Phenobarbital for Benzodiazepine Withdrawal

Some rehab centers use phenobarbital to manage withdrawal from Xanax, Klonopin, Valium, Ativan, and other benzodiazepines. This approach involves stopping the benzodiazepine abruptly and using phenobarbital, in diminishing doses, for a short period. However, this method can be dangerous, and the evidence supporting its effectiveness is questionable.

The safest way to discontinue a prescribed benzodiazepine for physically dependent patients is by gradually and hyperbolically tapering the dose over months or years, adjusting based on symptoms. Detoxing in a rehab center can result in severe withdrawal symptoms and benzodiazepine-induced neurological dysfunction (BIND), both of which can persist for months or even years after stopping the drug. These symptoms may include seizures, psychosis, tardive akathisia, and suicidality, with some symptoms potentially being permanent.

About Phenobarbital

Phenobarbital was developed in Germany over a century ago as part of a class of sedatives called barbiturates. It was the first barbiturate introduced to the market in 1912 by Bayer under the brand name Luminal. Other barbiturates, such as Seconal (secobarbital) and Nembutal (pentobarbital), were also released by German pharmaceutical companies.

By the time the U.S. entered World War II in 1941, Americans consumed over one billion barbiturates annually. While these drugs aided relaxation and sleep, they also caused tolerance, physical dependence, and carried a high overdose risk. Withdrawal could be severe and sometimes fatal. In 1951, Congress passed a law requiring a doctor’s approval for the purchase of barbiturates.

Barbiturates continued to be widely used as sedatives and sleep aids until the 1960s, when benzodiazepines were introduced. Today, barbiturates are less commonly prescribed for anxiety and stress, with newer treatments often preferred.

Phenobarbital is still used for its antiepileptic properties in some patients with epilepsy and, in certain facilities, for inpatient alcohol detoxification. Its antiepileptic effectiveness has been studied in only a few controlled trials. One study for alcohol withdrawal found that while phenobarbital can shorten hospital stays it does not significantly affect ICU stay length or the risk of intubation. The study also noted that other reports have shown mixed results. 

Phenobarbital and Benzodiazepine Detoxification

All abrupt benzodiazepine detox protocols, including those using phenobarbital, lack evidence and cannot guarantee good outcomes. These programs rarely follow up with their former patients, so their initial promises are likely anecdotal and primarily aimed at selling their services.

Phenobarbital is not an equivalent substitute for benzodiazepines. It does not prevent benzodiazepine withdrawal. It may prevent seizures in some patients. There is no evidence that phenobarbital use prevents or reduces the known problems associated with benzodiazepine cessation, such as protracted withdrawal and benzodiazepine-induced neurological dysfunction.

Phenobarbital is used for benzodiazepine withdrawal in two ways:

1. The initial benzodiazepine is abruptly stopped and replaced with phenobarbital for seizure prevention, which is then tapered off over a week or so.
2. The initial benzo is abruptly stopped and phenobarbital is used as a substitute. The phenobarbital is then tapered slowly.

The patient may still experience benzodiazepine withdrawal despite phenobarbital on board, putting them at risk for severe withdrawal and Benzodiazepine-Induced Neurological Dysfunction (BIND).

Addiction medicine specialists frequently justify that phenobarbital has less “abuse potential.” This ignores that the entire barbiturate drug class was replaced by benzodiazepines because benzodiazepines are safer. While both classes can produce life-threatening withdrawal, fatal accidental overdoses are more likely with barbiturates. Barbiturate doses are difficult to predict. Just a slight overdose can cause a coma, or be fatal.

It is unclear why a physician would opt for a more risky agent, like phenobarbital, when they could follow a slow stepwise crossover protocol like The Ashton Manual or those found in the Maudsley Deprescribing Guidelines, using a longer-acting benzodiazepine like diazepam, chlordiazepoxide or clorazepate dipotassium, and then just slowly taper the longer-acting benzodiazepine. 

The issue with using phenobarbital for benzodiazepine withdrawal isn’t just with the medication itself but also the accelerated tapering approach. Abrupt benzodiazepine cessation should almost never occur in the prescribed population.

Studies Used as Evidence for Phenobarbital in Benzodiazepine Withdrawal

When looking at the three studies often used to support phenobarbital for benzodiazepine withdrawal, there are four main issues:

1. Not the Target Population: The studies mostly focus on people with substance use disorders, primarily opioid use disorders. They don’t focus on people who are taking benzodiazepines as prescribed by their doctors.
2. Lack of Follow-Up Data: There is no information on outcomes beyond 30 days, and very little, if any, beyond 7 days. Some of the worst outcomes of abrupt cessation can be tardive, taking weeks or months to show up, and may last for years.
3. Unclear Physical Dependence: It’s unclear if the people in the studies were physically dependent on benzodiazepines. For unknown reasons, some patients don’t develop physical dependence even with long-term use and can stop taking benzodiazepines with little to no problems, no matter how they stop.
4. Unclear Goals: If a primary goal of stopping benzodiazepines is to prevent severe outcomes after withdrawal, such as long-lasting neurological injury, akathisia, or even death, including from suicide, the studies do not measure these outcomes.

Below are three studies frequently cited to support phenobarbital use.

Phenobarbital use in benzodiazepine and z-drug detoxification: a single-centre 15-year observational retrospective study in clinical practice.

Sartori S, Crescioli G, Brilli V, et al. Phenobarbital use in benzodiazepine and z-drug detoxification: a single-centre 15-year observational retrospective study in clinical practice. Intern Emerg Med. 2022;17(6):1631-1640. doi:10.1007/s11739-022-02976-0. Read the study here.

• Not the Target Population: The study reports that 30.14% of patients were on buprenorphine or methadone, a higher percentage than those who abused other drugs (29.01%). Are there prescribed benzodiazepine patients in this study?
• Unclear Physical Dependence: Patients reportedly took 150-970 mg of diazepam equivalent per day, which are not typical prescribed doses. Physical dependence requires regular access to benzodiazepines over time. The study does not clarify whether patients were physically dependent, undermining its relevance as a withdrawal study.
• “Supportive” Benzodiazepine Use: During treatment, long-half-life benzodiazepines were used to manage withdrawal. 42.25% of patients required one benzodiazepine, and 11.55% required two or more. At least 35% were discharged still on a benzodiazepine to be tapered later.
• Lack of Follow-Up Data: There is no information on post-discharge outcomes. Are patients well, harmed, or even alive? Did the 35% of patients discharged on a benzodiazepine ever successfully stop the medication?

Safety and effectiveness of a fixed-dose phenobarbital protocol for inpatient benzodiazepine detoxification

Kawasaki SS, Jacapraro JS, Rastegar DA. Safety and effectiveness of a fixed-dose phenobarbital protocol for inpatient benzodiazepine detoxification. J Subst Abuse Treat. 2012;43(3):331-334. doi:10.1016/j.jsat.2011.12.011. Read the study here.

• Outcome Measures: The study’s success metrics (“no seizures, falls, or injuries reported”) is inadequate for capturing the complexity of benzodiazepine withdrawal. While these are important safety outcomes, they don’t necessarily reflect overall withdrawal success.Reported readmission rates (6%) and emergency department visits (7%) within 30 days are concerning and raise questions about the intervention’s long-term efficacy and safety.
• Patient Population: 57.1% of patients were also undergoing opioid detoxification, complicating result interpretation and limiting the findings’ generalizability to those solely taking prescribed benzodiazepines. The high rate of patients leaving against medical advice (17.1%) and those requiring readmission or further treatment for withdrawal symptoms suggests some patients were harmed.
• Methadone Group: Patients on methadone were less likely to leave against medical advice (8.9% vs. 22.1%). This stability likely stems from opioid dependence rather than benzodiazepine dependence, making these results less relevant for benzodiazepine patients. The 22.1% of patients who left against medical advice and were not on methadone might have included those on prescribed benzodiazepines who did not benefit from the treatment.The study may have focused on opioid withdrawal and not included patients physically dependent on prescribed benzodiazepines. Additionally, opioids like methadone are sometimes used to treat akathisia—a serious risk of abrupt benzodiazepine cessation—which may have masked severe withdrawal symptoms.
• Severe Withdrawal Cases: The presence of ongoing hallucinations, delirium, and psychosis in some patients necessitating a switch to a diazepam taper or transfer to psychiatric services indicates phenobarbital is insufficient for all patients, particularly those with severe withdrawal symptoms. More detailed patient histories would have been valuable, but it’s clear from this study that some were harmed.

The Use of a Single Dose of Phenobarbital for Inpatient Management of Benzodiazepine Withdrawal: A Case Report

Messinger JC, Hakimi E, Vercollone L. The Use of a Single Dose of Phenobarbital for Inpatient Management of Benzodiazepine Withdrawal: A Case Report. J Addict Med. 2023;17(2):230-232. doi:10.1097/ADM.0000000000001071. Read the study here.

• Relies on a Single Patient (N=1): This is a single case report of a 61-year-old woman consuming multiple substances, along with 3-4 mg of Xanax daily. The outcomes of a single individual are insufficient to define medical standards. It would be easy to conduct another case study on a patient harmed by abrupt cessation with phenobarbital. Their outcomes would directly contradict this study’s result.
• Physical Dependence May Not Be Present:  It’s unclear in the case study whether she represents the target population of prescribed, physically dependent patients. Not all patients who consume Xanax are physically dependent on it. In other words, this patient may have withdrawn without issue regardless of the cessation method employed.
• Dangerous Approach: The report suggests that a “single loading dose” of IV phenobarbital is sufficient instead of a benzodiazepine taper. This speed of cessation contradicts modern benzodiazepine cessation guidance. Years of anecdotes gathered from prescribed benzodiazepine patients (n=many more than 1) indicate that this approach can be severely disabling and even deadly.
• Lack of Follow Up: The abstract lacks follow-up details, so we have no information on her current status (living, deceased, harmed, etc.).

These studies raise more questions than they answer about phenobarbital’s role in benzodiazepine cessation. Overall, all of the study’s methodology and reporting raise doubts about its conclusions that phenobarbital can be used safely in clinical practice, making it difficult to draw meaningful insights for prescribed benzodiazepine patients or any population. Given the risk of severe, long-lasting symptoms that may lead to disability or even death, it’s important that patients considering this approach receive accurate information to make an informed decision.

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Further Reading

Detox, Cold Turkey, Abrupt Cessation
Why Prescribed Benzo Patients Shouldn’t Go To Detox Or Rehab