Phenobarbital for Severe Acute Alcohol Withdrawal Syndrome

• Status: Not yet recruiting
• Trial end date: 2022-11-01
• Target enrollment: 0
• Participant gender: All

Summary

Severe acute alcohol withdrawal syndrome is a potentially life-threatening condition characterized by agitation, confusion, abnormal heart rhythms and seizures. Typically, clinicians treat the symptoms of alcohol withdrawal with a class of medications known as benzodiazepines (e.g., Valium). These medications have a short duration of activity and require repeated administration, often every hour or less, to reduce the symptoms of alcohol withdrawal. Many patients suffer complications related to inadequate treatment of alcohol withdrawal (e.g., abnormal heart rhythms, aspiration, seizures) resulting in admission to an intensive care unit and prolonged hospital stay, all of which increase healthcare costs. Although alcohol withdrawal is common, especially among disadvantaged (e.g., homeless) patients, limited funding is available to advance the care of patients suffering from alcohol withdrawal. A safe and effective treatment for severe alcohol withdrawal would benefit patients and our healthcare system.

Phenobarbital is an inexpensive, commonly available medication that is typically used to treat seizures. A key advantage of phenobarbital is that its calming effect lasts for a long period of time and it can be given as a 'one-time-dose' intravenously, so that it both prevents and treats withdrawal symptoms and reduces the need for repeated benzodiazepines. Through better symptom control, phenobarbital is expected to reduce the costs and complications of alcohol withdrawal. At present, physicians rarely use phenobarbital for this purpose, and additional research is needed for this medication to become part of routine care in clinical practice.

The PHENOMANAL pilot trial will assess safety and whether clinicians can administer a single dose of phenobarbital intravenously, in addition to benzodiazepines, compared to benzodiazepines alone for treating patients with severe alcohol withdrawal. This information will inform the design of a larger clinical trial. For patients, the PHENOMANAL trial has the potential to revolutionize how patients suffering from severe alcohol withdrawal are treated. For society and the healthcare system, phenobarbital is expected to reduce the complications and costs associated with severe alcohol withdrawal.

• Phase: N/A
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: St. Michael's Hospital, Toronto; Unity Health Toronto
• Treatments: Diazepam; Ethanol; Phenobarbital

Criteria

Inclusion Criteria:

1. Alcohol withdrawal syndrome (regardless of admitting diagnosis).

2. Severe symptoms, as defined by a 'Clinical Institute for Withdrawal Assessment Adult revised' (CIWA-Ar) score of 16 or more, or delirium severe enough to prohibit assessment with the CIWA-Ar, or observed withdrawal seizures, in each case despite treatment with at least 60 mg of diazepam (or an equivalent dose of another benzodiazepine) in the previous 16 hours, regardless of route of administration..

3. Early alcohol withdrawal, broadly defined as the first 16 hours after the diagnosis of acute alcohol withdrawal has been made. The time of diagnosis will be taken to be the time of prescription of symptom-triggered benzodiazepine therapy ("CIWA protocol"), or the time of consultation to ICU/Emergency Department, Internal Medicine, or the Addictions Service (Psychiatry) for the management of alcohol withdrawal.

4. Anticipated need for hospitalization (i.e. admission to ICU, medical step-up unit, or wards).

Exclusion Criteria:

1. an alternate etiology for delirium thought to be more likely than alcohol withdrawal;

2. age <16 years;

3. pregnancy (positive assay for ßhCG). A urine assay or blood test will be performed for all women < 55 yrs;

4. current breastfeeding;

5. severe acute hepatitis (AST or ALT >500); liver failure (INR >2 not otherwise explained);

6. a presenting complaint of neurotrauma, brain mass, or intra-cranial bleed; abnormal cell count or gram stain on lumbar puncture (if performed);

7. strong clinical suspicion of recent co-ingestion of depressant drugs (e.g. opioids, toxic alcohols, gamma-hydroxy-butyrate);

8. hemodynamic instability (systolic blood pressure [SBP] < 90 mmHg);

9. history of barbiturate allergy;

10. history of porphyria;

11. history of myasthenia gravis;

12. inability to obtain IV access;

13. anticipated transfer to another centre;

14. stated intent to leave against medical advice;

15. active outpatient prescription for anti-retroviral therapy for HIV

16. active outpatient prescription for one of the following anti-epileptic drugs: valproic acid, phenytoin, carbamazepine, clobazam, lacosamide, lamotrigine, levetiracetam, topiramate, primidone, or phenobarbital.

17. active outpatient prescription for an anticoagulant medication with a significant metabolic interaction with phenobarbital (i.e. warfarin or apixaban).

18. active outpatient prescription for a monoamine oxidase inhibitor (e.g., phenelzine, selegiline, tranylcypromine, isocarboxazid)

19. renal failure, as defined by a creatinine clearance <10 mls/minute (as calculated by Cockcroft-Gault equation) and/or active receipt of renal replacement therapy (dialysis).

20. administration of IV or oral phenobarbital during the index admission prior to randomization.