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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Gabapentin | Experimental | 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. |
|
| Benzodiazepine | Active Comparator | Patients will receive a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Gabapentin | Drug | Gabapentin administered as a taper |
|
|
| 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. |
| 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 |
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Inclusion criteria
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Ruth E Bates, MD | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic in Rochester | Rochester | Minnesota | 55905 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18052562 | Background | 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. | |
| 25969570 | Background | 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. |
| Label | URL |
|---|---|
| Mayo Clinic Clinical Trials | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Gabapentin | 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) |
| FG001 | Benzodiazepine | Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Gabapentin | 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) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Posted | Mean | Standard Deviation | hours | Time to discharge or time to CIWA-Ar score < 10 for 36 hours (whichever came first) up to 240 hrs. |
|
Adverse events were collected during the patient's hospitalization (from admission to discharge, up to 240 hours).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Gabapentin | 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) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Allergic reaction | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Angioedema attributed to allergic reaction to gabapentin |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ruth Bates | Mayo Clinic | 507-255-8716 | Bates.Ruth@mayo.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 14, 2018 | Feb 7, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000077206 | Gabapentin |
| D001569 | Benzodiazepines |
| D008140 | Lorazepam |
| D002707 | Chlordiazepoxide |
| D014635 | Valproic Acid |
| ID | Term |
|---|---|
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D005680 | gamma-Aminobutyric Acid |
| D000613 | Aminobutyrates |
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| Benzodiazepines | Drug | Benzodiazepines administered using a symptoms triggered protocol |
|
|
| Divalproex Sodium | Drug | Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history) |
|
|
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 |
| 25999438 | Background | 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. |
| 37469099 | Derived | DeFoster RE, Morgan RJ 3rd, Leung JG, Schenzel H, Vijapura P, Kashiwagi DT, Fischer KM, Philbrick KL, Kung S. Use of Gabapentin for Alcohol Withdrawal Syndrome in the Hospital Setting: A Randomized Open-Label Controlled Trial. Subst Use Misuse. 2023;58(13):1643-1650. doi: 10.1080/10826084.2023.2236223. Epub 2023 Jul 19. |
| Adverse Event |
|
| BG001 | Benzodiazepine | Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Benzodiazepine | Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol |
|
|
| Secondary | Number of Participants With Delirium Tremens (DT) | The number of participants experiencing delirium tremens during their hospitalization (between admission and discharge). | Posted | Count of Participants | Participants | During hospitalization (up to 240 hours) |
|
|
|
| Secondary | 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 | Posted | Mean | Standard Deviation | score on a scale | 4 days |
|
|
|
| Secondary | 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. | Those patients who completed baseline questionnaire and follow-up questionnaire 48 hours later | Posted | Mean | Standard Deviation | score on a scale | Baseline and 2 days |
|
|
|
| Secondary | Mean Total Benzodiazepine Use | The total amount of benzodiazepines administered. Measured by lorazepam equivalent, mg. | Posted | Mean | Standard Deviation | milligrams | Time to discharge or time to CIWA-Ar score < 10 for 36 hours (whichever came first) up to 240 hrs. |
|
|
|
| Secondary | Number of Participants Experiencing Seizure | The number of subjects who developed seizure during their hospitalization. | Posted | Count of Participants | Participants | During hospitalization (up to 240 hours). |
|
|
|
| Secondary | 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) | Those patients who completed baseline questionnaire and follow-up questionnaire 48 hours later | Posted | Mean | Standard Deviation | score on a scale | Baseline and 2 days |
|
|
|
| Secondary | 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. | Those patients who completed baseline questionnaire and follow-up questionnaire 48 hours later | Posted | Mean | Standard Deviation | score on a scale | Baseline and 2 days |
|
|
|
| 0 |
| 46 |
| 1 |
| 46 |
| 0 |
| 46 |
| EG001 | Benzodiazepine | Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale. Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol | 0 | 42 | 0 | 42 | 0 | 42 |
|
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| D002087 |
| Butyrates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D003509 | Cyclohexanecarboxylic Acids |
| D000146 | Acids, Carbocyclic |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D001570 | Benzodiazepinones |
| D010421 | Pentanoic Acids |
| D014631 | Valerates |
| D005232 | Fatty Acids, Volatile |
| D005227 | Fatty Acids |
| D008055 | Lipids |