Substance Use Disorders

How many people use mood-altering 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 Reinforcement-Protracted 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

Volkow et al, Neurobiology of Learning and Memory, 78:610-624, 2002

Over time chronic drug use may lead to reductions in dopamine systems

Sleep Recovery in AlcoholismDrummond et al, 1998

290

300

310

320

330

340

350

360

370

0 19 60 120

Weeks of Abstinence

Tot

al S

leep

Tim

e (m

in)

Alcoholic

Normal mean

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 5-10% +abuse (15%)– Women 2-3% +abuse (5%)

• Lifetime Prevalence Drug Abuse/Dependence– Men 7%– Women 4%

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, Co-existing 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”

Population Based Twin Study of Alcoholism in Men and Women

Kendler et al, 1992/99

0

510

15

20

2530

35

4045

50

% C

onco

rdan

ce

Men Women

DZMZ

Heritability 50-60%

Population Based Twin Study of Drug Use, Abuse and Dependence in Men

Kendler et al, 2000

0

10

20

30

40

50

60

70

80

% C

onco

rdan

ce

Use Abuse Dependence

DZMZ

Heritability 60-80%

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

0

10

20

30

40

50

60

%A

lcoh

olic

Men

SensitiveInsensitive

Men followed up 10 years after study

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

PopulationRegier et al, JAMA 21:264, 1990

0

20

40

60

80

100

Antisocial Bipolar Schiz Panic Unipolar Phobia

14.7

4.6 3.8 3.31.6 1.6

50-70% of bipolar pts. presenting for treatment will have coexisting substance use disorder

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

0

0.2

0.4

0.6

0.8

1

90 120 180 270 360

Days

% A

bsti

nent

AftercareOutpatient

N=1,726

Treatment Outcomes from Project MATCHReturn to Heavy Drinking

0

0.2

0.4

0.6

0.8

1

90 120 180 270 360

Time to 3 Consecutive Heavy Drinking Days

% N

o R

elap

se

AftercareOutpatient

N=1,726

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.

• 4. Made a searching and fearless moral inventory of ourselves.

• 5. Admitted to God, to ourselves and to another human being the exact nature of our wrongs.

• 6. Were entirely ready to have God remove all these defects of character.

• 7. Humbly asked Him to remove our shortcomings.

• 8. Made a list of all persons we had harmed, and became willing to make amends to them all.

• 9. Made direct amends to such people wherever possible, except when to do so would injure them or others.

• 10. Continued to take personal inventory and when we were wrong promptly admitted it.

• 11. Sought through prayer and meditation to improve our conscious contact with God as we understood Him,• praying only for knowledge of His will for us and the power to carry that out.

• 12. Having had a spiritual awakening as the result of these steps, we tried to carry this message to• alcoholics and to practice these principles in all our affairs.

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

0102030405060708090

100

No Disulfiram 1 mg Disulfiram 250 mgDisulfiram

p=NS

Reported Drinking Days (12 months)Fuller et al, 1986

0

102030

405060

708090

Reported Days Drinking

No Disulfiram 1 mgDisulfiram

250 mgDisulfiram

p<.05

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*

Treatment Weeks

10 2 3 4 5 6 7 8 9 10 11 120.0

0.1

0.2

0.4

0.5

0.6

0.70.8

0.9

1.0

0.3

Cu

mu

lati

ve P

rop

ort

ion

W

ith

No

Rel

apse

Naltrexone HCl (N=35)

Placebo (N=35)

Source: Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49:876-880.

*Time to first episode of heavy drinking; P<.01

Relapse Prevention by AcamprosateSass et al, 1996

0

20

40

60

80

100

120

Days

% A

bsti

nent

PlaceboAcamprosate

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!