Phenobarbital for Alcohol Withdrawal

Phenobarbital is a non-competitive gamma-Aminobutyric acid (GABA) agonist which is an equally effective and safe alternative to benzodiazepines (BZD) for the treatment of alcohol withdrawal syndrome (AWS). Though its use for AWS has waned and consequently many clinicians are now unfamiliar with this regimen, PB has both mechanistic and pharmacokinetic properties which make it more suitable for outpatient monotherapy than BZD.

IV/IM titrated PB is the first-line outpatient medication used for treatment of AWS at the Yukon-Kuskokwim Delta Regional Hospital. Its use is favored because substantial experience has shown that it is effective, it minimizes return visits, and it eliminates the need to dispense abuse-prone medications (i.e. BZD) to abuse-prone patients while in the midst of a substance abuse crisis. Indeed, minimizing high-risk dispensing of abuse-prone medication is important for improving the health of our community.

Evidence of Effectiveness and Safety

Systematic Review / Meta-analysis

• A 2016 systematic review by Mo et al. in the Journal of Critical Care concluded that "barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS." This review included three randomized controlled trials (RCT's) and four observational studies. While this review firmly establishes PB's similar pharmacological effectiveness compared to BZD's, only one of the included studies (an RCT by Hendey et al.) focused solely upon outpatient treatment. Though its sample size was small (25 in PB group, 19 in BZD group), Hendey et al. reported statistically nonsignificant trends toward better outcomes in the PB group.
• Other systematic reviews have only indirectly assessed the effectiveness of PB for AWS. These reviews have grouped all studies which compared any anti-convulsant to a BZD, and then concluded that anti-convulsants (as a group) are inferior to BZDs for treatment of AWS. This grouping of PB with other anti-convulsants badly biases the results against PB and does not seem justified. The mechanism of action of both PB and BZDs is non-competitive agonism of the GABA_A ion channel and both of these medication have been long known to display cross-tolerance with each other and alcohol. Conversely, the other anti-convulsants work via different mechanisms. Therefore grouping PB with the other anti-convulsants is inappropriate and seems to merely reflect how the authors think about the drugs rather than their pharmacological properties.

Studies of Outpatient Treatment

• Young et al. (1987, prospective uncontrolled study, n=62)
  

62 patients received IV PB loading dose in the emergency department. The mean loading dose was 598 mg (8.4 mg/kg) and the subsequent mean serum PB level was 13.9 mcg/mL. Four patients experience minor, self-limited adverse reactions (asymptomatic hypotension, ataxia, or lethargy) which resolved without intervention; no patients required admission.

Pharmacology

The following are the important properties of PB with regard to outpatient treatment of AWS.

Classification

Chemical Class

PB belongs to the chemical class barbiturate.

Clinical Class

1. Like all barbiturates, PB is a sedative/hypnotic. However, it is almost never used for this purpose.
2. PB is also classified as an anti-convulsant.
   

In anesthetic doses, all BBTs have an anti-convulsant effect. However, PB is the only BBT which has an anti-convulsant effect at sub-sedative doses. (Historically, two closely related derivatives [mephobarbital and metharbital] also had an anti-convulsant effect at sub-sedative doses).

Mechanism of Action

GABA agonist

The binding of GABA to its receptor inhibits nerve depolarization. Like all barbiturates, PB's sedative/hypnotic effect occurs primarily via noncompetitive agonism of the GABA_A receptor on the GABA-mediated ion channel. Like BZDs, PB/BBTs do not themselves open the channel and thus GABA is still required. PB/BBTs bind at a different site on the GABA_A receptor than BZDs.
When PB/BBTs bind to the GABA_A receptor, three effects occur:

1. Enhancement of the binding of GABA
   
2. Enhancement of the binding of BZDs
   
3. Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.
   

Both 2 and 3 indicate a potential synergistic effect when co-administered with BZDs. Studies have shown that dual therapy is superior to either PB or BZDs alone,(insert refs) indicating at least an additive effect.

Glutamate antagonist

The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype. This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.

Dosing

Intravenous

Initial: 260mg (or 4 mg/kg) slow push

Subsequent: 130mg (or 2 mg/kg) slow push every 30-45 minutes until adequate symptom relief

Intramuscular

Initial: 260mg (or 4 mg/kg)

Subsequent: 130mg (or 2 mg/kg) every 60-90 minutes until adequate symptom relief

Oral

• Oral dosing information is for hypothetical purposes only. There is no standard indication for this regimen at YKDRH, but in highly unusual circumstances this information might be useful.
• Oral PB has 95-100% bioavailability.
• Patients must never be discharge with a supply of oral PB for symptom-triggered dosing due to an extreme risk of unintended lethal overdose.
• Three uncontrolled observational studies have reported results of an orally titrated PB loading regimen for treatment of "sedative/hypnotic" withdrawal. The three studies involved a total of X patients, and they each administered PB 120mg orally each hour until the desired therapeutic affect was achieved. There were zero occurrences of adverse effects or over-sedation despite minimal monitoring (nursing contact once per hour). The average final doses were 1440mg, 1315mg, and X, respectively. The authors concluded the regimen is safe, effective, and efficient (i.e. requires minimal nursing resources).

Dosing Pearls

• Weight-based dosing should be considered for patients who are particularly under or overweight.
• Use of the shorter versus longer bounds of the dosing interval should depend upon effect. If the lower bound of the dosing interval has passed without significant effect, then PB can be safely repeated at the lower bound. Alternatively, if the shorter bound has passed and the patient seems close to adequate symptom relief, the patient should be reevaluated at the longer bound prior to considering further doses. The 30 minute interval should be safe for all patients, but the 45 minutes interval acknowledges that there may be more biological variability than that seen in studies.
• It is convenient to save two orders (i.e. one for 260mg and one for 130mg) which specify administration "over five minutes via infusion pump." This provides standardization, safety, and efficient use of nursing time.
• Patients must never be discharge with a supply of oral PB for symptom-triggered dosing due to an extreme risk of unintended lethal overdose.
• If adequate symptom relief cannot be obtained with a sub-sedative dose of PB, then the patient should be admitted for dual-treatment with a BZD. These patients warrant consideration for transfer for ICU care.

Authors

Andrew W. Swartz, MD

?