Transcript Pharmacological Treatment of Alcoholism: Has Something New

Substance Use Disorders
How many people use moodaltering substances?
Harm can occur from use with or
without a Substance Use
Disorder
Saitz, NEJM 352:596, 2005
What is Abuse?
• DSM-IV: Maladaptive pattern of use leading to
clinically significant impairment/distress as
manifested by at least one of the following over 12
months
– Recurrent use resulting in failure to fulfill major role
obligations
– Recurrent use in physically hazardous situations
– Recurrent use-related legal problems
– Continued use despite persistent social/interpersonal
problems
What is Dependence/Addiction?
• DSM-IV
– Maladaptive pattern of use leading to significant
impairment/distress over a 12 month period with at
least 3 of the following:
– 1) Tolerance (consumption) [physical dependence]
– 2) Withdrawal symptoms [physical dependence]
– 3) Efforts to cut down or control use
– 4) Great deal of time spent using/obtaining substance
– 5) Important social, occupational, recreational functions
given up because of the substance
– 6) Continued use despite adverse consequences
– 7) Substance often taken in larger amounts or longer
than intended
The Evolution of Addiction from
Physical Dependence to Behavioral
Compulsion
• Physical dependence can be induced in any
individual but does that in and of itself lead to
addiction—NO
– Chronic pain patients given opiates develop physical
dependence but does not usually evolve into addiction
and pts. frequently wish to get off opiates.
• Is failure to develop physical dependence evidence
of lack of addiction—NO
– 1970s thought that cocaine was not significantly
“addicting” because it did not produce traditional
tolerance/withdrawal
Compulsive Use—The Core
Concept of Addiction
• The drug becomes the primary motivating
force—thought and actions directed towards
obtaining and using the drug.
• “When I wasn’t occupied with using the
drug, I was preoccupied with it”
Pathophysiology of Substance
Use Disorders
Positive Reinforcement—The
Brain Reward System
Negative ReinforcementProtracted Withdrawal
Neural Circuitry of Goal-Directed Behavior
Kalivas and Volkow, Am J. Psych, 2005
Effects of Cocaine on Dopamine
Release in Nucleus Accumbens
Alcohol Promotes Dopamine
Release in the Nucleus Accumbens
Boileau I, et al. Synapse 49:226,
2003
Negative Reinforcement
Neuroadaptation and the
Neurobiology
of Protracted Withdrawal
Protracted Withdrawal
• Concept that chronic alcohol dependence
leads to brain alterations that may persist for
months after consumption has stopped.
–
–
–
–
–
Stress Intolerance
Sleep disturbances
Irritability
Anxiety/restlessness
Reduced hedonic response
Over time chronic drug use may lead to reductions in dopamine systems
Volkow et al, Neurobiology of Learning and Memory, 78:610-624, 2002
Sleep Recovery in Alcoholism
Total Sleep Time (min)
Drummond et al, 1998
370
360
350
340
330
320
310
300
290
Normal mean
Alcoholic
0
19
60
Weeks of Abstinence
120
Neurobiology of Protracted Withdrawal
[see Koob G, Alcoholism: Clin Exp Res 27:232, 2003]
• Impaired reinforcement systems
– Dopamine/opioid systems impaired
– An inability to experience the natural rewarding aspects
of life
• Increased activity of stress systems
–
–
–
–
–
Hyperactive brain stress hormone CRF
Irritability
Stress intolerance
Dysphoria
Sleep problems
Compulsive Use—The Core
Concept of Addiction
• The drug becomes the primary motivating
force—thought and actions directed towards
obtaining and using the drug.
• “When I wasn’t occupied with using the
drug, I was preoccupied with it”
Epidemiology of Substance Use
Disorders
• Lifetime Prevalence Alcohol Dependence
– Men
– Women
5-10%
2-3%
• Lifetime Prevalence Drug
Abuse/Dependence
– Men
– Women
7%
4%
+abuse (15%)
+abuse (5%)
Understanding the transition from
use to addiction
• The disease concept of addiction as a
biopsychosocial disease
• Biological: Genetics, Developmental
effects, Environmental effects (stress)
• Psychological: Personality, Stress, Coexisting emotional problems
• Cultural: Acceptance, legal sanctions,
economics/taxation
Genetics
• “When a baby looks like its father that’s
genetic; when it looks like its neighbor
that’s environment”
% Concordance
Population Based Twin Study of Alcoholism
in Men and Women
Kendler et al, 1992/99
50
45
40
35
30
25
20
15
10
5
0
Heritability 50-60%
DZ
MZ
Men
Women
Population Based Twin Study of Drug Use,
Abuse and Dependence in Men
Kendler et al, 2000
80
% Concordance
70
Heritability 60-80%
60
50
DZ
MZ
40
30
20
10
0
Use
Abuse
Dependence
Risk of Alcoholism in Offspring
• 4-10X risk if parent is alcoholic
What is Inherited?
• Alcoholism: Vulnerability Genes
–
–
–
–
NMDA subunits
GABA subunits
Dopamine receptors
Serotonin receptors/transporters
• Alcoholism: Protective Genes
– Alcohol dehydrogenase + aldehyde dehydrogenase
Phenotypic markers of Risk for
Alcoholism
• Decreased sensitivity to alcohol prior to
development of tolerance
• Altered P300 potential—a measure of
attending to and processing information
Decreased Sensitivity to Alcohol in High-Risk Offspring
Predictive Power of Decreased Sensitivity to
Alcohol in Men with Alcoholic Fathers
Schuckit et al, Am J Psych 151:184, 1994
60
Men followed up
10 years after
study
%Alcoholic
50
40
Sensitive
Insensitive
30
20
10
0
Men
Psychological Factors
• Is there an addictive personality? Probably not.
Certain temperamental traits may predispose to
alcohol problems including sensation seeking and
low harm avoidance
• Variety of mental illnesses associated with higher
risks for alcoholism and drug abuse
–
–
–
–
Bipolar Disorder
Anxiety Disorders (social phobia, PTSD)
Antisocial Personality
Depression does not increase risk that much
Frequency and Odds Ratios for Alcohol Dependence
in Various Psychiatric Disorders in a Community
Population
Regier et al, JAMA 21:264, 1990
100
50-70% of bipolar pts. presenting
for treatment will have coexisting
substance use disorder
80
60
40
14.7
4.6
3.8
3.3
1.6
20
1.6
0
Antisocial Bipolar
Schiz
Panic
Unipolar
Phobia
Cultural Factors
• What is acceptable—for example in France and
Italy regular drinking of wine culturally acceptable
and occurs; in Scandinavian countries binge
drinking of liquor more common.
• Government, industry and social policies can
affect rates of consumption and health
consequences
– Deaths from drunk driving have been reduced from
25,000 in mid 1980s to 16,653 in 2000
The Transition Process from Use to
Dependence
• May be subtle, gradual, e.g. starting to drink
in high-school, accelerating in college with
DWI, black-outs and then progressing in
adulthood to full blown dependence
• May be rapid—development of full
dependence on crack cocaine in weeks with
serious social, legal, and medical
consequences
Treatment: Basic Principles
Identification
• History from patient
– Drinking habits: how often, how much, most,
problems?
– Drugs: Using any, which ones, pattern, problems?
– Contrary to popular belief many patients will discuss
alcohol/drug use with a physician if questions are
presented in an empathic manner
• History from collateral (spouse, parent)
• Questionnaires, e.g., CAGE, AUDIT, rarely used
outside of research settings
Identification
• Physical Examination with suggestive findings
• Laboratory Tests: GGT, AST, ALT; CDT; MCV
• Blood Alcohol Level
– .08 gms/dl legal intoxication
– > .15 gms/dl highly suggestive of alcohol problem
– Alcohol metabolized at .015 gms/dl/hour
• Urine Toxicology, time positive post-use
–
–
–
–
Cocaine 2-3 days
amphetamine 2 days
Cannabinoids 3 days 1X use, 27 days chronic use
Barbiturates 1-7 days depending on half-life
PCP 8 days
Opiates 2-3 days
Treatment: The Transition from
Addiction to Long-Term Sobriety
• 1) Detoxification—the “easy” step
• 2) Acceptance of need for treatment and
engagement in treatment process
• 3) Maintenance of sobriety, change in life-style,
physical and emotional recovery.
• 4) Concept of harm reduction, goal of complete
abstinence important but common outcome is
reduced use and fewer consequences.
• 5) Value in viewing addictive disorders as
chronic diseases that wax and wane—like diabetes
or hypertension.
Treatment Outcomes from Project MATCH
Abstinence Rates from Alcohol
1
% Abstinent
0.8
0.6
Aftercare
Outpatient
0.4
0.2
N=1,726
0
90
120
180
Days
270
360
Treatment Outcomes from Project MATCH
Return to Heavy Drinking
% No Relapse
1
0.8
0.6
Aftercare
Outpatient
0.4
0.2
N=1,726
0
90
120
180
270
Time to 3 Consecutive Heavy Drinking Days
360
Detoxification
• Alcohol: Indicated to prevent seizures/DTs that
occur in 5% or so of withdrawing alcoholics.
Benzodiazepines recommended. Thiamine
required to prevent Korsakoff’s.
• Benzo/barbiturate:
BZs or Barbs may be used
to prevent delirium, seizures.
• Opiates: Methadone, buprenorphine or clonidine
will reduce withdrawal sx., not life threatening.
• Cocaine, Marijuana, Nicotine: Have withdrawal
effects but not life-threatening and no specific
treatment though nicotine patch will diminish sx.
Forms of Treatment
• Inpatient psychosocial treatment, “28 day”
programs, usually have strong 12 Step foundation
• Intensive outpatient, meet 4-6 X/week for 2-4
hours each visit, group and individual therapies,
connected to 12 Step programs
• Brief interventions may include 30 minute
sessions total of 3-4 X over several months,
usually targeted towards less dependent patients.
Methods of Treatment
• Motivational: Enhance patient’s motivation
to change, increase confidence that he/she
can change
• Cognitive-Behavioral: Learn new skills to
understand risk situations, learn refusal
techniques, “urge surfing”, how to handle
dysphoric states until they pass
• Marital/Family Therapy: Important to
engage famly
Alcoholics Anonymous
• Founded 1935 by Bill W. a stock-brocker
• The heart of the suggested program of personal
recovery is contained in Twelve Steps describing
the experience of the earliest members of the
Society:
•
1. We admitted we were powerless over alcohol
- that our lives had become unmanageable.
•
2. Came to believe that a Power greater than
ourselves could restore us to sanity.
•
3. Made a decision to turn our will and our
lives over to the care of God as we understood
Him.
Medication Management to
Prevent Relapse
• Alcohol
– Disulfiram (Antabuse) produces nausea,
weakness, vomiting, sweating, tachycardia,
headache, drop in blood pressure when alcohol
consumed. A psychological and a
pharmacological deterrent. Evidence suggests
limited overall efficacy but may be very useful
for patients who wish to be “locked out” of
drinking
Percent Continuously Abstinent (12 months)
Fuller et al, JAMA 256:1449, 1986
100
90
80
70
60
50
40
30
20
10
0
p=NS
No Disulfiram 1 mg Disulfiram
250 mg
Disulfiram
Reported Drinking Days (12 months)
Fuller et al, 1986
90
80
70
60
Reported Days 50
Drinking 40
30
20
10
0
p<.05
No Disulfiram
1 mg
Disulfiram
250 mg
Disulfiram
Medication Management to
Prevent Relapse
• Alcohol
– Naltrexone (ReVia): An opioid antagonist
reduces emotional response to alcohol
consumption and reduces relapse rates. May
help to reduce craving and enhance abstinence.
– Acamprosate: A NMDA modulator, may
reduce protracted withdrawal symptoms.
Shown to reduce drinking frequencies and to
enhance abstinence.
Naltrexone in the Treatment of
Alcohol Dependence: Primary Outcome
Cumulative Relapse Rate*
Cumulative Proportion
With No Relapse
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Naltrexone HCl (N=35)
Placebo (N=35)
0.1
0.0
0
1
2
3
4 5 6 7 8
Treatment Weeks
*Time to first episode of heavy drinking; P<.01
Source: Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49:876-880.
9 10 11 12
Relapse Prevention by Acamprosate
Sass et al, 1996
120
80
Placebo
Acamprosate
60
40
20
61
12
2
18
3
24
5
30
6
36
7
42
6
48
7
54
8
61
0
0
1
% Abstinent
100
Days
Medication Management to
Prevent Relapse
• Opiates
– Methadone: Long acting substitute for opiate drugs
such as heroin. When taken orally does not produce
“high” and allows individual to function. Adequate
dose important, > 80 mg/d. Clearly shown to reduce
relapse to heroin use, reduce HIV transmission and
reduce criminal activity. Under highly regulated
Federal oversight. Can be injected and abused.
– Buprenorphine: A mixed opioid agonist/antagonist that
can be prescribed after receiving DEA authorization,
less likely to be diverted because of opioid antagonist
properties.
Medication Management to
Prevent Relapse
• Cocaine: No clearly proven drug effective for
prevention of cocaine relapse. Some “promising”
medications include baclofen, topiramate,
modafanil.
• Marijuana: No medication therapy yet but
rimonabant, a CB1 antagonist, under review by
the FDA for dyslipidemia.
• Nicotine: Nicotine patch to substitute and
provide tapered withdrawal. Bupropion (Zyban or
Wellbutrin) can reduce nicotine cravings.
Bupropion +nicotine patch most effective. New
agents under development.
Take Home Message
• Addictive disorders are chronic diseases
that require long-term treatment.
• Many patients get better even though one
shouldn’t think of a “cure”.
• Ask your patients, offer hope and don’t give
up!