Gabapentin for Alcohol Withdrawal Syndrome

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT03012815
• Collaborator: (none)
• Enrollment: 88
• Location: 1
• Arms: 2
• Actual Duration (Months): 48.9
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Alcohol Withdrawal Syndrome	Drug: Gabapentin; Drug: Benzodiazepines; Drug: Divalproex Sodium	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 88 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective Randomized Controlled Open Label Trial of Symptom-triggered Benzodiazepine Versus Fixed-dose Gabapentin for Alcohol Withdrawal Syndrome
• Actual Study Start Date: Feb 1, 2017
• Actual Primary Completion Date: Mar 1, 2021
• Actual Study Completion Date: Mar 1, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Mean Length of Hospital Stay [Time to discharge or time to CIWA-Ar score < 10 for 36 hours (whichever came first) up to 240 hrs.]

   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

Secondary Outcome Measures

1. Number of Participants With Delirium Tremens (DT) [During hospitalization (up to 240 hours)]

   The number of participants experiencing delirium tremens during their hospitalization (between admission and discharge).

2. Maximun Alcohol Withdrawal Severity Per CIWA-Ar Scale [4 days]

   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

3. Change in Sleepiness as Assessed by the Epworth Sleepiness Scale [Baseline and 2 days]

   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.

4. Mean Total Benzodiazepine Use [Time to discharge or time to CIWA-Ar score < 10 for 36 hours (whichever came first) up to 240 hrs.]

   The total amount of benzodiazepines administered. Measured by lorazepam equivalent, mg.

5. Number of Participants Experiencing Seizure [During hospitalization (up to 240 hours).]

   The number of subjects who developed seizure during their hospitalization.

6. Change in Cravings as Assessed by the Penn Alcohol Craving (PACS) Scale [Baseline and 2 days]

   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)

7. Change in Anxiety Symptoms as Measured by the Generalized Anxiety Disorder-7 (GAD-7) Scale [Baseline and 2 days]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 14, 2018

More Information

Additional Information:

• Mayo Clinic Clinical Trials

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.
• 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. Review.
• 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.

• Responsible Party: Ruth E Bates, MD, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03012815
• Other Study ID Numbers: 16-008712
• First Posted: Jan 6, 2017
• Last Update Posted: Mar 24, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ruth E Bates, MD, Mayo Clinic: gabapentin; Alcohol Withdrawal Syndrome; benzodiazepine; symptom-triggered
• Additional relevant MeSH terms: Syndrome; Substance Withdrawal Syndrome; Chlordiazepoxide; Gabapentin; Lorazepam; Valproic Acid

Study Results

Participant Flow

Arm/Group Title	Gabapentin	Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
Period Title: Overall Study
STARTED	46	42
COMPLETED	41	40
NOT COMPLETED	5	2

Baseline Characteristics

Arm/Group Title	Gabapentin	Benzodiazepine	Total
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol	Total of all reporting groups
Overall Participants	46	42	88
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.4 (13.51)	46.7 (11.88)	47.6 (12.72)
Sex: Female, Male (Count of Participants)
Female	14 30.4%	9 21.4%	23 26.1%
Male	32 69.6%	33 78.6%	65 73.9%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	46 100%	42 100%	88 100%

Outcome Measures

1. Primary Outcome

Title	Mean Length of Hospital Stay
Description	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 Frame	Time to discharge or time to CIWA-Ar score < 10 for 36 hours (whichever came first) up to 240 hrs.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gabapentin	Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
Measure Participants	46	42
Mean (Standard Deviation) [hours]	44.91 (12.17)	50.50 (25.07)

2. Secondary Outcome

Title	Number of Participants With Delirium Tremens (DT)
Description	The number of participants experiencing delirium tremens during their hospitalization (between admission and discharge).
Time Frame	During hospitalization (up to 240 hours)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gabapentin	Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
Measure Participants	46	42
Count of Participants [Participants]	0 0%	0 0%

3. Secondary Outcome

Title	Maximun Alcohol Withdrawal Severity Per CIWA-Ar Scale
Description	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 Frame	4 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gabapentin	Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
Measure Participants	46	42
Mean (Standard Deviation) [score on a scale]	13.15 (5.70)	12.81 (6.94)

4. Secondary Outcome

Title	Change in Sleepiness as Assessed by the Epworth Sleepiness Scale
Description	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.
Time Frame	Baseline and 2 days

Outcome Measure Data

Analysis Population Description

Those patients who completed baseline questionnaire and follow-up questionnaire 48 hours later

Arm/Group Title	Gabapentin	Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
Measure Participants	19	10
Mean (Standard Deviation) [score on a scale]	-0.03 (4.02)	0.07 (5.35)

5. Secondary Outcome

Title	Mean Total Benzodiazepine Use
Description	The total amount of benzodiazepines administered. Measured by lorazepam equivalent, mg.
Time Frame	Time to discharge or time to CIWA-Ar score < 10 for 36 hours (whichever came first) up to 240 hrs.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gabapentin	Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
Measure Participants	46	42
Mean (Standard Deviation) [milligrams]	5.2 (6.8)	10.8 (14.9)

6. Secondary Outcome

Title	Number of Participants Experiencing Seizure
Description	The number of subjects who developed seizure during their hospitalization.
Time Frame	During hospitalization (up to 240 hours).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gabapentin	Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
Measure Participants	46	42
Count of Participants [Participants]	0 0%	0 0%

7. Secondary Outcome

Title	Change in Cravings as Assessed by the Penn Alcohol Craving (PACS) Scale
Description	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)
Time Frame	Baseline and 2 days

Outcome Measure Data

Analysis Population Description

Those patients who completed baseline questionnaire and follow-up questionnaire 48 hours later

Arm/Group Title	Gabapentin	Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
Measure Participants	19	10
Mean (Standard Deviation) [score on a scale]	-8.12 (9.15)	-8.45 (7.89)

8. Secondary Outcome

Title	Change in Anxiety Symptoms as Measured by the Generalized Anxiety Disorder-7 (GAD-7) Scale
Description	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.
Time Frame	Baseline and 2 days

Outcome Measure Data

Analysis Population Description

Those patients who completed baseline questionnaire and follow-up questionnaire 48 hours later

Arm/Group Title	Gabapentin	Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)	Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
Measure Participants	19	10
Mean (Standard Deviation) [score on a scale]	-0.07 (4.80)	-3.79 (6.08)

Adverse Events

Time Frame	Adverse events were collected during the patient's hospitalization (from admission to discharge, up to 240 hours).
Arm/Group Title	Gabapentin		Benzodiazepine
Arm/Group Description	Patients received gabapentin taper over 9 days with the option to add divalproex for patients who have a history of seizures or severe withdrawal. Still underwent CIWA-Ar scoring but did not receive a benzodiazepine. Gabapentin: Gabapentin administered as a taper Divalproex Sodium: Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)		Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol
All Cause Mortality
	Gabapentin		Benzodiazepine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		0/42 (0%)
Serious Adverse Events
	Gabapentin		Benzodiazepine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/46 (2.2%)		0/42 (0%)
Skin and subcutaneous tissue disorders
Allergic reaction	1/46 (2.2%)	1	0/42 (0%)	0
Other (Not Including Serious) Adverse Events
	Gabapentin		Benzodiazepine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		0/42 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.