In this episode, I’ll discuss the use of phenobarbital in severe alcohol withdrawal.
Severe alcohol withdrawal is a result of both the lack of GABA activity AND over stimulation of glutamate receptors. While benzodiazepines are considered the first-line treatment option, phenobarbital is used as an adjunct and, in recent years, has been studied as a potential monotherapy option. Phenobarbital, like benzodiazepines, targets gamma-aminobutyric acid (GABA) receptors and is also often claimed to have a 2nd mechanism of action applicable to alcohol withdrawal – inhibition of glutamate activity.
This discussion of phenobarbital’s effects on inhibiting glutamate activity is pervasive and extends to review articles, and expert society statements and newsletters.
However a group of authors recently published a letter to the editor in Annals of Emergency Medicine disputing whether any evidence exists to support phenobarbital having an effect on glutamate receptors at all.
These authors state that:
There is a common misconception that phenobarbital inhibits glutamate activity, which is propagated in many contemporary sources…
These authors further explain that studies using animal and human models of glutamate receptors often referenced might acutally not support an effect of phenobarbital on excitatory amino acid transmission. One 1984 study showed receptor inhibition in only 2 out of 5 excitatory amino acids and at a concentration that is nearly 6 times the upper level of what is considered therapeutic for phenobarbital. Another 2020 study showed phenobarbital receptor inhibition in only 1 out of 7 excitatory amino acid receptors studied, and this was at a concentration over 4 times the upper level of what is considered therapeutic for phenobarbital.
The editorialists further state:
As both these concentrations are far greater than concentrations ever achieved by routine phenobarbital dosing, it is unclear whether these citations should be used to support an effect of phenobarbital on excitatory amino acid transmission. The main mechanism by which phenobarbital affects alcohol withdrawal syndrome is by increasing the duration of gamma-aminobutyric acid class A channel activation…given the available experimental evidence, it does not pose a mechanistic benefit over benzodiazepines and thus should continue to be recommended as adjunctive therapy rather than monotherapy.
Members of the Hospital Pharmacy Academy have access to practical training on the treatment of severe alcohol withdrawal from a pharmacists point of view, including how to use phenobarbital for this indication. From practical training on clinical topics to support from myself and other members in the forums, the Hospital Pharmacy Academy has all you need to take your skills to the next level in one place. To get instant access go to pharmacyjoe.com/academy.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
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