David R. Spiegel, MD

Clinicians often use the symptom-triggered Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised (CIWA-Ar)1 to assess patients’ risk for alcohol withdrawal because it has well-documented reliability, reproducibility, and validity based on comparison with ratings by expert clinicians.2,3 The CIWA-Ar commonly is used to determine when to administer lorazepam to limit or prevent morbidity and mortality in patients who are at risk of or are experiencing alcohol withdrawal. Refined to a list of 10 signs and symptoms, the CIWA-Ar is easy to administer and useful in a variety of clinical settings. The maximum score is 67, and patients with a score >15 are at increased risk for severe alcohol withdrawal.1 For a downloadable copy of the CIWA-Ar, click here.

Despite the benefits of using the CIWA-Ar, qualitative description of certain alcohol withdrawal symptoms is prone to subjective misinterpretation and can result in falsely elevated scores, excessive benzodiazepine administration, and associated sequelae.⁴ This article describes such a scenario, and examines factors that can contribute to a falsely elevated CIWA-Ar score.

CASE REPORT: Resistant alcohol withdrawal

Mr. J, age 24, is referred to the consultation-liaison service at our teaching hospital for “overall psychiatric assessment and help with alcohol withdrawal.” When brought to the hospital, Mr. J was experiencing diaphoresis and tachycardia. During the interview, he says he “experiences withdrawal symptoms all the time, so I am familiar with the signs.”

Mr. J is cooperative with the interview. Psychomotor agitation or retardation is not noted. His speech is goal-directed, his mood is “calm,” and his affect is within normal range. His thought content is devoid of psychoses or lethal ideations. On Mini-Mental State Examination, Mr. J scores 28 out of 30, which indicates normal cognitive functioning. He reports drinking eight 40-oz bottles of beer daily for the past 3 months. He started drinking alcohol at age 14 and has had only one 1-year period of sobriety. He denies using illicit drugs and his urine drug screen is unremarkable. Mr. J has a history of delirium tremens (DTs), no significant medical history, and was not taking any medications when admitted. His psychiatric history includes generalized anxiety disorder (GAD) and antisocial personality disorder and his family history is significant for alcohol dependence.

Laboratory workup is unremarkable except for a blood alcohol level of 0.23%. Review of systems is significant for mild tremor but no other symptoms of alcohol withdrawal. Physical examination is within normal limits.

Mr. J is started on a symptom-trigger alcohol detoxification protocol using the CIWA-Ar. Based on an elevated CIWA-Ar score of 33, he receives lorazepam IV, 11 mg on his first day of hospitalization and 8 mg on the second day. On the third day, Mr. J is agitated and pulls his IV lines in an attempt to leave. Over the next 24 hours, his blood pressure ranges from 136/90 mm Hg to 169/92 mm Hg and his pulse ranges from 94 to 115 beats per minute. He is given lorazepam, 30 mg, and is transferred to the intensive care unit (ICU).

At this time, Mr. J’s Delirium Rating Scale (DRS) score is 20 (maximum: 32). He remains in the ICU on lorazepam, 25 mg/hr. After 3 days in the ICU, lorazepam is titrated and stopped 2 days later. After lorazepam is stopped, Mr. J’s DRS score is 0, his vital signs are stable, and he no longer demonstrates signs or symptoms of DTs or alcohol withdrawal. He is discharged 1 day later.

Symptom-triggered treatment

Alcohol withdrawal symptoms mainly are caused by the effects of chronic alcohol exposure on brain γ–aminobutyric acid (GABA) and glutamate systems; benzodiazepines are the standard of care (Box).^5,6 Mr. J had a history of DTs, which is a risk factor for more severe alcohol withdrawal symptoms and recurrence of DTs.⁷ Some authors report that fixed dosing intervals are the “gold standard therapy” for alcohol withdrawal, and may be preferable for patients with a history of DTs.⁸ However, Mr. J was placed on a symptom-triggered protocol, which is standard at our hospital. The decision to implement this protocol was based on concerns of oversedation and possible respiratory suppression. Clinical trials have demonstrated that compared with fixed scheduled therapy for alcohol withdrawal, symptom-triggered protocols result in a reduced need for benzodiazepines (Table).

This treatment strategy requires frequent patient reevaluations—particularly early on—with attention to signs and symptoms of alcohol withdrawal and excessive sedation from medications. Additionally, although most patients with alcohol withdrawal respond to standard treatment that includes benzodiazepines, optimal nutrition, and good supportive care, a subgroup may resist therapy (resistant alcohol withdrawal). Therefore, Mr. J—and others with resistant alcohol withdrawal—may require large doses of benzodiazepines and additional sedatives and undergo complicated hospitalizations.⁹ Nonetheless, as exemplified by Mr. J, symptom-triggered protocols for alcohol withdrawal can result in potential morbidity and mortality.

Box

Table

Benefits of symptom-triggered vs fixed scheduled therapy for alcohol withdrawal

Factors influencing CIWA-Ar score

Vital signs monitoring. One limitation of the CIWA-Ar is that vital signs—an objective measurement of alcohol withdrawal— are not used to determine the score. Indeed, Mr. J presented with vital sign dysregulation. However, research suggests that the best predictor of high withdrawal scores includes groups of symptoms rather than individual symptoms.¹⁰ In that study, pulse and blood pressure did not correlate with withdrawal severity. Pulse and blood pressure elevations occur in alcohol withdrawal, but other signs and symptoms are more reliable in assessing withdrawal severity. This is clinically important because physicians often prescribe medications for alcohol withdrawal treatment based on pulse and blood pressure measures.¹ This needs to be balanced against research that found a systolic blood pressure >150 mm Hg and axillary temperature >38°C can predict development of DTs in patients experiencing alcohol withdrawal.⁷

Lorazepam-induced disinhibition. Benzodiazepines affect functions associated with processing within the orbital prefrontal cortex,¹¹ including response inhibition and socially acceptable behavior, and impairment in this functioning can result in behavioral disinhibition.¹² This effect could account for the apparent paradoxical clinical observation of aggression in benzodiazepine-sedated patients.¹³ Because agitation is scored on the CIWA-Ar,^1,10 falsely elevated scores caused by interpreting benzodiazepine-induced aggression as agitation could result in patients (such as Mr. J) receiving more lorazepam, therefore perpetuating this cycle.

Comorbid anxiety disorders also could falsely accentuate CIWA-Ar scores. For example, the odds of an alcohol dependence diagnosis are 2 to 3 times greater among patients with an anxiety disorder.¹⁴ Additionally, the lifetime prevalence of comorbid alcohol dependence for patients with GAD—such as Mr. J— is 30% to 35%.^14,15

Alcohol withdrawal can be more severe in patients with alcohol dependence and anxiety disorders because evidence suggests the neurochemical processes underlying both are similar and potentially additive. Studies have shown that these dual diagnosis patients experience more severe symptoms of alcohol withdrawal as assessed by total CIWA-Ar score than those without an anxiety disorder.¹⁵ Although such patients may require more aggressive pharmacologic treatment, the dangers of higher benzodiazepine dosages may be even greater.

Benzodiazepine-induced delirium. A recent meta-analysis suggested that benzodiazepines may be associated with an increased risk of delirium.¹⁶ Longer-acting benzodiazepines may be associated with increased risk of delirium compared with short-acting agents, and higher doses during a 24-hour period may be associated with increased risk of delirium compared with lower doses. However, wide confidence intervals imply significant uncertainty with these results, and not all patients in the studies reviewed were undergoing alcohol detoxification.¹⁶ Benzodiazepines have been reported to accentuate delirium when used to treat DTs.¹⁷

We postulate that although Mr. J received lorazepam—a short- to moderate-acting benzodiazepine with a half-life of 12 to 16 hours¹⁸—the cumulative dose was high enough to have accentuated—rather than attenuated—delirium.¹⁶

Personality disorders. Comorbid alcohol use disorders (AUDs) and personality disorders are well documented. One study found the prevalence of personality disorders in AUDs ranged from 22% to 78%.¹⁹ Psychologically, drinking to cope with negative subjective states and emotions (coping motives) and drinking to enhance positive emotions (enhancement motives) may explain the relation between Cluster B personality disorders and AUDs.²⁰

Research on prefrontal functioning in alcoholics and individuals with antisocial personality disorder symptoms has suggested that both groups may be impaired on tasks sensitive to compromised orbitofrontal functioning.²¹ The orbitofrontal system is essential for maintaining normal inhibitory influences on behavior.²² Benzodiazepines can increase the likelihood of developing disinhibition or impulsivity, which are symptoms of antisocial personality disorder. Because Mr. J had antisocial personality disorder, treating his alcohol withdrawal with a benzodiazepine could have accentuated these symptoms, which were subsequently “treated” with additional lorazepam, therefore worsening the cycle.

Medical comorbidities. The CIWA-Ar relies on autonomic signs and subjective symptoms and was not designed for use in nonverbal patients in the ICU. It is possible that the presence of other acute illnesses may contribute to increased CIWA-Ar scores, but we are unaware of any studies that have evaluated such factors.²³

However, tremor, which is scored on the CIWA-Ar, can falsely elevate scores if it is caused by something other than acute alcohol withdrawal. Although essential tremors attenuate with acute alcohol use, chronic alcohol use can result in parkinsonism with a resting tremor, and cerebellar degeneration, which can include an action tremor and cerebellar 3-Hz leg tremor.²⁴ Finally, hepatic encephalopathy—a neuropsychiatric syndrome characterized by disturbances in consciousness, mood, behavior, and cognition—can occur in patients with advanced liver disease, which may be precipitated by alcohol use. The clinical presentation and symptom severity of hepatic encephalopathy varies from minor cognitive impairment to gross disorientation, confusion, and agitation,²⁵ all of which can elevate CIWA-Ar scores.

The role of disinhibition

Disinhibition could serve as the “final common pathway” through which CIWA-Ar scores can be falsely elevated.¹¹ For a Figure that illustrates this, see below. Mr. J presented with several variables that could have elevated his CIWA-Ar score; additional potential factors include other psychiatric diagnoses such as bipolar disorder, opiate withdrawal, dementia, drug-seeking behavior, or malingering.^26,27

Treating disinhibition in patients with alcohol withdrawal. Continuing to administer escalating doses of benzodiazepines is counterintuitive for benzodiazepine-induced disinhibition. In a study of alcohol withdrawal in rats, antipsychotics evaluated had some beneficial effects on alcohol withdrawal signs.²⁸ In this study, the comparative effectiveness of atypical antipsychotics was as follows: risperidone = quetiapine > ziprasidone > clozapine > olanzapine.

The American Society of Addiction Medicine’s practice guideline advises against using antipsychotics as the sole agent for DTs because these agents are associated with a longer duration of delirium, higher complication rates, and higher mortality.²⁸ However, antipsychotics have a role as an adjunct to benzodiazepines when benzodiazepines don’t sufficiently control agitation, thought disorder, or perceptual disturbances. Although haloperidol use is well established in this scenario, chlorpromazine is contraindicated because it is epileptogenic, and little information is available on atypical antipsychotics.²⁹ If Mr. J had not responded to tapering lorazepam, evidence would support using haloperidol.

Figure: Unifying concept for pathological BZ administration during alcohol withdrawal syndrome: Disinhibition
AWS: alcohol withdrawal syndrome; BZ: benzodiazepine; CIWA-Ar: Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised; GABA: γ-aminobutyric acid
Source: Reference 11Related Resources

• Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health & Research World. 1998;22(1):38-43. http://pubs.niaaa.nih.gov/publications/arh22-1/38-43.pdf.
• Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537.

Drug Brand Names

• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Flumazenil • Romazicon
• Haloperidol • Haldol
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Spiegel is on the speaker’s bureau of Sunovion Pharmaceuticals.

Drs. Kumari and Petri report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgement

The authors thank Amy Herndon for her help in preparing this article.

Clinicians often use the symptom-triggered Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised (CIWA-Ar)1 to assess patients’ risk for alcohol withdrawal because it has well-documented reliability, reproducibility, and validity based on comparison with ratings by expert clinicians.2,3 The CIWA-Ar commonly is used to determine when to administer lorazepam to limit or prevent morbidity and mortality in patients who are at risk of or are experiencing alcohol withdrawal. Refined to a list of 10 signs and symptoms, the CIWA-Ar is easy to administer and useful in a variety of clinical settings. The maximum score is 67, and patients with a score >15 are at increased risk for severe alcohol withdrawal.1 For a downloadable copy of the CIWA-Ar, click here.

Despite the benefits of using the CIWA-Ar, qualitative description of certain alcohol withdrawal symptoms is prone to subjective misinterpretation and can result in falsely elevated scores, excessive benzodiazepine administration, and associated sequelae.⁴ This article describes such a scenario, and examines factors that can contribute to a falsely elevated CIWA-Ar score.

CASE REPORT: Resistant alcohol withdrawal

Mr. J, age 24, is referred to the consultation-liaison service at our teaching hospital for “overall psychiatric assessment and help with alcohol withdrawal.” When brought to the hospital, Mr. J was experiencing diaphoresis and tachycardia. During the interview, he says he “experiences withdrawal symptoms all the time, so I am familiar with the signs.”

Mr. J is cooperative with the interview. Psychomotor agitation or retardation is not noted. His speech is goal-directed, his mood is “calm,” and his affect is within normal range. His thought content is devoid of psychoses or lethal ideations. On Mini-Mental State Examination, Mr. J scores 28 out of 30, which indicates normal cognitive functioning. He reports drinking eight 40-oz bottles of beer daily for the past 3 months. He started drinking alcohol at age 14 and has had only one 1-year period of sobriety. He denies using illicit drugs and his urine drug screen is unremarkable. Mr. J has a history of delirium tremens (DTs), no significant medical history, and was not taking any medications when admitted. His psychiatric history includes generalized anxiety disorder (GAD) and antisocial personality disorder and his family history is significant for alcohol dependence.

Laboratory workup is unremarkable except for a blood alcohol level of 0.23%. Review of systems is significant for mild tremor but no other symptoms of alcohol withdrawal. Physical examination is within normal limits.

Mr. J is started on a symptom-trigger alcohol detoxification protocol using the CIWA-Ar. Based on an elevated CIWA-Ar score of 33, he receives lorazepam IV, 11 mg on his first day of hospitalization and 8 mg on the second day. On the third day, Mr. J is agitated and pulls his IV lines in an attempt to leave. Over the next 24 hours, his blood pressure ranges from 136/90 mm Hg to 169/92 mm Hg and his pulse ranges from 94 to 115 beats per minute. He is given lorazepam, 30 mg, and is transferred to the intensive care unit (ICU).

At this time, Mr. J’s Delirium Rating Scale (DRS) score is 20 (maximum: 32). He remains in the ICU on lorazepam, 25 mg/hr. After 3 days in the ICU, lorazepam is titrated and stopped 2 days later. After lorazepam is stopped, Mr. J’s DRS score is 0, his vital signs are stable, and he no longer demonstrates signs or symptoms of DTs or alcohol withdrawal. He is discharged 1 day later.

Symptom-triggered treatment

Alcohol withdrawal symptoms mainly are caused by the effects of chronic alcohol exposure on brain γ–aminobutyric acid (GABA) and glutamate systems; benzodiazepines are the standard of care (Box).^5,6 Mr. J had a history of DTs, which is a risk factor for more severe alcohol withdrawal symptoms and recurrence of DTs.⁷ Some authors report that fixed dosing intervals are the “gold standard therapy” for alcohol withdrawal, and may be preferable for patients with a history of DTs.⁸ However, Mr. J was placed on a symptom-triggered protocol, which is standard at our hospital. The decision to implement this protocol was based on concerns of oversedation and possible respiratory suppression. Clinical trials have demonstrated that compared with fixed scheduled therapy for alcohol withdrawal, symptom-triggered protocols result in a reduced need for benzodiazepines (Table).

This treatment strategy requires frequent patient reevaluations—particularly early on—with attention to signs and symptoms of alcohol withdrawal and excessive sedation from medications. Additionally, although most patients with alcohol withdrawal respond to standard treatment that includes benzodiazepines, optimal nutrition, and good supportive care, a subgroup may resist therapy (resistant alcohol withdrawal). Therefore, Mr. J—and others with resistant alcohol withdrawal—may require large doses of benzodiazepines and additional sedatives and undergo complicated hospitalizations.⁹ Nonetheless, as exemplified by Mr. J, symptom-triggered protocols for alcohol withdrawal can result in potential morbidity and mortality.

Box

Table

Benefits of symptom-triggered vs fixed scheduled therapy for alcohol withdrawal

Factors influencing CIWA-Ar score

Vital signs monitoring. One limitation of the CIWA-Ar is that vital signs—an objective measurement of alcohol withdrawal— are not used to determine the score. Indeed, Mr. J presented with vital sign dysregulation. However, research suggests that the best predictor of high withdrawal scores includes groups of symptoms rather than individual symptoms.¹⁰ In that study, pulse and blood pressure did not correlate with withdrawal severity. Pulse and blood pressure elevations occur in alcohol withdrawal, but other signs and symptoms are more reliable in assessing withdrawal severity. This is clinically important because physicians often prescribe medications for alcohol withdrawal treatment based on pulse and blood pressure measures.¹ This needs to be balanced against research that found a systolic blood pressure >150 mm Hg and axillary temperature >38°C can predict development of DTs in patients experiencing alcohol withdrawal.⁷

Lorazepam-induced disinhibition. Benzodiazepines affect functions associated with processing within the orbital prefrontal cortex,¹¹ including response inhibition and socially acceptable behavior, and impairment in this functioning can result in behavioral disinhibition.¹² This effect could account for the apparent paradoxical clinical observation of aggression in benzodiazepine-sedated patients.¹³ Because agitation is scored on the CIWA-Ar,^1,10 falsely elevated scores caused by interpreting benzodiazepine-induced aggression as agitation could result in patients (such as Mr. J) receiving more lorazepam, therefore perpetuating this cycle.

Comorbid anxiety disorders also could falsely accentuate CIWA-Ar scores. For example, the odds of an alcohol dependence diagnosis are 2 to 3 times greater among patients with an anxiety disorder.¹⁴ Additionally, the lifetime prevalence of comorbid alcohol dependence for patients with GAD—such as Mr. J— is 30% to 35%.^14,15

Alcohol withdrawal can be more severe in patients with alcohol dependence and anxiety disorders because evidence suggests the neurochemical processes underlying both are similar and potentially additive. Studies have shown that these dual diagnosis patients experience more severe symptoms of alcohol withdrawal as assessed by total CIWA-Ar score than those without an anxiety disorder.¹⁵ Although such patients may require more aggressive pharmacologic treatment, the dangers of higher benzodiazepine dosages may be even greater.

Benzodiazepine-induced delirium. A recent meta-analysis suggested that benzodiazepines may be associated with an increased risk of delirium.¹⁶ Longer-acting benzodiazepines may be associated with increased risk of delirium compared with short-acting agents, and higher doses during a 24-hour period may be associated with increased risk of delirium compared with lower doses. However, wide confidence intervals imply significant uncertainty with these results, and not all patients in the studies reviewed were undergoing alcohol detoxification.¹⁶ Benzodiazepines have been reported to accentuate delirium when used to treat DTs.¹⁷

We postulate that although Mr. J received lorazepam—a short- to moderate-acting benzodiazepine with a half-life of 12 to 16 hours¹⁸—the cumulative dose was high enough to have accentuated—rather than attenuated—delirium.¹⁶

Personality disorders. Comorbid alcohol use disorders (AUDs) and personality disorders are well documented. One study found the prevalence of personality disorders in AUDs ranged from 22% to 78%.¹⁹ Psychologically, drinking to cope with negative subjective states and emotions (coping motives) and drinking to enhance positive emotions (enhancement motives) may explain the relation between Cluster B personality disorders and AUDs.²⁰

Research on prefrontal functioning in alcoholics and individuals with antisocial personality disorder symptoms has suggested that both groups may be impaired on tasks sensitive to compromised orbitofrontal functioning.²¹ The orbitofrontal system is essential for maintaining normal inhibitory influences on behavior.²² Benzodiazepines can increase the likelihood of developing disinhibition or impulsivity, which are symptoms of antisocial personality disorder. Because Mr. J had antisocial personality disorder, treating his alcohol withdrawal with a benzodiazepine could have accentuated these symptoms, which were subsequently “treated” with additional lorazepam, therefore worsening the cycle.

Medical comorbidities. The CIWA-Ar relies on autonomic signs and subjective symptoms and was not designed for use in nonverbal patients in the ICU. It is possible that the presence of other acute illnesses may contribute to increased CIWA-Ar scores, but we are unaware of any studies that have evaluated such factors.²³

However, tremor, which is scored on the CIWA-Ar, can falsely elevate scores if it is caused by something other than acute alcohol withdrawal. Although essential tremors attenuate with acute alcohol use, chronic alcohol use can result in parkinsonism with a resting tremor, and cerebellar degeneration, which can include an action tremor and cerebellar 3-Hz leg tremor.²⁴ Finally, hepatic encephalopathy—a neuropsychiatric syndrome characterized by disturbances in consciousness, mood, behavior, and cognition—can occur in patients with advanced liver disease, which may be precipitated by alcohol use. The clinical presentation and symptom severity of hepatic encephalopathy varies from minor cognitive impairment to gross disorientation, confusion, and agitation,²⁵ all of which can elevate CIWA-Ar scores.

The role of disinhibition

Disinhibition could serve as the “final common pathway” through which CIWA-Ar scores can be falsely elevated.¹¹ For a Figure that illustrates this, see below. Mr. J presented with several variables that could have elevated his CIWA-Ar score; additional potential factors include other psychiatric diagnoses such as bipolar disorder, opiate withdrawal, dementia, drug-seeking behavior, or malingering.^26,27

Treating disinhibition in patients with alcohol withdrawal. Continuing to administer escalating doses of benzodiazepines is counterintuitive for benzodiazepine-induced disinhibition. In a study of alcohol withdrawal in rats, antipsychotics evaluated had some beneficial effects on alcohol withdrawal signs.²⁸ In this study, the comparative effectiveness of atypical antipsychotics was as follows: risperidone = quetiapine > ziprasidone > clozapine > olanzapine.

The American Society of Addiction Medicine’s practice guideline advises against using antipsychotics as the sole agent for DTs because these agents are associated with a longer duration of delirium, higher complication rates, and higher mortality.²⁸ However, antipsychotics have a role as an adjunct to benzodiazepines when benzodiazepines don’t sufficiently control agitation, thought disorder, or perceptual disturbances. Although haloperidol use is well established in this scenario, chlorpromazine is contraindicated because it is epileptogenic, and little information is available on atypical antipsychotics.²⁹ If Mr. J had not responded to tapering lorazepam, evidence would support using haloperidol.

Figure: Unifying concept for pathological BZ administration during alcohol withdrawal syndrome: Disinhibition
AWS: alcohol withdrawal syndrome; BZ: benzodiazepine; CIWA-Ar: Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised; GABA: γ-aminobutyric acid
Source: Reference 11Related Resources

• Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health & Research World. 1998;22(1):38-43. http://pubs.niaaa.nih.gov/publications/arh22-1/38-43.pdf.
• Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537.

Drug Brand Names

• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Flumazenil • Romazicon
• Haloperidol • Haldol
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Spiegel is on the speaker’s bureau of Sunovion Pharmaceuticals.

Drs. Kumari and Petri report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgement

The authors thank Amy Herndon for her help in preparing this article.

Clinicians often use the symptom-triggered Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised (CIWA-Ar)1 to assess patients’ risk for alcohol withdrawal because it has well-documented reliability, reproducibility, and validity based on comparison with ratings by expert clinicians.2,3 The CIWA-Ar commonly is used to determine when to administer lorazepam to limit or prevent morbidity and mortality in patients who are at risk of or are experiencing alcohol withdrawal. Refined to a list of 10 signs and symptoms, the CIWA-Ar is easy to administer and useful in a variety of clinical settings. The maximum score is 67, and patients with a score >15 are at increased risk for severe alcohol withdrawal.1 For a downloadable copy of the CIWA-Ar, click here.

Despite the benefits of using the CIWA-Ar, qualitative description of certain alcohol withdrawal symptoms is prone to subjective misinterpretation and can result in falsely elevated scores, excessive benzodiazepine administration, and associated sequelae.⁴ This article describes such a scenario, and examines factors that can contribute to a falsely elevated CIWA-Ar score.

CASE REPORT: Resistant alcohol withdrawal

Mr. J, age 24, is referred to the consultation-liaison service at our teaching hospital for “overall psychiatric assessment and help with alcohol withdrawal.” When brought to the hospital, Mr. J was experiencing diaphoresis and tachycardia. During the interview, he says he “experiences withdrawal symptoms all the time, so I am familiar with the signs.”

Mr. J is cooperative with the interview. Psychomotor agitation or retardation is not noted. His speech is goal-directed, his mood is “calm,” and his affect is within normal range. His thought content is devoid of psychoses or lethal ideations. On Mini-Mental State Examination, Mr. J scores 28 out of 30, which indicates normal cognitive functioning. He reports drinking eight 40-oz bottles of beer daily for the past 3 months. He started drinking alcohol at age 14 and has had only one 1-year period of sobriety. He denies using illicit drugs and his urine drug screen is unremarkable. Mr. J has a history of delirium tremens (DTs), no significant medical history, and was not taking any medications when admitted. His psychiatric history includes generalized anxiety disorder (GAD) and antisocial personality disorder and his family history is significant for alcohol dependence.

Laboratory workup is unremarkable except for a blood alcohol level of 0.23%. Review of systems is significant for mild tremor but no other symptoms of alcohol withdrawal. Physical examination is within normal limits.

Mr. J is started on a symptom-trigger alcohol detoxification protocol using the CIWA-Ar. Based on an elevated CIWA-Ar score of 33, he receives lorazepam IV, 11 mg on his first day of hospitalization and 8 mg on the second day. On the third day, Mr. J is agitated and pulls his IV lines in an attempt to leave. Over the next 24 hours, his blood pressure ranges from 136/90 mm Hg to 169/92 mm Hg and his pulse ranges from 94 to 115 beats per minute. He is given lorazepam, 30 mg, and is transferred to the intensive care unit (ICU).

At this time, Mr. J’s Delirium Rating Scale (DRS) score is 20 (maximum: 32). He remains in the ICU on lorazepam, 25 mg/hr. After 3 days in the ICU, lorazepam is titrated and stopped 2 days later. After lorazepam is stopped, Mr. J’s DRS score is 0, his vital signs are stable, and he no longer demonstrates signs or symptoms of DTs or alcohol withdrawal. He is discharged 1 day later.

Symptom-triggered treatment

Alcohol withdrawal symptoms mainly are caused by the effects of chronic alcohol exposure on brain γ–aminobutyric acid (GABA) and glutamate systems; benzodiazepines are the standard of care (Box).^5,6 Mr. J had a history of DTs, which is a risk factor for more severe alcohol withdrawal symptoms and recurrence of DTs.⁷ Some authors report that fixed dosing intervals are the “gold standard therapy” for alcohol withdrawal, and may be preferable for patients with a history of DTs.⁸ However, Mr. J was placed on a symptom-triggered protocol, which is standard at our hospital. The decision to implement this protocol was based on concerns of oversedation and possible respiratory suppression. Clinical trials have demonstrated that compared with fixed scheduled therapy for alcohol withdrawal, symptom-triggered protocols result in a reduced need for benzodiazepines (Table).

This treatment strategy requires frequent patient reevaluations—particularly early on—with attention to signs and symptoms of alcohol withdrawal and excessive sedation from medications. Additionally, although most patients with alcohol withdrawal respond to standard treatment that includes benzodiazepines, optimal nutrition, and good supportive care, a subgroup may resist therapy (resistant alcohol withdrawal). Therefore, Mr. J—and others with resistant alcohol withdrawal—may require large doses of benzodiazepines and additional sedatives and undergo complicated hospitalizations.⁹ Nonetheless, as exemplified by Mr. J, symptom-triggered protocols for alcohol withdrawal can result in potential morbidity and mortality.

Box

Table

Benefits of symptom-triggered vs fixed scheduled therapy for alcohol withdrawal

Factors influencing CIWA-Ar score

Vital signs monitoring. One limitation of the CIWA-Ar is that vital signs—an objective measurement of alcohol withdrawal— are not used to determine the score. Indeed, Mr. J presented with vital sign dysregulation. However, research suggests that the best predictor of high withdrawal scores includes groups of symptoms rather than individual symptoms.¹⁰ In that study, pulse and blood pressure did not correlate with withdrawal severity. Pulse and blood pressure elevations occur in alcohol withdrawal, but other signs and symptoms are more reliable in assessing withdrawal severity. This is clinically important because physicians often prescribe medications for alcohol withdrawal treatment based on pulse and blood pressure measures.¹ This needs to be balanced against research that found a systolic blood pressure >150 mm Hg and axillary temperature >38°C can predict development of DTs in patients experiencing alcohol withdrawal.⁷

Lorazepam-induced disinhibition. Benzodiazepines affect functions associated with processing within the orbital prefrontal cortex,¹¹ including response inhibition and socially acceptable behavior, and impairment in this functioning can result in behavioral disinhibition.¹² This effect could account for the apparent paradoxical clinical observation of aggression in benzodiazepine-sedated patients.¹³ Because agitation is scored on the CIWA-Ar,^1,10 falsely elevated scores caused by interpreting benzodiazepine-induced aggression as agitation could result in patients (such as Mr. J) receiving more lorazepam, therefore perpetuating this cycle.

Comorbid anxiety disorders also could falsely accentuate CIWA-Ar scores. For example, the odds of an alcohol dependence diagnosis are 2 to 3 times greater among patients with an anxiety disorder.¹⁴ Additionally, the lifetime prevalence of comorbid alcohol dependence for patients with GAD—such as Mr. J— is 30% to 35%.^14,15

Alcohol withdrawal can be more severe in patients with alcohol dependence and anxiety disorders because evidence suggests the neurochemical processes underlying both are similar and potentially additive. Studies have shown that these dual diagnosis patients experience more severe symptoms of alcohol withdrawal as assessed by total CIWA-Ar score than those without an anxiety disorder.¹⁵ Although such patients may require more aggressive pharmacologic treatment, the dangers of higher benzodiazepine dosages may be even greater.

Benzodiazepine-induced delirium. A recent meta-analysis suggested that benzodiazepines may be associated with an increased risk of delirium.¹⁶ Longer-acting benzodiazepines may be associated with increased risk of delirium compared with short-acting agents, and higher doses during a 24-hour period may be associated with increased risk of delirium compared with lower doses. However, wide confidence intervals imply significant uncertainty with these results, and not all patients in the studies reviewed were undergoing alcohol detoxification.¹⁶ Benzodiazepines have been reported to accentuate delirium when used to treat DTs.¹⁷

We postulate that although Mr. J received lorazepam—a short- to moderate-acting benzodiazepine with a half-life of 12 to 16 hours¹⁸—the cumulative dose was high enough to have accentuated—rather than attenuated—delirium.¹⁶

Personality disorders. Comorbid alcohol use disorders (AUDs) and personality disorders are well documented. One study found the prevalence of personality disorders in AUDs ranged from 22% to 78%.¹⁹ Psychologically, drinking to cope with negative subjective states and emotions (coping motives) and drinking to enhance positive emotions (enhancement motives) may explain the relation between Cluster B personality disorders and AUDs.²⁰

Research on prefrontal functioning in alcoholics and individuals with antisocial personality disorder symptoms has suggested that both groups may be impaired on tasks sensitive to compromised orbitofrontal functioning.²¹ The orbitofrontal system is essential for maintaining normal inhibitory influences on behavior.²² Benzodiazepines can increase the likelihood of developing disinhibition or impulsivity, which are symptoms of antisocial personality disorder. Because Mr. J had antisocial personality disorder, treating his alcohol withdrawal with a benzodiazepine could have accentuated these symptoms, which were subsequently “treated” with additional lorazepam, therefore worsening the cycle.

Medical comorbidities. The CIWA-Ar relies on autonomic signs and subjective symptoms and was not designed for use in nonverbal patients in the ICU. It is possible that the presence of other acute illnesses may contribute to increased CIWA-Ar scores, but we are unaware of any studies that have evaluated such factors.²³

However, tremor, which is scored on the CIWA-Ar, can falsely elevate scores if it is caused by something other than acute alcohol withdrawal. Although essential tremors attenuate with acute alcohol use, chronic alcohol use can result in parkinsonism with a resting tremor, and cerebellar degeneration, which can include an action tremor and cerebellar 3-Hz leg tremor.²⁴ Finally, hepatic encephalopathy—a neuropsychiatric syndrome characterized by disturbances in consciousness, mood, behavior, and cognition—can occur in patients with advanced liver disease, which may be precipitated by alcohol use. The clinical presentation and symptom severity of hepatic encephalopathy varies from minor cognitive impairment to gross disorientation, confusion, and agitation,²⁵ all of which can elevate CIWA-Ar scores.

The role of disinhibition

Disinhibition could serve as the “final common pathway” through which CIWA-Ar scores can be falsely elevated.¹¹ For a Figure that illustrates this, see below. Mr. J presented with several variables that could have elevated his CIWA-Ar score; additional potential factors include other psychiatric diagnoses such as bipolar disorder, opiate withdrawal, dementia, drug-seeking behavior, or malingering.^26,27

Treating disinhibition in patients with alcohol withdrawal. Continuing to administer escalating doses of benzodiazepines is counterintuitive for benzodiazepine-induced disinhibition. In a study of alcohol withdrawal in rats, antipsychotics evaluated had some beneficial effects on alcohol withdrawal signs.²⁸ In this study, the comparative effectiveness of atypical antipsychotics was as follows: risperidone = quetiapine > ziprasidone > clozapine > olanzapine.

The American Society of Addiction Medicine’s practice guideline advises against using antipsychotics as the sole agent for DTs because these agents are associated with a longer duration of delirium, higher complication rates, and higher mortality.²⁸ However, antipsychotics have a role as an adjunct to benzodiazepines when benzodiazepines don’t sufficiently control agitation, thought disorder, or perceptual disturbances. Although haloperidol use is well established in this scenario, chlorpromazine is contraindicated because it is epileptogenic, and little information is available on atypical antipsychotics.²⁹ If Mr. J had not responded to tapering lorazepam, evidence would support using haloperidol.

Figure: Unifying concept for pathological BZ administration during alcohol withdrawal syndrome: Disinhibition
AWS: alcohol withdrawal syndrome; BZ: benzodiazepine; CIWA-Ar: Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised; GABA: γ-aminobutyric acid
Source: Reference 11Related Resources

• Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health & Research World. 1998;22(1):38-43. http://pubs.niaaa.nih.gov/publications/arh22-1/38-43.pdf.
• Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537.

Drug Brand Names

• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Flumazenil • Romazicon
• Haloperidol • Haldol
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Spiegel is on the speaker’s bureau of Sunovion Pharmaceuticals.

Drs. Kumari and Petri report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgement

The authors thank Amy Herndon for her help in preparing this article.

Discuss this article

Benzodiazepines are the mainstay of alcohol detoxification treatment, with extensive evidence supporting their efficacy and relative safety.¹ The risk of benzodiazepine-alcohol interaction, however, and psychomotor and cognitive impairments associated with benzodiazepine use may limit early rehabilitation efforts in hospitalized patients.² Cross-tolerance with alcohol also limits benzodiazepines’ potential benefit in outpatients with substance use disorders.

Adding anticonvulsants to acute benzodiazepine therapy has been shown to decrease alcohol withdrawal symptom severity, reduce seizure risk, and support recovery, particularly in patients with multiple alcohol withdrawal episodes. After detoxification, long-term anticonvulsant use may reduce relapse risk by decreasing post-cessation craving, without abuse liability.³

Although not all studies endorse adding anticonvulsants to benzodiazepines for managing alcohol withdrawal syndrome (AWS),⁴ we present 3 cases in which anticonvulsants were used successfully as adjuncts to lorazepam. Valproic acid, levetiracetam, and gabapentin offer advantages in acute and long-term therapy of alcohol dependence with efficacy in AWS, low abuse potential, benign safety profile, and mood-stabilizing properties.

Neurobiologic rationale

AWS manifests as a cluster of clinical symptoms including delirium tremens (DTs) and seizures (Table 1). Its pathophysiology can be explained by alcohol’s agonist effect on the gamma-aminobutyric acid (GABA) system and antagonist effect on the glutamatergic system (Table 2).⁵

Chronic alcohol intake leads to neuroadaptation in the brain in the form of down-regulation of GABA_A receptors and upregulation of N-methyl-D-aspartate receptors. During alcohol withdrawal, this neuroadaptation leads to a decrease in central GABA activity and an increase in glutamate activity, resulting in hyperexcitation, anxiety, and seizures.⁶

Little data exist regarding time to relapse after detoxification in alcohol-dependent patients. One theory—called “protracted withdrawal syndrome” (Table 1)—suggests that abstinent alcoholics return to drinking because of the same, but attenuated, neuroadaptations that trigger acute AWS.⁷

Advantages of adjunct therapy. Ntais et al⁸ evaluated benzodiazepines’ effectiveness and safety in treating AWS in a clinical review of 57 randomized, controlled trials totaling 4,051 patients. Benzodiazepines showed similar success rates as other drugs (relative risk [RR] 1.00) or anticonvulsants in particular (RR 0.88), as measured by changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment. Benzodiazepines also offered significant benefit for seizure control compared with nonanticonvulsants (RR 0.23), but less when compared with anti convulsants (RR 1.99).

Although the literature does not support anticonvulsant use for monotherapy in AWS, anticonvulsants show potential as adjunctive therapy. Valproic acid, levetiracetam, and gabapentin offer unique mechanisms of action (Table 3) and demonstrate advantages over benzodiazepine monotherapy for AWS. Adjunctive use of valproic acid,^8,9 levetiracetam,¹⁰ and gabapentin^11,12 in detoxification also has demonstrated efficacy in reducing risk of relapse and delaying relapse.

The neurobiologic rationale for using anticonvulsants in acute AWS is speculative, but these agents appear to:

• inhibit “kindling” (neuronal changes that may be associated with repeated intoxications)
• facilitate GABAergic mechanisms.⁹

Table 1

Alcohol withdrawal: Acute vs long-term symptoms

Table 2

How alcohol affects GABA and glutamate neurotransmitters

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants

CASE REPORT 1: Valproic acid for alcohol overdose

After attempting suicide with an alcohol overdose, Ms. J, age 45, is transferred from the emergency room (ER) to our psychiatry consult service 10 hours after admission. Her symptoms include nausea, tremor, headaches, agitation, disorientation, and auditory hallucinations.

Medical history reveals 25 years of alcohol dependence, multiple hospitalizations for withdrawal, and many failed attempts to quit. Ms. J reports consuming an average of 16 drink equivalents (eg, 12 oz beers) daily but denies illicit drug use.

Lab values on admission include blood alcohol concentration (BAC) 290 mg/dL (0.29%), mean corpuscular volume (MCV) 96 fL, gamma-glutamyltransferase (GGT) 164 U/L, aspartate aminotransferase (AST) 43 U/L, alanine aminotransferase (ALT) 31 U/L, and alkaline phosphatase (ALP) 151 U/L. Urine drug screen, acetaminophen, salicylate, vitamin B1 (thiamine), B12 (cyanocobalamin), B9 (folate), and electrolytes (including magnesium) are normal.

We assess alcohol withdrawal severity using the CIWA-Ar (Click here to view/download a copy of this scale). Ms. J’s initial score is 17, indicating a risk of moderate alcohol withdrawal if untreated.

In the ER, Ms. J is placed on a symptom-triggered benzodiazepine detoxification protocol with lorazepam. We add IV valproic acid, 1,250 mg (based on 20 mg/kg body weight)¹³ divided into 2 doses over the first 24 hours, then maintain IV valproic acid at 500 mg twice daily (Table 4). Within 12 hours of starting combination therapy, Ms. J scores 7 on the CIWA-Ar—indicating mild withdrawal—with subsequent scores <5. She scores 0 with no residual withdrawal symptoms within 36 hours.

Ms. J requires lorazepam, 7 mg, during the 10 hours before valproic acid is added. She requires only 2 mg lorazepam over the next 3 days and reports no side effects related to IV valproic acid. At discharge, Ms. J begins extended-release oral valproic acid, 1,250 mg (based on 25 mg/kg body weight)¹³ once daily for 2 weeks, until she can obtain outpatient follow-up.

Table 4

Benzodiazepines and anticonvulsants for alcohol detoxification

Less lorazepam needed

Adjunctive anticonvulsants can reduce the amount of lorazepam required during detoxification.^14,15 Compared with benzodiazepine monotherapy, the advantages of combination therapy—particularly in outpatient alcohol withdrawal treatment and relapse prevention—include:

• minimal interaction with alcohol (avoiding increased psychomotor deficits, cognitive impairment, and intoxication)¹⁵
• lower abuse potential
• possible efficacy in mood stabilization before, during, and after withdrawal (Table 5).¹⁶

Given the risk of seizures during AWS, anticonvulsants seem to make empirical sense. One study reported a 1% incidence of withdrawal-related seizures in 545 alcohol-dependent inpatients treated with valproic acid.¹⁷ Another case series of 37 patients found no acute sequelae when valproic acid was used for AWS.¹⁸

Anticonvulsants such as valproic acid may reduce the frequency and severity of alcohol relapse, whereas benzodiazepines may increase relapse risk.¹⁹ During a 6-week trial, patients receiving valproic acid maintenance therapy had greater abstinence rates and improved drinking outcomes compared with detoxification-only groups.⁹

One disadvantage of valproic acid is potential hepatotoxicity, an important consideration in patients with liver damage. Fortunately, Ms. J’s AST and ALT values remained within normal limits during valproic acid treatment.

Table 5

Pharmacologic profiles of benzodiazepines vs 3 anticonvulsants

CASE REPORT 2: Levetiracetam for withdrawal seizures

Mr. H, age 42, presents to the ER after suffering a seizure. His medical history includes hypertension, alcohol dependence, and seizures during alcohol withdrawal. He denies a history of psychiatric illness, and his family history is unknown. He is noncompliant with hypertension treatment, which includes clonidine. Mr. H reports his usual alcohol consumption as a 6-pack of beer nightly during the week and a 12-pack nightly on weekends. He says his last drink was 4 days before admission.

Mr. H scores 19 on the CIWA-Ar, placing him at risk for moderate withdrawal. Head CT shows diffuse atrophy, without evidence of an acute intracranial process. BAC is zero on admission, and urine drug screen is negative. Amylase, lipase, and lactate dehydrogenase (LDH) levels suggest acute pancreatitis. AST is elevated to 131 U/L, ALT is elevated to 42 U/L, but MCV is within normal limits.

The psychiatric service is consulted on day 2 of admission, and we prescribe levetiracetam, 500 mg IV every 8 hours.²⁰ IV lorazepam also is available as needed: 1 mg every 8 hours for the first 2 days, then 1 mg every 12 hours for 2 days, then 1 mg every 24 hours. The patient’s CIWA-Ar score is 9 on days 2 and 3 of admission, followed by scores consistently between 2 and 3 after scheduled levetiracetam administration. Mr. H requires 3 mg of lorazepam the remainder of his hospitalization. He is discharged on day 7 with a CIWA-Ar score of 2, and reports no adverse effects related to levetiracetam. He leaves the hospital with a 2-week prescription for oral levetiracetam, 500 mg tid.

Advantages of levetiracetam

Levetiracetam is FDA-approved for adjunctive treatment of adults with partial-onset seizures.²¹ Successful AWS treatment with adjunctive levetiracetam has been supported by few but promising studies.^10,20 Potential advantages of levetiracetam in detoxification include:

• a lack of GABAergic properties, which limits the risk of intoxication or respiratory insufficiency when combined with alcohol²¹
• low drug-drug interaction risk because of nonhepatic metabolism and primary renal excretion.^22,23

We selected levetiracetam for Mr. H because of his history of alcohol withdrawal seizures and acute pancreatitis. Anticonvulsants may be more effective than lorazepam in reducing the risk of alcohol withdrawal seizures,²⁴ and we felt valproic acid might not be safe for him because of its low but real risk of pancreatitis.¹³ We based our levetiracetam dosing on a small open-label trial²⁰ and product information for treating adults with partial-onset seizures.²⁵

Studies also demonstrate levetiracetam’s potential for relapse prevention during outpatient therapy. In a 10-week trial, levetiracetam decreased the number of standard drinks in alcohol-dependent patients from 5.3 to 1.7 per day.¹⁰ This was a small open trial, however, and large controlled trials support the usefulness of other, FDA-approved medications—including disulfiram, naltrexone, and acamprosate—for alcohol relapse prevention.

CASE REPORT 3: Gabapentin for acute withdrawal

Mr. B, age 38, presents to the ER after a 13-day alcohol binge. He has been drinking increasing amounts of alcohol over 6 weeks. Three months earlier, Mr. B was admitted for alcohol withdrawal treatment and received 49 mg of lorazepam over 3 days. This resulted in his transfer from the step-down unit to the intensive care unit for increased agitation, possibly caused by paradoxical disinhibition from excessive lorazepam use.²⁶

Mr. B’s medical history is significant for alcohol-induced seizures, DTs, traumatic brain injury related to craniotomy, and right arm amputation. Mr. B drinks approximately 24 beers per day. He denies tobacco use but admits to past use of cocaine, marijuana, and heroin.

On admission, Mr. B’s BAC is 360 mg/dL (0.36%), AST is elevated at 72 U/L, ALT at 42 U/L, and LDH significantly elevated at 384 U/L. Urine drug screen is negative, and his CIWA-Ar score is 23. His score of –1 on the Richmond Agitation and Sedation Scale (RASS)²⁷ correlates with very mild sedation.

Guided by Bonnet et al²⁸ and clinical experience, we start Mr. B on gabapentin, 1,200 mg tid, and IV lorazepam, 2 mg every 8 hours as needed for breakthrough withdrawal. We decrease lorazepam by 50% every other day until Mr. B is discharged. On days 2, 3, and 4, Mr. B’s CIWA-Ar scores are 6, 9, and 2, respectively. His RASS score drops from –1 on days 1 and 2 to 0 until discharge, indicating an alert and calm state.

Mr. B requires a total of 2 mg of lorazepam throughout hospitalization. He finishes alcohol detoxification on day 4 and is discharged with a prescription for gabapentin, 1,200 mg tid. Two weeks later, when he is admitted to a 28-day inpatient alcohol rehabilitation unit, Mr. B has not relapsed.

More abstinent days

Gabapentin is FDA-approved as adjunctive therapy for partial seizures. Off-label, it has been generally efficacious as an adjunct in alcohol detoxification.^29-32 We chose adjunctive anticonvulsant therapy for Mr. B because of his history of alcohol-induced seizures. We chose gabapentin instead of valproic acid because of Mr. B’s liver damage and gabapentin’s lack of hepatic metabolism.

Gabapentin may reduce alcohol consumption and craving in alcohol-dependent patients. By increasing the number of abstinent days, gabapentin may help patients maintain abstinence.³³ Gabapentin does not appear to interact clinically with alcohol, causing neither sedation nor synergistic effects.³⁴ Its relative lack of abuse potential may be valuable in outpatient alcohol withdrawal treatment and in maintaining alcohol abstinence after detoxification.

Related resource

• Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract. 2004;53(7):545-554. www.jfponline.com/Pages.asp?AID=1730.

Drug brand names

• Acamprosate • Campral
• Alprazolam • Xanax
• Carbamazepine • Carbatrol
• Cimetidine • Tagamet
• Clonazepam • Klonopin
• Clonidine • Catapres
• Diazepam • Valium
• Disulfiram • Antabuse
• Felbamate • Felbatol
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Isoniazid • Nydrazid
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lorazepam • Ativan
• Naltrexone • ReVia, Vivitrol
• Oxazepam • Serax
• Phenobarbital • Luminal
• Phenytoin • Dilantin
• Propranolol • Inderal
• Rifampin • Rifadin
• Ritonavir • Norvir
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakote, Depakene

Disclosures

Dr. Spiegel is a speaker for Pfizer Inc. and GlaxoSmithKline.

Dr. Radac reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The authors thank Rishi Laroia, MD, Robert Swanson, MD, and Adam W. Coe, MD for their contributions to this article.

Discuss this article

Benzodiazepines are the mainstay of alcohol detoxification treatment, with extensive evidence supporting their efficacy and relative safety.¹ The risk of benzodiazepine-alcohol interaction, however, and psychomotor and cognitive impairments associated with benzodiazepine use may limit early rehabilitation efforts in hospitalized patients.² Cross-tolerance with alcohol also limits benzodiazepines’ potential benefit in outpatients with substance use disorders.

Adding anticonvulsants to acute benzodiazepine therapy has been shown to decrease alcohol withdrawal symptom severity, reduce seizure risk, and support recovery, particularly in patients with multiple alcohol withdrawal episodes. After detoxification, long-term anticonvulsant use may reduce relapse risk by decreasing post-cessation craving, without abuse liability.³

Although not all studies endorse adding anticonvulsants to benzodiazepines for managing alcohol withdrawal syndrome (AWS),⁴ we present 3 cases in which anticonvulsants were used successfully as adjuncts to lorazepam. Valproic acid, levetiracetam, and gabapentin offer advantages in acute and long-term therapy of alcohol dependence with efficacy in AWS, low abuse potential, benign safety profile, and mood-stabilizing properties.

Neurobiologic rationale

AWS manifests as a cluster of clinical symptoms including delirium tremens (DTs) and seizures (Table 1). Its pathophysiology can be explained by alcohol’s agonist effect on the gamma-aminobutyric acid (GABA) system and antagonist effect on the glutamatergic system (Table 2).⁵

Chronic alcohol intake leads to neuroadaptation in the brain in the form of down-regulation of GABA_A receptors and upregulation of N-methyl-D-aspartate receptors. During alcohol withdrawal, this neuroadaptation leads to a decrease in central GABA activity and an increase in glutamate activity, resulting in hyperexcitation, anxiety, and seizures.⁶

Little data exist regarding time to relapse after detoxification in alcohol-dependent patients. One theory—called “protracted withdrawal syndrome” (Table 1)—suggests that abstinent alcoholics return to drinking because of the same, but attenuated, neuroadaptations that trigger acute AWS.⁷

Advantages of adjunct therapy. Ntais et al⁸ evaluated benzodiazepines’ effectiveness and safety in treating AWS in a clinical review of 57 randomized, controlled trials totaling 4,051 patients. Benzodiazepines showed similar success rates as other drugs (relative risk [RR] 1.00) or anticonvulsants in particular (RR 0.88), as measured by changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment. Benzodiazepines also offered significant benefit for seizure control compared with nonanticonvulsants (RR 0.23), but less when compared with anti convulsants (RR 1.99).

Although the literature does not support anticonvulsant use for monotherapy in AWS, anticonvulsants show potential as adjunctive therapy. Valproic acid, levetiracetam, and gabapentin offer unique mechanisms of action (Table 3) and demonstrate advantages over benzodiazepine monotherapy for AWS. Adjunctive use of valproic acid,^8,9 levetiracetam,¹⁰ and gabapentin^11,12 in detoxification also has demonstrated efficacy in reducing risk of relapse and delaying relapse.

The neurobiologic rationale for using anticonvulsants in acute AWS is speculative, but these agents appear to:

• inhibit “kindling” (neuronal changes that may be associated with repeated intoxications)
• facilitate GABAergic mechanisms.⁹

Table 1

Alcohol withdrawal: Acute vs long-term symptoms

Table 2

How alcohol affects GABA and glutamate neurotransmitters

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants

CASE REPORT 1: Valproic acid for alcohol overdose

After attempting suicide with an alcohol overdose, Ms. J, age 45, is transferred from the emergency room (ER) to our psychiatry consult service 10 hours after admission. Her symptoms include nausea, tremor, headaches, agitation, disorientation, and auditory hallucinations.

Medical history reveals 25 years of alcohol dependence, multiple hospitalizations for withdrawal, and many failed attempts to quit. Ms. J reports consuming an average of 16 drink equivalents (eg, 12 oz beers) daily but denies illicit drug use.

Lab values on admission include blood alcohol concentration (BAC) 290 mg/dL (0.29%), mean corpuscular volume (MCV) 96 fL, gamma-glutamyltransferase (GGT) 164 U/L, aspartate aminotransferase (AST) 43 U/L, alanine aminotransferase (ALT) 31 U/L, and alkaline phosphatase (ALP) 151 U/L. Urine drug screen, acetaminophen, salicylate, vitamin B1 (thiamine), B12 (cyanocobalamin), B9 (folate), and electrolytes (including magnesium) are normal.

We assess alcohol withdrawal severity using the CIWA-Ar (Click here to view/download a copy of this scale). Ms. J’s initial score is 17, indicating a risk of moderate alcohol withdrawal if untreated.

In the ER, Ms. J is placed on a symptom-triggered benzodiazepine detoxification protocol with lorazepam. We add IV valproic acid, 1,250 mg (based on 20 mg/kg body weight)¹³ divided into 2 doses over the first 24 hours, then maintain IV valproic acid at 500 mg twice daily (Table 4). Within 12 hours of starting combination therapy, Ms. J scores 7 on the CIWA-Ar—indicating mild withdrawal—with subsequent scores <5. She scores 0 with no residual withdrawal symptoms within 36 hours.

Ms. J requires lorazepam, 7 mg, during the 10 hours before valproic acid is added. She requires only 2 mg lorazepam over the next 3 days and reports no side effects related to IV valproic acid. At discharge, Ms. J begins extended-release oral valproic acid, 1,250 mg (based on 25 mg/kg body weight)¹³ once daily for 2 weeks, until she can obtain outpatient follow-up.

Table 4

Benzodiazepines and anticonvulsants for alcohol detoxification

Less lorazepam needed

Adjunctive anticonvulsants can reduce the amount of lorazepam required during detoxification.^14,15 Compared with benzodiazepine monotherapy, the advantages of combination therapy—particularly in outpatient alcohol withdrawal treatment and relapse prevention—include:

• minimal interaction with alcohol (avoiding increased psychomotor deficits, cognitive impairment, and intoxication)¹⁵
• lower abuse potential
• possible efficacy in mood stabilization before, during, and after withdrawal (Table 5).¹⁶

Given the risk of seizures during AWS, anticonvulsants seem to make empirical sense. One study reported a 1% incidence of withdrawal-related seizures in 545 alcohol-dependent inpatients treated with valproic acid.¹⁷ Another case series of 37 patients found no acute sequelae when valproic acid was used for AWS.¹⁸

Anticonvulsants such as valproic acid may reduce the frequency and severity of alcohol relapse, whereas benzodiazepines may increase relapse risk.¹⁹ During a 6-week trial, patients receiving valproic acid maintenance therapy had greater abstinence rates and improved drinking outcomes compared with detoxification-only groups.⁹

One disadvantage of valproic acid is potential hepatotoxicity, an important consideration in patients with liver damage. Fortunately, Ms. J’s AST and ALT values remained within normal limits during valproic acid treatment.

Table 5

Pharmacologic profiles of benzodiazepines vs 3 anticonvulsants

CASE REPORT 2: Levetiracetam for withdrawal seizures

Mr. H, age 42, presents to the ER after suffering a seizure. His medical history includes hypertension, alcohol dependence, and seizures during alcohol withdrawal. He denies a history of psychiatric illness, and his family history is unknown. He is noncompliant with hypertension treatment, which includes clonidine. Mr. H reports his usual alcohol consumption as a 6-pack of beer nightly during the week and a 12-pack nightly on weekends. He says his last drink was 4 days before admission.

Mr. H scores 19 on the CIWA-Ar, placing him at risk for moderate withdrawal. Head CT shows diffuse atrophy, without evidence of an acute intracranial process. BAC is zero on admission, and urine drug screen is negative. Amylase, lipase, and lactate dehydrogenase (LDH) levels suggest acute pancreatitis. AST is elevated to 131 U/L, ALT is elevated to 42 U/L, but MCV is within normal limits.

The psychiatric service is consulted on day 2 of admission, and we prescribe levetiracetam, 500 mg IV every 8 hours.²⁰ IV lorazepam also is available as needed: 1 mg every 8 hours for the first 2 days, then 1 mg every 12 hours for 2 days, then 1 mg every 24 hours. The patient’s CIWA-Ar score is 9 on days 2 and 3 of admission, followed by scores consistently between 2 and 3 after scheduled levetiracetam administration. Mr. H requires 3 mg of lorazepam the remainder of his hospitalization. He is discharged on day 7 with a CIWA-Ar score of 2, and reports no adverse effects related to levetiracetam. He leaves the hospital with a 2-week prescription for oral levetiracetam, 500 mg tid.

Advantages of levetiracetam

Levetiracetam is FDA-approved for adjunctive treatment of adults with partial-onset seizures.²¹ Successful AWS treatment with adjunctive levetiracetam has been supported by few but promising studies.^10,20 Potential advantages of levetiracetam in detoxification include:

• a lack of GABAergic properties, which limits the risk of intoxication or respiratory insufficiency when combined with alcohol²¹
• low drug-drug interaction risk because of nonhepatic metabolism and primary renal excretion.^22,23

We selected levetiracetam for Mr. H because of his history of alcohol withdrawal seizures and acute pancreatitis. Anticonvulsants may be more effective than lorazepam in reducing the risk of alcohol withdrawal seizures,²⁴ and we felt valproic acid might not be safe for him because of its low but real risk of pancreatitis.¹³ We based our levetiracetam dosing on a small open-label trial²⁰ and product information for treating adults with partial-onset seizures.²⁵

Studies also demonstrate levetiracetam’s potential for relapse prevention during outpatient therapy. In a 10-week trial, levetiracetam decreased the number of standard drinks in alcohol-dependent patients from 5.3 to 1.7 per day.¹⁰ This was a small open trial, however, and large controlled trials support the usefulness of other, FDA-approved medications—including disulfiram, naltrexone, and acamprosate—for alcohol relapse prevention.

CASE REPORT 3: Gabapentin for acute withdrawal

Mr. B, age 38, presents to the ER after a 13-day alcohol binge. He has been drinking increasing amounts of alcohol over 6 weeks. Three months earlier, Mr. B was admitted for alcohol withdrawal treatment and received 49 mg of lorazepam over 3 days. This resulted in his transfer from the step-down unit to the intensive care unit for increased agitation, possibly caused by paradoxical disinhibition from excessive lorazepam use.²⁶

Mr. B’s medical history is significant for alcohol-induced seizures, DTs, traumatic brain injury related to craniotomy, and right arm amputation. Mr. B drinks approximately 24 beers per day. He denies tobacco use but admits to past use of cocaine, marijuana, and heroin.

On admission, Mr. B’s BAC is 360 mg/dL (0.36%), AST is elevated at 72 U/L, ALT at 42 U/L, and LDH significantly elevated at 384 U/L. Urine drug screen is negative, and his CIWA-Ar score is 23. His score of –1 on the Richmond Agitation and Sedation Scale (RASS)²⁷ correlates with very mild sedation.

Guided by Bonnet et al²⁸ and clinical experience, we start Mr. B on gabapentin, 1,200 mg tid, and IV lorazepam, 2 mg every 8 hours as needed for breakthrough withdrawal. We decrease lorazepam by 50% every other day until Mr. B is discharged. On days 2, 3, and 4, Mr. B’s CIWA-Ar scores are 6, 9, and 2, respectively. His RASS score drops from –1 on days 1 and 2 to 0 until discharge, indicating an alert and calm state.

Mr. B requires a total of 2 mg of lorazepam throughout hospitalization. He finishes alcohol detoxification on day 4 and is discharged with a prescription for gabapentin, 1,200 mg tid. Two weeks later, when he is admitted to a 28-day inpatient alcohol rehabilitation unit, Mr. B has not relapsed.

More abstinent days

Gabapentin is FDA-approved as adjunctive therapy for partial seizures. Off-label, it has been generally efficacious as an adjunct in alcohol detoxification.^29-32 We chose adjunctive anticonvulsant therapy for Mr. B because of his history of alcohol-induced seizures. We chose gabapentin instead of valproic acid because of Mr. B’s liver damage and gabapentin’s lack of hepatic metabolism.

Gabapentin may reduce alcohol consumption and craving in alcohol-dependent patients. By increasing the number of abstinent days, gabapentin may help patients maintain abstinence.³³ Gabapentin does not appear to interact clinically with alcohol, causing neither sedation nor synergistic effects.³⁴ Its relative lack of abuse potential may be valuable in outpatient alcohol withdrawal treatment and in maintaining alcohol abstinence after detoxification.

Related resource

• Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract. 2004;53(7):545-554. www.jfponline.com/Pages.asp?AID=1730.

Drug brand names

• Acamprosate • Campral
• Alprazolam • Xanax
• Carbamazepine • Carbatrol
• Cimetidine • Tagamet
• Clonazepam • Klonopin
• Clonidine • Catapres
• Diazepam • Valium
• Disulfiram • Antabuse
• Felbamate • Felbatol
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Isoniazid • Nydrazid
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lorazepam • Ativan
• Naltrexone • ReVia, Vivitrol
• Oxazepam • Serax
• Phenobarbital • Luminal
• Phenytoin • Dilantin
• Propranolol • Inderal
• Rifampin • Rifadin
• Ritonavir • Norvir
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakote, Depakene

Disclosures

Dr. Spiegel is a speaker for Pfizer Inc. and GlaxoSmithKline.

Dr. Radac reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The authors thank Rishi Laroia, MD, Robert Swanson, MD, and Adam W. Coe, MD for their contributions to this article.

Discuss this article

Benzodiazepines are the mainstay of alcohol detoxification treatment, with extensive evidence supporting their efficacy and relative safety.¹ The risk of benzodiazepine-alcohol interaction, however, and psychomotor and cognitive impairments associated with benzodiazepine use may limit early rehabilitation efforts in hospitalized patients.² Cross-tolerance with alcohol also limits benzodiazepines’ potential benefit in outpatients with substance use disorders.

Adding anticonvulsants to acute benzodiazepine therapy has been shown to decrease alcohol withdrawal symptom severity, reduce seizure risk, and support recovery, particularly in patients with multiple alcohol withdrawal episodes. After detoxification, long-term anticonvulsant use may reduce relapse risk by decreasing post-cessation craving, without abuse liability.³

Although not all studies endorse adding anticonvulsants to benzodiazepines for managing alcohol withdrawal syndrome (AWS),⁴ we present 3 cases in which anticonvulsants were used successfully as adjuncts to lorazepam. Valproic acid, levetiracetam, and gabapentin offer advantages in acute and long-term therapy of alcohol dependence with efficacy in AWS, low abuse potential, benign safety profile, and mood-stabilizing properties.

Neurobiologic rationale

AWS manifests as a cluster of clinical symptoms including delirium tremens (DTs) and seizures (Table 1). Its pathophysiology can be explained by alcohol’s agonist effect on the gamma-aminobutyric acid (GABA) system and antagonist effect on the glutamatergic system (Table 2).⁵

Chronic alcohol intake leads to neuroadaptation in the brain in the form of down-regulation of GABA_A receptors and upregulation of N-methyl-D-aspartate receptors. During alcohol withdrawal, this neuroadaptation leads to a decrease in central GABA activity and an increase in glutamate activity, resulting in hyperexcitation, anxiety, and seizures.⁶

Little data exist regarding time to relapse after detoxification in alcohol-dependent patients. One theory—called “protracted withdrawal syndrome” (Table 1)—suggests that abstinent alcoholics return to drinking because of the same, but attenuated, neuroadaptations that trigger acute AWS.⁷

Advantages of adjunct therapy. Ntais et al⁸ evaluated benzodiazepines’ effectiveness and safety in treating AWS in a clinical review of 57 randomized, controlled trials totaling 4,051 patients. Benzodiazepines showed similar success rates as other drugs (relative risk [RR] 1.00) or anticonvulsants in particular (RR 0.88), as measured by changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment. Benzodiazepines also offered significant benefit for seizure control compared with nonanticonvulsants (RR 0.23), but less when compared with anti convulsants (RR 1.99).

Although the literature does not support anticonvulsant use for monotherapy in AWS, anticonvulsants show potential as adjunctive therapy. Valproic acid, levetiracetam, and gabapentin offer unique mechanisms of action (Table 3) and demonstrate advantages over benzodiazepine monotherapy for AWS. Adjunctive use of valproic acid,^8,9 levetiracetam,¹⁰ and gabapentin^11,12 in detoxification also has demonstrated efficacy in reducing risk of relapse and delaying relapse.

The neurobiologic rationale for using anticonvulsants in acute AWS is speculative, but these agents appear to:

• inhibit “kindling” (neuronal changes that may be associated with repeated intoxications)
• facilitate GABAergic mechanisms.⁹

Table 1

Alcohol withdrawal: Acute vs long-term symptoms

Table 2

How alcohol affects GABA and glutamate neurotransmitters

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants

CASE REPORT 1: Valproic acid for alcohol overdose

After attempting suicide with an alcohol overdose, Ms. J, age 45, is transferred from the emergency room (ER) to our psychiatry consult service 10 hours after admission. Her symptoms include nausea, tremor, headaches, agitation, disorientation, and auditory hallucinations.

Medical history reveals 25 years of alcohol dependence, multiple hospitalizations for withdrawal, and many failed attempts to quit. Ms. J reports consuming an average of 16 drink equivalents (eg, 12 oz beers) daily but denies illicit drug use.

Lab values on admission include blood alcohol concentration (BAC) 290 mg/dL (0.29%), mean corpuscular volume (MCV) 96 fL, gamma-glutamyltransferase (GGT) 164 U/L, aspartate aminotransferase (AST) 43 U/L, alanine aminotransferase (ALT) 31 U/L, and alkaline phosphatase (ALP) 151 U/L. Urine drug screen, acetaminophen, salicylate, vitamin B1 (thiamine), B12 (cyanocobalamin), B9 (folate), and electrolytes (including magnesium) are normal.

We assess alcohol withdrawal severity using the CIWA-Ar (Click here to view/download a copy of this scale). Ms. J’s initial score is 17, indicating a risk of moderate alcohol withdrawal if untreated.

In the ER, Ms. J is placed on a symptom-triggered benzodiazepine detoxification protocol with lorazepam. We add IV valproic acid, 1,250 mg (based on 20 mg/kg body weight)¹³ divided into 2 doses over the first 24 hours, then maintain IV valproic acid at 500 mg twice daily (Table 4). Within 12 hours of starting combination therapy, Ms. J scores 7 on the CIWA-Ar—indicating mild withdrawal—with subsequent scores <5. She scores 0 with no residual withdrawal symptoms within 36 hours.

Ms. J requires lorazepam, 7 mg, during the 10 hours before valproic acid is added. She requires only 2 mg lorazepam over the next 3 days and reports no side effects related to IV valproic acid. At discharge, Ms. J begins extended-release oral valproic acid, 1,250 mg (based on 25 mg/kg body weight)¹³ once daily for 2 weeks, until she can obtain outpatient follow-up.

Table 4

Benzodiazepines and anticonvulsants for alcohol detoxification

Less lorazepam needed

Adjunctive anticonvulsants can reduce the amount of lorazepam required during detoxification.^14,15 Compared with benzodiazepine monotherapy, the advantages of combination therapy—particularly in outpatient alcohol withdrawal treatment and relapse prevention—include:

• minimal interaction with alcohol (avoiding increased psychomotor deficits, cognitive impairment, and intoxication)¹⁵
• lower abuse potential
• possible efficacy in mood stabilization before, during, and after withdrawal (Table 5).¹⁶

Given the risk of seizures during AWS, anticonvulsants seem to make empirical sense. One study reported a 1% incidence of withdrawal-related seizures in 545 alcohol-dependent inpatients treated with valproic acid.¹⁷ Another case series of 37 patients found no acute sequelae when valproic acid was used for AWS.¹⁸

Anticonvulsants such as valproic acid may reduce the frequency and severity of alcohol relapse, whereas benzodiazepines may increase relapse risk.¹⁹ During a 6-week trial, patients receiving valproic acid maintenance therapy had greater abstinence rates and improved drinking outcomes compared with detoxification-only groups.⁹

One disadvantage of valproic acid is potential hepatotoxicity, an important consideration in patients with liver damage. Fortunately, Ms. J’s AST and ALT values remained within normal limits during valproic acid treatment.

Table 5

Pharmacologic profiles of benzodiazepines vs 3 anticonvulsants

CASE REPORT 2: Levetiracetam for withdrawal seizures

Mr. H, age 42, presents to the ER after suffering a seizure. His medical history includes hypertension, alcohol dependence, and seizures during alcohol withdrawal. He denies a history of psychiatric illness, and his family history is unknown. He is noncompliant with hypertension treatment, which includes clonidine. Mr. H reports his usual alcohol consumption as a 6-pack of beer nightly during the week and a 12-pack nightly on weekends. He says his last drink was 4 days before admission.

Mr. H scores 19 on the CIWA-Ar, placing him at risk for moderate withdrawal. Head CT shows diffuse atrophy, without evidence of an acute intracranial process. BAC is zero on admission, and urine drug screen is negative. Amylase, lipase, and lactate dehydrogenase (LDH) levels suggest acute pancreatitis. AST is elevated to 131 U/L, ALT is elevated to 42 U/L, but MCV is within normal limits.

The psychiatric service is consulted on day 2 of admission, and we prescribe levetiracetam, 500 mg IV every 8 hours.²⁰ IV lorazepam also is available as needed: 1 mg every 8 hours for the first 2 days, then 1 mg every 12 hours for 2 days, then 1 mg every 24 hours. The patient’s CIWA-Ar score is 9 on days 2 and 3 of admission, followed by scores consistently between 2 and 3 after scheduled levetiracetam administration. Mr. H requires 3 mg of lorazepam the remainder of his hospitalization. He is discharged on day 7 with a CIWA-Ar score of 2, and reports no adverse effects related to levetiracetam. He leaves the hospital with a 2-week prescription for oral levetiracetam, 500 mg tid.

Advantages of levetiracetam

Levetiracetam is FDA-approved for adjunctive treatment of adults with partial-onset seizures.²¹ Successful AWS treatment with adjunctive levetiracetam has been supported by few but promising studies.^10,20 Potential advantages of levetiracetam in detoxification include:

• a lack of GABAergic properties, which limits the risk of intoxication or respiratory insufficiency when combined with alcohol²¹
• low drug-drug interaction risk because of nonhepatic metabolism and primary renal excretion.^22,23

We selected levetiracetam for Mr. H because of his history of alcohol withdrawal seizures and acute pancreatitis. Anticonvulsants may be more effective than lorazepam in reducing the risk of alcohol withdrawal seizures,²⁴ and we felt valproic acid might not be safe for him because of its low but real risk of pancreatitis.¹³ We based our levetiracetam dosing on a small open-label trial²⁰ and product information for treating adults with partial-onset seizures.²⁵

Studies also demonstrate levetiracetam’s potential for relapse prevention during outpatient therapy. In a 10-week trial, levetiracetam decreased the number of standard drinks in alcohol-dependent patients from 5.3 to 1.7 per day.¹⁰ This was a small open trial, however, and large controlled trials support the usefulness of other, FDA-approved medications—including disulfiram, naltrexone, and acamprosate—for alcohol relapse prevention.

CASE REPORT 3: Gabapentin for acute withdrawal

Mr. B, age 38, presents to the ER after a 13-day alcohol binge. He has been drinking increasing amounts of alcohol over 6 weeks. Three months earlier, Mr. B was admitted for alcohol withdrawal treatment and received 49 mg of lorazepam over 3 days. This resulted in his transfer from the step-down unit to the intensive care unit for increased agitation, possibly caused by paradoxical disinhibition from excessive lorazepam use.²⁶

Mr. B’s medical history is significant for alcohol-induced seizures, DTs, traumatic brain injury related to craniotomy, and right arm amputation. Mr. B drinks approximately 24 beers per day. He denies tobacco use but admits to past use of cocaine, marijuana, and heroin.

On admission, Mr. B’s BAC is 360 mg/dL (0.36%), AST is elevated at 72 U/L, ALT at 42 U/L, and LDH significantly elevated at 384 U/L. Urine drug screen is negative, and his CIWA-Ar score is 23. His score of –1 on the Richmond Agitation and Sedation Scale (RASS)²⁷ correlates with very mild sedation.

Guided by Bonnet et al²⁸ and clinical experience, we start Mr. B on gabapentin, 1,200 mg tid, and IV lorazepam, 2 mg every 8 hours as needed for breakthrough withdrawal. We decrease lorazepam by 50% every other day until Mr. B is discharged. On days 2, 3, and 4, Mr. B’s CIWA-Ar scores are 6, 9, and 2, respectively. His RASS score drops from –1 on days 1 and 2 to 0 until discharge, indicating an alert and calm state.

Mr. B requires a total of 2 mg of lorazepam throughout hospitalization. He finishes alcohol detoxification on day 4 and is discharged with a prescription for gabapentin, 1,200 mg tid. Two weeks later, when he is admitted to a 28-day inpatient alcohol rehabilitation unit, Mr. B has not relapsed.

More abstinent days

Gabapentin is FDA-approved as adjunctive therapy for partial seizures. Off-label, it has been generally efficacious as an adjunct in alcohol detoxification.^29-32 We chose adjunctive anticonvulsant therapy for Mr. B because of his history of alcohol-induced seizures. We chose gabapentin instead of valproic acid because of Mr. B’s liver damage and gabapentin’s lack of hepatic metabolism.

Gabapentin may reduce alcohol consumption and craving in alcohol-dependent patients. By increasing the number of abstinent days, gabapentin may help patients maintain abstinence.³³ Gabapentin does not appear to interact clinically with alcohol, causing neither sedation nor synergistic effects.³⁴ Its relative lack of abuse potential may be valuable in outpatient alcohol withdrawal treatment and in maintaining alcohol abstinence after detoxification.

Related resource

• Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract. 2004;53(7):545-554. www.jfponline.com/Pages.asp?AID=1730.

Drug brand names

• Acamprosate • Campral
• Alprazolam • Xanax
• Carbamazepine • Carbatrol
• Cimetidine • Tagamet
• Clonazepam • Klonopin
• Clonidine • Catapres
• Diazepam • Valium
• Disulfiram • Antabuse
• Felbamate • Felbatol
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Isoniazid • Nydrazid
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lorazepam • Ativan
• Naltrexone • ReVia, Vivitrol
• Oxazepam • Serax
• Phenobarbital • Luminal
• Phenytoin • Dilantin
• Propranolol • Inderal
• Rifampin • Rifadin
• Ritonavir • Norvir
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakote, Depakene

Disclosures

Dr. Spiegel is a speaker for Pfizer Inc. and GlaxoSmithKline.

Dr. Radac reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The authors thank Rishi Laroia, MD, Robert Swanson, MD, and Adam W. Coe, MD for their contributions to this article.

Hospitalized patients who are not truthful about their alcohol consumption may be at risk for an unplanned withdrawal. Self-reports of alcohol use—such as CAGE and the Alcohol Use Disorders Identification Test (AUDIT)—are valid, inexpensive, and noninvasive, but patients easily can feign results.¹ Biochemical measures are more objective, and combinations of markers are an effective tool to detect recent heavy drinking in the 10% to 25% of patients who underreport alcohol use.²

Biochemical measures can detect acute alcohol intoxication and recent prolonged drinking. Because marker levels return to normal after long-term abstinence, ongoing monitoring can help detect a relapse before a patient admits to it.³

This article presents 3 cases in which biochemical markers helped prevent alcohol withdrawal in patients who denied alcohol abuse. We discuss why we ordered biochemical tests and which combinations provided highly sensitive results.

CASE 1: Depression and substance abuse

Ms. C, age 39, presents with bleeding gums due to excessive warfarin, which she takes prophylactically for a history of deep vein thrombosis. She is seen by the psychiatric consultation service for depression—which she says she has experienced since “the day I was born”—and substance abuse that includes a history binge drinking. Ms. C says she has stopped drinking and remained abstinent for the past year because she is fearful of further damaging her kidneys. She also denies psychosis. She does not have a history or symptoms of hepatobiliary or hematologic disease.

Challenge. Despite Ms. C’s self-reported 1 year of sobriety, her history of binge drinking and depression calls for evaluating her alcohol withdrawal risk. Laboratory markers of alcohol abuse are the only means to assess her recent drinking behavior.

Discussion. Lab results include serum albumin of 3.4 g/dL, total bilirubin of 0.3 mg/dL, total protein of 6.3 g/dL, aspartate aminotransferase (AST) of 13 U/L, alanine aminotransferase (ALT) of 19 U/L, alkaline phosphatase of 136 U/L, and blood ammonia level of 37 μg/dL. Gamma-glutamyl transferase (GGT) is elevated at 104 U/L (normal range for women: 0 to 45 U/L). Mean corpuscular volume (MCV) is elevated at 101 fL (normal range 80 to 100 fL).

The combination of elevated MCV and GGT has a 95% sensitivity for alcohol abuse.⁴ GGT levels become elevated after 24 hours to 2 weeks of heavy alcohol consumption and return to normal within 2 to 6 weeks of abstinence, which allows them to detect binge drinking. MCV takes 6 to 8 weeks of heavy drinking—we which we define as consuming ≥40 grams of alcohol/day⁵—to become elevated and returns to normal within 3 months of abstinence.

These data provide evidence that Ms. C recently consumed substantial amounts of alcohol. As a result, we start her on alcohol withdrawal precautions (AWP).

Markers of alcohol abuse

Biochemical markers commonly used to detect alcohol abuse (Table 1) include:

• blood alcohol level (BAL)
• MCV
• liver function tests (LFTs) such as ALT, AST, and GGT
• carbohydrate deficient transferrin (CDT).

Table 1

By the numbers: Biomarkers of excessive alcohol consumption

BAL can document acute alcohol intoxication, but its use is limited because alcohol has a 4-hour half-life and an elimination rate of 7 grams/hour—equivalent to 1 drink/hour.⁶ (A “drink” typically is defined as a 12-ounce bottle of beer or wine cooler, a 5-ounce glass of wine, or 1.5 ounces of 80-proof distilled spirits.) Therefore, BAL will identify as false negatives alcohol-dependent patients who abstain from alcohol within 24 hours of testing.

MCV is an index of the average volume of erythrocytes. Macrocytosis occurs when the volume exceeds 100 fL. Elevated MCV is the most typical morphologic abnormality associated with excessive alcohol consumption^7,8 and macrocytosis—sometimes without associated anemia—is often evident in persons with alcoholism. MCV elevates after 6 weeks of alcohol misuse and may remain elevated for up to 3 months after a person has stopped drinking.⁹

Because patients with disorders unrelated to alcohol use can have elevated MCV, alone it is not a useful screening marker for alcohol abuse.¹⁰ Additionally, because macrocytosis can persist under strictly controlled alcohol abstinence, MCV is not a reliable clinical indicator of relapse.¹¹

LFTs measure enzymes and proteins. ALT, AST, and GGT are the most relevant for detecting heavy drinking. An AST:ALT ratio >2:1 supports a suspicion of alcohol abuse.¹² More than 90% of patients with an AST:ALT ratio of 2:1 have alcoholic liver disease. This increases to more than 96% if the ratio is 3:1.¹³

GGT is an enzyme concentrated in the liver, bile ducts, and kidneys; normal range is 0 to 45 U/L (for females) or 53 U/L (for males).¹⁴ GGT levels >30 U/L correlate with alcohol consumption of >4 drinks per day.¹⁵ GGT has a half-life of 14 to 26 days and remains elevated for 4 to 6 weeks after drinking cessation, which make it useful for monitoring abstinence in treatment programs.¹⁶ Sensitivity ranges from 37% to 85% and specificity is as high as 93% in nonmedical populations.¹⁷ Although nonalcoholic liver disease can elevate GGT in persons who do not abuse alcohol, 50% to 72% of GGT elevations can be explained by excessive alcohol consumption.¹⁸

CDT is a newer biomarker used to monitor alcohol consumption. The most accurate way to express CDT level is as a percentage of total transferrin concentration. This method accounts for individual variations in transferrin levels, thus minimizing false positives.¹⁸ In persons who consume >4 or 5 drinks per day for 2 weeks or more, CDT is >1.3% of total transferrin.¹⁹ Unfortunately, because it is expensive and requires sophisticated test methodology, CDT testing is not available at most hospitals.²⁰

Combinations improve detection

Each biochemical measure has strengths and weaknesses as a marker for determining patients’ alcohol consumption (Table 2). CDT and GGT show the highest sensitivity for heavy drinking, and CDT has a higher specificity than GGT (Table 3).^21,22 Relapse to alcohol use after abstinence may be best identified by a simultaneous 30% increase in CDT and GGT.⁵

Because GGT has a longer half-life than CDT, its diagnostic efficiency in detecting alcohol relapse may not develop until 4 weeks after alcohol detoxification, whereas CDT may become clinically useful for detecting relapse as early as 1 week after detoxification.²³

Table 2

Biomarkers of alcohol use: Strengths and weaknesses

Table 3

Interpreting diagnostic test performance

There is evidence that combining tests can improve alcohol use detection.²⁴ For example, Dolman et al²⁵ found that the ability of the AUDIT questionnaire to correctly predict which patients would experience alcohol withdrawal increases when it is used in combination with biochemical markers. Specifically, the positive predictive value of an AUDIT score ≥8 increased from 17% to 47% when found in combination with ≥2 abnormal biochemical marker levels; the study looked at GGT, ALT, AST, and MCV. Sensitivity was 94% and specificity was 98%.

Similarly, combinations of biochemical markers—especially CDT and GGT—have improved detection of alcohol use and subsequent risk of withdrawal.²⁶Table 4 provides a summary of studies that evaluated using combinations of biochemical markers.^4,5,27-31

Table 4

Combining biomarker tests: An effective approach

Consider patients’ comorbidities

Patients at risk for underreporting alcohol use include those with unemployment histories, previous alcohol treatment, and higher scores on the Alcohol Dependence Scale (18.5, SD=8.1).² Interpret biochemical testing results in the context of a patient’s overall clinical picture.

The following 2 case patients denied or underreported recent alcohol use but we determined they were at high risk for an alcohol disorder because of their medical and/or psychiatric histories. Analysis of biochemical markers helped assess the risk of alcohol withdrawal.

CASE 2: Altered mental status

Family members bring Mr. N, age 44, to the hospital because of his odd behavior. He presents with paranoid delusions and an inappropriate elated mood. His medical history includes acquired immune deficiency syndrome (AIDS). After cerebrospinal fluid analysis, computed tomography of the head, electroencephalogram, and metabolic workup are within normal limits, the patient is diagnosed with human immunodeficiency virus (HIV) mania and is admitted.

On admission, Mr. N denies alcohol use. A blood alcohol/urine toxicity screen is negative. One day after admission, Mr. M develops elevated blood pressure and tachycardia and reports headache and nausea.

Challenge. Gathering a valid history of Mr. N’s alcohol use is difficult because of his acutely altered mental status and manic-like state. We use laboratory data to assess his risk of alcohol withdrawal. His liver function tests include an AST of 33 U/L, ALT of 30 U/L, and an alkaline phosphatase of 94 U/L. MCV is normal at 90 fL. Interestingly, the GGT level is elevated almost 4 times normal at 164 U/L.

Discussion. Although Mr. N denied alcohol use and presented with a negative BAL, laboratory data support alcohol dependence. His GGT was elevated well beyond normal limits, without evidence of hepatobiliary disease. GGT has a sensitivity as high as 85%³² and limited specificity for alcohol abuse. Because of his high probability of recent alcohol consumption, we place Mr. N on AWP.

We postulate that our patient’s autonomic instability, headache, and nausea are related to alcohol withdrawal. We are aware that delirium occurs frequently in patients with HIV infection, and although Mr. N’s medical workup is negative, HIV infection can produce an acute encephalopathy that could resemble our patient’s clinical picture.³³

Mr. N’s autonomic instability, headache, and nausea abated after treatment for alcohol withdrawal.

CASE 3: Suicide attempt?

Mr. S, age 28, presents to the trauma service with a self-inflicted gunshot wound to the face. He reports feeling depressed for the last year but denies a history of psychotic symptoms or heroin withdrawal symptoms. He also denies recent or past alcohol abuse and does not have a history of biliary tract disease or megaloblastic anemia. His mother tells us Mr. S has had a history of depression since childhood.

Challenge. Based on Mr. S’ apparent suicide attempt and history, we feel he is at high risk for alcohol abuse. We use laboratory markers to assess the likelihood of alcohol consumption and possibly decrease his risk of alcohol withdrawal.

Discussion. Mr. S’ lab data show an MCV of 91 fL, AST of 95 U/L, alanine ALT of 156 U/L, and alkaline phosphatase of 160 U/L. GGT was elevated at 122 U/L.

Although Mr. S’ MCV is within the normal range, his GGT is elevated, and the combination of an elevated GGT and MCV has a 95% sensitivity for the diagnosis of alcohol abuse. We place Mr. S on alcohol withdrawal precautions and discuss with him the potential life-threatening complications of alcohol withdrawal. Confronted with this information and the possible implication of his elevated LFTs, the patient admits his alcohol history—which consists of drinking 12 beers/day for at least the past 2 years. He admits this despite exhibiting no signs or symptoms of alcohol withdrawal.

Related Resources

• National Institute on Alcohol Abuse and Alcoholism Data/Statistical Tables. www.niaaa.nih.gov/Resources/DatabaseResources/QuickFacts.
• Maisto SA, Connors GJ, Allen JP. Contrasting self-report screens for alcohol problems: a review. Alcohol Clin Exp Res 1995;19(6):1510-6.
• Coulton S, Drummond C, James D, et al. Opportunistic screening for alcohol use disorders in primary care: comparative study. BMJ 2006;332:511-7.

Bottom line

Because CDT—the most accurate biomarker—is not available at most hospitals, we recommend using combinations of other measures to detect unreported recent alcohol consumption. If GGT and MCV are elevated, GGT is elevated and AST:ALT is >2:1, or MCV is elevated and AST:ALT is >2:1, consider initiating alcohol withdrawal precautions.

Acknowledgement

The authors acknowledge Daiana Radac, BA, a third-year medical student at Eastern Virginia Medical School, for her contributions to this article.

Hospitalized patients who are not truthful about their alcohol consumption may be at risk for an unplanned withdrawal. Self-reports of alcohol use—such as CAGE and the Alcohol Use Disorders Identification Test (AUDIT)—are valid, inexpensive, and noninvasive, but patients easily can feign results.¹ Biochemical measures are more objective, and combinations of markers are an effective tool to detect recent heavy drinking in the 10% to 25% of patients who underreport alcohol use.²

Biochemical measures can detect acute alcohol intoxication and recent prolonged drinking. Because marker levels return to normal after long-term abstinence, ongoing monitoring can help detect a relapse before a patient admits to it.³

This article presents 3 cases in which biochemical markers helped prevent alcohol withdrawal in patients who denied alcohol abuse. We discuss why we ordered biochemical tests and which combinations provided highly sensitive results.

CASE 1: Depression and substance abuse

Ms. C, age 39, presents with bleeding gums due to excessive warfarin, which she takes prophylactically for a history of deep vein thrombosis. She is seen by the psychiatric consultation service for depression—which she says she has experienced since “the day I was born”—and substance abuse that includes a history binge drinking. Ms. C says she has stopped drinking and remained abstinent for the past year because she is fearful of further damaging her kidneys. She also denies psychosis. She does not have a history or symptoms of hepatobiliary or hematologic disease.

Challenge. Despite Ms. C’s self-reported 1 year of sobriety, her history of binge drinking and depression calls for evaluating her alcohol withdrawal risk. Laboratory markers of alcohol abuse are the only means to assess her recent drinking behavior.

Discussion. Lab results include serum albumin of 3.4 g/dL, total bilirubin of 0.3 mg/dL, total protein of 6.3 g/dL, aspartate aminotransferase (AST) of 13 U/L, alanine aminotransferase (ALT) of 19 U/L, alkaline phosphatase of 136 U/L, and blood ammonia level of 37 μg/dL. Gamma-glutamyl transferase (GGT) is elevated at 104 U/L (normal range for women: 0 to 45 U/L). Mean corpuscular volume (MCV) is elevated at 101 fL (normal range 80 to 100 fL).

The combination of elevated MCV and GGT has a 95% sensitivity for alcohol abuse.⁴ GGT levels become elevated after 24 hours to 2 weeks of heavy alcohol consumption and return to normal within 2 to 6 weeks of abstinence, which allows them to detect binge drinking. MCV takes 6 to 8 weeks of heavy drinking—we which we define as consuming ≥40 grams of alcohol/day⁵—to become elevated and returns to normal within 3 months of abstinence.

These data provide evidence that Ms. C recently consumed substantial amounts of alcohol. As a result, we start her on alcohol withdrawal precautions (AWP).

Markers of alcohol abuse

Biochemical markers commonly used to detect alcohol abuse (Table 1) include:

• blood alcohol level (BAL)
• MCV
• liver function tests (LFTs) such as ALT, AST, and GGT
• carbohydrate deficient transferrin (CDT).

Table 1

By the numbers: Biomarkers of excessive alcohol consumption

BAL can document acute alcohol intoxication, but its use is limited because alcohol has a 4-hour half-life and an elimination rate of 7 grams/hour—equivalent to 1 drink/hour.⁶ (A “drink” typically is defined as a 12-ounce bottle of beer or wine cooler, a 5-ounce glass of wine, or 1.5 ounces of 80-proof distilled spirits.) Therefore, BAL will identify as false negatives alcohol-dependent patients who abstain from alcohol within 24 hours of testing.

MCV is an index of the average volume of erythrocytes. Macrocytosis occurs when the volume exceeds 100 fL. Elevated MCV is the most typical morphologic abnormality associated with excessive alcohol consumption^7,8 and macrocytosis—sometimes without associated anemia—is often evident in persons with alcoholism. MCV elevates after 6 weeks of alcohol misuse and may remain elevated for up to 3 months after a person has stopped drinking.⁹

Because patients with disorders unrelated to alcohol use can have elevated MCV, alone it is not a useful screening marker for alcohol abuse.¹⁰ Additionally, because macrocytosis can persist under strictly controlled alcohol abstinence, MCV is not a reliable clinical indicator of relapse.¹¹

LFTs measure enzymes and proteins. ALT, AST, and GGT are the most relevant for detecting heavy drinking. An AST:ALT ratio >2:1 supports a suspicion of alcohol abuse.¹² More than 90% of patients with an AST:ALT ratio of 2:1 have alcoholic liver disease. This increases to more than 96% if the ratio is 3:1.¹³

GGT is an enzyme concentrated in the liver, bile ducts, and kidneys; normal range is 0 to 45 U/L (for females) or 53 U/L (for males).¹⁴ GGT levels >30 U/L correlate with alcohol consumption of >4 drinks per day.¹⁵ GGT has a half-life of 14 to 26 days and remains elevated for 4 to 6 weeks after drinking cessation, which make it useful for monitoring abstinence in treatment programs.¹⁶ Sensitivity ranges from 37% to 85% and specificity is as high as 93% in nonmedical populations.¹⁷ Although nonalcoholic liver disease can elevate GGT in persons who do not abuse alcohol, 50% to 72% of GGT elevations can be explained by excessive alcohol consumption.¹⁸

CDT is a newer biomarker used to monitor alcohol consumption. The most accurate way to express CDT level is as a percentage of total transferrin concentration. This method accounts for individual variations in transferrin levels, thus minimizing false positives.¹⁸ In persons who consume >4 or 5 drinks per day for 2 weeks or more, CDT is >1.3% of total transferrin.¹⁹ Unfortunately, because it is expensive and requires sophisticated test methodology, CDT testing is not available at most hospitals.²⁰

Combinations improve detection

Each biochemical measure has strengths and weaknesses as a marker for determining patients’ alcohol consumption (Table 2). CDT and GGT show the highest sensitivity for heavy drinking, and CDT has a higher specificity than GGT (Table 3).^21,22 Relapse to alcohol use after abstinence may be best identified by a simultaneous 30% increase in CDT and GGT.⁵

Because GGT has a longer half-life than CDT, its diagnostic efficiency in detecting alcohol relapse may not develop until 4 weeks after alcohol detoxification, whereas CDT may become clinically useful for detecting relapse as early as 1 week after detoxification.²³

Table 2

Biomarkers of alcohol use: Strengths and weaknesses

Table 3

Interpreting diagnostic test performance

There is evidence that combining tests can improve alcohol use detection.²⁴ For example, Dolman et al²⁵ found that the ability of the AUDIT questionnaire to correctly predict which patients would experience alcohol withdrawal increases when it is used in combination with biochemical markers. Specifically, the positive predictive value of an AUDIT score ≥8 increased from 17% to 47% when found in combination with ≥2 abnormal biochemical marker levels; the study looked at GGT, ALT, AST, and MCV. Sensitivity was 94% and specificity was 98%.

Similarly, combinations of biochemical markers—especially CDT and GGT—have improved detection of alcohol use and subsequent risk of withdrawal.²⁶Table 4 provides a summary of studies that evaluated using combinations of biochemical markers.^4,5,27-31

Table 4

Combining biomarker tests: An effective approach

Consider patients’ comorbidities

Patients at risk for underreporting alcohol use include those with unemployment histories, previous alcohol treatment, and higher scores on the Alcohol Dependence Scale (18.5, SD=8.1).² Interpret biochemical testing results in the context of a patient’s overall clinical picture.

The following 2 case patients denied or underreported recent alcohol use but we determined they were at high risk for an alcohol disorder because of their medical and/or psychiatric histories. Analysis of biochemical markers helped assess the risk of alcohol withdrawal.

CASE 2: Altered mental status

Family members bring Mr. N, age 44, to the hospital because of his odd behavior. He presents with paranoid delusions and an inappropriate elated mood. His medical history includes acquired immune deficiency syndrome (AIDS). After cerebrospinal fluid analysis, computed tomography of the head, electroencephalogram, and metabolic workup are within normal limits, the patient is diagnosed with human immunodeficiency virus (HIV) mania and is admitted.

On admission, Mr. N denies alcohol use. A blood alcohol/urine toxicity screen is negative. One day after admission, Mr. M develops elevated blood pressure and tachycardia and reports headache and nausea.

Challenge. Gathering a valid history of Mr. N’s alcohol use is difficult because of his acutely altered mental status and manic-like state. We use laboratory data to assess his risk of alcohol withdrawal. His liver function tests include an AST of 33 U/L, ALT of 30 U/L, and an alkaline phosphatase of 94 U/L. MCV is normal at 90 fL. Interestingly, the GGT level is elevated almost 4 times normal at 164 U/L.

Discussion. Although Mr. N denied alcohol use and presented with a negative BAL, laboratory data support alcohol dependence. His GGT was elevated well beyond normal limits, without evidence of hepatobiliary disease. GGT has a sensitivity as high as 85%³² and limited specificity for alcohol abuse. Because of his high probability of recent alcohol consumption, we place Mr. N on AWP.

We postulate that our patient’s autonomic instability, headache, and nausea are related to alcohol withdrawal. We are aware that delirium occurs frequently in patients with HIV infection, and although Mr. N’s medical workup is negative, HIV infection can produce an acute encephalopathy that could resemble our patient’s clinical picture.³³

Mr. N’s autonomic instability, headache, and nausea abated after treatment for alcohol withdrawal.

CASE 3: Suicide attempt?

Mr. S, age 28, presents to the trauma service with a self-inflicted gunshot wound to the face. He reports feeling depressed for the last year but denies a history of psychotic symptoms or heroin withdrawal symptoms. He also denies recent or past alcohol abuse and does not have a history of biliary tract disease or megaloblastic anemia. His mother tells us Mr. S has had a history of depression since childhood.

Challenge. Based on Mr. S’ apparent suicide attempt and history, we feel he is at high risk for alcohol abuse. We use laboratory markers to assess the likelihood of alcohol consumption and possibly decrease his risk of alcohol withdrawal.

Discussion. Mr. S’ lab data show an MCV of 91 fL, AST of 95 U/L, alanine ALT of 156 U/L, and alkaline phosphatase of 160 U/L. GGT was elevated at 122 U/L.

Although Mr. S’ MCV is within the normal range, his GGT is elevated, and the combination of an elevated GGT and MCV has a 95% sensitivity for the diagnosis of alcohol abuse. We place Mr. S on alcohol withdrawal precautions and discuss with him the potential life-threatening complications of alcohol withdrawal. Confronted with this information and the possible implication of his elevated LFTs, the patient admits his alcohol history—which consists of drinking 12 beers/day for at least the past 2 years. He admits this despite exhibiting no signs or symptoms of alcohol withdrawal.

Related Resources

• National Institute on Alcohol Abuse and Alcoholism Data/Statistical Tables. www.niaaa.nih.gov/Resources/DatabaseResources/QuickFacts.
• Maisto SA, Connors GJ, Allen JP. Contrasting self-report screens for alcohol problems: a review. Alcohol Clin Exp Res 1995;19(6):1510-6.
• Coulton S, Drummond C, James D, et al. Opportunistic screening for alcohol use disorders in primary care: comparative study. BMJ 2006;332:511-7.

Bottom line

Because CDT—the most accurate biomarker—is not available at most hospitals, we recommend using combinations of other measures to detect unreported recent alcohol consumption. If GGT and MCV are elevated, GGT is elevated and AST:ALT is >2:1, or MCV is elevated and AST:ALT is >2:1, consider initiating alcohol withdrawal precautions.

Acknowledgement

The authors acknowledge Daiana Radac, BA, a third-year medical student at Eastern Virginia Medical School, for her contributions to this article.

Hospitalized patients who are not truthful about their alcohol consumption may be at risk for an unplanned withdrawal. Self-reports of alcohol use—such as CAGE and the Alcohol Use Disorders Identification Test (AUDIT)—are valid, inexpensive, and noninvasive, but patients easily can feign results.¹ Biochemical measures are more objective, and combinations of markers are an effective tool to detect recent heavy drinking in the 10% to 25% of patients who underreport alcohol use.²

Biochemical measures can detect acute alcohol intoxication and recent prolonged drinking. Because marker levels return to normal after long-term abstinence, ongoing monitoring can help detect a relapse before a patient admits to it.³

This article presents 3 cases in which biochemical markers helped prevent alcohol withdrawal in patients who denied alcohol abuse. We discuss why we ordered biochemical tests and which combinations provided highly sensitive results.

CASE 1: Depression and substance abuse

Ms. C, age 39, presents with bleeding gums due to excessive warfarin, which she takes prophylactically for a history of deep vein thrombosis. She is seen by the psychiatric consultation service for depression—which she says she has experienced since “the day I was born”—and substance abuse that includes a history binge drinking. Ms. C says she has stopped drinking and remained abstinent for the past year because she is fearful of further damaging her kidneys. She also denies psychosis. She does not have a history or symptoms of hepatobiliary or hematologic disease.

Challenge. Despite Ms. C’s self-reported 1 year of sobriety, her history of binge drinking and depression calls for evaluating her alcohol withdrawal risk. Laboratory markers of alcohol abuse are the only means to assess her recent drinking behavior.

Discussion. Lab results include serum albumin of 3.4 g/dL, total bilirubin of 0.3 mg/dL, total protein of 6.3 g/dL, aspartate aminotransferase (AST) of 13 U/L, alanine aminotransferase (ALT) of 19 U/L, alkaline phosphatase of 136 U/L, and blood ammonia level of 37 μg/dL. Gamma-glutamyl transferase (GGT) is elevated at 104 U/L (normal range for women: 0 to 45 U/L). Mean corpuscular volume (MCV) is elevated at 101 fL (normal range 80 to 100 fL).

The combination of elevated MCV and GGT has a 95% sensitivity for alcohol abuse.⁴ GGT levels become elevated after 24 hours to 2 weeks of heavy alcohol consumption and return to normal within 2 to 6 weeks of abstinence, which allows them to detect binge drinking. MCV takes 6 to 8 weeks of heavy drinking—we which we define as consuming ≥40 grams of alcohol/day⁵—to become elevated and returns to normal within 3 months of abstinence.

These data provide evidence that Ms. C recently consumed substantial amounts of alcohol. As a result, we start her on alcohol withdrawal precautions (AWP).

Markers of alcohol abuse

Biochemical markers commonly used to detect alcohol abuse (Table 1) include:

• blood alcohol level (BAL)
• MCV
• liver function tests (LFTs) such as ALT, AST, and GGT
• carbohydrate deficient transferrin (CDT).

Table 1

By the numbers: Biomarkers of excessive alcohol consumption

BAL can document acute alcohol intoxication, but its use is limited because alcohol has a 4-hour half-life and an elimination rate of 7 grams/hour—equivalent to 1 drink/hour.⁶ (A “drink” typically is defined as a 12-ounce bottle of beer or wine cooler, a 5-ounce glass of wine, or 1.5 ounces of 80-proof distilled spirits.) Therefore, BAL will identify as false negatives alcohol-dependent patients who abstain from alcohol within 24 hours of testing.

MCV is an index of the average volume of erythrocytes. Macrocytosis occurs when the volume exceeds 100 fL. Elevated MCV is the most typical morphologic abnormality associated with excessive alcohol consumption^7,8 and macrocytosis—sometimes without associated anemia—is often evident in persons with alcoholism. MCV elevates after 6 weeks of alcohol misuse and may remain elevated for up to 3 months after a person has stopped drinking.⁹

Because patients with disorders unrelated to alcohol use can have elevated MCV, alone it is not a useful screening marker for alcohol abuse.¹⁰ Additionally, because macrocytosis can persist under strictly controlled alcohol abstinence, MCV is not a reliable clinical indicator of relapse.¹¹

LFTs measure enzymes and proteins. ALT, AST, and GGT are the most relevant for detecting heavy drinking. An AST:ALT ratio >2:1 supports a suspicion of alcohol abuse.¹² More than 90% of patients with an AST:ALT ratio of 2:1 have alcoholic liver disease. This increases to more than 96% if the ratio is 3:1.¹³

GGT is an enzyme concentrated in the liver, bile ducts, and kidneys; normal range is 0 to 45 U/L (for females) or 53 U/L (for males).¹⁴ GGT levels >30 U/L correlate with alcohol consumption of >4 drinks per day.¹⁵ GGT has a half-life of 14 to 26 days and remains elevated for 4 to 6 weeks after drinking cessation, which make it useful for monitoring abstinence in treatment programs.¹⁶ Sensitivity ranges from 37% to 85% and specificity is as high as 93% in nonmedical populations.¹⁷ Although nonalcoholic liver disease can elevate GGT in persons who do not abuse alcohol, 50% to 72% of GGT elevations can be explained by excessive alcohol consumption.¹⁸

CDT is a newer biomarker used to monitor alcohol consumption. The most accurate way to express CDT level is as a percentage of total transferrin concentration. This method accounts for individual variations in transferrin levels, thus minimizing false positives.¹⁸ In persons who consume >4 or 5 drinks per day for 2 weeks or more, CDT is >1.3% of total transferrin.¹⁹ Unfortunately, because it is expensive and requires sophisticated test methodology, CDT testing is not available at most hospitals.²⁰

Combinations improve detection

Each biochemical measure has strengths and weaknesses as a marker for determining patients’ alcohol consumption (Table 2). CDT and GGT show the highest sensitivity for heavy drinking, and CDT has a higher specificity than GGT (Table 3).^21,22 Relapse to alcohol use after abstinence may be best identified by a simultaneous 30% increase in CDT and GGT.⁵

Because GGT has a longer half-life than CDT, its diagnostic efficiency in detecting alcohol relapse may not develop until 4 weeks after alcohol detoxification, whereas CDT may become clinically useful for detecting relapse as early as 1 week after detoxification.²³

Table 2

Biomarkers of alcohol use: Strengths and weaknesses

Table 3

Interpreting diagnostic test performance

There is evidence that combining tests can improve alcohol use detection.²⁴ For example, Dolman et al²⁵ found that the ability of the AUDIT questionnaire to correctly predict which patients would experience alcohol withdrawal increases when it is used in combination with biochemical markers. Specifically, the positive predictive value of an AUDIT score ≥8 increased from 17% to 47% when found in combination with ≥2 abnormal biochemical marker levels; the study looked at GGT, ALT, AST, and MCV. Sensitivity was 94% and specificity was 98%.

Similarly, combinations of biochemical markers—especially CDT and GGT—have improved detection of alcohol use and subsequent risk of withdrawal.²⁶Table 4 provides a summary of studies that evaluated using combinations of biochemical markers.^4,5,27-31

Table 4

Combining biomarker tests: An effective approach

Consider patients’ comorbidities

Patients at risk for underreporting alcohol use include those with unemployment histories, previous alcohol treatment, and higher scores on the Alcohol Dependence Scale (18.5, SD=8.1).² Interpret biochemical testing results in the context of a patient’s overall clinical picture.

The following 2 case patients denied or underreported recent alcohol use but we determined they were at high risk for an alcohol disorder because of their medical and/or psychiatric histories. Analysis of biochemical markers helped assess the risk of alcohol withdrawal.

CASE 2: Altered mental status

Family members bring Mr. N, age 44, to the hospital because of his odd behavior. He presents with paranoid delusions and an inappropriate elated mood. His medical history includes acquired immune deficiency syndrome (AIDS). After cerebrospinal fluid analysis, computed tomography of the head, electroencephalogram, and metabolic workup are within normal limits, the patient is diagnosed with human immunodeficiency virus (HIV) mania and is admitted.

On admission, Mr. N denies alcohol use. A blood alcohol/urine toxicity screen is negative. One day after admission, Mr. M develops elevated blood pressure and tachycardia and reports headache and nausea.

Challenge. Gathering a valid history of Mr. N’s alcohol use is difficult because of his acutely altered mental status and manic-like state. We use laboratory data to assess his risk of alcohol withdrawal. His liver function tests include an AST of 33 U/L, ALT of 30 U/L, and an alkaline phosphatase of 94 U/L. MCV is normal at 90 fL. Interestingly, the GGT level is elevated almost 4 times normal at 164 U/L.

Discussion. Although Mr. N denied alcohol use and presented with a negative BAL, laboratory data support alcohol dependence. His GGT was elevated well beyond normal limits, without evidence of hepatobiliary disease. GGT has a sensitivity as high as 85%³² and limited specificity for alcohol abuse. Because of his high probability of recent alcohol consumption, we place Mr. N on AWP.

We postulate that our patient’s autonomic instability, headache, and nausea are related to alcohol withdrawal. We are aware that delirium occurs frequently in patients with HIV infection, and although Mr. N’s medical workup is negative, HIV infection can produce an acute encephalopathy that could resemble our patient’s clinical picture.³³

Mr. N’s autonomic instability, headache, and nausea abated after treatment for alcohol withdrawal.

CASE 3: Suicide attempt?

Mr. S, age 28, presents to the trauma service with a self-inflicted gunshot wound to the face. He reports feeling depressed for the last year but denies a history of psychotic symptoms or heroin withdrawal symptoms. He also denies recent or past alcohol abuse and does not have a history of biliary tract disease or megaloblastic anemia. His mother tells us Mr. S has had a history of depression since childhood.

Challenge. Based on Mr. S’ apparent suicide attempt and history, we feel he is at high risk for alcohol abuse. We use laboratory markers to assess the likelihood of alcohol consumption and possibly decrease his risk of alcohol withdrawal.

Discussion. Mr. S’ lab data show an MCV of 91 fL, AST of 95 U/L, alanine ALT of 156 U/L, and alkaline phosphatase of 160 U/L. GGT was elevated at 122 U/L.

Although Mr. S’ MCV is within the normal range, his GGT is elevated, and the combination of an elevated GGT and MCV has a 95% sensitivity for the diagnosis of alcohol abuse. We place Mr. S on alcohol withdrawal precautions and discuss with him the potential life-threatening complications of alcohol withdrawal. Confronted with this information and the possible implication of his elevated LFTs, the patient admits his alcohol history—which consists of drinking 12 beers/day for at least the past 2 years. He admits this despite exhibiting no signs or symptoms of alcohol withdrawal.

Related Resources

• National Institute on Alcohol Abuse and Alcoholism Data/Statistical Tables. www.niaaa.nih.gov/Resources/DatabaseResources/QuickFacts.
• Maisto SA, Connors GJ, Allen JP. Contrasting self-report screens for alcohol problems: a review. Alcohol Clin Exp Res 1995;19(6):1510-6.
• Coulton S, Drummond C, James D, et al. Opportunistic screening for alcohol use disorders in primary care: comparative study. BMJ 2006;332:511-7.

Bottom line

Because CDT—the most accurate biomarker—is not available at most hospitals, we recommend using combinations of other measures to detect unreported recent alcohol consumption. If GGT and MCV are elevated, GGT is elevated and AST:ALT is >2:1, or MCV is elevated and AST:ALT is >2:1, consider initiating alcohol withdrawal precautions.

Acknowledgement

The authors acknowledge Daiana Radac, BA, a third-year medical student at Eastern Virginia Medical School, for her contributions to this article.