Foundation of Addiction Medicine 2019

Answer

A relationship exists between the amount of
alcohol consumed and the risk of developing
ALD. The vast majority (90–100%) of chronic
heavy drinkers develop AFL. However, only
10–20% of chronic heavy drinkers develop
advanced ALD; therefore, additional factors
may modify the course of the disease

Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, Mathurin P, Mueller S, Szabo G, Tsukamoto H.
Alcoholic liver disease. Nature Reviews Disease Primers. 2018 Aug 16;4(1):16.

451

Multiple Risk factors contribute in
progression to Advanced Liver Disease !

Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, Mathurin P, Mueller S, Szabo G, 452
Tsukamoto H. Alcoholic liver disease. Nature Reviews Disease Primers. 2018 Aug 16;4(1):16.

What is the amount of Alcohol to

cause ALD !!!

• 30ml of spirit (whisky/Brandy/Vodka)= 1 unit drink= 10

gm of absolute alcohol India

• Chronic, heavy alcohol consumption, which is classified

as the consumption of >40 g of pure alcohol per day

over a sustained period of time (years) leads to the

highest risk of ALD

• A recent meta-analysis has shown that even the chronic

consumption of 12–24 g of alcohol per day ( one to two

unit drink has an increased risk of cirrhosis (a late stage

of ALD) as compared with non-drinking

Rehm, J. et al. Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev. 29, 437–445 453
(2010).
Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, Mathurin P, Mueller S, Szabo G, Tsukamoto H. Alcoholic liver
disease. Nature Reviews Disease Primers. 2018 Aug 16;4(1):16.

Pathophysiology

454

Alcoholic Fatty liver disease (AFLD)

First stage of ALD- excessive accumulation of fat inside
the liver cells

AFLD is generally an asymptomatic condition.

• Mild hepatomegaly may be appreciated on USG
abdomen

At times, non-hepatic symptoms
• Numbness (peripheral neuropathy)
• dyspnea or fatigue (cardiomyopathy),
• weight loss and diarrhea (pancreatic insufficiency)

455

Alcoholic Hepatitis (AH)

The second stage of ALD-Alcoholic Hepatitis is

characterized by the inflammation of the liver leading to the
degeneration of liver cells.

• Precursor

– Acute liver failure
– Cirrhosis

• AH typical symptoms include- jaundice,
nausea, malaise, fatigue, anorexia, and
fever.

456

Diagnosis of Alcoholic Hepatitis

Alcoholic hepatitis consortium provides a
working definition of alcoholic hepatitis that
includes
1. Jaundice within 60 days of heavy

consumption (> 50 g/day) of alcohol for a
minimum of 6 months,
2. Serum bilirubin > 3 mg/dl,
3. Elevated AST:ALT ratio > 1.5 and no other
obvious cause for hepatitis.

O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases;
Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 51:307–32485.7

Liver Cirrhosis (LC)

Liver cirrhosis is the last stage-permanent
scarring of liver tissue.

Chronic ALD

Asymptomatic Cirrhosis

Compensated

Decompensated/ESLD

ESLD: End-Stage Liver Disease

458

Symptoms & Signs of
Liver Cirrhosis and its complications

AE
BF

CG
DH

459

Laboratory Findings in ALD

Liver synthetic function •Hyperbilirubinemia (usually conjugated)
•Prolonged prothrombin time
•Hypoalbuminemia (A:G ratio reversal)

Liver enzyme levels •Aspartate aminotransferase (AST) and alanine
Hematologic aminotransferase (ALT) levels elevated, usually < 300
Metabolic U/L;
•AST/ALT ratio ~ 2:1

•Anemia
•Leukocytosis or leukopenia
•Thrombocytopenia
•Increased serum globulin levels

•Elevated blood ammonia level 460
•Hyperglycemia
•Respiratory alkalosis
•Hypomagnesemia
•Hypophosphatemia
•Hyponatremia
•Hypokalemia

Other Investigations

• Imaging of liver

– Ultrasonography abdomen

• Hyperechoic large liver → fatty liver; shrunken liver →
cirrhosis

– CT abdomen
– MRI

• Liver biopsy via trans jugular approach- Gold
standard* (not commonly practiced)

461

No one laboratory test
confirms or excludes
ALD, thus requiring
the clinician to
understand the
relevance and utility
of each test for a given
patient.

462

Diagnosis

• Clinical diagnosis of alcoholic liver disease,
using a combination of physical findings,
laboratory values, and clinical acumen, is
accurate up to 70%.

• Liver biopsy indicated before live
transplantation.

O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice
Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 51:307–328.
463

Treatment of Alcoholic hepatitis

• Medical treatment

– Corticosteroids: Prednisolone as specific therapy
for alcoholic hepatitis having mortality
benefits.(level 1 evidence)

– Anticytokine therapy- Pentoxyphylline

O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases;
Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 464
51:307–328.

Alcoholic liver disease

Hepatology, Volume: 51, Issue: 1, Pages: 307-328, First published: 23 December 2009, DOI: (10.1002/hep.23258)

465

Alcoholic liver disease

Hepatology, Volume: 51, Issue: 1, Pages: 307-328, First published: 23 December 2009, DOI: (10.1002/hep.23258)

466

Long term management of ALD

A. Abstinence- the foundation of therapy for ALD

• In patients with evidence of alcohol-induced liver
disease, strict abstinence must be recommended,
because continued alcohol use is associated with
disease progression (Class I, level B).

• Naltrexone or acamprosate may be considered in
combination with counseling to decrease the
likelihood of relapse in patients with alcohol
abuse/dependence in those who achieve
abstinence (Class I, level A).

O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of

Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease.

Hepatology 2010; 51:307–328. 467

Treatment contd…

• Nutritional Support

– Treat protein-calorie malnutrition- preferably
Branched-chain amino acids by enteral nutrition.

– 1 to 1.5 g protein and 30 to 40 kcal/kg body weight for
adequate recovery is recommended.

• Patients with alcoholic cirrhosis should receive
frequent interval feedings, emphasizing a night
time snack and morning feeding, to improve
nitrogen balance (Class I, level A).

O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of

Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease.

Hepatology 2010; 51:307–328. 468

Complementary and Alternative
Medicine Treatment Options

• S-adenosyl L-methionine (SAMe), a precursor to
glutathione has anti-oxidant property.

• Silymarin, the presumed active ingredient in milk
thistle, is postulated to protect patients from ALD
on the basis of its antioxidant properties.

• The use of complementary or alternative
medicines in the treatment of either acute or
chronic alcohol-related liver disease has shown
no convincing benefit and should not be used out
of the context of clinical trial (Class III, level A).

O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases;
Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 469
51:307–328.

Liver transplantation

• Patients with end-stage liver disease
secondary to alcoholic cirrhosis should be
considered for liver transplantation, just as
other patients with decompensated liver
disease.

• Rates of recidivism between 11%-49% at 3-5
years after LT.

* Recidivism- defined as any alcohol
consumption after transplantation

470

ALD
summary

Types of ALD Diagnosis Prognosis Reversible

Alcoholic Fatty History, Physical Excellent Yes
liver examination and Variable
Alcoholic hepatitis Laboratory Guarded Variable
investigations. Generally no
Cirrhosis

471

Thanks and time for
Q/A

Further readings

1. O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the
American Association for the Study of Liver Diseases; Practice Parameters
Committee of the American College of Gastroenterology. Alcoholic liver disease.
Hepatology 2010; 51:307–328.

2. Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, Mathurin
P, Mueller S, Szabo G, Tsukamoto H. Alcoholic liver disease. Nature
Reviews Disease Primers. 2018 Aug 16;4(1):16.

3. Bajaj JS. Alcohol, liver disease and the gut microbiota. Nature Reviews
Gastroenterology & Hepatology. 2019 Jan 14:1

4.

472

APPROVED ANTICRAVING
AGENTS:

Alcohol Use Disorder

(DISULFIRAM, NALTREXONE,
ACAMPROSATE)

Presenter

DR. PAWAN ARUN KHADSE

DPM, MD (Psychiatry)
PDF, DM (Addiction Psychiatry)
National Institute of Mental Health and Neurosciences, Bangalore

Icon made by Freepik from 30-04-24703 19
www.flaticon.com

Introduction

• Alcohol use disorder is a devastating disease with profound clinical
and economic impact

• Pharmacotherapy can be quite effective at reducing alcohol
consumption and improving outcomes

• Despite strong evidence that pharmacotherapy for AUD is
appropriate for many patients with the disease, it is significantly
underused

• Choosing the best medication to treat AUD depends on treatment

goals, the presence or absence of various comorbidities,

medication adherence considerations, and drug availability and

cost. 474

Educational Objectives

Disulfiram • Background
Naltrexone • Pharmacology
Acamprosate • Prescribing methods
• Adverse Drug Effects
• Drug-drug Interactions
• Indications
• Contraindications
• Important studies
• Special points

475

Disulfiram

476

Disulfiram

Background

• In 1937 Williams noted that rubber factory workers were
hypersensitive to alcohol

• Article in The Lancet, 1948

• First approved for the treatment of alcohol dependence in 1948

477

Disulfiram

Pharmacology

• In its pure state, is a white to off-white,
odorless, almost tasteless powder, which is soluble
in water and alcohol

• Absorption of disulfiram from the GI tract is rapid

• Overall elimination of disulfiram is slow, and up

to 20 % of a single dose may remain in the

body for a period of 7 days or more 478

Disulfiram

Mechanism of Action

• Irreversible inhibition of ALDH by an active metabolite Me-DTC
• Acetaldehyde concentration in the blood increase to 5 to 10 times

which causes an unpleasant DER
• Re-establishment of the ALDH enzymatic activity is dependent

on new synthesis which requires up to 2 weeks

479

Disulfiram

An aversive physiological state that functions through negative
reinforcement and behavioral counter-conditioning to extinguish an
unwanted behavior (alcohol consumption)

480

Disulfiram

Disulfiram–Ethanol Reaction

Occur within 10 to 30 minutes after the ingestion of alcohol
Severity is proportional to amount of disulfiram & alcohol consumed

• Mild cases: facial flushing, sweating, headache, nausea, vomiting,
tachycardia, palpitations, hyperventilation, dyspnea

• Severe cases may develop arrhythmias, respiratory depression,
myocardial infarction, acute congestive heart failure,
unconsciousness, convulsions and death

481

Disulfiram

Prescribing methods

FDA approved dose: 125-500 mg

The average maintenance dose is 250 mg daily

To reduce sedation it may be taken at bedtime or initial dosage
may be reduced

A review of the effectiveness of therapy should be undertaken
before continuation on a longer-term basis.

Brewer (1984), Christensen (1991)

482

Disulfiram

Adverse Drug Effects

• Most common: drowsiness, headache, fatigue, allergic
dermatitis, stomach upset, dizziness, acneform eruption,
halitosis, and impotence

• Metallic or garlic-like aftertaste during the first 2 weeks of
therapy. Disappear spontaneously or by reducing dosage.

• Symptoms of sensorimotor peripheral neuropathy & optic neuritis.
Symptoms improve when disulfiram is discontinued

483

Disulfiram

Adverse Drug Effects

• Varying degrees of hepatotoxicity (altered liver function tests,
jaundice, and hepatic necrosis) can occur

• Disulfiram-induced hepatitis (1 in 25,000) patient years of
treatment

• Psychiatric side effects (psychosis, mania, delirium) reported

484

Disulfiram

Drug-drug Interactions

• Elevate phenytoin or theophylline plasma levels

• Inhibits warfarin’s metabolism and may prolong prothrombin
time

• Co-administration with isoniazid may cause ataxia and even
mental status changes

• Inhibits rifampin’s oxidation and renal excretion

• Mental status changes (e.g., psychosis and confusion) have also
been demonstrated with concurrent use of metronidazole

485

Disulfiram

Precautions

• All patients should be fully informed of the DER

• Advised not to use any alcohol-containing preparations
Example, certain cough syrups, sauces, vinegar, tonics, foods
prepared with wine, aftershave lotions and moisturizers

• Patient should carry an Identification Card describing DER and
contact information in case of emergency

• Contraindications: severe myocardial disease or ischemic heart
disease, pregnancy, advanced hepatic and renal disease,
psychotic states, and serious organic brain damage

486

Disulfiram

Management of DER

• Blood disulfiram/ acetaldehyde levels are not of value

• Stabilize the patient’s respiratory and cardiovascular systems
(may require supplemental oxygen, intubation, IV fluids, and/or
pressor agents)

• Other interventions include intravenous use of vitamin C,
ephedrine sulfate, and antihistamines

• Potassium levels should be monitored (hypokalemia),
particularly in patients treated with digitalis

487

Disulfiram

Important studies

Veterans Administration Cooperative Study
• The largest disulfiram treatment study

• A cohort of 605 males with alcoholism
– 202 participants received disulfiram 250 mg daily
– 204 participants were administered disulfiram 1 mg QD
– 200 participants were prescribed riboflavin

After 1 year of treatment, there was no difference in the
percentage of patients from the three groups in total
abstinence, time to first drink, employment, or social stability.

Only 19 % of patients took disulfiram consistently!

488

Disulfiram

Important studies

The first systematic meta-analysis (2011)

– 11 RCTs included with a total of 1,527 patients
– Studies published from 1979 to 2010
– India, Denmark, USA, Austria, Finland, and Italy

This review concluded that disulfiram had some short-term
clinical benefits including short-term abstinence, number of
drinking days, and days until relapse

489

Naltrexone

490

Naltrexone

Background

FDA Approvals

1994 Oral Naltrexone Alcohol dependence

2006 ER/ once-a-month/ injectable suspension Alcohol dependence

2010 XR-NTX Opioid dependence

2014 ER/ Naltrexone + bupropion Obesity

491

Naltrexone

Pharmacokinetics

• Rapidly and complete absorption following oral dose
• Peak plasma concentrations being achieved within 1 hour
• Oral bioavailability of naltrexone is 60 percent
• 20 percent of the drug bound to plasma proteins
• A plasma half-life of 10.5 hours regardless of whether it is

administered via the oral or intravenous route
• Metabolized in liver

492

Naltrexone

Mechanism of action

> κ(13 to 33 times) receptor

Antagonistic potency at μ receptor

(5 to 10 times) > δ receptor

493

Alcohol (& Other Substances)

Endogenous Opioids (Endorphin & Enkephalin)

µ-opioid receptors

(nucleus accumbens, amygdala, cingulate gyri, and basal ganglia)
(reward pathway)

NALTREXONE

Pleasure, High, Intoxication, Craving and Relapse

494

µδ

G
A
B
A

VTA

Dopaminergic neurons

D
A

NA

Naltrexone decrease dopamine release in NA through
disinhibition of GABAergic input to dopamine neurons in VTA495

Naltrexone

Prescribing methods

1. Oral
2. Extended release injections
3. Implant

496

Oral Naltrexone

Morning administration is recommended for improved compliance

497

Injectable Naltrexone

A single-use kit
Naltrexone microspheres (380mg) + Diluent
To be suspended prior to administration
Intramuscular gluteal injection
Once a month

498

Naltrexone

Adverse Drug Effects

• GI distress (nausea, vomiting, diarrhea, and abdominal pain)
• Anxiety, restlessness, dysphoria
• Mild hypertension
• Headache
• Insomnia

• 10-20% patients may discontinue medication in the first month
of treatment due to reminiscent of opioid withdrawal

• 32% of opioid-dependent patients discontinued treatment after
the first injection

499

Naltrexone

Drug-drug Interactions

Opioid analgesics Pain-relieving effects are blocked

Cessation of oral naltrexone treatment 72
hours prior to elective surgery is recommended

Disulfiram Frequent monitoring of LFT is recommended

NSAIDS Elevation in LFT
[with high-dose naltrexone, 250mg daily]

Antidepressants Higher rates of nausea

500