MY CUP RUNNETH OVER: IDENTIFYING AND TREATING ALCOHOL USE DISORDER - - PowerPoint PPT Presentation

MY CUP RUNNETH OVER: IDENTIFYING AND TREATING ALCOHOL USE DISORDER

Learning Objectives

• Describe the neurobiological impact of alcohol abuse
• Improve identification of patients with alcohol misuse and abuse
• Integrate currently available practices to treat alcohol abuse with

individualized treatment plans

The Cost of Alcohol

• Worldwide, the estimated 12-month adult

prevalence of alcohol use disorder (AUD) is 8.5%

• Estimated lifetime prevalence of AUD is

20%

• In the US, AUD has been estimated at

13.9% for 12-month prevalence and 29.1% for lifetime prevalence

• Alcohol is the third-leading preventable

cause of death in the US

• AUD costs the US $223.5 billion annually

Reus et al. AM J Psychiatry 2018;175(1):86-90.

The COVID-19 Pandemic and the Rise of AUD

• Following the outbreak of COVID-19, governments across the world implemented social

distancing measures to slow the rate of infection

• Individuals with addiction are more likely to be impacted by poverty, physical and mental

health vulnerabilities, and disrupted access to services which were exacerbated by the pandemic

• Social isolation may result in negative consequences for those with AUD, including serious

withdrawal effects if alcohol is limited

• Social isolation, financial pressures, and stress resulting from social distancing practices may

lead to the initiation or exacerbation of addictive behaviors

• In the United Kingdom (UK), alcohol sales had increased by 67% by March 2, 2020, while

food increased by 43%

• In the United States (US), total alcohol sales had increased by 34.2% the week of May 13,

2020 compared to the same week last year

Finlay et al. BMJ 2020;369:1-2; Clay & Parker The Lancet 2020;5:e258-e259; Responsibility.org

What is “heavy drinking?”

• Losing count?
• Over a 6-pack of beer?
• Over a case of beer?
• When the bottle or glass of alcohol is too “heavy” to pick

up any longer?

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) defines heavy drinking as 4

• r more drinks in 2 hours for women, and 5 or more drinks in 2 hours for men.

Is this too much drinking?

Neurobiological Consequences of Heavy Drinking: MRI

• 483 adolescents (ages 12–21) before initiation
• f drinking, and 1 and 2 years later
• At 2 years:
• 65 had initiated moderate drinking
• 62 had initiated heavy drinking (1–10 drinks

per occasion, several times weekly)

• Heavy drinking group
• Accelerated frontal cortical gray matter

trajectory

• Abnormal cortical volume: contributing

factors include peak consumption in the past year and family history of alcoholism

Pfefferbaum et al. American Journal of Psychiatry 2017 doi: 10.1176/appi.ajp.2017.17040469.

Effective Diagnostic Criteria

DSM-IV DSM-5 Two distinct disorders, each with specific criteria: Alcohol abuse Alcohol dependence Integrates alcohol abuse and alcohol dependence into a single disorder called alcohol use disorder (AUD) Mild, moderate, and severe sub-classifications Abuse diagnosis: anyone meeting one or more of the “abuse” criteria (items one through four) within a 12-month period Dependence diagnosis: anyone with three

• r more of the “dependence” criteria (items

five through eleven) during the same 12- month period AUD diagnosis: anyone meeting any two of the eleven criteria during the same 12-month period Severity based on number of criteria met Craving was added as a criterion for AUD

Tyberski et al. AMS 2014;10(6):1191-7.

Effective Diagnostic Criteria: APA Guidelines

• Initial psychiatric evaluation: assess misuse of any other substances, prescribed or
• therwise
• Include quantitative behavioral measures and biological markers to monitor alcohol

use

• Assess for co-occurring psychiatric conditions when selecting pharmacotherapy for

AUD

• Initial goals of treatment should:
• Be agreed upon by patient and clinician, and documented in medical record
• Involve discussion about patient’s legal obligations
• Include discussion of risks to self and others from continued use of alcohol (e.g.,

impaired driving)

Reus et al. AM J Psychiatry 2018;175(1):86-90.

Psychosocial Risk Factors

Deckel and Hesselbrock. Alcoholism: Clinical and Experimental Research 1996;20(7):1-6; Conrod et al. Alcoholism: Clinical and Experimental Research 1995;19(2):482-98.

Early-life trauma/abuse Family history

• f alcoholism

Parental psychopathy other than alcohol Negative affect Hyperactivity to stress Poor executive functioning

Psychosocial Risk Factors (cont.)

Deckel and Hesselbrock. Alcoholism: Clinical and Experimental Research 1996;20(7):1-6; Conrod et al. Alcoholism: Clinical and Experimental Research 1995;19(2):482-98.

Poor parenting Deficits in emotional reactivity/self

Conduct problems as early as preschool

Adolescent risk factors:

Parental/peer substance using Academic delinquency/low competence Male Little parental support

Childhood Trauma and Problem Alcohol Use

• Prospective study from early childhood to adolescence
• 1064 children and their parents in a longitudinal study
• Baseline assessments at age 3–5
• At ages 12–14, self-reports, internalizing behavior, and drinking expectancies

were obtained

• At ages 18–20, drinking measures were assessed
• Results: children living in homes with parental violence are more likely to use

ineffective coping strategies such as using alcohol

• Findings support the self-medication theory
• Long-term effects of early-life experience on drinking behavior in adulthood

Jester et al. Journal of Studies on Alcohol and Drugs 2015;76:781-9.

Genetic Contributions to AUD

• Gene variants encoding several of the alcohol-metabolizing enzymes: alcohol

dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), are among the largest genetic associations with risk for alcohol dependence

• Particularly the ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles have

been associated with lower rates of alcohol dependence

• The prevalence of these alleles differs among ethnic groups
• Alleles interact to influence the risk of AUD
• Environmental influences on these alleles that affect peoples’ alcohol

involvement include: developmental stage, individual characteristics, and environmental factors

What About Dopamine? Genetic Variations and AUD

Celorrio et al. Alcohol and Alcoholism 2016;51(3):258-67.

In a recent review, the relationship between 56 genetic variants and 7 genes associated with the dopaminergic reward pathway and excessive alcohol consumption (EAC) were examined

653 heavy drinkers 880 Very low drinkers

Single nucleotide polymorphisms (SNPs) were genotyped Lifestyle factors assessed Dopamine receptor D2 (DRD2) Rs10891556

• nly SNP positively

correlated to alcohol consumption DRD2 rs1800497 and rs877138 were significantly associated with EAC in men DRD2 rs17601612, DRD2 rs493627, and MAOA rs5906898 were associated with EAC in women Lifestyle factors associated with EAC were predominantly men who smoked, consumed large amounts of meat, a low level of education, and low physical activity levels

Neurobiology: Actions of Alcohol on Reward Circuits

VTA

glu

alcohol alcohol Nucleus Accumbens (NA)

Neurobiology: Detail of Alcohol Actions in the VTA

PFC glu neuron

VTA DA neuron

GABA inter- neuron

VTA glu DA

arcuate nucleus

• piate

neuron

alcohol alcohol alcohol VSCC GABA

enkephalin

GABA-A receptor GABA-B receptor NMDA receptor MGlu receptor

• piate

receptor

Pharmacological Treatment Options

• Opioid antagonists: naltrexone, nalmefene
• NMDA receptor/Ca2+ channels: acamprosate
• Direct GABAB agonist: baclofen
• GABA-activated chloride channel activation: topiramate
• Topiramate is superior to nalmefene, naltrexone, and acamprosate
• n consumption outcomes, but its safety profile is known to be

poor

• Study concluded there is currently no high-grade evidence for

pharmacological treatment for AUD, only low to medium efficacy in reducing drinking

Palpacuer et al. Addiction 2017;113:220-37.

AUD pharmacy first line second line

AUD "Pharmacy"

naltrexone acamprosate gabapentin topiramate disulfiram

nonpharmacological Reus et al. AM J Psychiatry 2018;175(1):86-90.

CBT CET CAT CST

CST= communication skills training CBT= cognitive behavioral therapy CET= cue-elicited therapy CAT= chemical aversion therapy

Naltrexone

mu

• piates

_

PFC glu neuron

VTA DA neuron

GABA inter- neuron

VTA glu DA

arcuate nucleus

• piate

neuron

VSCC GABA

enkephalin

GABA-A receptor GABA-B receptor NMDA receptor MGlu receptor

• piate

receptor

Actions of Naltrexone in the VTA: Reducing the Reward Associated With Drinking

naltrexone naltrexone

Extended-Release Naltrexone

• Extended-Release Naltrexone (XRNTX) has resulted in a 34% reduction in

total medical costs, 36% reduction in total pharmacy costs, and 52% reduction in alcohol-related hospitalization costs

• In a recent study, 88% of participants perceived XRNTX as helping with their

drinking

• In another study, alcohol-craving scores decreased from 19 to 5.7 after the first

dose of XRNTX

• At the first follow-up, 79.8% reported no alcohol use and 77.8% reported no

alcohol use at the second follow-up

• XRNTX may be related to significant decreases in alcohol craving and use

while a patient is in treatment, as well as 30–60 days after the final dose

Crevecoeur-MacPhail et al. Journal of Substance Abuse Treatment 2018:105-8; Smith-Bernardin et al. Journal of Substance Abuse Treatment 2018;85:109-15.

Acamprosate

GABA glu

_ +

PFC glu neuron

VTA DA neuron

GABA inter- neuron

VTA glu DA

arcuate nucleus

• piate

neuron

VSCC GABA

enkephalin

GABA-A receptor GABA-B receptor NMDA receptor MGlu receptor

• piate

receptor

Actions of Acamprosate in the VTA: Reducing Excessive Glutamate Release to Relieve Withdrawal

acamprosate

Goals of Treatment

• Ideal: abstinence
• Majority of patients do not achieve abstinence,

and those who do may require multiple tries

• Abstinence isn’t the only

possible positive outcome

Moderate Drinking Abstinence Problem Drinking

Abstained ¾ days; reduced alcohol consumption by 87%

Miller et al. J Stud Alcohol 2001.

The Sinclair Method: Drink Your Way Sober

The Sinclair Method

• Uses the nervous system’s own mechanism to induce pharmacological

extinction

• Alcohol is a learned behavior and patients with AUD experience enhanced

reinforcement (via the opioid system) when they drink

• Detoxification and alcohol deprivation do not stop alcohol craving, but increase

subsequent alcohol drinking

• Tested in over 90 clinical studies worldwide, and has demonstrated success in

80% of alcoholics who have used it

• Involves taking an opioid antagonist (e.g., naltrexone, naloxone, or nalmefene)

approximately 1 hour prior to consuming alcohol

• Effective when paired with drinking, but ineffective when given during

abstinence

Impulsivity and Reward

ventral

Compulsivity and Motor Response Inhibition

dorsal

IMPULSIVITY COMPULSIVITY

amygdala

hippocampus

Reward conditioning Memory ACC VMPFC ventral striatum T Reward/Affect OFC dorsal striatum T Cognition OFC dorsal striatum T Response Inhibition

IMPULSIVITY “high” Binge drinking/intoxication/excessive behavior abstinence/withdrawal/negative affect anticipation/preoccupation/ craving/arousal

“naughty” transition to addiction compulsivity

Reward: DA mesolimbic pathway

NA VTA

Natural highs Behaviorally induced highs Substance-induced highs

Habits

COMPULSIVITY

Anticipation Absence Alcohol Favorable Outcome Behavior Pleasurable reward Favorable

• utcome

Pleasurable reward Favorable

• utcome

Maladaptations of the Reward Pathway Can Shift Behavior From Normal to Impulsive to Compulsive

IMPULSIVITY NORMAL

"Liking"

Endogenous Opioids

Salient stimulus Salient stimulus Learning Knowing & anticipating Wyvell CL, Berridge KC. J Neurosci 2000;20(21):8122-30; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013. Pleasurable reward "Wanting" Dopamine Stimulus

Take opioid antagonist (e.g., naltrexone) (50mg) Alcohol cravings Wait one hour (most important part!) DRINK!

The Sinclair Method of Extinction

PFC glu neuron

VTA DA neuron

GABA inter- neuron

VTA glu DA

arcuate nucleus

• piate

neuron

VSCC GABA

enkephalin

GABA-A receptor GABA-B receptor NMDA receptor MGlu receptor

• piate

receptor

The Sinclair Method: Pharmacological Extinction

naltrexone naltrexone

Non-Pharmacological Treatment Options

• Cue-elicited therapy (CET)
• Social learning approaches
• Cognitive behavioral therapy (CBT)
• Chemical aversion therapy (CAT)
• Repetitive transcranial magnetic stimulation (rTMS)

Habit Formation

Ventral striatum: evaluation can still

• ccur

Dorsal striatum: no evaluation (drinking, gambling addiction, drug addiction)

Cue-Elicited Therapy

Robbins & Ehrman. Addictive Behaviors 1992;17:491-9; Carter & Tiffany. Addiction 1999;94(3):327-40.

Based on classical conditioning model of learning for addiction Unconditioned Stimulus (US) Unconditioned Response (UR) Conditions under which the drug is used = conditioned stimulus (CS) CS evokes conditioned response (CR) that moderates/mediates alcohol-seeking behavior

Addicts confronted with cues associated with past drug use exhibit increases with craving and autonomic activity

Effectiveness of Cue-Elicited Therapy

• Recent meta-analysis on 16 CETs found that superior efficacy of CET over
• ther nonpharmacological treatment paradigms has not been demonstrated
• May be helpful in combination with other therapeutic approaches
• CET showed no to small additional effects on drinking intensity and drinking

frequency, a small additional effect on total drinking score, and a moderate additional effect on latency of relapse

• CET combined with urge-specific coping skills may be the better option for

treating AUD than conventional CET

Martin et al. The Open Addiction Journal 2010;3:92-101; Mellentin et al. Clin Psychol Rev 2017; 57:195-207.

Social Learning Approaches

• Communication skills training (CST)
• Communication skills training with family participation (CSTF)
• Cognitive behavioral mood management training (CBMMT)
• CET with urge-specific coping skills training = significantly smaller number of

drinking days and fewer drinks than standard care 3–6 months after treatment

• CST vs. education crossed with CET vs. meditation/relaxation in a 2x2 RCT:
• CET group had fewer heavy drinking days than control when they relapsed during the

12-month follow-up

• CET and CST combined had significantly fewer drinks on the days that they

drank than those in other conditions

Monti et al. J Stud Alcohol 1990;51:263-70; Monti et al. J Consult Clin Psychol 1993;61:1011-9; Rohsenow et al. Addiction 2001;96:1161-74.

Cognitive Behavioral Theory (CBT)

• CBT is widely recognized as one of the

psychological treatments for alcohol problems for which evidence is most robust

• CBT focuses on what we think about

what has happened to us

• Thought-tracking: recognizing automatic

thought patterns to understand core beliefs

• Thought-stopping
• Cognitive reframing

CBT For Treatment of AUD

Sundstrom et al. BMC Psychiatry 2017;17(197):1-12.

Pilot Study: n=13 12 weeks Internet-based CBT program Therapist-guided 3-month follow-up Significant reductions in alcohol consumption Secondary Outcome Measures: significant improvements in craving, self- efficacy, depression, and quality of life  Therapist-guided internet-based CBT may be a feasible alternative for people with AUD

Chemical Aversion Therapy (CAT)

• Utilizes emetic counterconditioning that targets

alcohol craving

• Research studies show correlations between

craving and severity of alcohol dependence

• Emetic CAT targets unconscious/habit-formed

memories and associations with alcohol craving, thus craving reduction is one of the primary treatment goals

• Gustatory alcohol cue reactivity paradigm resulted

in alcohol-related brain activity in the following five regions: hippocampus, amygdala, inferior frontal gyrus, temporal cortex, and occipital cortex

Elkins et al. Frontiers in Behavioral Neuroscience 2017;11(182):1-8.

CAT Effectiveness

Elkins et al. Frontiers in Behavioral Neuroscience 2017;11(182):1-8.

N=13 participants with AUD (abstinent for 48 hours) Before CAT: 10 min fMRI: patient viewed self- generating images of drinking alcohol or no alcohol After CAT: 10 min fMRI: patient viewed self-generating images of drinking alcohol or no alcohol 10-Day Treatment CAT Before CAT sessions, patients reported a mild craving/desire for alcohol After 4 CAT sessions, patients reported avoidance/aversion to alcohol Booster CAT sessions at 30–90 days post-discharge 69% reported sober 12 months post-treatment fMRI scans showed significant pre- to post-treatment reductions in craving-related brain activity in the occipital cortex

rTMS and AUD Treatment

Accelerated HF-rTMS Protocol

A rate-dependent effect on dACC activation in alcohol-dependent patients: an open-label feasibility study

Herremans et al. Alcoholism: Clinical and Experimental Research 2016;40(1):196-205.

Summary

• Increased understanding of the neurobiological mechanisms underlying AUD

and clearer diagnostic criteria for AUD is resulting in better treatment development

• Pharmacological methods demonstrate promise, however they have currently

demonstrated only low to medium efficacy in reducing drinking

• The Sinclair method may be very effective for some patients with AUD
• A combination of pharmacological and nonpharmacological treatment is more

effective than either alone

• Future research should examine effectiveness of combination therapies
• Reduced drinking, rather than abstinence, may be a more effective option for

some patients with AUD

Posttest Question 1

What updates were made to effective diagnostic criteria for AUD, according to the DSM-5? 1. DSM-5 integrates “alcohol abuse” and “alcohol dependence” into a single disorder, AUD 2. Severity of symptoms no longer matters 3. Craving was added as a criterion for AUD 4. 1 and 3

Posttest Question 2

The Sinclair method for the treatment of AUD involves: 1. Cognitive behavioral therapy 2. Taking a low-dose opioid antagonist and abstaining from alcohol 3. Taking an opioid antagonist approximately one hour prior to consuming alcohol 4. Developing coping skills to completely abstain from alcohol

Posttest Question 3

Deep repetitive transcranial magnetic stimulation (drTMS) may be helpful in treating AUD, because it has been shown to:

• 1. Reduce cravings for alcohol
• 2. Improve withdrawal effects
• 3. Reduce intake of alcohol
• 4. 1 & 3
• 5. All of the above