Editors: Tom Jones, Master of Advanced Nursing Practice and Hannah Stephens, Independent Prescriber - Substance Misuse Services
Phenobarbital to manage severe gamma-hydroxybutyrate withdrawal: A case series.
Freeman, G., Siefried, K. J., Roberts, D. M., et al. Drug and Alcohol Review. 2023;42(1), 27-32.
This case series describes the use of phenobarbital for the management of persistent or progressive benzodiazepine-resistant gamma-hydroxybutyrate (GHB) withdrawal in an Australian hospital setting.
Thirteen cases (12 individual patients; 7 women, 5 men) with a median age of 31 (range 26-47) and median daily GHB use of 50 mL (range 30-120 mL) received a median cumulative dose of 120 mg diazepam (range 80-255 mg) before commencing phenobarbital. Twelve cases also received a median cumulative dose of 60 mg baclofen (range 0-100 mg) prior to phenobarbital. The median time from last GHB use to commencing phenobarbital was 24 hours (range 7-57 hours), and the duration of phenobarbital treatment ranged from 1 to 27 days. Eight cases received oral phenobarbital on a general hospital ward and 5 cases received intravenous treatment in an intensive care unit (ICU). Five cases received phenobarbital loading of 30 mg 1-2 hourly (maximum loading dose ranged from 60-120 mg), whilst the remaining 8 cases were prescribed phenobarbital as required. Four of the 5 cases in ICU were intubated.
In all cases an improvement in GHB withdrawal symptoms was observed after phenobarbital and there were no adverse events related to phenobarbital. This case series suggests that phenobarbital for the management of benzodiazepine-resistant GHB withdrawal can be safe and may avert the progression of delirium. The authors acknowledge the limitations inherent to a retrospective record review, and the lack of validated measures of GHB withdrawal severity. Further prospective trials are required to establish an evidence base for therapeutic approaches to managing GHB withdrawal.
Commentary:
There is a real lack of randomised controlled trials (RCTs) investigating treatment approaches for GHB withdrawal. Current clinical practice generally involves treatment with high-dose benzodiazepines (usually diazepam) and baclofen, and is typically based on guidelines informed by case series and expert opinion. Whilst benzodiazepines and baclofen are effective for managing GHB withdrawal for most people, there is a subset of patients in whom these drugs are inadequate. Although this study – a case series – is low in the hierarchy of evidence, it is encouraging to see there is another potential treatment option for those patients.
In clinical practice there are three notable limitations to effective GHB withdrawal management: 1) GHB withdrawal is not consistently recognised in a timely manner, 2) the GHB withdrawal syndrome is variable and not particularly well-defined, and 3) there are no validated withdrawal scales to measure withdrawal severity and guide treatment. Whilst GHB withdrawal typically looks like withdrawal from other GABA-ergic drugs (alcohol and benzodiazepines), there is a whole host of other subjective withdrawal symptoms that may be explained by the vast number of neurotransmitter systems GHB interacts with (GABA, glutamate, serotonin, dopamine, norepinephrine, and cholinergic). This leads to a very individualised withdrawal syndrome, where the most common autonomic and neurological symptoms (tachycardia, tremor, sweating, anxiety) are not always present. Furthermore, the presence or absence of specific symptoms does not seem to predict the withdrawal course or risk of progression to agitated delirium.
I have observed in practice the variability of the GHB withdrawal syndrome, and this variability complicates frontline staff’s ability to decide when to start treatment, which treatment to use, and the appropriate dosage and frequency for administering medication. This can lead to under-treatment, or delayed treatment, and progression to severe withdrawal. Additionally, individuals may be simultaneously experiencing concurrent withdrawal syndromes or lingering intoxication, most often from amphetamine-type stimulants, which further complicates the clinical picture. These factors make it quite difficult to predict the course of an individual’s withdrawal. In these cases, an individual’s past experience of withdrawal is probably the most reliable indicator of the likely withdrawal course.
Arguably the most important factor in successfully managing GHB withdrawal and preventing delirium is to start treatment (diazepam and baclofen) early, before acute withdrawal symptoms emerge, typically within 40 minutes to four hours after the last dose of GHB. This can be very difficult to achieve, however, when the withdrawal is unplanned (e.g. when someone arrives in the emergency department having ran out of GHB 12 hours ago). And, as this study demonstrates, even when treatment with benzodiazepines and baclofen is initiated within four hours of the last dose of GHB, delirium can still emerge. This is when medications like phenobarbital may be a useful adjunct.
It is heartening to see there were no adverse effects associated with phenobarbital in this study (noting that the number of participants is very small), but further prospective RCTs are required to determine whether or not phenobarbital truly alters the GHB withdrawal course and averts delirium progression. I suspect it may be some time before we begin using other novel treatments like pharmaceutical GHB to manage GHB withdrawal (as they do in the Netherlands), so until then we must persist with a patient-centred, polypharmacy approach, which is not without risks.
Written by Tom Jones, Master of Advanced Nursing Practice
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