1. Medication-Assisted Treatment: What’s in the Cupboard and Why
Walter Ling, M.D
Director
Integrated Substance Abuse Programs
UCLA
LA County Drug Court Conference
May 16, 2013
Los Angeles, California

2. 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?
First l should like to thank Tom and his group for giving me this opportunity to speak to you.
What we have; what we do with them, where are we going with them.
What’s in a name? Name, memory and value.

3. Opioid Addiction Treatment
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:
Outcome correspond to most current “recovery” : Abstinence from drugs; health, personal responsibility and citizenship.
Dole VP & Nyswander ME (1965) A Medical Treatment for Diacetylmorphine (Heroin) Addiction JAMA 193:
Here’s what is generally regarded as the first report of what herald in the modern era of opioid addiction treatment. The title is “medical treatment, but the results were measured in terms of changes that clearly are elements of harm reduction: reduced criminal activities and gainful employment in addition to reduced heroin use and improved general health.

4. 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
Methadone is recognised as the ‘gold standard’ of treatment for managing opioid dependence and has been found to be an effective public health and harm reduction measure. Methadone has been available in all jurisdictions since 1969, although to date remains unavailable in the Northern Territory. Its use is generally restricted to specific medical conditions, such as opioid dependence and the management of chronic pain
Methadone is provided by public government services (public programs) and privately through trained GP prescribers
Methadone is highly effective when taken orally. When used repeatedly, such as during maintenance for opioid dependence, its effects persist and the duration of its effect is extended
Although a potent analgesic for chronic pain, the analgesic effect lasts for less than 24 hours because of its variable half-life.
Methadone:
is detectable in plasma for 30 minutes following ingestion
has a peak concentration after about 4 hours
has a single dose half-life of 15–22 hours (high variability)
has a maintenance dosing half-life of 22 hours and suppression of withdrawal for 24–36 hours
stability varies with metabolic rate, which varies according to genetic makeup, environmental and disease-state factors (e.g. pregnancy increases methadone metabolism)
oral form only marginally less potent than IM form.
Source: CDHA (Commonwealth Department of Health and Ageing) 2002, Illicit Drug Training for Pharmacists, CDHA, Canberra, p.86.

5. Methadone Treatment vs Untreated Heroin Addicts: Mortality Rate
Methadone Treatment can make a difference in life and death of our patients.
After 8 years 85% of addicts in treatment are alive; more than half of those untreated are dead
Untreated addicts mortality rate is 9 times that of methadone patients

6. Methadone Maintenance: HIV Rate and Costs
HIV Rates
47%
23%
17%
12.5% 6% 0%
10%
20%
30%
40%
50%
Not in Tx
Currently in Tx
In Tx 5 years
C&D
No needle use since
admission to Tx A B C D
It can also reduce diseases and safe money.

7. What Really Matters in Methadone Treatment
Dose and Duration of Treatment are the two things in methadone treatment that make a difference.

8. Detoxification: Opioids
The most common outcome of detoxification, by whatever means and for however long, is relapse.
But we want detox and more and better detox
“Detoxification may be good for a lot of things; staying off drugs is not one of them”

9. 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
Successes as noted in previous slide;
24 hrs long enough medically but not enough for rehab—jobs
15% market penetration after 40 yrs.
Poorsocietal acceptance: our own ambivalence.

10. 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
We approach problems according to our values and beliefs

11. 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.

12. Naltrexone: The “Perfect” Drug Ten Reasons to Take
1. Orally Effective
2. Rapid onset of action
3. Long duration of action
4. Safe
5. Few side effects
6. Completely blocks effects of heroin
7. Non-addicting
8. No tolerance
9. No dependence
10. No withdrawal
EN 1639-A Blumberg 1967 ; apologies to David Letterman “ten top reasons”
EN 1639-A

13. 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

14. 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

15. 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
No problem if they don’t like it; we’ll give them a shot that they can’t run away from. We finally have it after 30 yrs. Will it work? Time alone can tell.

16. Alkermes Medisorb®Microspheres
Porous polymer matrix
Naltrexone drug particles d
Initial Release (diffusion)
Sustained Release (polymer erosion)
6-beta naltrexol conc
Days Following Injection 30 3 7
Drug Plasma Levels
(Initial Release)
(Sustained Release)
Alkermes, Inc.
Cambridge, Massachusetts

17. Vivitrol: The Russian study Key Efficacy Outcomes
3A. % Opioid-Free Urines by Week B. Mean Change From Baseline in Craving C. Time-to-Discontinuation (Kaplan-Meier)

18. 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:
Lancet 2011; 377: 1506–13
Published Online
April 28, 2011
DOI: /S0140-
6736(11)
See Comment page 1468

19. 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

20. 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

21. No Crystal Ball But Time and Chance
Those who live by the crystal ball end up eating glass
“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
Perhaps next year we’ll have a better story to tell but in the long run, when some archiological student kicks over our skulls, I doubt what we do or say here today is going to make any real difference.

22. Buprenorphine and the Opioid Receptor Family
Potentially lethal dose
Positive
effect =
addictive
potential
Negative
Full agonist -
morphine/heroin
hydromorphone
Antagonist - naltrexone
dose
Antagonist + agonist/partial agonist
Agonist + partial agonist
Super agonist
fentanyl
Partial agonist
- buprenorphine
Wait, we have something that feels like methadone when we give it to them but ended up like naltrexone. It’s buprenorphine.

23. 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
All you need to know about buprenorphine.

24. 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”
It took an act of Congress because it’s giving the patient back to the doctors. It’s a great social experiment alright. On the doctors and society.

25. 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.
So will buprenorphine succeed? It really depends on us and that brings us back to what we understand what addiction is. A Brain Disease

26. 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.
It’s a form of extreme take over. It is, in a nut shell, how your brain got its disease.
Dopamine is key to reward driven learning—conditioned response-- which creates heightened-value memory that determines the behavioral basis of addiction. Slide 2A trigger is a stimulus which has been repeatedly associated with the preparation for, anticipation of or the use of drugs and/or alcohol. These stimuli include drugs, cues, people, things, places, times of day, and emotional states.
Conditioned response is reward-driven learning which involves dopamine.
Definition of a trigger.
“First the man takes a drink,
then the drink takes a drink,
then the drinks takes the man”.
Japanese proverb

27. 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
Detoxification may be good for a lot of things, staying off drugs is not one of them
Next time you talk about substitution therapy, remember it’s the memories, not the drugs, you are trying to substitute.

28. 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.

29. 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”

30. 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.
Forgetting old drug memories and creating non-drug memories the old fashion way.

31. 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.

32. 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.

33. Thank you, thank you, and thank you…
“ 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…