Medication-Assisted Treatment: What’s in the Cupboard and Why

Walter Ling, M.DDirector

Integrated Substance Abuse Programs

UCLA

LA County Drug Court ConferenceMay 16, 2013

Los Angeles, California

lwalter@ucla.edu

www.uclaisap.org

Scope of the Talk• From methadone to naltrexone and

buprenorphine

• The role of medication in overcoming the brain disease addiction

• So addiction is a brain disease: Now what?

• Reduced heroin use

• Improved general health

• Increased gainful employment

• Reduced criminal activities– Dole VP & Nyswander ME (1965) A Medical Treatment for Diacetylmorphine (Heroin)

Addiction JAMA 193: 646-650

Opioid Addiction Treatment

Methadone: Clinical Properties

Morphine-like synthetic analgesic and CNS depressant

Orally active, quick absorption, slow elimination, long half-life up to 24 hours; once daily dosing

Prevents withdrawal, reduces craving and use

Long term use normalizes physiological functions

Facilitates rehabilitation

CH3 CH2CH2 CH N

CH3CH3

CH3

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Methadone Treatment vs Untreated Heroin Addicts: Mortality Rate

0

2

4

6

8

MatchedCohort

Methadone VoluntaryDischarge

InvoluntaryDischarge

Untreated

0.150.85

1.65

6.91 7.20

Death Rates in Treated and Untreated Heroin Addicts

An

nu

al R

ate

Untreated addicts mortality rate is 9 times that of methadone patients

After 8 years 85% of addicts in treatment are alive; more than half of those untreated are dead

Methadone Maintenance: HIV Rate and Costs

0

5,000

10,000

15,000

20,000

25,000

Untreated Incarceration Adolescent Adult Methadone Drug Free

Residential Outpatient

$1,575$1,750

$8,250$9,825

$20,000$21,500No Treatment

In Treatment Program

Compare the CostsCosts are for a 6 month

period, per person

47%

23%

17% 12.5

%6%

0%

10%

20%

30%

40%

50%Not in Tx

Currently in TxIn Tx 5 years

C&D

No needle use since admission

to TxA B C D

HIV Rates

What Really Matters in Methadone Treatment

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12

In Treatment

Rate

28.9%

Months Since Drop Out

1-3Months

Later

4-6Months

Later

45.5%

57.6%

72.7%

82.1%

7-9Months

Later

10-12Months

Later

Ball, JC, Ross A. The Effectiveness of Methadone Maintenance Treatment, Springer-Verlag, New York, 1991

Pe

rce

nt

IV U

se

rs

Relapse to IV Drug Use After Termination of Methadone Maintenance Treatment

Detoxification: Opioids• The most common

outcome of detoxification, by whatever means and for however long, is relapse.

“Detoxification may be good for a lot of things; staying off drugs is not one of them”

Methadone: An Appraisal

• Pioneering role as first effective medication• Most widely used—gold standard • Moderate clinical success• Significant draw backs• Marginal commercial enterprise• Public health failure

Opioid Pharmacotherapy Development

• Preoccupation with detoxification

• Societal-political ambivalence about methadone

• Enthusiasm about non-dependence producing medications: antagonists (naltrexone)

Addicts are sick, they need help;

But they also sin, don’t help them too much

Opioid Antagonist: Background

• Based on Extinction in animal behavioral studies.

• By blocking the positive reinforcing effects of agonists, an antagonist leads to extinction of drug seeking behavior.

• Prevents—re-addiction

• Antagonists are not abused and may prevent overdose when agonist is used.

Naltrexone: The “Perfect” DrugTen Reasons to Take

1. Orally Effective2. Rapid onset of action3. Long duration of action4. Safe5. Few side effects6. Completely blocks effects of heroin7. Non-addicting8. No tolerance9. No dependence10. No withdrawal

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Naltrexone Successes: Motivations

• Prisoners on work release program

• Physicians, pharmacists, nurses and other medical professionals with ready access to narcotics under threat of license loss

• Other professionals under similar threats

• People with no other, more palatable options: prison, exile, lions den

• “Dollar a-day” contingency

FDA Approval• 1984: FDA approves Naltrexone as a treatment

for heroin addiction 

• DuPont brand-names the drug Trexan

• Marketing issues become problematic– Difficult to convince patients to use medication– Resistance on part of methadone clinics - cost– Trexan fails to impact treatment community in a

significant way

Only Reason Not to Take Naltrexone: Can’t get high!

• A near “perfect medication” proved to be a “Victimless cure”. Why?

• There were a few successes in people who actually took the medication.

• We need a better naltrexone: one that once taken patients cannot get away from.

• Answer: sustained-release naltrexone

Alkermes Medisorb®Microspheres

Initial Release (diffusion) Sustained Release (polymer erosion)

d d d

Naltrexone drug particlesPorous polymer matrix

6-b

eta

nal

trex

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on

c

Days Following Injection0 303 7

Dru

g P

las

ma

Le

ve

ls

(Initial Release) (Sustained Release)

Alkermes, Inc.

Cambridge, Massachusetts

Vivitrol: The Russian study Key Efficacy Outcomes

3A. % Opioid-Free Urines by Week 3B. Mean Change From Baseline in Craving 3C. Time-to-Discontinuation (Kaplan-Meier)

Vivitrol for Opioid Addiction

• Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomized trial

• Evgeny Krupitsky, Edward V Nunes, Walter Ling, Ari Illeperuma, David R Gastfriend, Bernard L Silverman– Lancet 2011; 377: 1506-13

Vivitrol

• October 13, 2010 Alkermes received FDA approval for Vivitrol as treatment for opioid addiction

• Criticisms: directed at FDA– Single study in Russia– Not “made in USA” but “made AS in USA”?– Ethical considerations– No “ post treatment” safety data– Compared to other treatment—buprenorphine

Reflection: Will Power vs Wouldn’t Power

• People don’t behave like animals

• Not extinction but cognition

• What drives the compulsive gambler to act?

• “Coercive treatment” does work

• Dr. Jaffe’s reflections

• Who decides what’s good? Personal nature of addiction

No Crystal Ball But Time and Chance

“I returned, and saw under the sun, that the race is not to the swift, nor the battle to the strong, neither yet bread to the wise, nor yet riches to men of understanding, nor yet favor to men of skill; but time and chance happeneth to them all”. Ecclesiastes 9: 11

Those who live by the crystal ball end up eating glass

Potentially lethal dosePositive effect

=

addictive

potential

Negative effect

Full agonist -morphine/heroinhydromorphone

Antagonist - naltrexone

dose

Antagonist + agonist/partial agonist

Agonist + partial agonist

Super agonist -fentanyl

Partial agonist - buprenorphine

Buprenorphine and Buprenorphine and the Opioid Receptor Family the Opioid Receptor Family

Buprenorphine: Pharmacological Characteristics

Partial Agonist (ceiling effect)

• high safety profile

• low dependence

Tight Receptor Binding• long duration of action

• slow onset of mild abstinence on cessation

02468

1012141618

p 1 2 4 8 16 32

Buprenorphine (mg)

Bre

ath

s/m

inu

te

0

20

40

60

80

100

p 0.5 2 8 16 32

Buprenorphine (mg)

Peak

Sco

re

3.75 15 60

Methadone (mg)

Drug Addiction Treatment Act of 2000(Enacted September 27, 2000

signed into law by President Clinton October 17, 2000)

Allows practitioner to prescribe narcotics in schedule III IV V approved for treatment of opioid dependence to treat opioid addicted patients.

Practitioner must meet certain requirements– Provide or refer for counseling– Limit # of patients

“The Great Social Experiment”

Will Buprenorphine Succeed?• As a medication? Yes. (Safety and efficacy)

• As a treatment strategy? Yes. (Ease of delivery and high patient acceptance)

• As a new treatment philosophy? It depends– “The great social experiment”: return of opioid addiction

treatment to the physician– Change your chemistry, change your brain; change your

brain, change your lives– The role of the clinicians; we must change before our

patients’ lives can change.

Addiction: How The Brain Got its Disease

• Drugs release dopamine which makes you feel good and want to repeat the experience and you remember.

• Conditioned learning incorporates meaning and value to the drug memory giving it higher and higher power to drive to repeat the drug experience.

• Repeated seeking of drug use experience

becomes your way of life.

“First the man takes a drink, then the drink takes a drink, then the drinks takes the man”. Japanese proverb

Becoming Addicted and Staying Addicted: Getting Off and Staying Off Drugs

• Becoming addicted depends drug effects • Staying addicted depends on drug memory• The problem of addiction is not getting off drugs; it’s

staying off.• Detoxification helps getting off drugs, not staying off .• Relapse is a matter of memory: no memory, no relapse• All Substitution pharmacotherapies are for relapse

prevention; it is not substituting one drug for another, but one memory for another

Relapse: A Three Character Play • Drug memories: …everything, seems to bring memories

of you…(Eubie Blake)• Cues and triggers: external and internal; craving and

desire for love lost—regression & comfort• Emotional buildup: justification for use—the internal

dialogue making use ok and natural

• Relapse does not happen by accident.

Medications to Prevent Relapse • Medications to help staying off illicit opioids

– Methadone– buprenorphine – Naltrexone – Depo-naltrexone

• No approved medications to help staying off stimulants“Sorry, no water. We’re just a support group”

Creating Non-Drug Memories: The Old Fashion Way

• Experience –activities—leads to protein synthesis

• Protein synthesis activates new gene expressions

• Gene expressions create new brain connections

• New brain connections produce new memories

• New non-drug memories create non-drug belief systems which determine behaviors that determine how life turns out.

• The only way to change your life is to do things differently so they will turn out differently.

Eight Steps to Relapse Prevention and to a Drug Free Balanced Life

• Sound physical health• Sound mental health• Stay off drugs and stay busy• Take care of business: out of jail and on the job• Taking personal responsibilities• Live in harmony with family and friends• Be a good member of the community

• Search for a meaning in life.

Summing Up• Methadone introduced the modern era of addiction

pharmacotherapy and we now have medications ranging from agonists to antagonists

• Addiction medicine has unfortunately been largely outside main stream medical practices.

• Socio-political forces influence our development and application of medications; they reflect our value and our view of addiction and addicts

• Our understanding of addiction as a brain disease should change us, not just inform us.

“ Yes, you can change a person’s life by altering his genes, but you can also do that by paying off his credit card”.

James Watson

Thank you, thank you,

and thank you…