[PLEASE NOTE: For the most complete & updated material on alcohol withdrawal, please see the Internet Book of Critical Care Chapter on this topic here]
Case example
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A middle-aged man was admitted to the ICU for refractory alcohol withdrawal. Prior to arriving in the ICU he had been treated aggressively with an escalating regimen of IV diazepam, without any improvement. Upon arrival in the ICU he had impressive tremors but was not delirious.
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He was given an initial dose of 260 mg IV phenobarbital followed by 130 mg IV Q30 minutes as needed. With each dose, his symptoms improved incrementally. After receiving about 1200 mg of phenobarbital his symptoms resolved, leaving him awake and calm. He was observed for a day prior to transfer out of the ICU, but required no additional treatment.
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Introduction
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Benzodiazepines have traditionally been the mainstay of treatment for alcohol withdrawal. This dates back to a RCT in 1969 which compared a benzodiazepine (chlordiazepoxide), antipsychotics, antihistamines, and thiamine. Unfortunately, there has never been an adequate RCT comparing a benzodiazepine versus barbiturate.
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Recently there has been increasing recognition that phenobarbital has advantages compared to benzodiazepines. Phenobarbital has been shown to be beneficial both for initial up-front loading, and also for patients with symptoms refractory to benzodiazepines. As explored in a prior post, this led to a treatment strategy which started and ended with phenobarbital:
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Over time, emerging evidence and clinical experience has led us to doubt whether benzodiazepines offered an advantage compared to phenobarbital monotherapy:
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Advantages of phenobarbital monotherapy
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Neuroscience: Phenobarbital is theoretically superior to benzodiazepines
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Alcohol suppresses the brain via multiple mechanisms, including enhancement of inhibitory GABA receptors and suppression of excitatory glutaminergic receptors. The brain adapts to chronic alcoholism by down-regulatinginhibitory GABA receptors and up-regulatingexcitatory glutaminergic receptors (Rao 2015). Such adaptation allows alcoholics to survive with blood alcohol levels which would kill most people. Unfortunately, this also causes withdrawal: both down-regulation of inhibitory GABA receptors and up-regulation of excitatory glutamate receptors excites the brain.
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Benzodiazepines stimulate inhibitory GABA receptors, which may improve alcohol withdrawal. However, low GABA activity is only part of the problem. In contrast, barbiturates have dual activity, simultaneously enhancing GABA activity and suppressing glutaminergic activity. This dual mechanism of action is well matched to the pathophysiology of alcohol withdrawal, making barbiturates theoretically superior to benzodiazepines.
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Clinical experience: Barbiturates are more powerful than benzodiazepines
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Synergistic activity on two of the most important neurotransmitter systems makes barbiturates more powerful than benzodiazepines. This power is observed in other neurologic disorders as well (e.g. seizures are often refractory to benzodiazepines, but rarely refractory to barbiturates). Barbiturates are the hammer of neurotherapeutics: there is no positive symptom which will not respond to a barbiturate. Regarding alcohol withdrawal, it is widely recognized that a subset of patients with severe withdrawal will fail to respond to benzodiazepines, yet will subsequently respond to phenobarbital (as in the case above; Hack 2006).
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Less delirium & paradoxical reactions?
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Benzodiazepines are notorious for causing delirium. For example, one study of intubated ICU patients found that nearly all patients who received >20 mg of lorazepam developed delirium (Pandharipande 2006). Less commonly, lower doses of benzodiazepine elicit agitated delirium, known as a paradoxical reaction. As discussed last week, paradoxical reactions are more common in alcoholism, with a rate of ~2% in this population (Tae 2014). Is it possible that benzodiazepine-induced delirium and paradoxical reactions complicate the treatment of alcohol withdrawal without our being aware of these reactions?
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Moore 2014 reported a retrospective case series describing the use of flumazenil to evaluate for benzodiazepine-induced delirium in patients undergoing alcohol withdrawal. Their general practice was to suspect benzodiazepine-induced delirium and trial flumazenil among patients with persistent confusion whose withdrawal seemed to have resolved (e.g. normal vital signs, no hyperreflexia). Among 74 patients in whom a response to flumazenil was recorded, 84% improved while only two patients experienced increased anxiety. This study suggests that much of the prolonged delirium observed in patients undergoing alcohol withdrawal may actually be benzodiazepine-induced delirium rather than alcohol withdrawal itself:
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Unlike benzodiazepines, phenobarbital doesn't cause paradoxical reactions (Ives 1991). This may reflect phenobarbital's more balanced inhibitory effect on the brain via two neurotransmitters, which protects against disinhibition.
Unlike benzodiazepines, phenobarbital doesn't cause paradoxical reactions (Ives 1991). This may reflect phenobarbital's more balanced inhibitory effect on the brain via two neurotransmitters, which protects against disinhibition.
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Simplified pharmacology: Choose one GABAergic medication
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Benzodiazepines and barbiturates act synergistically on the GABA receptors (benzodiazepines increase the frequency of channel opening, whereas barbiturates increase the duration of channel opening). In some situations, this may cause patients to be unexpectedly sensitive to these medications. For example, a patient loaded with 2,000 mg of phenobarbital might be at risk from over-sedation if treated with a usual dose of benzodiazepine.
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The clinical effect of phenobarbital alone is more predictable. As discussed previously, phenobarbital administration elicits very predictable serum level of drug (figure below). In the absence of confounding factors (e.g., benzodiazepines, other neurologic problems), the safe level of phenobarbital is well established. This dose-response relationship may be helpful when considering safe drug doses and monitoring patient response to therapy. Removing benzodiazepines from the picture simplifies this pharmacology and allows these relationships to be used more reliably.
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| Relationship between cumulative phenobarbital dose and plasma phenobarbital concentration among patients treated for alcohol withdrawal (Tangmose 2010). We have added green lines indicating the plasma therapeutic range for phenobarbital (64-172 micromol/L = 15-40 ug/ml), an orange line indicating the level at which mild signs of toxicity are usually noted such as ataxia and nystagmus (225 micromol/L = 50 ug/ml), and a red line indicating the lowest level which has been associated with stupor or coma (>280 micromol/L = 65 ug/ml)(Lee 2013). |
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Seizure prophylaxis
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Seizure is one of the most dangerous complications of alcohol withdrawal. Among the agents used to treat alcohol withdrawal, barbiturates probably have the greatest anti-epileptic activity. Combining this efficacy with the long duration of phenobarbital may provide patients with excellent seizure prophylaxis.
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There is little evidence regarding the relative efficacy of benzodiazepines versus barbiturates for alcohol withdrawal seizure. One report found that the addition of primidone (a phenobarbital precursor) to chlordiazepoxide reduced the seizure rate (table below; Smith, 1976). This suggests that in alcohol withdrawal, as with other causes of seizure, barbiturates offer anti-epileptic activity above and beyond that of a long-acting benzodiazepine.
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Improved pharmacokinetics with intravenous phenobarbital?
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Historically, phenobarbital has often been given orally for the management of alcohol withdrawal. When administered orally, the time of onset is less reliable compared to intravenous administration. Thus, oral administration could increase the risk of administering several doses before the first doses are fully absorbed (“dose stacking”), with eventual overdose.
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Theoretically, intravenous phenobarbital should allow greater control over pharmacokinetics, with avoidance of dose stacking and improved safety. It is unclear how much added benefit intravenous administration provides compared to oral phenobarbital. For critically ill patients, the intravenous route is typically used to err on the side of safety. However, for less ill patients without gastrointestinal problems, slower administration of oral phenobarbital has been demonstrated to be safe (Tangmose 2010).
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Evidence regarding phenobarbital monotherapy
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In Denmark barbital, a long-acting barbiturate, has been the drug of choice in the treatment of DT for many years. It was introduced in the beginning of this century (Moller 1909). In following discussions the importance of repeated, often large doses, (that is, 0.5-1 gram), in the initial stage of the disorder was stressed. The aim of the treatment was to sedate the patient to such a degree that he fell asleep and then slept for several hours. After this “critical sleep” the symptoms often disappeared completely. The treatment as outlined in the first reports was found so favorable that barbital has been preferred by Danish psychiatrists for several decades – Kramp 1978
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Although barbiturate monotherapy is currently perceived as a new idea, it is actually a very old idea. In Denmark, barbiturate monotherapy was used for over a century with considerable success. In the United States, a survey of inpatient alcohol treatment programs performed in 1992 estimated that 11% of all patients received barbiturates (Saitz 1995). Unfortunately this practice largely pre-dated evidence-based medicine. Available studies are as follows:
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Kramp 1978 This is the only available prospective RCT that compares barbiturate to benzodiazepine for patients with severe alcohol withdrawal. 91 patients were randomized to receive intramuscular diazepam vs. oral barbital (an early long-acting barbiturate). To preserve blinding of physicians and patients, all patients were treated simultaneously with intramuscular injections and oral medication, one of which was a placebo. Although this study has substantial methodological flaws, barbiturate was found to be superior among the patients with the most severe withdrawal symptoms (table below). Three patients in the diazepam group were initially refractory to therapy, leading clinicians to un-blind themselves. Overall these results are consistent with our current recognition that a subset of patients with severe withdrawal will be refractory to benzodiazepines.
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Ives 1991 These authors describe a protocol involving a loading dose of 15 mg/kg phenobarbital followed by a fixed taper over a week. For breakthrough agitation, patients were allowed to receive low doses of lorazepam. Although little data is provided, they reported that this protocol was used successfully in over seventy patients at the University of North Carolina at Chapel Hill from 1982-1990. We are aware of success utilizing a similar protocol more recently at some hospitals in the Northeast USA.
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Michaelsen 2010 This is a retrospective cohort study comparing outcomes from the treatment of delirium tremens at two hospitals in Denmark between 1998-2006. During this period one hospital (Rigshospitalet) used oral phenobarbital, whereas the other hospital (Bispebjerg) transitioned from oral phenobarbital to intravenous diazepam in 2002. There was no difference between diazepam and phenobarbital in terms of length of delirium tremens, mortality, or pneumonia (table below). A sub-population (9%) in the diazepam group failed treatment and required phenobarbital.
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Transition to diazepam correlated with an increase in the rate of delirium associated with alcohol withdrawal at Bispebjerg (53 cases from 1998-2002 vs. 88 cases from 2002-2006). Perhaps this reflects some patients who developed benzodiazepine-induced delirium.
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Hendey 2011 This is a RCT comparing phenobarbital vs. lorazepam for patients presenting to the emergency department with mild to moderate alcohol withdrawal. 44 patients were randomized to treatment with lorazepam or phenobarbital (260 mg IV followed by 130 mg IV PRN), with the majority subsequently discharged home. The two treatments were equivalent, although the study was underpowered.
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Phenobarbital monotherapy: Nuts and bolts
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Phenobarbital monotherapy is extremely simple, as it amounts to a dose-titration using a single medication. Phenobarbital has a half-life of about three days, so successive doses will accumulate in an additive fashion. The main requirement for using phenobarbital is patience, because it may take some time to reach an effective level. However, this time investment is worth it, because once a therapeutic level is reached, little additional therapy may be needed (the phenobarbital will gradually auto-titrate off, providing therapy for days).
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The main decision which needs to be made is whether the patient qualifies for an initial loading dose of 10 mg/kg ideal body weight (1). For most patients who are initially presenting with alcohol withdrawal, 10 mg/kg of phenobarbital may be given safely (discussed previously here). This dose will produce a serum level of phenobarbital around 15 ug/ml, which by itself isn't nearly enough to cause respiratory suppression. Indeed, Ives 1991 used a 15 mg/kg loading dose divided over three doses. However, if the patient has other active neurologic issues or has received a significant amount of sedating medication (especially benzodiazepine), there is a possibility that this dose could cause excessive sedation. When in doubt, it is safer (albeit slower) to omit the loading dose and simply use an incremental IV phenobarbital titration:
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As discussed above, we prefer to use intravenous phenobarbital initially until there is resolution of symptoms (which will typically occur in the emergency department or intensive care unit). Following improvement and transfer out of these locations, patients may be located in a psychiatric or medical ward, which is unfamiliar with the use of intravenous phenobarbital. In this situation, oral or intramuscular phenobarbital may be used for mild or moderate withdrawal symptoms (Tangmose 2010).
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Phenobarbital and benzodiazepines act synergistically on the GABA receptors. Therefore, after receiving a large cumulative dose of phenobarbital (>>10 mg/kg), patients may be at increased risk of over-sedation if they receive benzodiazepines. This should be communicated to providers who will be caring for these patients after leaving the ICU or ED. Ideally, patients who have been stabilized using a large dose of phenobarbital should continue with a phenobarbital monotherapy strategy.
- Although benzodiazepines are regarded as the mainstay of treatment for alcohol withdrawal, there has never been an adequately powered RCT comparing benzodiazepines vs. phenobarbital.
- Benzodiazepines occasionally fail to control alcohol withdrawal, and may promote agitated delirium. In contrast, phenobarbital is more effective and doesn't cause paradoxical agitation.
- Some countries have extensive experience treating alcohol withdrawal with phenobarbital monotherapy. Available evidence supports the safety and efficacy of this approach.
- Phenobarbital monotherapy consists of a gradual dose titration as shown below. Once a therapeutic phenobarbital level is reached, this will gradually auto-taper and provide ongoing protection from seizures or recurrent withdrawal.
[PLEASE NOTE: For the most complete & updated material on alcohol withdrawal, please see the Internet Book of Critical Care Chapter on this topic here]
Coauthored with Dr. Ryan Clouser, neurointensivist colleague and drinking buddy.
Related posts: Delerium Tremens part I – Posted last year, this covers some background about alcohol withdrawal. Our current approach has changed from the algorithm described in that post, but the general rationale and pharmacology is the same.
Notes
(1) We use ideal body weight based as previously described in alcohol withdrawal (e.g. Ives 1991). Since phenobarbital is water-soluble, dosing based on actual weight in the setting of morbid obesity could lead to excessive doses.
Image credits: https://en.wikipedia.org/wiki/Shaolin_Kung_Fu#/media/File:Shi_DeRu_and_Shi_DeYang.jpg
Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.
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A major difference between benzodiazepines and barbiturates is the greater safety profile and wide therapeutic window of the former. The move to benzodiazepines in the 60s as common sedative saw a significant mortality reduction in inadvertent or intentional overdoses. Many withdrawals are managed in low-resourced settings and there is a valid concern of inappropriate dosing, lack of monitoring, toxicity and adverse events. 10m/kg as a single dose might not be much but I would be concerned about repeated dosing on a general medical ward particularly if co-ingestions are involved. In a high acuity setting it probably doesn’t matter as much… Read more »
As toxicologists say, the dose makes the toxin. An unwise dosing scheme with any drug can be dangerous. In my experience phenobarbital has a much higher margin of safety than is generally thought in the context of alcohol withdrawal. I think the real problems start to arise when either of these drugs are used for the wrong diagnosis. For example, an alcoholic with meningitis gets treated with phenobarbital with a working diagnosis of “delirium tremens.” As long as the patient truly has isolated alcohol withdrawal, I think a rational (ideally protocoled) approach with phenobarb is likely to be safe and… Read more »
I was treated years ago with both valium (benzo) and phenobarbital. It was a smooth 4 day process. Combined they worked well. I wanted to re assure myself now that I’m dealing with a similar patient. Seems like both work well with a proper weaning process as well as a vitamin B boost (especially thiamine to replace lost nutrients and help with nuerotoxicity) Thanks for the posts.
Dr Rob
I believe this sentence is written backwards, at least it is written in the opposite way on the initial DT post – (benzodiazepines increase the duration of channel opening, whereas barbiturates increase the frequency of channel opening). –> barb = duration, and benzo = freqency
I think the toxicity/ceiling on Barbituates can be explained by it causing opening of GABA without the need for actual neurotransmitter.
Thanks, you’re right. I’ve corrected the text. Peer review in action.
George Hughes is correct Barbs = Duration and Benzos = frequency of channel openings.
Yes, again, thanks. Have corrected the text.
Hello! Thank you for an interesting post
Is it possible to use thiopental instead of phenobarbital (due to its inaccessibility)?
I don’t think thiopental would be very useful because it has a fairly short half-life. Interestingly, this is the opposite of my situation in the US (we don’t have thiopental here, but we do have phenobarbital). You could potentially consider pentobarbital, which has a decently long half-life (but not as long as phenobarbital). You really want a barbiturate with a very long half-life, which facilitates dose-titration in an additive fashion and auto-tapering. The other agent that might be considered is primidone, which is metabolized into phenobarbital. This has historically been used at times for alcohol withdrawal. However, this wouldn’t be… Read more »
I’ve had excellent success with 2400-3200mg of gabapentin PO or via OG in the first 24 hours with a fixed taper of 400mg/day. Gabapentin has more RCTs than phenobarb, and even beats phenobarb in an RCT. I wish gabapentin came in IV form.
Is there evidence for gabapentin for ICU-level alcohol withdrawal?
Not jet, just because gabapentin has no clinical studies in critical care. But it should. It changes the actual brain structure in great way, slowly but surely. Even has some effect of lowering BP. If used with benzodiazepines it would be very effective. Some people don’t respond to benzodiazepines for some really strange reason, but other people totally resistant to barbiturates. I believe that both slow double infusion is the best treatment together with oral gabapentin and tons of vit b complex .
Question I received via e-mail (posted anonymously with permission of author) “Dr. Farkas, We have implemented a thus far very successful pilot program using phenobarbital rather than benzodiazepines for the initial ED “loading” medication for alcohol withdrawal. Unfortunately some of our patients feel so much better after the 10 mg/kg infusion, they refuse to go to our detox unit and we discharge them with instructions not to drink alcohol for at least 12 hours. How much risk are we exposing ourselves to in a population that often consumes half a gallon of vodka daily? We are hoping to expand this… Read more »
Henley et al 2011 was a randomized prospective trial of lorazepam vs. phenobarbital in the ED prior to discharge home (http://www.ncbi.nlm.nih.gov/pubmed/20825805). Patients in the lorazepam group were discharged home with a chlordiazepoxide taper, whereas patients in the phenobarbital group received no additional medication after discharge. Patients in the phenobarbital group received a mean of 509 mg phenobarbital, which is a reasonable dose. This was a small study (44 patients total), but notably both groups had equivalent outcomes. So there is *some* evidence in the literature that it’s OK to give patients phenobarbital and send them home. If patients are going… Read more »
Biggest danger is the misuse of DTs..for any tremulous patient who missed their drink that morning during their overnight slumber in the ed.
Hence would be the misuse of benzodiazepines or barbiturates.
I had gotten up to 60 mg ivp with the bellevue valium DT protocol after it was almost impossible to get an iv line in a patient. Micu took the patient.
I will consider the phenobarbital bolus. Thank you for the post.
I meant the misused diagnosis of Delirium Tremens.
What if ED would not check for level of corticosteroids in blood or urine, TSH level, hormonal levels of secretive tumors? They will send you to primary care, or medical floor detox ? With malignant hypertension. Medically ill people like to drink too. As like prejudice you drunk a beer when is not asked. You are a mechanical alcoholic.
Thanks for this excellent review! You bring up some great points and I agree with you that phenobarbital may indeed be a solid choice for managing patients with alcohol withdrawal. I’m not familiar with NMDA-antagonism playing a significant role (if any role) in phenobarbital’s pharmacology. Your discussion seems to indicate this is a major reason why it would be preferred over benzodiazepines. Do you have any references for this activity?
Thanks, you’re right. Sorry I missed this earlier. I’ve corrected this in a newer version of the blog here: https://emcrit.org/pulmcrit/phenobarbital-reloaded/#comment-274039. Phenobarbital affects AMPA-type glutamate channels, not NMDA-type glutamate channels.
I guess phenobarbital is much easier and cheaper to produce. And Oh God, it is cheaper alternative. Like hydrocsizine use in Prisons and Jails to detox. The number 1 death in Jail is acute withdrawal, only later on goes suicide.
Thank you so much for such a wonderful post. I thoroughly enjoy your blog and have learned a lot about controversial topics as well as Medicine as a whole. Please continue to enlighten us with your views and in-depth analysis of such topics.
I had a question regarding using phenobarbital in patients with known cirrhosis or liver dysfunction, since most alcoholic’s do have cirrhosis. I’ve tried to use it in my hospital before but have received some push back from the pharmacist, mainly the concern of increased toxicity. Do you have any thoughts about this?
EM resident from Phoenix here. This post was awesome! It was like a stat curbside consult. This morning I had a guy in our critical care area that was in DT’s and going through a ton of Ativan. My attending suggested Phenobarb. I followed your recipe and it worked incredibly well! The patient’s nurse was annoyed with me because she wanted to bolus it in, but I wouldn’t let her. Then she was annoyed again because the guy was still going bonkers for a few minutes after the bolus. I said, “We’re going to give it 30 minutes, then we’ll… Read more »
My Q is there is phobia going around in medical World that an administration of Ativan and phenobarbital at the same time, or close enough timing will suppress respiratory system? Is is in reality true very well researched fact ?
What if to administer that kind of patient just a gram of ethanol with less Ativan, and less Phenobarbital ? Would it ease his suffering potentially? Who knows.
Phenobarbital saved my wife life she had a seizure after trying to cut back on 30 years of binge drinking. It took 4 days in ICU lot of Phenobarbital to stop the DT’s. She woke up a new person hasn’t touched a drink again she goes to AA as well took 2-3 weeks for her to recover from the ordeal.
I wanted to clarify that this bolus dose is given as a drip over 30 minutes. So 700mg for a 70kg patient over 30 minutes? Wonder if my pharmacist will get a heart attack when I order this.
yep. it’s exciting the first time you do it. then nothing happens… and folks get less excited about it. for the most up to date stuff on phenobarbital see the IBCC chapter here: https://emcrit.org/ibcc/etoh/
If the patient did well on phenobarbital. What happens next. Po or more iv.. my patient had gotten midzolam 10mg imx1.. then ativan 2mg ivp. Then ativan 4mg every 15min x3 rounds. Then phenobarbital 65mg ivp and then in 30 minutes 130mg ivp. Almost got 260mg ivp. But finally no longer climbing out of bed, no longer agitated or diaphoretic or tachycardic.. still able to breath spontaneously. Admitted to micu.. then overnight had a seizure. And was intubated and placed on propofol. Had only been given ativan around the clock. Should more phenobarbital been given po or iv? With what… Read more »
It is wrong assuming that Ativan and Phenobarbital will work in 15 or even 30 mins. It Those are misconceptions. Let this meds find there way through liver, spleen, kidneys, cross brain barrier, bind to their appropriate receptors, act on autonomous nervous system. This rapid magical change in a body will not accrue. I personally would give him Roger lactate Iv or NS bollus of 1 litter with magnesium pint, based on electrolytes, some BV, CMP. Give an any anticonvulsant of your professional choice. And even perhaps give him 1 gram of pure ethanol, joke. Quiet, dark personal space without… Read more »
53 year old male, dual diagnosed bipolar 1 & alcohol use disorder. He has had phenobarbital detox about 15 times over the past 2 years; while continuing on multiple prescribed medications including mood stabilizers, sleep medication, benzodiazepines. Physiologic/psychologic issues? Any specific protocols in extreme cases as such? Thank you.
Hi there. 10 year EM doctor here about to start working in a rural detox unit. On your main alcohol withdrawl page you mention pharmaceutical influence as possibly being behind the emergence of benzodiazapines in the 1960’s. I totally would believe this but I wonder if you know of any documentation or evidence to back up this claim? I only ask because I am looking to promote some of these ideas to my colleagues and having some historical context would be very helpful. Thank you!
A remarkable number of americans were using barbiturates in the 60s, i think one in 8, and the new benzodiazepines were seen as safer. Then, the nature of depression changed from a rare, melancholic condition needing ECT, to include those with depressed mood and neurotic anxiety which opened up millions of people to treatment. (in the late 1960s, the makers of amitriptiline purchased a book on depression and sent it to every primary care doctor in the US, promoting the use of antidepressants for depression with anxiety). Benzodiazepines, particularly alprazolam, was remarketed as an antidepressant, because it too consisted of… Read more »