Benzodiazepine-Sparing Alcohol Withdrawal (Maldonado, 2/10/2021)

Great thanks to Dr. Jose Maldonado, a Stanford psychiatrist and neuropsychiatrist, who literally wrote the benzodiazepine-sparing alcohol withdrawal protocols that we have been utilizing at SSRRH for the last few years. He gave us a deep dive into the science behind them this week! If you want to see the whole presentation, it is archived here: VIDEO: Benzo Sparing Alcohol Withdrawal 

For those of you who prefer the written word, here is Dr. Maldonado's paper, and for those who prefer an abbreviated version, here are my notes from Grand Rounds:

Alcohol Use Disorder is extremely common in our society, particularly among hospitalized patients: 20-42%of hospitalized medical patients; ~7% are identified by physician. Check out these numbers:

• 40% of ED patients
• 43-81% surgical and head and neck patients
• 42% of hospitalized veterans 
• 59-67% of trauma patients
• up to 44% elderly patients admitted to acute geriatric units

Remember that legal driving limit is a blood alcohol concentration (BAC) of 0.08. Alcohol follows zero order kinetic metabolism, which means there is nothing we can do to slow down or speed up its rate of metabolism.  Ethanol is metabolized at rate of 0.015% per hour,which means a  person with BAC of 0.15 (twice the legal driving limit) will have no measurable alcohol in the bloodstream after 10 hours. 

Alcohol Withdrawal Syndromes

This is something I did not really know before this presentation: alcohol withdrawal CAN present even if BAC is still quite elevated. In fact, signs and symptoms of withdrawal occur once a person's BAC drops by 30% from their usual level; this means that you don't have to be at a BAC of zero to have symptoms of alcohol withdrawal. In fact, you can be in DTs even with an extremely elevated BAC, if it is just lower than where you normally live.

Here is another pearl: 80% of patients withdrawing from alcohol do NOT require aggressive medical treatment; supportive management is enough. If we treat everyone who walks through the door for alcohol withdrawal, we will definitely over treat--> leading to respiratory depression, toxicity, falls, oversedation, etc.

There are FOUR unique alcohol withdrawal syndromes: 2 are dangerous/complicated, 2 are not

1. Uncomplicated Alcohol Withdrawal ("The Shakes")
• 80% of all patients
• tremor, usually fine (but can be coarse)
• GI distress, anxiety, difficulty sleeping/insomnia, violent and unpleasant dreams, mild sx of autonomic instability
• sx decrease usually by day 5, more severe symptoms last 10-14 days
2. Alcohol Withdrawal Seizures ("Rum Fits")--> complicated 
• 5-15% of all patients
• peaks quite early: 12-48 hours (much earlier than DTs)\
• the greater the amount of alcohol consumed, the greater the risk of seizure
3. Alcoholic Hallucinosis  ("The Horrors")
• up to 30% of all patients
• onset: ~8 hours, peak 24-96 hours
• related to length and amount of alcohol exposure
• auditory, visual, tactile hallucinations in context of CLEAR sensorium, stable VS
4. Delirium Tremens ("DTs")--> complicated
• ~5% of all patients
• peak can be relatively late, up to 7 days after stopping alcohol
• "autonomic storm"
• 1% mortality in healthy person, but can be as high as 20% if elderly and multiple medical issues

What is the problem with benzodiazepines?  Well, you and I know that there are too many things to count. . . here are a few:

1. Benzos have serious abuse liability; plus there is 29-76% concurrent alcohol and benzo use
2. Benzo use may increase craving, early relapse to alcohol use, and increased alcohol consumption
3. Benzos are CNS depressants and really prolong withdrawal rather than treat it
4. Benzos cause psychomotor retardation, cognitive blunting, ataxia, poor balance, and decreased mobility
5. Benzos disrupt circadian rhythms of melatonin release, interfering with sleep
6. Benzos disrupt thalamic gating
7. Benzos are associated with an increased risk of delirium (40% of the time)

The Neurotransmitter-imbalances of Alcohol Withdrawal

Alcohol withdrawal is a complicated cascade of neurotransmitter imbalances involving all kinds of brain chemistry (this takes me way back to my neuroscience degree from undergrad). For the purposes of the algorithm, key imbalances include: excess of norepinephrine (NE), glutamate, dopamine, as well as a defective GABA-ergic system

The very imbalances of these neurotransmitters is what is being addressed in the benzo-sparing protocol, aimed at evening things out.

1) Alpha 2 agonists are the basis of the benzo sparing protocol: taking you way back to pharmacology 101, the alpha 2 agonists work at the presynaptic receptor, preventing the release of massive amounts of NE and Glutamate that occurs in alcohol withdrawal--> this, in essence treats, rather than masks (in contrast, Beta blockers mask alcohol withdrawal (post synaptic), but patient will still seize)

There are three alpha-2 agonists (in order of efficacy)

• clonidine: cheap, easy, readily available, comes in PO/IV/patch
• dexmedetomidine (precedex): highly selective alpha 2>alpha 1: offers more anxiolysis, less hypotension and bradycardia. BUT it is only IV, and has to be administered in ICU/monitored bed (there are not great papers, but lots of good anecdotal evidence, intensivists use it all the time at SSRRH)
• guanfacine: more highly selective than even dexmedetomidine, but has long half life (takes a bit to kick in)

There are at least 11 studies showing a benefit of alpha-2 agonists OVER  benzos (better in terms of withdrawal, anxiety, agitation, progression to DTs), Dr. Maldonado says these agents overall are about 3x better than benzos.

2) The other major component of the benzo-sparing protocol are the Antiglutamatergic agents/calcium channel modulators. These include carbamazepine, valproic acid (VPA), gabapentin, and pregabalin to name a few. Dr. Maldonado prefers pregabalin>gabapentin>VPA.

• 13 studies: head to head, cbz, VPA are equal to or superior to benzos without all the problems benzos have
• VPA (available PO/IV)
• Gabapentin multiple studies showing equal to or superior to benzo
• Pregabalin: same mechanism of action, but gabapentin only absorbed in small intestine, more gabapentin you give, the less you absorb. Pregabalin absorbed throughout entire GI tract, peak plasma concentration 1 hour (compared to 3-4 for gabapentin),

How do we distinguish which patients who will go through withdrawal need treatment?

To distinguish those 80% who only need supportive care from those who needs medical management, you can use the PAWSS Score, close to sens 100%, spec 100% to predict alcohol withdrawal

• PAWSS<4, pt might withdraw but will not have complicated withdrawal
• PAWSS>4: pt WILL have severe or complicated withdrawal
• if already withdrawing, treat
• if not, ppx arm

Summary of Stanford Benzo Sparing Protocol

A. Alpha 1 agonist: 0.1mg clonidine patch x 2 (#1 removed day 4, #2 removed day 7) PLUS 0.1mg PO/IV q 8 hours x 3 doses 
B. IF vital signs unable to tolerate alpha 2 effect OR patient has excess anxiety--> you can instead use high dose gabapentin (1200mg loading, 800mg TID w/taper) OR high dose pregabalin 150 mg loading (see here for protocol) OR VPA 250mg PO/IV BID + 500mg QHS

• IF patients at extremely high risk for AWS (PASS>7 or BAL>300 on admission) USE both A+B
• For adjunct medication: melatonin 10 mg PO qhs, hydroxyzine prn anxiety, doxylamine prn insomnia
• benzos (PO lorazepam) should only be used if high breakthrough sx despite adequate treatment with A+ B (e.g. CIWA>15 or >20) 

Random pearls:

• Electrolyte abnormalities are particularly common in patients with alcohol use disorder and alcohol withdrawal: watch K+ (QT prolongation), Mg
• of note, hypomagnesemia is #1 electrolyte abnormality that predicts seizure in patients with withdrawal
• Thiamine deficiency is also endemic patients with alcohol use disorder: all patients with AUD should get thiamine 500 mg IV/PO/Im TID x 3-5 days
• Dr Maldonado says that they do discharge folks from their ER to home on these regimens with outpatient follow-up

In summary, per Dr. Maldonado, using a benzo-sparing protocol is safe and effective, decreases the risk of delirium as well as other adverse effects of benzodiazepines, decreases LOS, and ultimately hopefully helps the patient in the long-run. Go forth and get folks off their alcohol.