BACKGROUND
Alcohol use disorder is estimated to occur in about 14 million US adults with a male predominance.1 Of patients admitted with alcohol use disorder, it is estimated that about 8% of them will develop alcohol withdrawal syndrome (AWS).2 There are a variety of medications that have effectiveness in the treatment of AWS mainly through activity on the gamma-aminobutyric acid receptors. The mainstay of treatment in the United States has been through the use of benzodiazepines. There is evidence for the effectiveness of other agents including phenobarbital and antiepileptics such as carbamazepine. Other agents are used to manage aspects of the AWS including antipsychotics such as haloperidol and alpha-2 agonists, such as clonidine. Previous studies have reported that there is substantial variability in the management of AWS.3 Further, where protocols exist for the management of AWS, evidence indicates that those protocols are followed in a minority of instances.4
The purpose of this study was to assess trends in the use of medications for the treatment of inpatients with alcohol use syndrome. We were particularly interested in the use of adjunctive medications in addition to benzodiazepines and to assess whether those trends had changed over the recent past. We wished to assess whether adjunctive medications such as the antiepileptics, including carbamazepine were commonly used.
METHODS
This study used the Explorys IBM Watson Database, a health data repository that collects data from various participating health care organizations. The data is collected from electronic health records, billing systems, imaging, and laboratory systems. It is then deidentified, standardized, and normalized.5 The database is available for searches by investigators from the participating organizations. As this is deidentified data, the study was deemed by our Institutional Review Board as not meeting criteria for review under current regulations.
We searched the database universe for adult patients with a diagnosis of AWS and an inpatient encounter for the years 2016-2019. The nature of the search is such that patients without a coding diagnosis of AWS would not have been identified, such as those who were coded for related diagnoses such as psychosis, dehydration, seizures, or other comorbidities of AWS without a cooccurring diagnosis of AWS. We conducted searches for benzodiazepines as a drug class and then within that, commonly used benzodiazepines. As there are close to 100 different benzodiazepines we searched for representative agents and not a comprehensive list of each individual agent. We searched for medications with varying recommendations for use in AWS. Linear regression analysis was performed using the Excel analysis toolpak.
RESULTS
We identified 96,050 patients meeting our search criteria. This included only adults, of whom 16% were over the age of 65. Sixty-four percent of patients were between the ages of 40 and 60. Eighty-one percent of patients identified as white and 95% reported English as their primary language. Seventy-two percent of the patients were identified as male. Forty-seven percent of patients were covered by either Medicaid (30%) or Medicare (17%), while 42% had private insurance. In addition to the diagnosis of AWS, 66% of patients were diagnosed with a traumatic injury. Psychiatric diagnoses were common in this cohort of patients with a history of mood disorders reported in 59%, anxiety in 45%, suicidal thoughts in 23%, depressive disorders in 56%, and schizophrenia in 5% of patients.
The data is summarized in Table 1. There was billing for benzodiazepines in a frequency that exceeded the number of patients. This suggests that multiple agents were used as the billing codes for each agent is distinct. There was substantial use of both short and longer-acting agents. The use of lorazepam, midazolam, and diazepam decreased over the study period, while the use of temazepam and alprazolam increased. Only the change in the use of temazepam was statistically significant (P=0.02).
TABLE 1 -
Trends in the Use of Medications for
Alcohol Withdrawal Syndrome
|
n (%) |
|
2016 |
2017 |
2018 |
2019 |
Overall=96,050 |
| Patients |
21,490 |
23,390 |
24,690 |
26,480 |
0 |
| Benzodiazepines |
23,970 (112) |
26,950 (115) |
27,790 (113) |
29,470 (111) |
108,180 (113) |
| Lorazepam |
8030 (37) |
6740 (29) |
6300 (26) |
5720 (22) |
26,790 (28) |
| Midazolam |
4330 (20) |
3870 (17) |
3520 (14) |
3110 (12) |
14,830 (15) |
| Diazepam |
4680 (22) |
4100 (18) |
3420 (14) |
2770 (10) |
14,970 (16) |
| Oxazepam |
600 (3) |
60 (0) |
70 (0) |
40 (0) |
770 (1) |
| Temazepam |
680 (3) |
510 (2) |
340 (1) |
1540 (6) |
3070 (3) |
| Alprazolam |
1850 (9) |
1590 (7) |
1390 (6) |
4880 (18) |
9710 (10) |
| Chlordizepoxide |
3940 (18) |
3770 (16) |
3620 (15) |
3290 (12) |
14,620 (15) |
| Haloperidol |
9940 (46) |
10,930 (47) |
11,250 (46) |
11,650 (44) |
43,771 (46) |
| Clonidine |
9040 (42) |
9900 (42) |
10,430 (42) |
11,020 (42) |
40,391 (42) |
| Dexmedetomidine |
1750 (8) |
1700 (7) |
1610 (7) |
1400 (5) |
6460 (7) |
| Baclofen |
1270 (6) |
1490 (6) |
1560 (7) |
1660 (8) |
5980 (6) |
| Phenobarbital |
1040 (5) |
1250 (5) |
1600 (6) |
1650 (6) |
5540 (6) |
| Gabapentin |
3750 (17) |
3520 (15) |
3300 (13) |
2910 (11) |
13,480 (14) |
| Carbamazepine |
1000 (5) |
1120 (5) |
1210 (5) |
1250 (5) |
4580 (5) |
| Oxcarmazepine |
230 (1) |
260 (1) |
630 (3) |
650 (2) |
1770 (2) |
| Valproic acid |
1800 (8) |
1960 (8) |
2060 (8) |
2000 (8) |
7820 (8) |
Note all changes from 2016 to 2019 were nonsignificant for trends by linear regression analysis with the exception of temazepam which was significant at the 0.02 level.
Although there are recommendations and literature support for the use of antiepileptics, their prescribing was limited. Carbamazepine, was used only 5% of the time, while gabapentin was used 14% of the time. There was little use of oxcarmazepine. The use of valproic acid exceeded that of carbamazepine.
The antipsychotics are useful for managing the agitation that occurs with AWS, although there are concerns about lowering seizure thresholds. We did find that haloperidol use occurred in about 46% of instances. We searched for droperidol but did not find any use of that medication in this patient population.
We saw substantial use of clonidine in this database and it appeared in a frequency similar to that of haloperidol. Dexmedetomidine has similar alpha-adrenergic agonist effects and it was used 7% of the time. There is little evidence supporting the use of baclofen, although in this study we found the usage of 6%. Phenobarbital has utility in AWS although it appears to be infrequently used.
DISCUSSION
Not surprisingly, there is substantial use of benzodiazepines for inpatients with AWS. In many guidelines, the benzodiazepines are considered the primary mode of treatment.6 The shorter-acting agents may be needed due to their rapid onset of action in cases where prompt control of patients symptom are needed. The short onset agent midazolam were used 15% of the time. Longer-acting agents such as chlordioxepide and diazepam are used frequently although their usage decreased over the time period of the study. We saw an increase in the use of temazepam and alprazolam. The nature of this data is such that we cannot ascribe a reason to that change. While temazepam has utility in the management of patients with severe liver dysfunction we did not find an increase in the usage of agents with similar benefits such as lorazepam or oxazepam. We cannot discern whether any of the benzodiazepines were utilized in the management of AWS or for any of the other indications for these medications.
The literature support for antiepileptics shows varying results. A recent report did not find that the addition of gabapentin reduced benzodiazepine use.7 There is for the use of carbamazepine, both for primary treatment of AWS, particular in moderate cases, as well as an adjunctive medication in addition to benzodiazepines.8,9 This study outlines the limited use of carbamazepine among inpatients with AWS. Gabapentin, which has multiple uses including pain management, was used in a frequency almost three times as much as carbamazepine. Valproic acid was used more commonly than carbamazepine and there is some support for that strategy.10 There appears to be opportunity for further elucidation of the utility of these agents for the inpatient management of AWS, particularly as adjunctive agents.
Phenobarbital is infrequently used for the management of AWS. There are theoretical considerations that support its use including a longer duration of action, facilitation administration and the lack of delirium that may accompany prolonged use of benzodiazepines. In some studies, phenobarbital had similar treatment outcomes compared with benzodiazepines.11 There are advocates for the use of phenobarbital although the side effects and therapeutic index may limit its use.
Previous studies have also found substantial practice variation in the management of AWS. While it is an older report, a survey of medical directors of inpatient treatment programs reports substantial variability and infrequent use of protocols for the management of AWS.12 An intensive care unit–based survey found that the most common adjunctive medications for severe AWS were haloperidol, clonidine, phenobarbital, and propofol.13 A majority of respondents did not report the use of phenobarbital. Where protocols do exist, prior evidence indicates a lack of compliance with those standardize practices.5 Mo and colleagues reported that about two third of hospitals in their survey had protocols or guidelines in place to treat AWS. In their survey, the agents most commonly used in association with benzodiazepines were haloperidol, clonidine, and phenobarbital. Haloperidol was the most common agent, reported to be used by half of the participants.3
The nature of this study is one limited by the nature of the database. We cannot ascribe the reasons behind the administration of any of these medications. They may have been used for purposes other than the treatment of AWS. The database is populated by the participation of various organizations. Changes in submissions may account for some of the changes over time and we have no means of further elucidating this. The data is based on a collection of data from electronic health records and billing data. As such, it is limited by the completeness and accuracy of that data.
SUMMARY
Consistent with current recommendations, in this sample benzodiazepines were used in most cases. There appears to be an underutilization of medications with utility as adjunctive agents for AWS. As guidelines and protocols are developed for the management of inpatients with AWS, consideration should be given to the inclusion of these agents.
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