013;31:734-42 Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Physiology in the Presence of Alcohol – Chronic Setting Inhibitory Decrease in number of GABA receptors Decrease in sensitivity of GABA receptors to GABA and EtOH Excitatory Increase in number of NMDA receptors Increase in NMDA sensitivity to glutamate That compensation makes GABA less sensitive and decreases the number of GABA receptors And increase NMDA receptors and sensitivity This is what we call tolerance: b/c the gaba receptors are fewer in number and less sensitive, alcoholics need more and more etoh to have the same effect. http://www.med.unc.edu Stehman CR. Am J Emerg Med. 2013;31:734-42 Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Pathophysiology – Alcohol Withdrawal Removal of Alcohol Glutamate activates highly sensitive NMDA receptors Little GABA present to act on small number of GABA receptors Agitation When alcohol is withdrawan in an alcoholic, there is no longer that chronic inhibitory stimulus at the receptors. The increase amount of glutamate released by the body act on the NMDA receptors (they have increase in number and sensitity)  excitatatory reaction Normally, the body would keep this in balance by releasing GABA, but it can‘t because alcohol has served as an inhibitory molecule for so long that the body has down regulated the amount of GABA released, the sensitivity of GABA receptors and the # of GABA receptors. (we don’t have an inhibitory balance) AGITATION Stehman CR. Am J Emerg Med. 2013;31:734-42

Sign and Symptoms of Withdrawal Abnormal vital signs, N/V, tremulousness, diaphoresis Hallucinations, seizures Delirium tremens Time from last drink: 2-6 hours 7-48 hours 48-72 hours 2-6 hours: abnormal vitals: HTN, tachy cardia, hyperthermia, tachypenia  these may be masksed by BB 7-48 hours: Hallucinations – usually auditory (up to 25% of pts)  usually they hear noises that they think are voices – but they have a clear sensorum= they may know tha tthese hallucination are not real Seizures in 10% of pts (tonic clonic)  rarely become status epilipticus are are usually self limited DT: the most serious complication of alcohol withdrawal Stehman CR. Am J Emerg Med. 2013;31:734-42 Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Confusion, delirium, psychosis Hallucinations Seizures Delirium Tremens Confusion, delirium, psychosis Hallucinations Seizures Usually lasts ~5 days May be fatal Risk factors for development: Previous Delirium Tremens Others - unknown 5% of untreated patients Hallucination – they don’t have a clear sensorum  they don’t know that they aren’t real Before current treatment options, DT was fatal in ~35% of cases  that has been reduced to 5%  emphasizes the need for rapid pharmacologic action Only RELIABLE predictor is DT is previous DT – We have not been able to identify any other risk factors Stehman CR. Am J Emerg Med. 2013;31:734-42 Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Treatment of Alcohol Withdrawal

Mainstay of Therapy: Benzodiazepines Reduce the severity and duration of symptoms Reduce mortality Ease of administration MOA in EtOH withdrawal: Enhance GABA activity  increase inhibition No clear benefit of one particular agent Usually choose IV options: Diazepam Midazolam Lorazepam Benzos - Sx: This includes seizures and delirium\ -Multiple routs of admin making them easy to admister to all types of pts - enhnace gaba activity  which we know has been suppressed by alcohol  increases inhibition Unclear which agent is the best  tend to stick with the IV medications b/c most pts in active withdrawal are unable to swallow pills + they’re faster for actively withdrawing pts IM route Stehman CR. Am J Emerg Med. 2013;31:734-42 Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11. Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Choosing a Benzodiazepam: Pros and Cons Midazolam Lorazepam Onset of action 1-5 min 2-5 min 5-20 min Half life 30-60 hours (30-100 hours metabolite) 2-6 hours 9-21 hours Active Metabolite? Yes no Metabolism Hepatic Excretion Renal Renal/fecal Dose adjustments Hepatic/renal impairment Clcr<10 Renal impairment Special considerations: Erratic IM absorption, propylene glycol toxicity at very large doses Longer sedation in obese pts and those with low albumin Risks of lactic acidosis and ATN Diazepam: shortest time ot onset, vVERY long T1/2 Midaz: shortest half life than the other 2, still rapid onset Lorazepam: Less liver metabolism bc it doesn’t have an active metabolite - than the other 2 which may be beneficial in alcoholics w/ hepatic impariment but much slower onset  may nto want to use if pt acutely agitated Risk of Acute tubluar necrosis in infusion of lorazepam >25mg /hr Stehman CR. Am J Emerg Med. 2013;31:734-42 Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.

Initial Treatment Load Benzodiazepine: Diazepam: 5-20 mg q 5-10 minutes Lorazepam: 1-4 mg q 10-15 minutes 2) Benzodiazepine doses PRN 3) Determine the need for further treatment May require large doses because of decreased sensitivity of the GABA receptor Goal of IV benzos: achieve normal vital signs (signifies that you’ve decreases the sympathetic tone and stabilized the autonomic NS), appropriate sedation -Loading is impt b/c it has been shown to achieve earlier symptom control, decrease the total amt of medication used and prevent seizures Even though Lorazepam has a shorter duration of action, it takes a while to onset of action, so the initial doses should be spaced out to avoid stacking doses Want to give benzos until the pt is calm, not having hallucination, not seizing, normal vitals This is pt specific (one pt on 6 had 1600 mg diazepam. Other case reports have used 2640 mg diazepam in 48 hrs, and 2850 mg midazolam over 5 days) Require large doses b/c of decreases sensitivity of GABA Stehman CR. Am J Emerg Med. 2013;31:734-42 Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.

Benzodiazepam Resistance Kindling Phenomenon Episodes of EtOH withdrawal become harder to treat Benzodiazepam resistance Due to permanent alterations in neurotransmitters/receptors Consider diagnosis after: >40 mg lorazepam 200 mg diazepam Consider other treatment options Stehman CR. Am J Emerg Med. 2013;31:734-42

Propylene glycol toxicity Propylene Glycol (PG) Solvent T1/2 = 1.4-3.3 hrs Metabolized by liver  lactate, acetate, pyruvate Excreted in urine 12-45% unchanged Clearance decreases as dose increases = saturation No established acceptable level of IV PG PO level max = 25mg/kg/day Toxicity profile: Serum hyperosmolality, lactic acidosis, kidney failure, SIRS Diagnosis: osmolar gap at 48hrs Poor indicators: anion gap and lactic acidosis Treatment: Hemodialysis Why would we want to consider other treatment options – why not just keep loading pts w/ benzos? Lorazepam and diazepam IV are mixed with propylene glycol as a solvent with in large doses can be toxic T1/2 in pts with normal renal and kidney fxn Lactate is acidic  makes proylene glycol a source for acidosis Thought to saturate the proximal tubule b/c it can’t continue to excerete as the dose of PG increases There is no established level of PG that’s safe to give PO  only give a max PO dose Thankfully, HD removes pg b/c it is a small molecule (76kd) that is not very protien bound, non-ionic. Vd = 0.7-0.9l/kg Zar T. Seminars in Dialysis. 2007;20(7):217-9.

How much Propylene glycol is too much? Drug Amount of PG (mg/ml) Drug dose = 69g/day PG Lorazepam 2 mg/ml 828 166 mg/day Phenobarbital 130 mg/ml 702 12.8 g/day Diazepam 5 mg/ml 414.4 832 mg/day Pentobarbital 50 mg /ml 8.3 g/day Phenytoin 50 mg/ml Bactrim 16:80 mg/ml 2.7:13.3 g/day Etomidate 2 mg/ml 362.6 381 mg/day Article that extrapolated the max rate of IV lorazepam to determine how much propylene glycol was okay. EtOh may inhibit metabolism of PG – this is seem with increased toxicity when anti-freeze and alcohol are co-ingested Children may be at risk b/c they have impaired EtOH dehydrogenase enzyme needed to break down PG Risk Factors for PG accumulation: Long term EtOH abuse Children Pregnant women Hepatic disease CKD Zar T. Seminars in Dialysis. 2007;20(7):217-9.

Non-Benzodiazepine Options Barbituates MOA: Directly open Chloride channel in GABA, enhance GABA binding, increase duration of opening Promotes benzodiazepine binding to GABA ADE: respiratory depression, cardiac depression Phenobarbital: 65-260 mg q 15-30 minutes until symptom control Time to onset: 5-30 minutes Hepatic metabolism/Renally eliminated Max: 600mg/24hrs Barbs: Can work w/o native GABA which is a big advantage - B/c alcoholics have reduced GABA - can also increase the action of benzo by helping them to bind -the combo has been shown to decrease ICU LOS -max dose = 260mg before moving onto another option (max dose/day according to package insert = 600 mg/d) Stehman CR. Am J Emerg Med. 2013;31:734-42 Phenobarbital sodium powder for IV injection package insert. Hospira, Lake Forest, IL, 2008.

Non-Benzodiazepine Options Propofol MOA in EtOH withdrawal: Slowing closure of Chloride channel in GABA receptor, NMDA antagonist Requires mechanical ventillation Time to onset= 1-2 minutes Dose: 0-5mg/kg/hr PRN continuous infusion 0.25-2 mg/kg intermittent Stehman CR. Am J Emerg Med. 2013;31:734-42 Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.

Non-Benzodiazepine Options Ketamine MOA: NMDA receptor antagonist May be useful in the treatment of EtOH withdrawal “Ethanol-like effects” Does not cause EtOH cravings ADE: HTN, tachycardia, pulmonary secretions, respiratory depression, out of body experience Initial doses = 0.2-0.5mg/min Current Phase 2 clinical trial for the use of Ketamine in the treatment of depression and alcohol dependence There haven’t really been any studies for the treatment of withdrawal, but several looking at the effect of ketamine. Many studies using ketamine in EtOH studies in rats to see what receptor EtOH work on. Several studies have described ketamine as having alcohol like effects – this would be expected considering that they have similar mechanisms  high doses of ketamine look like the person is drunk  this effect is not seen as much in etoh dependent pts -In one study done by kristal and colleges published in 1998 – looked at how ketamine affected recovering alcoholics  these men had been abstinent from etoh for at least 10 days  ketamine produced an effect similar to etoh but did not cause the men to have cravings for alcohol.  this is good b/c in the treatment of etoh withdrawal, we want to prevent these cravings No approved dose for EtOH withdrawal – we can look to anesthesia – low dose would be 0.2-05mg/min. Can do wt based at 0.01-0.03 mg/kg/min and titrate up Krystal JH. Arch Gen Psychiatry. 1998;55:354-60 Krystal JH. Ann of NY Acad Sci. 2003;1003:176-184. Dickerson D. J Psychopharm. 2010; 24(2):203-11 Harrison YE. Behavor Pharm. 1998;9:31-40. Ketamine for Depression and Alcohol Dependence. Clinical trials.gov Ketamine Package insert. Bioniche Pharma USA LLC, Lake Forest, IL, 2008.

Adjunct Treatment Options Carbamazepine Limited data No IV formulation – for mild AWS only Antipsychotics Haloperidol – only use when patient is already adequately treated May be beneficial for hallucinations Cardiac Medications Alpha agonists (Dexmedetomidine, clonidine), BB Only mask s/s AWS Use only as adjunct therapy Carbamazepine – small studies in ER – only in pts w/ mild withdrawal – only available PO Haloperidol used to be used frequently, however, it doesn’t have any Gaba action – more masks the s/s of AWS - more of an adjunct to treat agitation/hallucination BB may cause delirium Stehman CR. Am J Emerg Med. 2013;31:734-42 Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11. Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Nutritional Supplementation Supportive Care Hydration IV dextrose for hypoglycemia Nutritional Supplementation Thiamine 100 mg x 3 days Magnesium NMDA antagonist Folic Acid Elevate head of bed to prevent aspiration http://blog.hqperformance.com/2013/04/14/going-bananas-who-knew/ Dehydration: from sweating, vomiting, diarrhea, fever  also EtOH is a diuretic, so this can cause dehydration if they aren’t repleting loses Alcholics are often malnurished  etoh, and liver dx decrease thiamine HypoMg looks like AWS, severity of Delerium tremens may correlate with amt of Mg depletion -Banana bag: Magnesium 4 mg, folic acid (we do 3 days, some sources say up to 14 days), MVI, thiamine and a liter of fluid Stehman CR. Am J Emerg Med. 2013;31:734-42 Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11. Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

Why is Thiamine so important? Role in the body: Coenzyme for sugar and protein metabolism Needed for production of GABA and acetylcholine Give thiamine before glucose Lack of thiamine can cause: Wernicke’s encephalopathy confusion, loss of motor control, abnormal vision Korsakoff syndrome Memory loss, hallucination, confabulation Giving glucose before thiamie will just deplete it more than it already is depleted Lack of thiamine  brain damage called Wernicke’s encephalopathy/korsakoff syndrome -progress where the patient can not longer form new memories and they have confabulation where they make up stories - These can lead to death and the memory impairment may be irreversible Brust JCM. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Saunders Elsevier; 2007:chap 443. Walker B. J Trauma Acute Care Surg. 2013;74(3):926-31.

Controversial use of EtOH Ethanol is not recommended for treatment of withdrawal: Variable metabolism – difficult to predict kinetics Compared to benzodiazepines: Shorter duration Narrow therapeutic window Lowers the seizure threshold Irritates stomach Damages the liver Toxic for neutrophils and macrophages Acetaldehyde accumulation  respiratory failure Prescribing EtOH condones alcoholism Is the patient going to drink on discharge? Lack of controlled studies Can be even more difficult to predict kinetics in alcholics because pts have liver disease Effect on immune system  impaired wound healing (as we have seen in the trauma unit, these pts have trauma) Accumulation of a toxic metabolite (acetaldehyde)  respiratory depression (potentially fatal) which can be worse in elderly and hepatically compromised Mayo-Smith MF. Arch Intern Med. 2004;164:1405-11.

Clinical Institute Withdrawal Assessment Scale for alcohol Monitoring - CIWA Clinical Institute Withdrawal Assessment Scale for alcohol Scale 0-7 10 areas of observation: N/V Tremor Paroxysmal Sweats Anxiety, Agitation Tactile, Auditory, Visual disturbances HA Orientation/sensorium Interpreting the score: <9 = Minimal/absent withdrawal 10-19 = Mild – moderate >20 = Severe CIWA is a scale from 1-7 that tries to descire the severity of etoh withdrawal and can be used to determine how treatment is working 7 is the worst sx. 0 is no sx May be difficult to use b/c it’s on a scale from 1-7, but not every number is labeled with a description – some categories only label 0,1,4,7….what do the numbers inbetween mean? Grading bias Cannot be used if the pt is intubated b/c they have to answer questions  can use a sedation score like the RASS or RIKER scale

Withdrawal Assessment Scale (WAS) UPMC Protocol Withdrawal Assessment Scale (WAS) Similar to CIWA Addition of vital signs, flight of ideas, quality of contact Only on a scale from 1-6 Not useful for intubated patients Initiate: Lorazepam 2 mg PO q2hr per WAS Protocol attaches directions to scores WAS <10 – no action needed, repeat WAS in 4 hrs Was 10-14 – PRN benzo, repeat WAS in 4 hrs WAS >14 – PRN benzo + call treating MD for reassessment, repeat WAS in 2hrs Scheduled benzos Symptoms have been stabilized with WAS PRN for >24 hrs OR Pt requires >6 mg lorazepam in 12 hrs of treatment Still ahs similar problems in that it doesn’t label every number for every category – subjective Can’t be done while intubated

Social Hx: Drink 3-4 beer x ~3nights/wk, marijuana use 3x/month Patient Case: TW 41 yo male PMH: EtOH withdrawal-related seizures Seizures not related to EtOH Tourette syndrome Anxiety/depression Tremors EtOH abuse Social Hx: Drink 3-4 beer x ~3nights/wk, marijuana use 3x/month HPI: Three intoxicated falls. Last fall was off a curb. Presented to OSH on 10/12/13 @22:53 Tourette’s - make repeated, quick movements or sounds that they cannot control. These movements or sounds are called tics

Claims compliance with medications Patient Case - TW Home Medications: Zonisamide (Zonegran®) 100 mg BID Lamotrigine (Lamictal®) 200 mg daily Paroxetine (Paxil®) 10 mg daily Quetiapine (Seroquel®) 300 mg HS Trazodone (Desyrel®) 100 mg HS PRN Folic acid 100 mg BID Claims compliance with medications Zonisamide – anticonvulsant (sulfonamide) MOA unknown studies suggest a blockade of sodium channels, with consequent stabilization of neuronal membranes whereas other in vitro studies have shown zonisamide to suppress synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses

Diagnosed with Tibia/fibula fractures and transported Labs: Patient Case - TW Diagnosed with Tibia/fibula fractures and transported Labs: Blood alcohol: 277 Pretty much everything looks normal, plts are a little low, Hbg is low – may have bled Watch potassium – may need to be replenished Magnesium is boardering on low, but we’re going to replace that Take notice of his Scr – good!

What steps should we take to adequately treat this patient and prevent withdrawal? WAS protocol – benzos PRN Banana bag (dextrose, thiamine, MVI, Mg, folate, hydration) Good! Let’s say that we treat him adequately innitially

D1 – patient does not receive home medications Patient Case - TW D1 – patient does not receive home medications Starting to become fairly agitated Recieves 8 mg Lorazepam per WAS D2 – Agitation uncontrollable Escalating doses of IV diazepam 1125 mg diazepam total Phenobarbitol 500 mg IV Soft tissue infection suspected – start IV vancomycin D4 – restart home lamictal at slow titration Vanco level came back low Infection progressing  added Zosyn D5 D1- including his anti-seizure meds, D2 – getting doubling of doses of valium up to 200 mg per PRN dose - cellulitis suspected on R ankle (erythma, fluid filled blisters) Continuing to get large doses of diazepam, but not quite so large, also received a second dose of diazepam

Patient Case - TW D5 – AKI Repeat K @ 9:37 = 3.4 Repeat Scr @9:37 = 3.2 Vancomycin level = 56 Repeat random level = 53.7 Just as a reminder, he came in with a Scr of 0.7, on D5, it spiked to 3.0. They’re kind of doubting that the vanco is that high…but on repeat later that day, it was53.7 (not a mistake) -AKI and this lingering vanco level are what they have been dealing with recently – let’s take a look at the trend

Increased Vanco dose to 1.5 q 8hr, added Zosyn 10/14 10/15 10/16 10/17 10/18 10/19 10/20 10/21 10/22 Valium dose (mg) 1125 800 400 50 20 60 280 160 40 Phenobarb (mg) 500 Propylene glycol (gram) 95.7 69 33.2 4.1 1.7 4.9 23.2 38.2 3.3 Scr 0.7 3 5.2 6.7 7.5 9.9 10.8 Vancomycin levels Start 5.8 56 53.7 51.7 44.6 UO 850 700 755 Received a total of 2635 mg of diazepam over these 10 days = 243.25 grams of propylene glycol Phenobarb 1 gram = 5.4 grams propylene glycol UO still good. What could be causing this AKI? Ruled out pre-renal causes by looking at the FENa – plus adding volume did not help imporve function which we would expect with pre-renal Unlikely acute tubular nephritis after just 2 doses of zosyn (plus no eosinophils in urine) Increased Vanco dose to 1.5 q 8hr, added Zosyn

What are the possible causes for his AKI?

What other treatment options for alcohol withdrawal do we have? We already used phenobarb – could continue that, or ketamine, or propofol (but we don’t want to intubate him)