Bioethics Paper 2

Treatment of Alcohol Use Disorder in Patients with Alcoholic Liver Disease

Lorenzo Leggio, M.D., Ph.D., M.Sc.1,2 and Mary R. Lee, M.D.1

1Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD

2Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI

Abstract

Alcohol is a leading cause of liver disease worldwide. Although alcohol abstinence is the crucial

therapeutic goal for patients with alcoholic liver disease, these patients have less access to

psychosocial, behavioral and/or pharmacological treatments for alcohol use disorder. Psychosocial

and behavioral therapies include 12-step facilitation, brief interventions, cognitive behavioral

therapy, and motivational enhancement therapy. In addition to medications approved by the Food

and Drug Administration (FDA) for alcohol use disorder (disulfiram, naltrexone and acamprosate),

recent efforts to identify potential new treatments have yielded promising candidate

pharmacotherapies. Finally, more efforts are needed to integrate treatments across disciplines

toward patient-centered approaches in the management of patients with alcohol use disorder and

alcoholic liver disease.

Keywords

alcohol use disorder; liver disease; alcoholic liver disease; treatment

INTRODUCTION

Despite the mortality and morbidity resulting from alcohol use disorder(1), <10% of patients

receive treatment for alcohol use disorder(2). There is a paucity of clinical trials in patients

with alcoholic liver disease and little integration of addiction specialists into the medical

Contact information: [email protected] (L. Leggio) and [email protected] (M.R. Lee), Section on Clinical Psychoneuroendocrinology, and Neuropsychopharmacology, NIAAA & NIDA, NIH, 10 Center Drive (10CRC/15330), Room 1-5429, Bethesda, MD 20892-1108, Phone: +1 301 435 9398.

AUTHOR CONTRIBUTIONS Both authors contributed equally to all aspects of this manuscript.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

HHS Public Access Author manuscript Am J Med. Author manuscript; available in PMC 2018 February 01.

Published in final edited form as: Am J Med. 2017 February ; 130(2): 124–134. doi:10.1016/j.amjmed.2016.10.004.

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teams that care for these patients. This deficiency reflects nihilism, stigma, and a failure to

link behavioral and traditional medical research.

ALCOHOL USE DISORDER

Neurobiology of Alcohol Use Disorder

Alcohol use disorder is characterized by loss of control over alcohol consumption

accompanied by changes in brain regions responsible for the execution of motivated

behaviors, e.g.: midbrain, limbic and prefrontal cortex(3). Positive and negative reinforcement mechanisms play a role in the maladaptive pattern of alcohol consumption.

As the severity of alcohol use disorder worsens, negative reinforcement mechanisms

predominate where negative affective state is relieved by alcohol consumption, thus leading

to relapse.

Alcohol’s reinforcing effects are primarily mediated by dopamine, opioid peptides, gamma-

aminobutyric-acid, and endocannabinoids(4), while negative reinforcement involves

increased recruitment of corticotropin-releasing factor and glutamatergic systems, and

down-regulation of gamma-aminobutyric-acid transmission(3, 4).

Screening and Diagnosis of Alcohol Use Disorder

Screening instruments for problematic drinking include the Cut down-Annoyed-Guilty- Eye

opener (CAGE) and the Alcohol Use Disorders Identification Test (AUDIT) (Tables 1 and 2)

(5, 6). The CAGE is short, may be easily implemented in primary care settings and assesses

consequences of drinking. The latter makes it less sensitive as a screening tool for at-risk

drinking and gives inconsistent results across different ethnicities(7). The AUDIT actually

quantifies alcohol consumption and has been validated across different ethnicities(7). There

is a brief version of the AUDIT, developed for use in primary care settings(8).

The diagnosis of alcohol use disorder, set forth in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), is defined as a problematic pattern of drinking leading to clinically significant impairment and distress for at least 12 months (Table 3)(9).

The gold standard to quantify alcohol consumption is the Timeline Followback, a semi-

structured interview that is used mostly in research settings(10).

Objective biomarkers of alcohol use are blood, breath or urine ethanol levels which are

highly specific but only reflect very recent use. Ethyl glucuronide, a conjugated ethanol

metabolite, is detected in urine several days after drinking and can be used reliably in regular

drinkers(11). However, for a single drinking episode, the window of detection depends on

the quantity of alcohol consumed.(12, 13) Carbohydrate-deficient transferrin (CDT) is a

desialylated isoform of transferrin, increases with chronic heavy alcohol intake and is the

most specific marker of alcohol use(14); however its sensitivity is limited, particularly in

women, end-stage liver disease and overweight/obese individuals(15). Increased serum liver

enzymes, alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl

transferase (GGT), are markers of inflammation and oxidative stress, and have low

specificity for detecting alcohol use. Moderate drinking may cause elevations in liver

enzymes in obese but not normal weight individuals(13); notably, ALT is more sensitive to

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BMI and GGT to alcohol consumption. Phosphatidylethanol is an abnormal phospholipid

generated from phosphatidylcholine in the presence of ethanol and is positive in blood more

than 2 weeks after ethanol is cleared from the body(16). It is more sensitive than ethyl

glucuronide for identification of current drinking(12) and is more sensitive compared to

GGT and CDT(17). A combination of CDT with GGT improves the sensitivity of detecting

heavy drinking without loss in specificity(13).

CLINICAL STAGES OF ALCOHOLIC LIVER DISEASE

The risk for alcoholic liver disease rises with increasing daily alcohol consumption with a

threshold of 12–22 g/day in women and 24–46 g/day in men(18), however, this relationship

is not dose-dependent(19). There are individual differences and risk factors, including

genetic predisposition, age, gender, metabolic syndrome, diabetes, obesity, smoking, iron

overload, and chronic hepatitis B or C(20, 21) that modify risk.

Alcoholic liver disease comprises several forms ranging from relatively mild and reversible

steatosis (fatty liver) and alcoholic hepatitis, to fibrosis and finally cirrhosis and hepatic

failure(22). Fatty liver develops in about 90% of individuals who drink >60g/day of alcohol

and is generally reversible with 4–6 weeks abstinence(23, 24). About 25% of patients with

alcohol use disorder develop alcoholic hepatitis. Treatments for alcoholic hepatitis (e.g.: prednisone and pentoxifylline) may have limited efficacy(25), which further highlights the

critical importance of treating the underlying alcohol use disorder(26). The severity of

alcoholic hepatitis can range from mild to severe and can be superimposed on chronic liver

disease(27). Prospective studies indicate that the recent, rather than lifetime alcohol

consumption, predicts alcoholic cirrhosis(19, 28, 29). While treatments for alcoholic liver

disease have been extensively reviewed elsewhere(30–34), this review (Box 1) focuses on

the treatment of the underlying problem in these patients, i.e. alcohol use disorder.

Box 1

Review Criteria

In April 2016, we searched PubMed using the following search terms: ‘alcohol use

disorder’, ‘liver disease’, ‘alcoholic liver disease’, ‘treatment’. The references from initial

papers identified were searched to identify additional references. We focused only on

papers written in English.

TREATMENT FOR ALCOHOL USE DISORDER IN PATIENTS WITH

ALCOHOLIC LIVER DISEASE

Despite evidence that outcomes improve with integration of psychosocial and medical

care(35), there are almost no randomized studies for behavioral and/or pharmacological

treatments in patients with alcohol use disorder and alcoholic liver disease. Alcohol

abstinence is the most important therapeutic goal for patients with alcoholic liver disease, as

abstinence can improve outcome at all stages of disease(36–38).

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Psychosocial and behavioral treatments

Brief interventions (Table 4) are a counseling strategy that can be delivered by a health care

provider during a 5–10 minute medical office visit. The intervention is aimed at educating

the patient about problematic drinking, increasing motivation to change behavior, and

reinforcing skills to address problematic drinking(39). In primary care settings, studies

support the use of brief interventions to reduce drinking(40, 41) particularly when the

intervention is repeated over multiple visits with follow-up telephone consultations(39).

Although brief interventions are not sufficient by themselves in those with very heavy use or

dependence(42), they can reinforce other therapeutic approaches such as compliance to

medications(43) and/or referral to treatment programs(44, 45). This approach is typically

referred to with the acronym SBIRT: screening, brief intervention and referral to

treatment(26, 46).

Specific psychosocial and behavioral therapies for alcohol use disorder include 12-step

facilitation, cognitive behavioral therapy (CBT), and motivational enhancement therapy

(MET). Twelve-step facilitation is abstinence-based, and involves participation in Alcoholics

Anonymous meetings. The program is grounded in acceptance, spirituality and moral

inventories (47). CBT focuses on identifying triggers and maladaptive behaviors that

engender relapse. The approach encourages coping mechanisms to allow replacement of

alcohol-laden with alcohol-free circumstances(48). MET seeks to frame the decision to stop

or modify drinking in terms of a dilemma and helps the patient work through the dilemma

by “rolling with the resistance” to change (49). Lastly, mobile phone applications are

beginning to be used to support reduction in risky drinking(50).

It is not established if any of these therapies is superior. Indeed, the Matching Alcoholism

Treatments to Client Heterogeneity (MATCH) trial(51) showed that they are equivalent.

Similarly, the United Kingdom Alcohol Treatment Trial compared social/network therapy to

MET and found no difference in outcome(52). The large Combining Medications and

Behavioral Interventions (COMBINE) study examined whether combining medications and

a behavioral intervention improves drinking outcomes in patients with alcohol use

disorder(53). The intervention was a combination of all three interventions used in the

MATCH trial. In addition, COMBINE tested Medical Management, an intervention that

focuses on medication compliance, management of side-effects and goals toward harmful

drinking reduction and/or abstinence(54). The results showed that combination of the

behavioral intervention with medications was superior to medication alone and that

naltrexone combined with Medical Management can be a cost-effective way to treat alcohol

use disorder(53).

Clinical research on the use of psychosocial and behavioral treatments for alcohol use

disorder in patients with liver disease is limited. A landmark study integrating treatment for

both alcoholic liver disease and alcohol use disorder was conducted by Lieber and

colleagues(55). In this study, addition of a brief intervention to a pharmacologic treatment

trial for liver fibrosis resulted in a significant reduction in alcohol drinking. Other studies

examined behavioral approaches like CBT and MET for alcohol abstinence in patients with

alcoholic liver disease and these studies were recently reviewed systematically (13 studies;

N = 1,945) by Khan and colleagues(35). While psychosocial interventions alone were not

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effective in maintaining abstinence, combining comprehensive medical care and behavioral

approaches such as CBT and MET did increase abstinence rates. This indicates that the use

of integrated care to treat alcohol use disorder in the context of alcoholic liver disease may

lead to better outcomes.

Pharmacological treatments: management of alcohol detoxification

Alcohol withdrawal syndrome is characterized by a constellation of acute symptoms, which

may include anxiety, tremors, nausea, insomnia, and in severe cases seizures and delirium

tremens(56). Delirium tremens may occur at any time during withdrawal, most commonly

between 48–72 hours of abstinence. While up to 50% of alcoholic individuals manifest

alcohol withdrawal symptoms after stopping drinking, only a small percentage requires

medical treatment. The severity of withdrawal is typically measured with ranked scales such

as the Clinical Institute Withdrawal Assessment for Alcohol—revised (CIWA-Ar) (Table 5)

(57). While CIWA-Ar scores ≥8 but ≤15 indicate a potential need for a pharmacological

treatment, an alcohol withdrawal syndrome with a CIWA-Ar score >15 must be treated

pharmacologically. Benzodiazepines are the mainstay of treatment as they are the only class

of medications that reduces the risk of withdrawal seizures and/or delirium tremens.

In alcoholic patients with alcoholic liver disease, lorazepam or oxazepam are preferred as

they do not undergo phase I biotransformation, rather, undergo only glucuronidation which

is preserved even if liver function is compromised. Benzodiazepines may be administered on

a fixed or symptom-triggered schedule. In patients with alcohol use disorder and liver

disease, a symptom-triggered schedule (i.e. only when symptoms exceed a threshold of severity) is preferred, with assessment at least every 4 hours or more frequently if

withdrawal symptoms are present. This strategy requires close and expert monitoring to

ensure appropriate medication is provided and is preferable as it avoids unnecessary dosing

of sedative hypnotic medication. Finally, it is important to distinguish withdrawal symptoms

from those of alcohol intoxication or hepatic encephalopathy as benzodiazepines should not

be administered in the latter cases. Other factors to consider are supportive care including

fluid and electrolyte balance. Caution is needed in preventing the precipitation of Wernicke’s

encephalopathy, especially in those patients with end-stage liver disease who present with

encephalopathy. Since prolonged glucose supplementation without the addition of thiamine

can be a risk factor for the development of Wernicke’s encephalopathy, thiamine

supplementation should be given promptly(58).

Pharmacological treatments to promote abstinence and prevent relapse

Consistent with the increasing knowledge of the neurobiology of addictions(3, 4),

medications have been developed (Table 6)(59). In the US, acamprosate, disulfiram and

naltrexone (oral and intramuscular) are approved by the Food and Drug Administration

(FDA) for treatment of alcohol use disorder. A recent meta-analysis supports the efficacy of

naltrexone and acamprosate, but not disulfiram, for alcohol use disorder(60). Efforts have

also been made to test other pharmacotherapies as potential new treatments for alcohol use

disorder. These medications are FDA-approved for other indications, some of them have

shown efficacy for alcohol use disorder in Phase 2/3 trials, but are not FDA-approved for

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alcohol use disorder. Among them, the most promising are baclofen, gabapentin,

ondansetron, topiramate and varenicline(59).

There is, however, a lack of formal clinical trials that have tested the role of

pharmacotherapies in patients with alcohol use disorder and alcoholic liver disease (26).

Although hepatotoxicity with naltrexone is rare(61), naltrexone could induce liver injury and

is contraindicated in patients with liver diseases as specified in an FDA ‘‘black box”(26).

Acamprosate has not formally been tested either in patients with alcoholic liver disease,

however it is the preferable FDA-approved medication in this population as it does not

undergo hepatic metabolism; there are no reports of hepatotoxicity.

Baclofen, gabapentin, ondansetron, topiramate and varenicline have no evidence of liver

toxicity, therefore they might also be useful in patients with alcohol use disorder and

alcoholic liver disease (see Table 6 for details). However, only baclofen has been formally

tested in patients with alcohol use disorder and clinically significant alcoholic liver disease

in a randomized controlled trial (62, 63) and in observational studies(64, 65); as such,

although further research with baclofen is needed, its potential utility for treatment of

alcohol use disorder in hepatology settings has been highlighted(66, 67). Unexplored are the

combinations of pharmacotherapies and behavioral treatments and of different medications

in patients with alcohol use disorder and alcoholic liver disease.

Liver Transplantation

Liver transplantation represents a life-saving treatment for patients with end-stage liver

disease. Patients with alcohol use disorder must demonstrate 6 months’ abstinence to be

placed on a liver transplant waiting list. Relapse to drinking results in removal from the list

with the requirement to demonstrate another 6 months’ abstinence for relisting, a timeframe

that is often incompatible with the prognosis of these patients. While 6 months abstinence is

commonly required, few transplant programs include treatment programs for alcohol use

disorder(68). One-year relapse rates range from 67 to 81%(69) in patients with alcoholic

liver disease therefore, effective, ongoing rehabilitation for alcohol addiction is necessary to

achieve sustained abstinence(70). Of note, liver transplantation without the 6-month

abstinence requirement has been used to treat patients with severe, acute alcoholic hepatitis

who fail to respond to steroid therapy(71, 72). Liver transplantation in this population results

in long-term survival benefits with recidivism to drinking at rates comparable or below those

liver transplant patients who were required to have 6 months abstinence. For an extensive

review on the management of alcohol use disorder in patients requiring liver transplant,

see(68).

SHIFTING CLINICAL LANDSCAPE: COMORBIDITIES IN PATIENTS WITH

ALCOHOL USE DISORDER AND ALCOHOLIC LIVER DISEASE

There is a shifting clinical landscape of alcoholic liver disease which includes a younger age

at presentation and increasing comorbid obesity(73). By contrast, with the emergence of

efficacious direct acting antiviral (DAA) drugs for Hepatitis C (HCV)(74), the comorbid

etiology of alcohol use disorder and HCV will diminish in importance. Alcohol can be a

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singular etiology of liver disease or can be one of several etiologies, as is the case for

example, with comorbid viral hepatitis and/or obesity-related non-alcoholic steatohepatitis.

Comorbidity of HCV and alcohol confers a poorer prognosis (20). HCV is the most common

blood borne pathogen in the US with an estimated 2.7 million persons living with chronic

HCV infection(75). The prevalence of HCV is 3- to 30-fold higher in alcoholic individuals

compared with the general population(76). Alcoholism represents an independent risk factor

for HCV infection(77, 78). Concomitant alcohol use accelerates HCV disease progression.

While the threshold level of drinking responsible for this progression is not well-

established(20), the two conditions have a synergistic effect(79). As a consequence, there are

no safe levels of alcohol consumption in HCV-infected individuals, therefore alcohol

abstinence is necessary for optimal treatment of HCV infection, especially in this new era of

effective treatments for HCV.

Alcohol-induced symptoms of depression, anxiety, and insomnia are common and often

indistinguishable from a primary psychiatric disorder(80). However, these abate with

abstinence, usually within a month, though there is a protracted abstinence syndrome that

can persist for months(81). Treatment for these symptoms is sometimes required. This may

be particularly challenging in those patients with alcohol use disorder and HCV infection

who are taking DAAs, which are substrates as well as inhibitors of cytochrome P450 3A4

and P-glycoprotein. There are clinically important drug-drug interactions between these

drugs and common medications used to treat withdrawal (e.g., alprazolam; midazolam), sleep problems (e.g., zolpidem; trazodone), and psychiatric symptoms (e.g., escitalopram; St John’s Wort; carbamazepine)(82).

Finally, obesity increases risk for all stages of alcoholic liver disease(83). Prospective cohort

studies show that alcohol use disorder and obesity exert a greater than additive effect on

development of liver disease and share a common pathophysiology(84). Treating alcohol use

disorder in obese patients with liver disease and obesity will be integral to the management

of these patients. As HCV decreases in importance as an etiology for liver disease(85),

alcohol use disorder and non-alcoholic steatohepatitis will be the most common etiologies

for end-stage liver disease. As such, patients with alcohol use disorder will be prominent

among those seen in hepatology practices.

CONCLUSIONS

Alcohol abstinence represents the cornerstone in the treatment of alcoholic liver disease. The

clinical literature summarized here indicates that treatments for patients with alcoholic liver

disease exist and providing these treatments is critical. To this end, it is important to educate

physicians in addiction medicine (86). The National Institute on Alcohol Abuse and

Alcoholism has developed several professional education materials for health care

providers(87). Figure 1 outlines multimodal treatments based on the severity of alcoholic

liver disease.

These treatment approaches for alcohol use disorder help patients, including those with

alcoholic liver disease, reduce alcohol consumption, achieve abstinence and prevent relapse.

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Integration of addiction medicine into the multidisciplinary teams that care for these patients

may improve outcomes.

Acknowledgments

The authors would like to thank: Lisa Farinelli, Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism (NIAAA) and National Institute on Drug Abuse (NIDA), for providing support with the preparation of the manuscript; Melinda Moyer and Fred Donodeo, Communications and Public Liaison Branch, NIAAA, for technical assistance with the preparation of the figure; Dr. David Kleiner, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, for providing comments on the figure; and Karen Smith, National Institutes of Health (NIH) Library, for bibliographic assistance. The work was supported by NIH intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; PI: Leggio), jointly supported by NIAAA and NIDA.

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Clinical Significance

• Alcohol use disorder is a leading cause of mortality and morbidity

• Alcohol is a leading cause of liver disease; indeed, new effective treatments for HCV make even more critical to address alcohol use disorder

• Psychosocial, behavioral and/or pharmacologic treatments may help patients with alcohol use disorder to achieve abstinence

• There is a critical need to expand the use of these treatment tools in general medicine and hepatology clinical settings

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Figure 1. Outline of the different stages of alcoholic liver disease and possible treatments, behavioral

and pharmacologic, for alcohol use disorder in patients with alcoholic liver disease. The

figure outlines the different and/or complementary options that clinicians may consider

when treating alcohol use disorder at each stage of alcoholic liver disease. Multidisciplinary

approaches may include behavioral and/or pharmacological interventions. While brief

medical and psychosocial interventions (in green) may suffice in helping some patients quit

alcohol drinking, more complex and comprehensive treatments (behavioral and

pharmacological; in blue) may be needed as the severity of alcohol use disorder worsens and

becomes critical with increasing severity of alcoholic liver disease. The figure also

highlights the pharmacological interventions that should be avoided in advanced alcoholic

liver disease.

Abbreviations: ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; AUD:

Alcohol use disorder; CBT: Cognitive Behavioral Therapies; GGT: Gamma-glutamyl

transpeptidase; INR: International normalized ratio; MET: Motivational Enhancement

Therapy; PT: Prothrombin time

Photo Credit: Science Picture Co / Science Source

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Table 1

Cut down-Annoyed-Guilty-Eye opener (CAGE) Questionnaire

Have you ever felt you should Cut down on your drinking?

Have people Annoyed you by criticizing your drinking?

Have you ever felt bad or Guilty about your drinking?

Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (Eye opener)?

Scoring: item responses on the CAGE are scored no (0) or yes (1). A total score of 2 or greater is considered clinically significant.

The CAGE Questionnaire is public domain and no permission is necessary unless used in a profit-making endeavor. The exact wording can be found in the following source reference: Ewing, J.A. Detecting alcoholism: The CAGE questionnaire. JAMA 252, 1905–1907 (1984).(88)

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Leggio and Lee Page 16

Ta b

le 2

T he

A lc

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U se

D is

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w he

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1 –2

3 –

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– 6

7 –

9 10

+

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5 or

m or

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o n

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? N

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g th

e la

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ea r

ha ve

y ou

f ou

nd t

ha t

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w er

e no

t ab

le t

o st

op d

ri nk

in g

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y ou

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s ta

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? N

ev er

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s th

an m

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ai ly

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g th

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ha t

w as

n or

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kl y

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il y

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g th

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dr in

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Table 3

Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 criteria for Alcohol Use Disorder

1 Alcohol is often taken in larger amounts or over a longer period than was intended

2 There is a persistent desire or unsuccessful efforts to cut down or control alcohol use

3 A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects

4 Craving, or a strong desire or urge to use alcohol

5 Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home

6 Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol

7 Important social, occupational, or recreational activities are given up or reduced because of alcohol use

8 Recurrent alcohol use in situations in which it is physically hazardous

9 Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol

10 Tolerance, as defined by either of the following:

a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect

b. A markedly diminished effect with continued use of the same amount of alcohol

11 Withdrawal, as manifested by either of the following:

a. The characteristic withdrawal syndrome for alcohol (refer to criteria A and B of the criteria set for alcohol withdrawal)

b. Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms

The presence of at least 2 of these symptoms indicates an Alcohol Use Disorder (AUD).

The severity of the AUD is defined as:

• Mild: The presence of 2 to 3 symptoms

• Moderate: The presence of 4 to 5 symptoms

• Severe: The presence of 6 or more symptoms

For a comparison of DSM-5 criteria for AUD versus DSM-IV criteria for alcohol abuse or dependence, see NIH/NIAAA website: http:// pubs.niaaa.nih.gov/publications/dsmfactsheet/dsmfact.pdf

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association.

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Table 4

Outline of Steps in Brief Intervention

Step I. Ask About Alcohol Use Ask questions regarding alcohol consumption, CAGE questions, AUDIT

Step II. Negotiation and Goal Setting Is patient willing to focus on drinking; Suggestions for reducing drinking

Step III. Behavioral Modification Techniques Identify high risk situations; Devise coping strategies

Step IV: Self-Help-Directed Bibliography Dispense educational materials

Step V. Follow-up and Reinforcement Drinking log; follow-up appointment and or phone consultation

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Table 5

Clinical Institute Withdrawal Assessment for Alcohol—revised (CIWA-Ar) scale

Nausea/Vomiting - Rate on scale 0 – 7

0 – None

1 - Mild nausea with no vomiting

2

3

4 - Intermittent nausea

5

6

7 - Constant nausea and frequent dry heaves and vomiting

Anxiety - Rate on scale 0 – 7

0 - no anxiety, patient at ease

1 - mildly anxious

2

3

4 - moderately anxious or guarded, so anxiety is inferred

5

6

7 - equivalent to acute panic states seen in severe delirium or acute schizophrenic reactions.

Paroxysmal Sweats - Rate on Scale 0 – 7.

0 - no sweats

1- barely perceptible sweating, palms moist

2

3

4 - beads of sweat obvious on forehead

5

6

7 - drenching sweats

Tactile disturbances - Ask, “Have you experienced any itching, pins & needles sensation, burning or numbness, or a feeling of bugs crawling on or under your skin?”

0 – none

1 - very mild itching, pins & needles, burning, or numbness

2 - mild itching, pins & needles, burning, or numbness

3 - moderate itching, pins & needles, burning, or numbness

4 - moderate hallucinations

5 - severe hallucinations

6 - extremely severe hallucinations

7 - continuous hallucinations

Visual disturbances - Ask, “Does the light appear to be too bright? Is its color different than normal? Does it hurt your eyes? Are you seeing anything that disturbs you or that you know isn’t there?”

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0 - not present

1 - very mild sensitivity

2 - mild sensitivity

3 - moderate sensitivity

4 - moderate hallucinations

5 - severe hallucinations

6 - extremely severe hallucinations

7 - continuous hallucinations

Tremors - have patient extend arms & spread fingers. Rate on scale 0 – 7.

0 - No tremor

1 - Not visible, but can be felt fingertip to fingertip

2

3

4 - Moderate, with patient’s arms extended

5

6

7 - severe, even w/ arms not extended

Agitation - Rate on scale 0 – 7

0 - normal activity

1 - somewhat normal activity

2

3

4 - moderately fidgety and restless

5

6

7 - paces back and forth, or constantly thrashes about

Orientation and clouding of sensorium - Ask, “What day is this? Where are you? Who am I?” Rate scale 0 – 4

0 – Oriented

1 – cannot do serial additions or is uncertain about date

2 - disoriented to date by no more than 2 calendar days

3 - disoriented to date by more than 2 calendar days

4 - Disoriented to place and / or person

Auditory Disturbances - Ask, “Are you more aware of sounds around you? Are they harsh? Do they startle you? Do you hear anything that disturbs you or that you know isn’t there?”

0 - not present

1 - Very mild harshness or ability to startle

2 - mild harshness or ability to startle

3 - moderate harshness or ability to startle

4 - moderate hallucinations

5 - severe hallucinations

6 - extremely severe hallucinations

7 - continuous hallucinations

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Headache - Ask, “Does your head feel different than usual? Does it feel like there is a band around your head?” Do not rate dizziness or lightheadedness.

0 - not present

1 - very mild

2 – mild

3 – moderate

4 - moderately severe

5 – severe

6 - very severe

7 - extremely severe

The CIWA-Ar is not copyrighted and may be used freely. Source: Sullivan, J.T., Sykora, K., Schneiderman, J., Naranjo, C.A. & Sellers, E.M. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 84:1353–1357 (1989).(57)

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Table 6

FDA-approved medications and others tested in alcohol use disorder patients

FDA-approved Medications for alcohol use disorder

Dosage Pharmacological target Possible use in alcohol use disorder patients with alcoholic liver disease?

Acamprosate 666 mg TID Possibly NMDA receptor agonist Yes (no hepatic metabolism)

Disulfiram 250–500 mg QD Inhibition of Acetaldehyde dehydrogenase No (hepatic metabolism; cases of liver toxicity have been reported)

Naltrexone* PO or IM

PO: 50 mg QD IM: 380 mg monthly

Mu opiate receptor antagonist With caution (perceptions of liver toxicity limit use in advanced alcoholic liver disease)

Not FDA-approved Medications tested for alcohol use disorder

Baclofen 10 mg TID; 80 mg QD max

GABAB receptor agonist Yes (minimal hepatic metabolism) Baclofen has been formally tested in clinical studies with alcohol use disorder patients with liver cirrhosis

Gabapentin 900–1800 mg QD Unclear-modulates GABA transmission Yes (no hepatic metabolism)

Ondansetron 1–16 mcg/kg BID 5HT3 antagonist Yes, but with caution because liver toxicity has been reported, albeit relationship to ondansetron administration is not determined

Topiramate 300 mg QD Anticonvulsant multiple targets: -Glutamate/ +GABA

Yes (partial hepatic metabolism mostly by glucoronidation). In patients with hepatic encephalopathy, use with caution: topiramate-related cognitive side-effects may confound the clinical course and treatment of hepatic encephalopathy

Varenicline 2 mg QD Nicotinic acetylcholine receptor partial agonist Yes (minimal hepatic metabolism)

* Nalmefene is not-FDA approved but was recently approved in Europe for alcohol use disorder. Compared to naltrexone, nalmefene has a longer

half-life and no evidence of hepatotoxicity.

FDA: Food and Drug Administration; TID: three times a day; NMDA: N-methyl-D-aspartate; QD: once a day; PO: per os (oral); IM: intramuscular; GABA: gamma-aminobutyric acid; BID: twice a day; HT: serotonin

Am J Med. Author manuscript; available in PMC 2018 February 01.