Gabapentin for Alcohol Withdrawal Syndrome

A Prospective Randomized Controlled Open Label Trial of Symptom-triggered Benzodiazepine Versus Fixed-dose Gabapentin for Alcohol Withdrawal Syndrome

The current "gold-standard" for the management of alcohol withdrawal syndrome (AWS) is symptom-triggered administration of benzodiazepines. This method of treatment has several drawbacks that have been described in the literature. Thus benzodiazepine sparing agents have been evaluated for use in AWS. One of these agents that has not only shown benefit for AWS but also benefits on complete abstinence, reducing a return to heavy drinking, and cravings is gabapentin. In clinical practice at Mayo Clinic gabapentin is used for this purpose. Due to the limited reports of the safety and efficacy of a protocol involving gabapentin for AWS, a study to compare gabapentin to symptom-triggered lorazepam will be completed.

Study Overview

• Status: Completed
• Conditions: Alcohol Withdrawal Syndrome
• Intervention / Treatment: Drug: Gabapentin; Drug: Divalproex Sodium; Drug: Benzodiazepines

Detailed Description

The current "gold-standard" for the management of alcohol withdrawal syndrome is symptom-triggered administration of benzodiazepines. Benzodiazepines and use of a symptom-triggered approach has several drawbacks such as over administration of medication due to many subjective patient reported symptoms. Benzodiazepines may contribute to a drug-induced delirium or high dosage may necessitate transfer to an ICU setting. Abrupt withdrawal of benzodiazepines also contribute to cravings, rebound insomnia, and anxiety that have been shown to increase the risk of a return drinking.

Clinical use of gabapentin for alcohol withdrawal has been presented by Maldonado at Stanford University Hospitals. (Academy of Psychosomatic Medicine Annual Meeting, 2013-2015) At Mayo Clinic, the Psychiatry Consultation-Liaison hospital service has been recommending the use of a modified gabapentin protocol since January 2015, which has been clinically accepted on medical, surgical, and psychiatric hospital services. The purpose of this research is to investigate the reactive benzodiazepine versus proactive gabapentin approaches to AWS in a prospective, randomized, open-label study.

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

1. Prediction of Alcohol Withdrawal Severity Scale (PAWSS) score >4.
2. Adults age 18 or older.
3. Sufficient understanding of English.
4. Hospitalized on Hospital Internal Medicine or Generose.

Exclusion criteria

1. Severe renal impairment (estimated CrCl < 30).
2. Intensive Care Unit (ICU) level of care.
3. Not responsive due to alcohol intoxication or withdrawal.
4. Already taking gabapentin more than 300 mg three times a day.
5. Prescribed pregabalin.
6. Primary seizure disorder.
7. Acute benzodiazepine withdrawal.
8. Concurrent substance use disorders (such as opioid use disorder, stimulant use disorder) if the disorder is assessed to be clinically significant. Cannabis use disorder will be allowed.
9. Concurrent anticonvulsant medications for psychiatric indications (e.g. bipolar disorder) will be allowed.
10. Pregnancy.
11. Involuntary legal status (e.g., on court commitment).
12. Patients admitted greater than 12 hours prior to potential enrollment.
13. Patients receiving therapeutic dose of gabapentin (rather than continuation of home dose) prior to enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gabapentin; Patients will receive gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Will still undergo CIWA-Ar scoring but will not be administered a benzodiazepine.	Drug: Gabapentin; Gabapentin administered as a taper; Other Names: Neurontin; Drug: Divalproex Sodium; Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history); Other Names: Depakote
Active Comparator: Benzodiazepine; Patients will receive a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale.	Drug: Benzodiazepines; Benzodiazepines administered using a symptoms triggered protocol; Other Names: lorazepam; chlordiazepoxide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Length of Hospital Stay	The length of hospital stay for Alcohol withdrawal syndrome. The time interval between admission and either discharge or the time at which Clinical Institute Withdrawal Assessment - Alcohol revised (CIWA-Ar) scores are <10 for 36 hours (up to 240 hours). Measured in hours. CIWA-Ar measures severity of 10 observed or measured alcohol withdrawal signs or symptoms. Zero to 7 points are assigned to each item, except for the last item, which is assigned 0-4 points, with a total possible score of 67. Total score ranges from 0 (best possible outcome)-67 (worst possible outcome). Lower scores (0-8) represent fewer withdrawal symptoms and less severity, scores > 8 represent more withdrawal symptoms and greater severity	Time to discharge or time to CIWA-Ar score < 10 for 36 hours (whichever came first) up to 240 hrs.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Delirium Tremens (DT)	The number of participants experiencing delirium tremens during their hospitalization (between admission and discharge).	During hospitalization (up to 240 hours)
Maximun Alcohol Withdrawal Severity Per CIWA-Ar Scale	CIWA-Ar measures severity of 10 observed or measured alcohol withdrawal signs or symptoms. Zero to 7 points are assigned to each item, except for the last item, which is assigned 0-4 points, with a total possible score of 67. Total score ranges from 0 (best possible outcome)-67 (worst possible outcome). Lower scores (0-8) represent fewer withdrawal symptoms and less severity, scores > 8 represent more withdrawal symptoms and greater severity	4 days
Change in Sleepiness as Assessed by the Epworth Sleepiness Scale	The ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. Most people engage in those activities at least occasionally, although not necessarily every day. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person's average sleep propensity in daily life (ASP), or their daytime sleepiness.	Baseline and 2 days
Mean Total Benzodiazepine Use	The total amount of benzodiazepines administered. Measured by lorazepam equivalent, mg.	Time to discharge or time to CIWA-Ar score < 10 for 36 hours (whichever came first) up to 240 hrs.
Number of Participants Experiencing Seizure	The number of subjects who developed seizure during their hospitalization.	During hospitalization (up to 240 hours).
Change in Cravings as Assessed by the Penn Alcohol Craving (PACS) Scale	PACS is a 5 item self-rated scale of alcohol craving (0 = none to 6 = strong urge). Total scores range from 0 (little craving for alcohol) to 30 (irresistible urge to drink alcohol)	Baseline and 2 days
Change in Anxiety Symptoms as Measured by the Generalized Anxiety Disorder-7 (GAD-7) Scale	GAD-7 is GAD-7 is a 7-item self-administered scale of Generalized Anxiety Disorder symptoms (0 = not at all to 3 = nearly every day). Total scores range from 0 to 21. Total scores of 0-4 = minimal anxiety, Total scores of 5-9 = mild anxiety, total scores of 10-14 = moderate anxiety and total scores of 15-21 = severe anxiety.	Baseline and 2 days

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Ruth E Bates, MD, Mayo Clinic

Publications and helpful links

General Publications

• Furieri FA, Nakamura-Palacios EM. Gabapentin reduces alcohol consumption and craving: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007 Nov;68(11):1691-700. doi: 10.4088/jcp.v68n1108.
• Leung JG, Hall-Flavin D, Nelson S, Schmidt KA, Schak KM. The role of gabapentin in the management of alcohol withdrawal and dependence. Ann Pharmacother. 2015 Aug;49(8):897-906. doi: 10.1177/1060028015585849. Epub 2015 May 12.
• Maldonado JR, Sher Y, Das S, Hills-Evans K, Frenklach A, Lolak S, Talley R, Neri E. Prospective Validation Study of the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) in Medically Ill Inpatients: A New Scale for the Prediction of Complicated Alcohol Withdrawal Syndrome. Alcohol Alcohol. 2015 Sep;50(5):509-18. doi: 10.1093/alcalc/agv043. Epub 2015 May 21.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2017
• Primary Completion (Actual): March 1, 2021
• Study Completion (Actual): March 1, 2021

Study Registration Dates

• First Submitted: December 27, 2016
• First Submitted That Met QC Criteria: January 4, 2017
• First Posted (Estimate): January 6, 2017

Study Record Updates

• Last Update Posted (Actual): March 24, 2022
• Last Update Submitted That Met QC Criteria: March 1, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: gabapentin; benzodiazepine; Alcohol Withdrawal Syndrome; symptom-triggered
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Substance-Related Disorders; Disease; Syndrome; Substance Withdrawal Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Antiemetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Antimanic Agents; Gabapentin; Valproic Acid; Lorazepam; Chlordiazepoxide
• Other Study ID Numbers: 16-008712

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No