Neuroscience of Addiction Day 21 Neuroscience of Addiction Part 2 Study Workshop: Overcoming...

Neuroscience of Addiction Day 2 1

Neuroscience of Addiction Part 2

Study Workshop: Overcoming Barriers to Engagement withDifficult and Different Clients

Review

Addiction is Complex

• Psychological

• Social

• Spiritual

• Biological

Addiction

“Addiction at its core is a biological process”Biological Agent

Biological Substrate

Nestler and Aghajanian, 1997

Biological Agents

• Drugs, which bind to specific receptors

• Directly or indirectly increase dopamine transmission

Biological Target

• Brain cells in nucleus accumbens get “rush” of dopamine

• Changes in cell after chronic exposure– Decreased dopamine transmission– Other structural and functional changes

Neuroscience of Addiction

• Craving

• Compulsion

• Cognitive problems

• Poor insight

Review of Workshop Goals

• Part 1 Neuroscience– Review brain– Reward circuit– Changes from drug use– Who gets addicted?

• Genetics• Environment

Review of Workshop/ Goals

• Part 2 Applied Neuroscience– Understanding craving– Correlates of compulsion– Cognitive aspects of drug use– Emerging pharmacology for treatment of

addiction

Overall Goal

• Understanding the neuroscience of addiction will allow you to treat your clients’ behaviors in a new way

Other Housekeeping

• Breaks

• Lunch

• Evaluations

OFCOFCSCC

PFCPFC

ACGACG

CONTROL

MOTIVATION/DRIVE

(saliency)

MOTIVATION/DRIVE

(saliency)

Review: Brain Circuits Involved in Drug Addiction

HippHipp

AmygAmygMEMORY/LEARNING MEMORY/

LEARNING

NAcc VPVP

REWARDREWARD

Network of Circuits

• Reward Pathway

• Motivation/ Drive Pathway

• Memory and Learning Pathway

• Control

What do these Circuits have in Common?

• All receive dopamine directly from dopamine neurons

• Connected to each other through direct or indirect neuronal projections – glutamate transmission– No current PET tracers

Review: Key Structures in these Circuits

• Nucleus Accumbens

• Amygdala

• Forebrain/ Frontal Lobe

• Ventral Tegmental Area

Part 2 Applied Neuroscience

– Understanding craving– Correlates of compulsion– Cognitive aspects of drug use– Emerging pharmacology for treatment of

addiction

Craving

• “The most persistent and insidious clinical component of addictive illness.”

• Dackis and O’Brien, 2005

Addiction Cycle

Understanding Craving

Cue Induced Craving*

• Environmental cues can trigger cravings

• What examples have you seen or heard?

• Have you seen relapse following long abstinence from cue induced craving?

Responses to Cocaine Video

Environmental Cues

FIGURE 2

Activation of Orbitofrontal Cortex

Functional Imaging of Craving

• Drug related craving linked to functional natural drives– Sex– Food

Functional Neuroimaging and Craving

• PET, fMRI

• Activation of amygdala and anterior cingulate cortex

• Degree of cue activation correlated with craving severity

• Degree of activation correlated with likelihood of relapse– Cocaine, alcohol, heroin, nicotine

Cues for Cocaine and Normal Pleasures Activate

Brain Sites• Cues for Cocaine

– Cocaine abusers may experience a powerful urge to use when they encounter environmental cues associated with use

– Brain areas are activated when watching cocaine- related videos

Childress, 1999

Persistent Effects of Drug

• As a result of intracellular changes, the previously cocaine addicted brain has persistently altered functioning (craving)

• Implications for Treatment– Understand the importance environmental

cues play in initiating the craving process– Review program educational materials to

ensure that potential environmental cues for drug use are eliminated

– Normalize cue and craving responses for clients

– Teach clients how to “urge surf” and to identify potential environmental cues

Treatment Applications for Childress’ Cue-Induced Cocaine

Craving Study

Functional Imaging of Craving

• Frontal activation also with: – Cocaine addicted patients watching cue

video– Normal subjects watching sexually explicit

video– Normal subjects reporting hunger in

response to food cues

“Expected Reward”: Craving

• Reward processed by dopamine neurons going to nucleus accumbens

• Memory processed by amygdala and hippocampus

• Expected reward for drugs far outweighs other reinforcers/ rewards

• Resetting of reward thresholds?

• What can compete with drugs?

Memory and Craving

• Place, person or thing: other wise neutral stimulus that can trigger craving

• Conditioned Learning– Paired associations– Nucleus accumbens/ amygdala

• Habit Learning– Well learned sequences become automatic– Caudate/ putamen (neighbors to Nucleus

accumbens, the “striatum”)

Applications*

• What do you need to look for in your treatment materials (videos, handouts)?

• What do you need to listen for in your group therapy sessions?

Sensitization*

• Small amounts of substance lead to high levels of craving and relapse– Have you seen this?

• Cross-sensitization Rats sensitized with 6 days of amphetamine

• 7 days later become hyperactive after 1 minute of sugar• Consume more sugar when allowed to drink it for an hour

» Avena and Hoebel, 2003

– Alcoholics relapsing after pain meds• Other examples?

Orbitofrontal Cortex

• Low activity during drug withdrawal

• Overactivity when craving

• Degree of activity proportional to intensity of craving

Orbitofrontal Cortex and Craving

Long Term Frontal Brain Changes in Cocaine Abusers

• Up to 3 months drug free

• Decreased frontal lobe metabolism in cocaine abusers compared to controls

• “Clinically silent” brain dysfunction– Craving?– Decreased executive functioning?

» Volkow 1992

Other Aspects of Craving

• Neuroadaptation– Depletion of dopamine in the nucleus

accumbens

Exercise*

• In groups of 3 or 4, write an essay test question to test knowledge of content on craving

addiction

Correlates of Compulsion*

• Weakened brain “braking” or inhibitory mechanisms

• When else do humans pursue pleasure/ desire with a similar lack of rational thought?

Biology of “Drive”

• Natural drives: food, water, sex

• Romantic love may overlap with addiction– Dopamine– Dark side: depression, stalking, suicide

Correlates of Compulsion: Loss of control

• Hallmark of addiction

• Source of societal stigma

• Even when the pleasure is gone

What’s the worst consequence you have seen?*

Compulsions and Hypofrontality

• Reduced baseline metabolism in frontal lobe associated with addiction

• Same regions become hypermetabolic during active craving

• “Hypo” –less active as measured by blood flow

• Frontal Lobes= executive functioning– “Top down” decision making– Risk/ reward assessment– Impulse control

• Poor functioning of frontal lobes may contribute to – Poor impulse control– Lack of resolve– Poor decision making– Impaired control even when someone

expresses desire to not do something

Effect of Cocaine on PFC Cells

• Changes in branching and the number of spines

• Changers in synaptic connections

• Related to changes in decision-making or judgment?

• Loss of self-directed behavior?

• Increase in automatic behavior?

Dopamine Receptors

• D2 receptor changes associated with addiction in people and animals

• Chronic exposure to stimulants, opioids or alcohol leads to decreased dopamine activity– Downregulation of D2 receptors– Decreased sensitivity to everyday rewards– Increase drug seeking due to reward

intensity?

Decreased Sensitivity to Natural Rewards

• Dopamine regulated reward centers fail to activate in response to experimental rewards (money)– Opiate addicts– Tobacco smokers– Cocaine abusers

Decreased Dopamine Function

• Correlates with dysfunction of prefrontal regions

• Correlates with – Poor judgment, impulse control– Decreased response to natural rewards

Comparison Subject METH AbuserComparison Subject METH Abuser

Dopamine Transporter Loss AfterHeavy Methamphetamine Use

(PET analysis)

Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001. Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001.

FIGURE 5

Phineus Gage: Posterboy for Hypofrontality

• Vermont railroad construction

• Mild mannered and responsible

• Accident with tamping rod and dynamite

Phineus Gage*

Phineus Gage

• After the accident: Personality Change– Rude– Sexually inappropriate– Poor impulse control

Animal Models of Relapse

• In animals, the most potent stimulus for relapse is a “free” (non contingent) “priming” injection of the training drug– Equivalents in detoxified addicts

Drug-triggered relapse

• In animals, “cross-priming” from one class to another has been widely demonstrated– ie. priming with cocaine can lead to opiate

self administration and vice versa– Stewart J: Reinstatement of heroin and cocaine self

administration in the rat by intracerebral application of morphine in the ventral tegmental area Pharmacol Biochem Behav 1984:20 917-923

Effect of Drug Use on Decision Making

• Iowa Gambling Task

• Compare with patients with damaged Ventromedial Prefrontal Cortex

Correlates of Iowa Gambling task

• Oblivious to future positive or negative consequences

• Guided by immediate prospects

– Bechara Nature Neuroscience 2005

Iowa Gambling Task Experiments

Cocaine Addiction and Iowa Gambling Task

• 63% of addicts as impaired as brain damaged patients (some variability)

• Impaired decision making

• Unable to learn from recent feedback

-£1500

+200+100

-1000+100

+50+25

"Bad" decks "Good" decks

Iowa gambling task

0 10 20 30 40 50 60 70 80 90 100

Bad Decks

GoodDecks

Trial number

Normal subject

Neuroscience of Addiction Day 2 630 10 20 30 40 50 60 70 80 90 100

Trial number

Orbitofrontal lesion

Bad Decks

GoodDecks

Skin conductance response

Impairments in Decision Making

• Alcohol, cannabis, cocaine, opioid, methamphetamine– Meth may be more harmful than others– Some people will NOT have impaired

decision making– More functional, less likely to “bottom out”

and enter treatment

Back to Stress

The Stress Hormone CycleThe Stress Hormone Cycle

HypothalamusHypothalamus

PituitaryGland

AdrenalGlands

KidneysKidneys

CRFCRF

ACTHACTHCORTISOLCORTISOL

Stress ResponsesStress Responses

CRF:Corticotropin ReleasingFactor

Stress Reliably Reinstates Drug Seeking in Rats

SalineSaline NicotineNicotine

Nicotine-trained ratsNicotine-trained rats

FootshockFootshock

SalineSaline CocaineCocaine FootshockFootshock WaterWater AlcoholAlcohol FootshockFootshock

Cocaine-trained ratsCocaine-trained rats Alcohol-trained ratsAlcohol-trained rats

40406060

8080100100

ses Inactive LeverInactive Lever

Active LeverActive Lever

SalineSaline HeroinHeroin FootshockFootshock

Heroin-trained ratsHeroin-trained rats

40406060

8080100100

From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996

Another Look at Stress

Addiction Cycle

addiction

Neurobiological Aspects of Chronic Drug Use (Meth)

• Cognitive

• Psychiatric

• Motor

Neurotoxicity Methamphetamine

• Brain changes resulting from prolonged use of psychostimulants, such as methamphetamine may be reflected in compromised cognitive and motor functioning

Neurotoxicity Methamphetamine

• Poor Motor & Memory Performance• 33 year old male- 80 days post detox• Low Severity- Parkinson Disease• Transporter losses may not recover• Volkow, et al. 2001

MOTOR FUNCTIONMOTOR FUNCTION

• Slowed gait• Slowed gait

•Impaired balance•Impaired balance

• Impairment correlates with damage to dopamine system• Impairment correlates with damage to dopamine system

Psychiatric Effects of Methamphetamine

Self-Reports of Criminal Behavior

• Legal charges (assault and weapons)– 47% “Violent Crime”

– Wright 2001

• Aggressive actions– 43% of ER patients using exclusively

methamphetamine– Compared: 20% of those with other drug

and alcohol-induced disorders– Szuster 1990

Self Reports of “Anger Problems” in Meth Users

– 62% of interviewees “problems with aggression”

– Wright 2001

– 50% of patients in psych emergency room : “Aggressive Ideation”

• Compare: 24% other drug and alcohol users– Szuster 1990

– 43% entering outpatient program– Zweben 2004

Implication of Aggression in Meth Users

• Experienced aggression may motivate some for treatment

• Safety concerns

• Violence history

• Anger management integrated into treatment programs

Other Effects of Use Over Time

• Brain damage

• Long-lasting psychosis

• Thinking problems

Animal Studies of Brain Damage

• Repeated low doses or single high dose methamphetamine in rats– Nerve endings die off– Nerve cells dies off

• Decreased brain chemicals (dopamine and serotonin)

Effects of Damage to Dopamine Receptors

• D2 receptor availability decreased– Caudate and putamen

• Motor impaired

• Cognitive impaired

Amphetamine and Psychosis

• First reported three years after the first clinical trial in 1935

• Paranoia, delusions of reference, vivid hallucinations (esp. visual), formication

Amphetamine and Psychosis

• Experimental induction of amphetamine psychosis– Non-users

• Abrupt onset of paranoia (Griffith, 1968)

– Amphetamine users• Psychosis in all subjects after 1-90 hours of ad

lib use (Bell,1973)• Psychosis in 3 of 4 subjects after 72 hours

(Angrist, 1970)

Methamphetamine and Psychosis

• Variable course – Some persistent psychosis– Some recurrent psychosis

• With repeat use– Smaller, single doses for some– Low dose Haldol prevented psychosis in some

» Sato, 1986

• With significant stress» Yui, 2001

Cognitive Deficits From Methamphetamine Use

• Animal studies

• Human studies• Sara Simon 2002, 2004

Cognitive Effects in Naïve Adults

• Improved performance in reaction time, coordination, vigilance

• Effects most consistent in fatigued subjects

Abstinence and Cognitive Changes in Users

• Baseline: meth users vs non-users

• Meth users vs. early abstinence

• Meth users vs. relapse– Relapses between weeks 1 and 14 of

abstinence– Relapses lasted between 1 and 14 days

» Simon 2004

Cognitive Tests*

• Manipulation of information and perceptual speed

• Ability to ignore irrelevant information

• Executive Functioning

• What do you see clinically that suggests cognitive problems?

Cognitive Tests Cont.**

• Mental Flexibility

• Logical abilities

• Learning

• Memory

Findings

• Meth users did worse than non-users– Many of the deficits similar to those in

normal aging (episodic vs semantic memory)

– Length of use did not seem to correspond to performance

– Daily users significantly more impaired• Daily users > 10 times a day did worst

» Simon 2000

Findings

• Active users of methamphetamine did BETTER than newly abstinent subjects – Recall of words and Trailmaking B– Stroop Test – Relapse group did worst

Stroop Test**

Impact of Cognitive Changes

• Treatment providers can expect cognitive problems to worsen, at least during the first three months of abstinence

• Treatment may require strategies to compensate for cognitive problems

• Unclear if cognitive performance ever returns to baseline

• Dopamine transporters decreased

• Correlates with cognitive and motor deficits

Effect of Dopamine transporter decrease on performance

Impact of Cognitive Changes

• Cognitive impairment related to treatment drop out

• Neuropsychological testing may help tailor treatment

Abstinence and the Brain

• Higher whole brain metabolism even after 11+ months abstinence– Inflammation?

Gliosis?– Volkow, Am J

Psychiatry 2001

Recovery of Dopamine Transporters

• PET scan shows levels of dopamine transporters• Lower levels of dopamine transporters were

associated with poorer performance on tests of memory and motor skills

• Impairments in motor skills and memory continued• Volkow, et al. 2001

Implications of Cognitive Impairment*

Matrix ModelObert, et al. 2002

• Impairment – Word recognition

• Patient handouts were created that used primarily pictures

• Family education lectures were video-taped

Brain Imaging Studies Conclude:

• In drug addiction, the value of the drug and drug related stimuli is enhanced at the expense of other reinforcers [natural rewards].

Brain Imaging Studies Conclude

• This is a consequence of conditioned learning and of the resetting of reward thresholds as an adaptation to the high levels of stimulation induced by drugs of abuse.

» Volkow, Fowler, Wang 2003

And more conclusions form imaging studies:

• During exposure to the drug (or related cues) the memory of the expected reward results in overactivation of the reward and motivation circuits while decreasing activity in the cognitive control circuit.

• An inability to inhibit [no brakes] the drive to seek and consume drugs.

Volkow, Fowler, Wang 2003

Get Rewired by Drug UseGet Rewired by Drug Use

Brains… Brains…

Summary

• Interactive circuits: craving, drive memory, impulse control

• Choices among available alternatives

addiction

Pharmacology of Addiction

• Pharmacologic Targets– Euphoria– Craving– Responsivity to cues– Impulse– Denial

Pharmacology of Addiction

• Additional layer of understanding of the neuroscience of addiction

Pharmacology of Addiction: Blocking Euphoria*

• Each drug of abuse has a specific receptor it needs to bind to for effect

• What happens if that receptor becomes unavailable for binding?

Targets of MedicationTargets of Medication

• Methadone and Buprenorphine• Methadone and Buprenorphine

Activate opioid receptorsActivate opioid receptors

• Nicotine gum/patch• Nicotine gum/patch

Activate nicotinic receptorsActivate nicotinic receptors

• Naloxone• NaloxoneBlock opioid receptorsBlock opioid receptors

Pharmacologic treatment• Methadone

– Slow release synthetic that eliminates w/d. Relieves craving

– Some treatment centers have majority Rx opioid patients

• Buprenorphine– Mixed agonist/ antagonist

• Naltrexone– Long acting– Highly motivated patients– Support abstinence by blocking drug effects

• Naloxone– Treat overdoses

Blocking Euphoria with Naltrexone

An opiate receptor antagonist

Blocks opiates access to receptor

Heroin, methadone, Oxycontin: no where to bind

Blocks drug effect

Naltrexone: Opioid Antagonist

• Does not effect craving

• Drug cravings leads to stopping Naltrexone and restarting drug

• Long lasting Naltrexone injections may help with this

• Not in US

Naltrexone: Opioid Antagonist

• Alcohol effects mediated by beta-endorphins (endogenous opioid)

• Reduce “reward” from alcohol by blocking receptor so endorphins cannot bind

• Significant reduction in daily drinking• May be especially helpful for those with

genetic predisposition – Opioid gene variant higher binding and

higher risk of alcoholism and heroin addiction

Pharmacology of Addiction: Craving

• Naltrexone decreased alcohol craving

• Decreased and slowed alcohol consumption following “priming” compared to placebo

Craving as a Biological Event

• Withdrawal Craving = GABA, Glutamate

• Euphoric Recall = Dopamine, Endorphins, Glutamate

• “Stress” = Serotonin, (dopamine)

Pharmacologic Treatment

• Methadone and Buprenorphine require special license

• Methadone managed in a program

• MD needs training in how to effectively use buprenorphine

Pharmacology of Addiction: Euphoria and Craving

• Buprenorphine for opioid addiction– Partial mu-opioid antagonist: blocks

binding– Partial mu-opioid agonist: blocks craving

Suboxone

• Buprenorphine plus Naloxone

• Bup absorbed sublingually

• Naloxone not absorbed– But if injected–

precipitates withdrawal

Buprenorphine• Partial agonist• Controls cravings

– Still some sense of euphoria

• Safer than heroin– Not as addictive, little risk of overdose

• Longer-lasting than methadone, not as long as LAAM– 24-60 hours

• Lowest category drug for treatment of heroin addiction (cat. III)

• Easier than methadone to manage

Buprenorphine

• Opioids attach to receptors and lead to dopamine release

• Stimulation of reward system

Buprenorphine

• As opioids leave receptors, stimulation ends

• Withdrawal and cravings

Buprenorphine• Bup attaches to empty opioid receptors

• Mild stimulation of receptors (agonist)– “Ceiling” to amount of agonist effect

• Prevent w/d and craving

Ceiling Effect

Buprenorphine

• Bup binds tightly

• Opioids cannot bind (antagonist)

Buprenorphine

• At maintenance doses, bup remins tightly bound

• Mild stimluation

• Block other opioids

Buprenorphine• History

– A treatment plan was approved by the FDA in 2003• It included a buprenorphine pill during the initial tolerance phase• The maintenance phase uses a different pill, containing

buprenorphine and naloxone

**Not all buprenorphine is approved for heroin addiction treatment! Buprenorphine is not safe in an unsupervised setting!

Buprenorphine

• Problems and Questions– There is little information on the effect of

buprenorphine on pregnant women• A few cases have showed no problems

– The withdrawal effects are not completely masked by buprenorphine

• They are much milder

Clinical Case Studies Involving Buprenorphine

• Buprenorphine is equally effective as moderate (60 mg per day) doses of methadone.

• It is unclear if buprenorphine can be as effective as higher doses of methadone.

• Buprenorphine is mildly reinforcing, encouraging good patient compliance.

• After a year of buprenorphine plus counseling, as many as 75 percent have been retained in treatment compared to none in a placebo plus counseling condition.

Clinical Case Studies Involving Buprenorphine

Bupropion Blocks Binding Sites

Buprenorphine Taper

• Buprenorphine is a partial mu opiate receptor agonist

• Withdrawal symptoms are milder and course is shorter

• Can be Rx in the community

• Difficult to overdose and die

• Typically, 3 day dosing than stop

Buprenorphine Taper

• Still requires specialty training to Rx

• In tolerant individuals can cause withdrawal if dose is to high or too low

Alcohol Dependence

Medications tried in Alcohol Dependence

• Naltrexone• SSRI’s and other antidepressants• Buspirone• Ondansterone• Acamprosate• Valproic acid, carbamazepine, gabapentin• Corticotrophin Releasing Factor• Topiramate

Naltrexone for Alcohol Dependence

• “In the Lab” Subjects reported decreased stimulation from Etoh and decreased craving. “Still needs further study”

• Fairly large number of studies. Different methodologies with heterogeneous populations

• Results have been mixed, but tend to be positive

Most studies in abstinent subjects show:

1. Prolonged time to first relapse

2. Increased % of days abstinence

3. In one study, Increased days to first drink

4. In one study at follow-up, relapse rates approached placebo after study ended

Two studies in non-abstinent subjects with relapse as outcome:

1. CBT and naltrexone better than CBT and placebo

2. Supportive therapy and naltrexone no better than supportive therapy and placebo

• Eligible:

1. Etoh dependent, medically stable and not on opiates

2. Willing to begin a supportive relationship with health care provider or support group and work toward abstinence

3. Willing to take medication

• Not eligible:1. Liver failure

2. Acute hepatitis

3. Pregnant or Nursing

4. Possibly the very obese

• Watch Drug Interactions with NonSteroidals

SSRI’s for Alcohol Dependence

• In the laboratory, alcohol consumption decreased in animals given SSRI’s

• But human studies have been mixed and disappointing

• In various studies and to various degrees each of the following disorders has been linked to Serotonin Dysregulation: 1. Alcohol Dependence2. Major Depression3. Anxiety Disorders4. Impulse Control Disorders5. Compulsive Disorders

• Studies involving SSRI treatment of Alcohol Dependence and other disorders which may involve serotonin dysregulation, when taken as a whole showed

1. Poor tolerance

2. Poor outcome

3. In some cases, worse outcome than placebo

• Researchers are now hypothesizing that subtypes of Alcohol dependent subjects account for uneven test results and that medications that effect different parts of the serotonin system may be effective for each different subtype.

Depression In Alcohol Dependence

• In some studies, Depressed Alcoholics showed improvement in abstinence commensurate with their improvement in depression

• In other studies, mild improvement in abstinence over what would be expected with improved depression

• Some only showed improvement in Etoh and depression when naltrexone was added.

Buspirone and Alcohol Dependence

• Buspirone is a partial agonist of a specific serotonin receptor, which has effects on large portions of serotonin system.

• Buspirone is used in humans to treat anxiety. Takes several weeks to work. Well tolerated. Approved for doses up to 30mg/day, but higher doses routinely used.

• Rats showed less drinking when on buspirone.

Buspirone and Alcohol Dependence

• Studies in Anxious Alcoholics comparing buspirone to placebo showed:1. Better retention2. Slower return to heavy drinking3. Fewer drinking days4. Decreased anxiety5. Decreased anxiety did not fully account

for medication effect

Ondansteron for Alcohol Dependence

• Alcoholic subtypes 1 & 2 or A & B

• Type 2 or B show early onset, high impulsivity and consistent serotonin dysregulation

• Type 2 or B show increased side effects from SSRI’s and Increase in drinking with SSRI’s

• Ondansteron is an antagonist of (blocks) a specific serotonin receptor subtype

• In humans it is used for severe nausea and vomiting from radiation or chemotherapy

• In several studies comparing ondansteron to placebo:1. Increased number of days abstinent

2. Decreased number of drinking days

• This was true for early onset alcoholics and not nearly as much for late onset

Disulfuram

• Block aldehyde dehydrogenase and leads to build up of toxic metabolites when exposed to alcohol

• Flushing, nausea, vomiting, Autonomic dysregulation. Occasionally Death

• Does not appear to block biologic effects of Etoh. Thus, can “drink on top of it” if subject can do two things

Disulfuram

• Two VA studies:1. No better than placebo

2. Beneficial in older, more motivated and more medically ill patient population

• “Impaired Impulsivity with Intact Intelligence”

Disulfuram

• Disulfuram has been found to increase dopamine by inhibiting it’s metabolism

• One study has shown that disulfuram & naltrexone had better outcome on drinking than each drug alone

Acamprosate (Campral) for Alcohol Dependence

• Acamprosate decreases the effects of glutamate at a specific receptor

• Takes a week to achieve “steady state”

• Takes weeks to show effect• Usual dose is 2 grams per day• Major side effect is diarrhea• Increase in SI?

Acamprosate for Alcohol Dependence

• 16 European studies involving 4500 subjects

• Better consistency of findings compared to Naltrexone database

• Similar findings to Naltrexone:1. Increased total abstinence days

2. Increased time to first drink

Acamprosate for Alcohol Dependence

• Abstinence rates remained higher in treated group compared to placebo for up to 12 month after treatment was stopped.

• Some other TX effects were lost• In one US study, better outcome if pts

wanted abstinence and if not multi drug dependent

• Current study in US of naltrexone & acamprosate (COMBINE)

Topiramate for Alcoholism

• Anti-seizure medication

• Used in some mood disorders

• One study: promising

“Treating The Disease”

• “Ingestion as a problem solving Technique”1. Can reinforce technique

2. Can perpetuate use

3. Can prevent adaptation and growth

4. Can collude with “the great obsession”

Addiction as a Biological Event

• Withdrawal Craving = GABA, Glutamate

• Euphoric Recall = Dopamine, Endorphins, Glutamate

• “Stress” = Serotonin, (dopamine)

The Stress Hormone CycleThe Stress Hormone Cycle

HypothalamusHypothalamus

PituitaryGland

AdrenalGlands

KidneysKidneys

CRFCRF

ACTHACTHCORTISOLCORTISOL

Stress ResponsesStress Responses

CRF:Corticotropin ReleasingFactor

CRF Agonist/ Antagonist

• Address the stress / relapse connection

• Must avoid disrupting natural axis

Cocaine

• Many medications tested

• Recent promise from modafinil– Medication targeting narcolepsy– Wakefulness

Modafinil

• Enhances transmission of glutamate

• Appears to decrease reward and craving in cocaine users

• Three trials underway

Methamphetamine Phase I Phase IIBupropion BaclofenDisulfiram GabapentinLobeline IsradipineReserpine OlanzapineSelegiline Ondansetron

SelegilinePlanned VenlafaxineAripiprazole

Methamphetamine Medications in Development

Beyond Pharmacology

• Natural reinforcers

• Devaluing drug reinforcers

• Strengthen inhibitory control

• Strengthen executive function

Devaluing drug reinforcers

• Even if drug euphoria is blocked, what about the cues that motivate drug seeking?

• How to devalue the addicts biologically learned perception of the drug?

Addiction Cycle

Experimental Drug Vaccines

• Antibodies to bind and deactivate drugs

• Use animal immune system or manufacture antibodies

What would a perfect medication be?*

• What would be general properties?

• What would the neurobiological targets be?

• Can you draw a picture of the mechanism of action?

Future of Addiction Pharmacology

Case 1

39 year-old white divorced female – alcohol abuse disorder. History of both inpatient/outpatient detoxification with rehab multiple times. Longest period of abstinence - 4 days. No improvement with AA.

Design a Treatment Plan

• Initial treatment

• What assessment tools would you use?

• What would be the initial placement?

Treatment Plan

• What are the brain structures that lead to relapse?

• What would the role of medication be?

• What is your chronic care plan?

Case 2

• 24 year old man who began to abuse Rx stimulants in college and progressed to methamphetamine. Now smoking daily, legal problems, homeless, hearing voices and often paranoid.

Treatment Plan

• What are the cues in his environment to watch out for?

• Special challenges?

Case 3

• 54 year old woman who lost her nursing license after she began to abuse narcotic pain medications. Was caught “doctor shopping” and is starting to buy meds off the street.

Treatment Plan

• What would she do if she needed dental surgery?

• Special challenges?

Final Exercise*

• Write down two or three ways that information from this workshop will impact your clinical work.

• Describe a few specific examples

Wrap up*

• Questions?

• Comments?

• How close to our goals did we come?

The End!

• Thank you

Selected Bibliography• Dackis, C. and O’Brien, C. Neurobiology of addiction: treatment and

public policy ramifications. Nature Neuroscience 8:11 1431-36• Everitt, B.J. and Robbins, T.W. Neural systems of reinforcement for

drug addiction:frokm actions to habits to compulsion, Nature Neuroscience 8:11 1481-89*

• Nestler E. and Aghajan, G. (1997) Molecular and cellular basis of addiction. Science 278; 58-63*

• Volkow, N. and Li, T. (2005) The neuroscience of addiction. Nature Neuroscience 8:11 1429-30*

• Kreek M.J., Nielsen D.A., Butelman, E.R. and LaForge S. (2005) Genetic Influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction Nature Neuroscience 8:11 1450-57*

• Nestler E. and Aghajan G. Molecular and cellular basis of addiction. Science 278; 58-63*

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