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

2. 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

3. 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: billion dollars
7% of the US population abuses or is dependent on alcohol
- CDC. Fact sheets – Alcohol use and health
Stehman CR. Am J Emerg Med. 2013;31:
Mayo-Smith MF. Arch Intern Med. 2004;164:
Walker B. J Trauma Acute Care Surg. 2013;74(3):

4. 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, Web. [access date: 1 June 2013]. dsm.psychiatryonline.org

5. 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, Web. [access date: 1 June 2013]. dsm.psychiatryonline.org

6. Pathophysiology of Alcohol Withdrawal

7. 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
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

8. 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
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

9. 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.
Stehman CR. Am J Emerg Med. 2013;31:734-42
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

10. 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

11. 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

12. 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

13. Treatment of Alcohol Withdrawal

14. 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:
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

15. 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
( 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:

16. Initial Treatment
Load Benzodiazepine:
Diazepam:
5-20 mg q 5-10 minutes
Lorazepam:
1-4 mg q 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:

17. 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

18. Propylene glycol toxicity
Propylene Glycol (PG)
Solvent
T1/2 = 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 = l/kg
Zar T. Seminars in Dialysis. 2007;20(7):217-9.

19. 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.

21. 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:
mg q 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.

22. 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
mg/kg intermittent
Stehman CR. Am J Emerg Med. 2013;31:734-42
Mayo-Smith MF. Arch Intern Med. 2004;164:

23. 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 = mg/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 mg/min. Can do wt based at mg/kg/min and titrate up
Krystal JH. Arch Gen Psychiatry. 1998;55:354-60
Krystal JH. Ann of NY Acad Sci. 2003;1003:
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.

24. 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:
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

25. 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
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:
Walker B. J Trauma Acute Care Surg. 2013;74(3):926-3

26. 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):

27. 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:

28. 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

29. 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 – 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

30. 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
Tourette’s - make repeated, quick movements or sounds that they cannot control. These movements or sounds are called tics

31. 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

32. 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!

33. 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

34. 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

35. Patient Case - TW D5 – AKI Repeat K @ 9:37 = 3.4
Repeat = 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

36. 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 = 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

37. What are the possible causes for his AKI?

38. 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)