Alcohol Withdrawal Syndrome
Conditions
Keywords
gabapentin, Alcohol Withdrawal Syndrome, benzodiazepine, symptom-triggered
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.
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.
Interventions
DRUGGabapentin
Gabapentin administered as a taper
DRUGBenzodiazepines
Benzodiazepines administered using a symptoms triggered protocol
DRUGDivalproex Sodium
Given in addition to gabapentin in high risk patients (i.e. seizures, TBI history, DT history)
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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. |
| 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). |
| 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) |
| 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. |
| Number of Participants Experiencing Seizure | During hospitalization (up to 240 hours). | The number of subjects who developed seizure during their hospitalization. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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) | 46 |
| Benzodiazepine Patients received a benzodiazepine if scoring greater than 9 on the CIWA-Ar scale.
Benzodiazepines: Benzodiazepines administered using a symptoms triggered protocol | 42 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 3 | 2 |
Baseline characteristics
| Characteristic | Benzodiazepine | Total | Gabapentin |
|---|---|---|---|
| Age, Continuous | 46.7 years STANDARD_DEVIATION 11.88 | 47.6 years STANDARD_DEVIATION 12.72 | 48.4 years STANDARD_DEVIATION 13.51 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 42 participants | 88 participants | 46 participants |
| Sex: Female, Male Female | 9 Participants | 23 Participants | 14 Participants |
| Sex: Female, Male Male | 33 Participants | 65 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 42 |
| other Total, other adverse events | 0 / 46 | 0 / 42 |
| serious Total, serious adverse events | 1 / 46 | 0 / 42 |
Outcome results
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
Time frame: Time to discharge or time to CIWA-Ar score < 10 for 36 hours (whichever came first) up to 240 hrs.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gabapentin | Mean Length of Hospital Stay | 44.91 hours | Standard Deviation 12.17 |
| Benzodiazepine | Mean Length of Hospital Stay | 50.50 hours | Standard Deviation 25.07 |
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.
Time frame: Baseline and 2 days
Population: Those patients who completed baseline questionnaire and follow-up questionnaire 48 hours later
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gabapentin | Change in Anxiety Symptoms as Measured by the Generalized Anxiety Disorder-7 (GAD-7) Scale | -0.07 score on a scale | Standard Deviation 4.8 |
| Benzodiazepine | Change in Anxiety Symptoms as Measured by the Generalized Anxiety Disorder-7 (GAD-7) Scale | -3.79 score on a scale | Standard Deviation 6.08 |
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)
Time frame: Baseline and 2 days
Population: Those patients who completed baseline questionnaire and follow-up questionnaire 48 hours later
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gabapentin | Change in Cravings as Assessed by the Penn Alcohol Craving (PACS) Scale | -8.12 score on a scale | Standard Deviation 9.15 |
| Benzodiazepine | Change in Cravings as Assessed by the Penn Alcohol Craving (PACS) Scale | -8.45 score on a scale | Standard Deviation 7.89 |
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.
Time frame: Baseline and 2 days
Population: Those patients who completed baseline questionnaire and follow-up questionnaire 48 hours later
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gabapentin | Change in Sleepiness as Assessed by the Epworth Sleepiness Scale | -0.03 score on a scale | Standard Deviation 4.02 |
| Benzodiazepine | Change in Sleepiness as Assessed by the Epworth Sleepiness Scale | 0.07 score on a scale | Standard Deviation 5.35 |
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
Time frame: 4 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gabapentin | Maximun Alcohol Withdrawal Severity Per CIWA-Ar Scale | 13.15 score on a scale | Standard Deviation 5.7 |
| Benzodiazepine | Maximun Alcohol Withdrawal Severity Per CIWA-Ar Scale | 12.81 score on a scale | Standard Deviation 6.94 |
Secondary
Mean Total Benzodiazepine Use
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gabapentin | Mean Total Benzodiazepine Use | 5.2 milligrams | Standard Deviation 6.8 |
| Benzodiazepine | Mean Total Benzodiazepine Use | 10.8 milligrams | Standard Deviation 14.9 |
Secondary
Number of Participants Experiencing Seizure
The number of subjects who developed seizure during their hospitalization.
Time frame: During hospitalization (up to 240 hours).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gabapentin | Number of Participants Experiencing Seizure | 0 Participants |
| Benzodiazepine | Number of Participants Experiencing Seizure | 0 Participants |
Secondary
Number of Participants With Delirium Tremens (DT)
The number of participants experiencing delirium tremens during their hospitalization (between admission and discharge).
Time frame: During hospitalization (up to 240 hours)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gabapentin | Number of Participants With Delirium Tremens (DT) | 0 Participants |
| Benzodiazepine | Number of Participants With Delirium Tremens (DT) | 0 Participants |