Medication and Addiction Treatment

Karen Miotto, M.D.

UCLA School of Medicine

Addiction Studies Program for Journalists

December 2005

Does Treatment forSubstance Abuse Work?

Treatment

Treatment InterventionsTreatment Interventions Detoxification Narcotic Treatment

Programs Pharmacotherapy Residential treatment Therapeutic community Sober living Motivational Enhancement Cognitive behavioral

therapy (CBT) Relapse prevention 12-Step oriented support

Individual therapy: supportive

Brief intervention Group therapy Couple/family therapy Network therapy Vocational Training

“Self-Directed Cessation” or “Natural Recovery” Factors

Recognition of health/legal/family hazards Financial considerations Conflict with career goals Social mores and peer pressure Reduced access/availability of drugs Conflict with personal values “Maturation”

ContinuingContinuingProblemProblemDrug UseDrug Use

INTERVENTIONINTERVENTIONProfessionalProfessional

FamilyFamilyConsequentialConsequential

No Further No Further ProblemProblemDrug useDrug use

ContinuedContinuedProblemProblemDrug UseDrug Use

UnsuccessfulUnsuccessful

Successful

Successful

“Interventions”Professional

Primary care physicians Mental health professionals EAP’s Clergy Law enforcement personnel School counselors

“Interventions”Family

Any family member or friend

“Intervention”Consequential

Accident Arrest Job loss (last chance agreements) Relationship loss Work place drug test Negative drug experience Sanctions in school Loss of health

Factors AffectingTreatment Consideration

Recognition of drug use as a problem Medical/legal/financial problems Employer influence (EAP) Family influence Awareness of treatment Perception of treatment

Factors AffectingTreatment Participation

Access issues (time of day, transportation, child care, etc) Treatment environment Treatment context Treatment content External pressure Participant need/treatment service match Family participation

Effective Treatment Strategies

Accurate information Contingency management techniques Cognitive-Behavioral approaches Family participation Drug and alcohol testing Self-help support Adequately trained staff

Medication/Detoxification

Role of Pharmacotherapy “Cure” of withdrawal or overdose To increase the holding power of outpatient

treatment and thus reduce costs To create a “window of opportunity” during

which patients can receive psycho-social intervention to decrease the risk of relapse

To serve as a long-term maintenance agents for patients who can’t function without them, but can lead productive lives with them

Types of Pharmacotherapy

Anti-withdrawal

Agonists

Antagonists

Anti-craving

Treatment of co-morbid disorders

When Drugs Make You Feel Normal

No Drugs = Danger

Alcohol withdrawal – DT’s and seizures GHB – “I go crazy when I stop” Sedatives – “crawling out of my skin” Heroin - kicking with medication or cold

turkey Stimulants – sad and fat Marijuana – “wet dog shakes” Nicotine – irritable and fat

GHB marketed to bodybuilders in 1980’s

Purported effects of muscle mass increase and fat loss

Euphoric and sexual effects led to more widespread use as a “party drug”

No data at that time about addictiveness or lethality of GHB

Agonists: Methadone Partial Agonists: Buprenorphine Antagonists: Naltrexone Anti-Withdrawal &Anti-Craving:

– Methadone

– Buprenorphine

– Clonidine

Opiate Addiction Pharmacotherapy

Locus Coeruleus in Opiate Withdrawal

located in the pontine tegmentum

largest group of NE-containing neurons

activated by pain, blood loss and cardiovascular collapse

LC hyperactivity - neural substrate for opiate withdrawal

clonidine or lofexidine (alpha-2 agonist) and opiates inhibit the LC

Opiate DetoxificationAnesthesia-aided Rapid Opiate Detoxification

(AROD)

Shortens withdrawal to 4-6 hours• especially useful for “detox phobic” • controlled study of risk/benefit ratio

• withdrawal symptoms can persist for significant period post detoxification

• expensive

• large increase in stress hormones

Opiate Detoxification:Pros & Cons of Various Techniques

Methadone taperPro:

Simple to use few side effects

Con: Requires special license longest withdrawal rebound symptoms associated with relapse

Maintenance Opiate Agonist

Reduce medical complications and death Satisfy drug hunger, reduce craving, prevent

withdrawal Blocks effects of abused opiates Reduce medical care burden and costs Reduce crime rate Reduce “hassle” of addict lifestyle Social rehabilitation (e.g. tax eater to tax payer)

Methadone Maintenance

Best studied & most effective opiate treatment program so far, but also most controversial

Treatment provided in licensed clinics Methadone is an orally effective, 24-hour opioid drug used to

maintain heroin or other opiate addicts Patients maintained usually several years, but many need

maintenance for many years

. . . As long as patient desires and benefits from continued treatment

Opioid Agonist Treatment of Addiction - Payte - 1998

22

Maintenance Opiate Agonist

Reduce medical complications and death 8-10 fold reduction in death rate

Satisfy drug hunger, reduce craving, prevent withdrawal

Blocks effects of abused opiates Reduce medical care burden and costs Reduce crime rate Reduce “hassle” of addict lifestyle Social rehabilitation (e.g. tax eater to tax payer)

Buprenorphine

Detoxification or Maintenance Treatment – Physician Office Based High affinity partial mu agonist & kappa antagonist Reduced opioid agonist effects, with less respiratory

depression Withdrawal easier than from methadone or heroin Combo form (buprenorphine/naloxone) may further

decrease diversion potential & will be main maintenance form

-10 -9 -8 -7 -6 -5 -40

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30

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50

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70

80

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100

Intrinsic Activity

Log Dose of Opioid

Full Agonist(Methadone)

Partial Agonist(Buprenorphine)

Antagonist (Naloxone)

Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone)

Naltrexone

Opioid antagonist approved by FDA in 1984 Blocks opioids without agonist effects Need to be off opiates to begin Can be abruptly stopped without withdrawal No tolerance to antagonist effect even after years “Ideal” drug but most addicts uninterested in

using it

Ideal ‘Anti-Cocaine’ Medication

In active users it will induce abstinence (or significantly decrease cocaine use)

It will decrease withdrawal dysphoria in binge users

In abstinent patients it will attenuate the reactivity to drug-related cues

In abstinent patients who lapse it will block the progression to the full relapse

Safe in combination with cocaine, low abuse potential, no dysphoric effects

Treatment of Stimulant Addiction: Current Status

There are several effective psychotherapies for stimulant dependence but no effective medication

Medication development was predominantly centered on dopamine receptor and models of drug reinforcement

Medication that may prevent relapse in abstinent patients may be a more viable option

Stimulant Addiction is a behavioral disorder and behavioral interventions must play a major role in any treatment paradigm

Determinants of Stimulant Use

Euphoria and reinforcement Effect of Cues

– Exteroceptive (environmental)

– Interoceptive (stress, emotions, drug euphoria)

Availability of alternative reinforcers Presence of psychopathology Withdrawal dysphoria

Amphetamine-Induced Disorders 292.89 Amphetamine Intoxication 292.0 Amphetamine Withdrawal 292.81 Amphetamine Intoxication Delirium 292.11 Amphetamine-Induced Psychotic

Disorder, With Delusions 292.12 Amphetamine-Induced Psychotic

Disorder, With Hallucinations

292.84 Amphetamine-Induced Mood Disorder 292.89 Amphetamine-Induced Anxiety Disorder

Alcohol PharmacotherapyAgonists: None yet

Antagonists: Disulfiram (Antabuse)

Anti-withdrawal: BenzodiazepinesAnti-convulsants

Anti-craving: Naltrexone (ReVia), CampralOndansatron, Topamax

Antabuse (disulfiram)

Helpful in maintaining abstinence Inhibits aldehyde dehydrogenase Leads to the accumulation of

acetaldehyde if alcohol is consumed Acetaldehyde is toxic and produces

nausea and hypotension Daily dose 250 mg, or 3-4 day interval

dosing

Disulfiram

Use for cocaine and methamphetamine dependence

Inhibits Dopamine beta Hydroxylase (catalyzing the synthesis of NE from DA)

Indirectly increases the ratio of DA to NE Increasing the dopamine availability ,

enhances the aversive effects of stimulants.

Adjunctive medication for alcohol craving - naltrexone

Opiate antagonist Proposed mechanism of action Dosing and side effects Clinical efficacy

Topiramate

Inhibition of mesocortical dopamine release via facilitation of GABA activity

Inhibition of glutamate function Hypothesis:

– Decreases mesocorticolimbic dopamine activity after alcohol intake

– Antagonize chronic changes induced by alcohol in the glutamate system

Oral Topiramate for Treatment of Alcohol

Dependence Bankole Johnson et al (2003) Abstinence-initiation trial N=150 N=150 Double-blind randomized control trial 12

week Topiramate (up to 300 mg per day) Outcomes

– 2.9 fewer drinks per day– 3.1 fewer drinks per drinking day– 27.6% fewer drinking days– 26.2% more abstinent days– Reduced craving

Acamprosate

Amino acid derivative - acetyl-homotaurine similar to homocysteic acid (NMDA receptor) mimics GABA (GABAA receptor) interacts with calcium channel proteins

Reduces alcohol craving (conditioned withdrawal) Reduces severity and frequency of relaspe Suppress physical signs of withdrawal in animal

models» (J Littleton Addiction 1995)

Acamprosate

Amino acid derivative - acetyl-homotaurine similar to homocysteic acid (NMDA receptor) mimics GABA (GABAA receptor) interacts with calcium channel proteins

Reduces alcohol craving (conditioned withdrawal) Reduces severity and frequency of relaspe Suppress physical signs of withdrawal in animal

models» (J Littleton Addiction 1995)

CAMPRALNORMAL EQUILIBRIUM-Glutamate and GABA balanced

This figure represents the brain (triangle) in a regular state of equilibrium with regard to excitation and inhibition processes.

ACUTE ALCOHOL INTAKE-Increased levels of GABA

Acute alcohol intake disrupts the equilibrium by exaggerating the inhibitory

processes

Excitation Inhibition

Excitation Inhibition

Excitation Inhibition

Alcohol

Neuro-

Adaptation Alcohol CHRONIC ALCOHOL CONSUMPTION-Increased levels of glutamate

Chronic alcohol consumption induces neuroadaptation (increase in glutamate) to counteract the inhibitory action of alcohol.

CAMPRALEnvironmental/

Learned Cues No Alcohol

Excitation Inhibition

Excitation Inhibition

Environmental/

Learned Cues CAMPRAL

ACUTE WITHDRAWAL AND POST-ACUTE WITHDRAWAL-Increased glutamate

Acute Withdrawal of alcohol triggers a hyperexcitatory state because of the excess of glutamate present dur to the neuroadaptation. This results in withdrawal symptoms.

Post-Acute Withdrawal stage follow. Environmental of learned cues associated with alcohol intake may trigger a hyperexcitatory state similar to acute withdrawal in abstinent patients. This precipitates mini-withdrawal symptoms in the post-acute stage-eg, anxiety tremors, sweating-that may contribute to relapse.

CAMPRAL-Modulation of glutamate restores balance

CAMPRAL interacts with the glutamate neurotransmitter system to block the response to environmental and learned cues. CAMPRAL is though to restore the normal balance.

The mechanism of action of CAMPRAL is believed to address the biochemical aspect of alcohol dependence, complementing psychosocial therapy that targets the emotional and behavioral components of the disease.

ADDICTION VOCABULARY

Slang Medical

Addict Addicted patient, patient with the disease of addiction

Junkie , dope fiend Opiate addicted patient, cocaine addicted patient

Clean urine Urine negative for illicit or non-prescribed drugs

Dirty urine Urine pos itive for x,y,or z

Drunk, smashed, bombed Alcohol addicted, intoxicated

Crack head, pot head Cocaine addicted, THC abuse

La La Land Intoxicated

Street addict, hard-core addict Patient with the disease of addiction

Speed-balling Us ing heroin and cocaine together

Meth Methadone or Methamphetamine

Strung out Debilitated, intoxicated

Cop/Fix Obtain, purchase /Dosed, took

Hooked Addicted

Kicking Withdrawal Syndrome

Conclusion

Addiction is a complex chronic medical disorder

Opioid - methadone, buprenorphine Stimulants - vaccine Alcohol - campral New developments in medication for

addiction