SUD 3: Alcohol Use Disorder Treatment

SUBSTANCE-RELATED AND ADDICTIVE DISORDERS III:
PHARMACOTHERAPY OF ALCOHOL DEPENDENCE
Ximena Sanchez-Samper, MD
Instructor Harvard Medical School
Medical Director Spring Hill Recovery Center
Board-Certified Addictions Psychiatrist
xsanchezmd@gmail.com
Question Based Learning

Lecture Modules
• Disulfiram
• Acamprosate
• Naltrexone
Medication Treatment
• Disulfiram: 125-500 mg PO/daily
• Acamprosate: 666 mg PO tid
• Naltrexone (PO): 50 mg PO daily
• Naltrexone XR (IM): 380 mg IM monthly
What Parameters Are Used to Determine Treatment Efficacy for Alcohol Dependence?
• Percent days abstinent
• Percent days heavy drinking
• Likelihood of any drinking (abstinence rate)
• Likelihood of heavy drinking
• Drinks per drinking day
• Time to first drink/relapse
• Consequences of drinking
• Biological markers
Psychiatry Review: Substance-Related and Addictive Disorders III: Pharmacotherapy of Alcohol Dependence
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Under-treatment of Alcohol Use Disorders
Millions of people
Source: Grant BF et al. Arch Gen Psychiatry. 2004;61:807-816 SAMHSA, Office of Applied Studies, Substance Dependence, Abuse and Treatment
Tables; 2003 IMS – MAT March 2006.
Cortex role:
Decision-making
Intervention:
Psychotherapy
Limbic System
role:
Drive generation
Intervention:
Pharmacotherapy
Challenges of Current Therapies

• High relapse rate with psychosocial support alone
– 50% at 12 months
– 90% at 48 months
• Poor medication adherence is common and associated with higher relapse rates
• NIAAA guidelines: consider adding medication in active ETOH dependence or if stopped but experiencing
cravings/slips
Module: Disulfiram
Question: Which of the following enzymes is inhibited by disulfiram?

A. Alcohol dehydrogenase
B. Aldehyde dehydrogenase
C. Sulfuryl dehydrogenase
D. Glucose-6-phosphatase
E. Acetate dehydrogenase
Alcohol Acetaldehyde
dehydrogenase dehydrogenase
Disulfiram: Side Effects

• Most common: dermatitis, garlicky or metallic taste
• More serious side effects
– Hepatic: hepatitis
– Neurologic: peripheral neuropathy
– Ophthalmic: optic neuritis
– Psychiatric: depression, psychotic disorder or exacerbation
• Do baseline and follow-up LFTs
• Severe hepatotoxicity frequently occurs early, so getting LFTs more often early in the course of treatment
is recommended
• Use in motivated and reliable patients only
Disulfiram: Contraindications
• Alcohol-containing products or paraldehyde within 14 days of discontinuing disulfiram
• Recent use of metronidazole
• Severe coronary occlusion or myocardial disease
• Hypersensitivity to disulfiram or other thiuram derivatives used in pesticides and rubber vulcanization
• Psychosis
Module: Acamprosate
Question: The symptoms associated with acute alcohol withdrawal are related to overactivity of which
neurotransmitter?
A. Dopamine
B. GABA
C. Glutamate
D. Nitric oxide
E. Serotonin
Question: Which of the following medications is most strongly contraindicated in patients with advanced
renal disease?
A. Acamprosate
B. Buprenorphine
C. Disulfiram
D. Sertraline
E. Naltrexone
Acamprosate: Overview
• Glutamate receptors and transmission
• Moderation of prolonged withdrawal
– Insomnia, fatigue, mood lability, anxiety
– Possible effect on attenuating cravings
• European data >3000 subjects, superior to placebo in maintaining abstinence
• Optimal treatment → combination with naltrexone, psychosocial therapy, 12-step
Source: Fox et al, 2003. Ait-Daoud et al, 2003.
Relapse: Features of Alcohol Dependence
Source: De Witte. Addict Behav. 2004;29(7):1325-1339.
Relapse and Conditioning
• Repeated alcohol use has caused “conditioning” to occur in related circuits
• Now “cues” associated with alcohol use can activate the reward and withdrawal circuit
• This can evoke anticipation of alcohol or feelings similar to withdrawal that can precipitate relapse in an
abstinent patient
Source: Messing RO. Harrison’s Principles of Internal Medicine. 2001:2557-2561.
Pathophysiology of Potential Relapse
Relapse: Balancing Pathophysiology
Relapse: Balancing Pathophysiology
Acamprosate: Indications and Usage

• Maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at
treatment initiation
• Should be part of a comprehensive management program that includes psychosocial support
• Precaution: acamprosate does not eliminate or diminish acute withdrawal symptoms
Acamprosate: Dosage and Administration

• Initiate as soon as possible after alcohol withdrawal when patient achieves abstinence
– Maintain treatment if patient relapses
• Recommended dose: two 333 mg tablets tid
• Eliminated via kidneys
• Patients with moderate renal impairment
– Starting dose of 1 x 333 mg tid
• Can be taken with or without meals.
• *Creatinine clearance of 30-50 mL/min
Acamprosate: Safety
Relapse and Conditioning
Advantages
• Won’t make you sick if you drink
• May reduce desire to drink
• Helpful for those with liver disease
• Increases likelihood of abstinence
Disadvantages
• Relatively small effect size
• Recent negative trials, though recent positive Japanese trial; may reflect length of sobriety prior to
initiation of acamprosate
• Requires 3x a day dosing
Module: Naltrexone
Question: Naltrexone exerts its mechanism of action by acting primarily as?

A. Full Opioid agonist
B. Kappa Antagonist
C. Partial Opioid Agonist
D. Opioid Antagonist
E. Glutamate Modulator
Naltrexone for Alcohol Use Disorders

• Alcohol increases dopamine in the nucleus accumbens
• β-endorphin stimulates dopamine release either directly (in the nucleus accumbens) or indirectly (in the
ventral tegmental area)
• Naltrexone in animal models leads to a reduction of dopamine levels in the nucleus accumbens and a
reduction in alcohol intake
Source: Volpicelli et al., (1992).
Naltrexone for Alcohol Use Disorders: Mechanism of Action

• May reduce alcohol-induced craving
• May reduce craving independent of drinking
• Differences in the experience of a slip
• Does not make someone a controlled drinker
• Helps a patient get back to abstinence faster
• Mostly positive studies, but some negative
Naltrexone: Dosage
• Can be used safely without prior detox
• Effective even if only taken when drinking is expected
• 50 mg/day effective, if compliant with psychosocial therapy (some patients respond to 25 mg)
• Starting with lower doses may reduce side effects
• COMBINE study used 100 mg/day, but 50 mg/day is more typical
• Adverse events: nausea (10%), headaches (7%), dizziness and fatigue (4%), sleepiness (2%)
Source: Srisurapanont et al. 2003.
Naltrexone for Alcohol Use Disorders: Contraindications
1. Concomitant or recent use of opioids
2. Hypersensitivity to naltrexone
3. Liver failure or acute hepatitis
4. Naloxone challenge test failure
Precautions
• Hepatic impairment
• History of suicide attempts
• Black box warning about hepatocellular injury with higher doses
Naltrexone: Monitoring
• Do baseline and follow-up LFTs
• No generally accepted guidelines about what level is acceptable to start or unacceptable to continue
• Hepatotoxicity more likely with higher doses
Naltrexone: Oral vs. IM

• Monthly intramuscular preparation Naltrexone XR (Vivitrol)
– Improved compliance, enhanced steady state plasma levels, fewer GI side effects
– I.M. = reduction first pass hepatic metabolism
• Medical alert card carried at all times
• Emergency pain management (IM/Vivitrol)
– Regional analgesia, conscious sedation with a benzo and non-opioid analgesic, general anesthesia
• Comprehensive management w/ psychosocial support
Naltrexone IM: Potential Side Effects

• Nausea/vomiting
• Headache
• Fatigue/dizziness
• Injection site reaction
• Contraindicated in acute hepatitis, liver failure and opioid dependence
– Min. 7-10 days opioid-free
• Eosinophilic pneumonia
– Rare; dyspnea; hypoxemia
• No significant change in LFT’s
Naltrexone: Advantages vs. Disadvantages

Advantages
• Won’t make you sick if you drink
• May reduce desire to drink
• May be particularly helpful for combined alcohol and opioid dependence
Disadvantages
• Promotes reduction in heavy drinking, not necessarily abstinence
• Problem for those who need opioids on an emergency basis
• May work only in subgroup of alcohol dependent patients
Alcoholic Subtypes
• Type I/A = less severe dependence, later onset >25, fewer childhood problems,
fewer alcohol-related problems, less psychopathology
• Type II/B = more severe dependence, early onset <25, childhood risk factors,
family history, polydrug use, psychopathology, life stress
Source: Pettinati et al, 2000. Johnson et al, 2000.
2017 APA Practice Guideline for the Pharmacologic Treatment of Patients with
Alcohol Use Disorder
Assessment and Determination of Treatment Goals
• APA recommends that the initial psychiatric evaluation of a patient with
suspected AUD include assessment of current and past use of tobacco and
alcohol as well as any misuse of other substances, including prescribed or over-
the-counter medications or supplements
• APA suggests that physiological biomarkers be used to identify persistently
elevated levels of alcohol consumption as part of the initial evaluation of
patients with AUD or in the treatment of individuals who have an indication for
ongoing monitoring of their alcohol use
• APA recommends that patients be assessed for co-occurring conditions (including substance use disorders,
other psychiatric disorders, and other medical disorders) that may influence the selection of
pharmacotherapy for AUD
• APA suggests that the initial goals of treatment of AUD (e.g., abstinence from alcohol use, reduction or
moderation of alcohol use, other elements of harm reduction) be agreed on between the patient and
clinician and that this agreement be documented in the medical record
• APA suggests that the initial goals of treatment of alcohol use disorder include discussion of risks to self
(e.g., physical health, occupational functioning, legal involvement) and others (e.g., impaired driving) from
continued use of alcohol and that this discussion be documented in the medical record
• APA recommends that patients with alcohol use disorder have a documented comprehensive and person-
centered treatment plan that includes evidence-based nonpharmacological and pharmacological
treatments
Selection of a Pharmacotherapy
• APA recommends that naltrexone or acamprosate be offered to patients with moderate to severe alcohol
use disorder who have a goal of reducing alcohol consumption or achieving abstinence, prefer
pharmacotherapy or have not responded to nonpharmacological treatments alone, and have no
contraindications to the use of these medications
• APA suggests that disulfiram be offered to patients with moderate to severe alcohol use disorder who
have a goal of achieving abstinence, prefer disulfiram or are intolerant to or have not responded to
naltrexone and acamprosate, are capable of understanding the risks of alcohol consumption while taking
disulfiram, and have no contraindications to the use of this medication
• APA suggests that topiramate or gabapentin be offered to patients with moderate to severe alcohol use
disorder who have a goal of reducing alcohol consumption or achieving abstinence, prefer topiramate or
gabapentin or are intolerant to or have not responded to naltrexone and acamprosate, and have no
contraindications to the use of these medications
2017 APA Practice Guideline for the Pharmacologic Treatment of Patients with Alcohol Use Disorder
Recommendations Against Use of Specific Medications
• APA recommends that antidepressant medications not be used for treatment of alcohol use disorder
unless there is evidence of a co-occurring disorder for which an antidepressant is an indicated treatment
• APA recommends that in individuals with alcohol use disorder, benzodiazepines not be used unless
treating acute alcohol withdrawal or unless a co-occurring disorder exists for which a benzodiazepine is an
indicated treatment
• APA recommends that for pregnant or breastfeeding women with alcohol use disorder, pharmacological
treatments not be used unless treating acute alcohol withdrawal with benzodiazepines or unless a co-
occurring disorder exists that warrants pharmacological treatmens
• APA recommends that acamprosate not be used by patients who have severe renal impairment
• APA recommends that for individuals with mild to moderate renal impairment, acamprosate not be used
as a first-line treatment and, if used, the dose of acamprosate be reduced compared with recommended
doses in individuals with normal renal function
• APA recommends that naltrexone not be used by patients who have acute hepatitis or hepatic failure
• APA recommends that naltrexone not be used as a treatment for alcohol use disorder by individuals who
use opioids or who have an anticipated need for opioids
Treatment of Alcohol Use Disorder and Co-occurring Opioid Use Disorder

• APA recommends that in patients with alcohol use disorder and co-occurring opioid use disorder,
naltrexone be prescribed to individuals who wish to abstain from opioid use and either abstain from or
reduce alcohol use and are able to abstain from opioid use for a clinically appropriate time prior to
naltrexone initiation
Answer Key
Question: Which of the following enzymes is inhibited by disulfiram?

A. Alcohol dehydrogenase
B. Aldehyde dehydrogenase
C. Sulfuryl dehydrogenase
D. Glucose-6-phosphatase
E. Acetate dehydrogenase
Answer Explanation
• Disulfiram inhibits metabolism (aldehyde dehydrogenase) → accumulation of acetaldehyde → unpleasant
physical symptoms on exposure to alcohol
– Reaction occurs 10-15 minutes after drinking
– Reaction can be quite severe, occasionally fatal; severity is related to dose and individual characteristics
– Disulfiram acts as an aversive agent
– Since disulfiram works via the FEAR of its effects, low doses can be as effective as higher doses to start
• Can prescribe 125-500 mg/day
Source: Fuller et al, 1986.
Question: The symptoms associated with acute alcohol withdrawal are related to overactivity of which
neurotransmitter?
A. Dopamine
B. GABA
C. Glutamate
D. Nitric oxide
E. Serotonin
Answer Explanation
• Glutamate is the major excitatory neurotransmitter in the brain
• However, excessive glutamate can lead to neurotoxicity. Evidence suggests that a hyperglutamatergic
brain state is the core pathology behind alcohol withdrawal syndrome (AWS)
• This hyperglutamatergic state results from upregulation of glutamate receptors, dysregulation of
glutamate metabolism, and reduction of synaptic glutamate clearance
Source: Anton, R. E. and Becker, H. C. (1995) Pharmacotherapy and pathophysiology of alcohol withdrawal, in The Pharmacology of Alcohol Abuse (
Kranzler, H. R. ed.), Springer-Verlag, Berlin, pp. 315–367. Dodd, P. R., (2000) Glutamate-mediated transmission, alcohol, and alcoholism. Neurochem.
Int. 37 (5–6), 509–533.
Question: Which of the following medications is most strongly contraindicated in patients with advanced
renal disease?
A. Acamprosate
B. Buprenorphine
C. Disulfiram
D. Sertraline
E. Naltrexone
Answer Explanation
• ACAMPROSATE has been used in Europe for the treatment of alcohol use disorders since 1989; in 2004 it
became the third drug to receive approval from the U.S. FDA for this indication
• Structural analogue of γ-aminobutyric acid (GABA); believed to decrease alcohol intake by affecting
calcium channels and modifying transmission along GABA and glutamine pathways in the brain, resulting
in decreased positive reinforcement of alcohol intake and decreased withdrawal cravings
• The typical dosage is 2tabs PO tid (666 mg PO tid)
Answer Explanation
• The dosage should be reduced to 1 PO tid tablet in patients with moderate renal failure (i.e. creatinine
clearance 30-50 mL/min) and is contraindicated in patients with severe renal impairment (i.e. creatinine
clearance less than 30 mL per minute
• Acamprosate does not need to be discontinued in the event of a relapse
Source: Bouza C, Angeles M, Munoz A, Amate JM. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a
systematic review [published correction appears in Addiction 2005;100:573]. Addiction. 2004;99:811–28.
Question: Naltrexone exerts its mechanism of action by acting primarily as?

A. Full Opioid agonist
B. Kappa Antagonist
C. Partial Opioid Agonist
D. Opioid Antagonist
E. Glutamate Modulator
Answer Explanation
• NALTREXONE is a synthetic opioid antagonist
• FDA approved as adjunct to psychotherapy in alcohol use disorders
• World Health Organization (1996): “safe and effective treatment for alcohol dependence”
– Reduces drinking frequency
– Reduces likelihood of relapse to heavy drinking
– Reduces reinforcing response to ETOH
• Safety and efficacy: >8 double-blind RCT
Source: Targeted Use of Naltrexone Without Prior Detoxification in the Treatment of Alcohol Dependence: A Factorial Double-Blind, Placebo
Controlled Trial. Heinälä, Pekka; Alho, Hannu; Kiianmaa, Kalervo; Lönnqvist, Jouko; Kuoppasalmi, Kimmo; Sinclair, John D. Less Journal of Clinical
Psychopharmacology. 21(3):287-292, June 2001.
End of Lecture

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SUBSTANCE-RELATED AND ADDICTIVE DISORDERS III:

PHARMACOTHERAPY OF ALCOHOL DEPENDENCE

Question Based Learning

Challenges of Current Therapies

Question: Which of the following enzymes is inhibited by disulfiram?

Disulfiram: Side Effects

Relapse: Features of Alcohol Dependence

Source: De Witte. Addict Behav. 2004;29(7):1325-1339.

Source: Messing RO. Harrison’s Principles of Internal Medicine. 2001:2557-2561.

Pathophysiology of Potential Relapse

Relapse: Balancing Pathophysiology

Acamprosate: Indications and Usage

Acamprosate: Dosage and Administration

Question: Naltrexone exerts its mechanism of action by acting primarily as?

Naltrexone for Alcohol Use Disorders

Naltrexone for Alcohol Use Disorders: Mechanism of Action

Naltrexone: Oral vs. IM

Naltrexone IM: Potential Side Effects

Naltrexone: Advantages vs. Disadvantages

Treatment of Alcohol Use Disorder and Co-occurring Opioid Use Disorder

Question: Which of the following enzymes is inhibited by disulfiram?

Question: Naltrexone exerts its mechanism of action by acting primarily as?

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