by Jeff Lapoint
“I was not proud of what I had learned, but I never doubted that it was worth knowing.”Hunter S. Thompson
I don’t know why I’ve been identifying with the works of Hunter S Thompson of late. It’s not because the political times seem eerily similar to that of 1972, nor because we seem to feel the same way about deadlines and writing. Maybe it’s because I think the best way to talk about a topic like alcohol withdrawal is to approach it in perhaps the same way as he would: roll up the sleeves, get down in the muck, grab the topic by the throat and editorialize the whole way through … concerns about data and bias be damned! Unfortunately, as many will remind me, that approach doesn't quite lend itself to toxicology, or medicine, or science in general . . . but what the hell?
Here’s the thing about the treatment of acute alcohol withdrawal – we suck at it. Sure there are individual exceptions (I’m sure you, dear reader, are amazing – I’m talking about everyone else– wink) but the most common systems and dreaded protocols out there set us up for at best less than optimal treatment, and at worst a dumpster fire of abject failure. So, if you’re at a shop where the plan is modest treatment in the ED, and then admit to medicine for the “Set It and Forget It” CIWA scale, this post is for you.
Alcohol withdrawal is a complex spectrum of psychomotor agitation and generally increased sympathetic tone. More severe presentations can involve perceptual disturbances and true autonomic instability. Just to spice things up a notch, regardless of the severity of acute alcohol withdrawal, treatment can be complicated both by the reasons the patient stopped drinking (e.g., infection, trauma, GIB, etc.) and consequences of chronic alcohol dependence (e.g., alcoholic ketoacidosis, Wernicke’s encephalopathy, hepatic failure, etc.). The point that I think is worth committing to the grey folds of your mind is that there is no one size fits all treatment for alcohol withdrawal. No protocol or dot phrase in whatever EMR overlord you bow to will be the best for everyone. The key is to gain control of withdrawal symptoms early.
Sins of the Past
The history of research in alcohol withdrawal is a fascinating one, and while the full discussion is beyond what I have in the space (or attention span) for here, it is a pursuit populated by giants (e.g., Osler, Mellanby, Victor and Adams). In those heady days, the existence of alcohol withdrawal, at least for physicians in the United States, was controversial. To me, one early study stands above the rest: Isbell et al., “An Experimental Study of the Etiology of “Rum Fits” and Delirium Tremens” – from 1955.1 Here, 10 former morphine addicts serving time for violations of the Harrison Narcotic Act were given free access to alcohol for as many days as they wanted to keep drinking and then, when finally tapped out, they stopped drinking entirely. Their real first names were used, and there are some classic (if not sad) lines of text.
Maurice was 33 years of age … His Rorschach test responses were interpreted as indicating considerable guilt, anxiety, and sexual sadism.
It is an amazing time capsule of medical literature that has it all. Experimentation on inmates! Locking up people with addiction problems! Terrifying study design, and shockingly good outcomes. Al was the winner of this macabre contest, with 87 days of heavy drinking. Truth be told, I was pulling for Slim, or maybe Red. Because everyone got sick to some degree when they stopped drinking, the study helped cement the existence of a real and predictable alcohol withdrawal syndrome, which was still in doubt prior to this. Almost everyone was more or less back to baseline after 72 hours, despite the tremors, autonomic instability, and terrifying hallucinations. Even the few who experienced generalized convulsions were mostly back to fighting shape after 16 or so grains of phenobarbital (about ~ 1000 mg).
We’ve come so far, right? Sure, in many ways. But, why then, is it not uncommon for our consulting services to hear of hospital lengths of stay averaging 5 days and sometimes greater?
The Great Protocol Trap
Fast forward to the early 1990s. Benzodiazepines have been shown to be safe and efficacious for the treatment of alcohol withdrawal. Previous protocols called for fixed dosing schedules until the advent of the CIWA protocol.2,3 The original CIWA contained a questionnaire the size of a standard tax return form and, based on scoring, dictated an amount of benzodiazepine (generally lorazepam or chlordiazepoxide) to be given. While certainly an improvement over set dosing regimens, the CIWA scale is not without its own baggage. First, it takes into account subjective information from the patient and gives it the same weight as objective clinical data. Have a bad headache, some nausea, and restlessness? Without any objective data, this patient is potentially getting some benzos. Second, this scoring system is deployed in busy clinical environments and requires inter-rater agreement between whomever on the team is charged with calculating it. I have seen less than stellar kappa values here, to say the least – we see a ton of withdrawal, and it is a real problem. Also, I can find references supporting the deliciousness of PB&J sandwiches, the dubious wisdom in urinating upwind, or the difficulty in swimming in open ocean waters with an anchor affixed to one's neck – but I digress! Third, this protocol is often used as a set it and forget it order set in the EMR, or worse, as standing orders. Taken together, a complicated scoring system, potentially poor inter-rater reliability, and a treatment regimen on rails, this is a set up to give patients less than ideal treatment. Finally, the CIWA scale is often misused as the first line of control, rather than a standardized monitoring tool for withdrawal severity after control has been established. Even if we score things accurately and agree on the scoring, we may not know if the patient is responding correctly until it is far too late. Finally, the protocol calls for the score to be recalculated on an hourly basis. When you don’t have control in the first place this is an eternity.
I see much fear and loathing regarding the use of benzodiazepines for alcohol withdrawal out there, in the prestigious halls of Pubmed, the back alleys of the interwebs, and the educational graffiti of the Twitterverse.
Benzodiazepines Aren’t the Problem (Until They Are)
I see much fear and loathing regarding the use of benzodiazepines for alcohol withdrawal out there, in the prestigious halls of Pubmed, the back alleys of the interwebs, and the educational graffiti of the Twitterverse. Toxicologists are often labeled as pure benzophiles (or at least benzo-curious), and perhaps that’s true. The best description of our affection, often attributed to toxicologist Suzanne White, was something along the lines of us digging “the liberal AND judicious use of benzodiazepines”. One without the other is meaningless. While benzos, cute little gifts from the pharmacology gods that they are, have consistently been shown to be safe and efficacious for the treatment of withdrawal, they aren’t always the best tool for the job. As it turns out, benzos require functional alpha-subunits of the GABA-A receptor to work their magic. As cruel fate would have it, many alcoholics downregulate their GABA-A receptor alpha-subunits, which helps to increase tolerance and sets them up for the withdrawal syndrome. In these patients, we will need to go down a different path. Phenobarbital works well in the setting of down-regulation because barbiturates don’t require functional alpha subunits to work, not because of some theoretical glutamate antagonism or other dark magic. Phenobarbital acts directly on the ion channel independent of normal expression of GABA-A receptor subunits.
If we keep to a standing order / fixed protocol for benzos when they aren’t working, we get prolonged withdrawal or benzodiazepine-induced delirium.4 Longer lengths of stay. Cats and dogs sleeping together. Mass hysteria, etc. You never fully appreciate how scary benzodiazepine delirium is until you’re standing at the bedside about to push flumazenil on a patient that has been in reported withdrawal for 10 days. This is a discussion for another time but I will say, despite being armed to the teeth with a bandolier filled with benzodiazepines and phenobarbital, the fear of the patients having a seizure is real even if the risk was relatively low.
You know all those studies touting every medication under the sun for the treatment of alcohol withdrawal? Antipsychotics, central alpha-adrenergic agonists, anticonvulsants, beta-adrenergic blockers, gabapentanoids . . . the only real thing the studies benefitted was making sure patients didn’t get benzodiazepine-related delirium or controlling the peripheral effects of alcohol withdrawal.5,6 Certainly not showing the best way to treat withdrawal by just preventing one side effect from occurring. Alcohol withdrawal is a disorder of central neurotransmitter balance that can result in both central (e.g., agitation, convulsions, delirium, etc.) and peripheral (e.g., hypertension, tachycardia, diaphoresis, etc) findings. The problem with most non-sedative hypnotic methods for treating withdrawal is that they concentrate on the peripheral effects, or simply making the numbers look pretty, rather than the central mechanisms that cause them. Treat the central features and the numbers will generally follow.
Physician > Technician and Control = Resuscitation
Some advocate for the blanket treatment of all alcohol withdrawal patients with large initial doses of phenobarbital. Called “The Hammer” in this series of posts, it certainly beats under-treatment. If everyone were automatically being admitted, it maybe could be an OK idea. But, here’s a major take-home point – alcohol withdrawal is a spectrum, not a binary disorder. Patients have varying pharmacogenetics and expression of receptor subunits. Many patients can be controlled and safely discharged with relatively small doses of oral benzodiazepines. Use the right tool for the job. Don’t be a hammer. Be a scalpel. To be clear, I do not disagree with the general pharmacology theory of phenobarbital mono-therapy for alcohol withdrawal, nor do I wish to partake in the bilious pleasure of an ill-conceived reference duel here. My objection to phenobarbital lies in the fact that this treatment regimen personifies the biggest problems (and yes, I know there are countless benefits to some protocols) caused by the protocolization of medicine: oversimplification, loss of individualized care, and potential to apply the treatment to an inappropriate patient group.7
Look, I’m a huge fan of phenobarbital. It is a crucial tool in my alcohol withdrawal tool kit but it is only one of many. I don’t disagree with the use of phenobarbital for withdrawal, only with the notion that it is the perfect therapy for every patient and that it is a completely predictable and benign medication. Fellow Hound Diane Calello put it best “phenobarbital is the poster child for inducible pharmacokinetics and drug interactions.” Indeed. Open your favorite pharmacopeia app and check out the drug interactions listed for phenobarbital and you’ll see more mentions than a trending cat video on twitter.
Moving Forward and Key Points
We have a rough guideline that we use despite the fact I’m always asked for some all-encompassing protocol. Our treatment in the ED centers on evaluating why they are in withdrawal, finding and treating sequelae of chronic alcohol abuse, and controlling the withdrawal prior to admission, discharge, or transfer to inpatient detox facilities.
What is control? We use a Richmond Agitation Sedation Score (RASS) of -1 (i.e., eyes closed, resting comfortably, wakes to voice) for one hour, without needing additional medications, as the definition of control. It’s easy to use, easy to communicate, and agreement between staff is generally good.
We give initial doses of benzodiazepines. If the withdrawal is mild, I use 50-100 mg of chlordiazepoxide (Librium™) every hour, up to 3 doses.
If I need to use parenteral medications, I start with 10 mg diazepam every 5 minutes, for 3 or 4 doses (if available). Use lorazepam if diazepam is unavailable (1:5 conversion; 2mg lorazepam = 10mg diazepam). I prefer diazepam because I can re-dose more rapidly and therefore gain control or at least see where things are headed more rapidly. If the patient responds to this initial benzodiazepine effort, I can give more, and dial everything in to get control. If they are getting worse or not responding after these initial efforts, I switch to phenobarbital in doses of 65 mg, 130 mg, or 260 mg IV every fifteen to thirty minutes until I get control.
Control in the ED is the same as the resuscitation of anything else, sepsis for example. This is a particularly fun example because it also demonstrates how mindless protocols can be. We don’t find pneumonia and hit the admit button without thinking about antibiotics and fluids and pressors. Why would we whip out the V-V ECMO for all flu patients? Why would we slam 2 mg of lorazepam in and then hit admit in alcohol withdrawal? Why use large doses of phenobarbital for minor withdrawal that can safely be discharged from the ED? Titrate to effect and you can learn to wield your sedative hypnotics like an artist. Remember, if you don’t have control, the CIWA score is for suckers plain and simple.
Early control in the ED has been shown to reduce the length of stay and while the data is still yet to be counted, will most likely reduce my general level of agitation.8Highway by Jakub Gorajek
- 1.ISBELL H, FRASER H, WIKLER A, BELLEVILLE R, EISENMAN A. An experimental study of the etiology of rum fits and delirium tremens. Q J Stud Alcohol. 1955;16(1):1-33. https://www.ncbi.nlm.nih.gov/pubmed/14372008.
- 2.Sullivan J, Sykora K, Schneiderman J, Naranjo C, Sellers E. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict. 1989;84(11):1353-1357. https://www.ncbi.nlm.nih.gov/pubmed/2597811.
- 3.Shaw J, Kolesar G, Sellers E, Kaplan H, Sandor P. Development of optimal treatment tactics for alcohol withdrawal. I. Assessment and effectiveness of supportive care. J Clin Psychopharmacol. 1981;1(6):382-389. https://www.ncbi.nlm.nih.gov/pubmed/7334148.
- 4.Lat I, McMillian W, Taylor S, et al. The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients. Crit Care Med. 2009;37(6):1898-1905. https://www.ncbi.nlm.nih.gov/pubmed/19384221.
- 5.Keaney F, Strang J, Gossop M, et al. A double-blind randomized placebo-controlled trial of lofexidine in alcohol withdrawal: lofexidine is not a useful adjunct to chlordiazepoxide. Alcohol Alcohol. 2001;36(5):426-430. https://www.ncbi.nlm.nih.gov/pubmed/11524309.
- 6.Kaim S, Klett C, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969;125(12):1640-1646. https://www.ncbi.nlm.nih.gov/pubmed/4890289.
- 7.Chang S, Sevransky J, Martin G. Protocols in the management of critical illness. Crit Care. 2012;16(2):306. https://www.ncbi.nlm.nih.gov/pubmed/22424130.
- 8.Lee J, Duby J, Cocanour C. Effect of early and focused benzodiazepine therapy on length of stay in severe alcohol withdrawal syndrome. Clin Toxicol (Phila). 2019;57(7):624-627. https://www.ncbi.nlm.nih.gov/pubmed/30729859.