slide1 l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Translation: From opioid receptors To a new treatment for Alcoholism PowerPoint Presentation
Download Presentation
Translation: From opioid receptors To a new treatment for Alcoholism

Loading in 2 Seconds...

play fullscreen
1 / 62

Translation: From opioid receptors To a new treatment for Alcoholism - PowerPoint PPT Presentation


  • 215 Views
  • Uploaded on

Translation: From opioid receptors To a new treatment for Alcoholism. Charles P. O ’ Brien, MD, PhD University of Pennsylvania. Disclosure. Consultant to Embera (Research) Alkermes (Depot Naltrexone, no patent, no stock) Gilead (drug development). Endogenous Opioid System.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Translation: From opioid receptors To a new treatment for Alcoholism' - mika


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

Translation: From opioid receptors

To a new treatment for Alcoholism

Charles P. O’Brien, MD, PhD

University of Pennsylvania

disclosure
Disclosure
  • Consultant to
  • Embera (Research)
  • Alkermes (Depot Naltrexone,
  • no patent, no stock)
  • Gilead (drug development)
endogenous opioid system
Endogenous Opioid System

Opiate Receptors

Simon 1973

Pert & Snyder 1973

Terenius 1973

Enkephalin 1975 ∂

B-Endorphin µ

Dynorphin k

Nociceptin OFQ/NOC 1990s

early studies of morphine alcohol connection
Early studies of morphine-alcohol connection
  • Low dose morphine stimulates alcohol drinking in rats
  • Naloxone reduces alcohol drinking
  • Claims that alcohol produced a condensation product – Salsolonol/

tetraisoquinolones

1979 Altshuler monkey study

series of lucky coincidences
Series of Lucky Coincidences
  • 1. Altshuler poster at 1979 CPDD
slide6

Naltrexone decreases Alcohol preference*

% Change from Saline Pretreatment

Response Levels (10 day mean)

Days Naltrexone

* Altshuler 1980

slide11

Post-Shock Drinking

25

20

15

Placebo

Change in % Ethanol Consumption

10

Naltrexone

5

0

-5

1-2 3-4 5-6

Days Post-Shock

slide12

Saline

.25 mg/kg Naltrexone

Ethanol Responses

Time (min)

Time (min)

slide13

IND 1983-Begin open studies (1983-85)-50 mg dose based on experience with heroin-VA Medical Research Center Grant (alcohol & other drugs)-Alcohol program: day hospital, 12 step, counselors in recovery

Propose an RCT of Heroin med in human

alcoholics because of animal data ??

protocol 1986
Protocol 1986

70 male alcoholics, DSM III

Day hospital 27 hours per week x 12

AA groups

Self report + breathalyzer 5x per week

Endpoint = Relapse to heavy drinking

“Slips” recorded, not as endpoint

Craving recorded

RECRUITMET OBSTRUCTIONS

series of lucky coincidences15
Series of Lucky Coincidences
  • 1. Altshuler poster at CPDD
  • 2. Joe Volpicelli decides on Fellowship
slide16

Any Alcohol Drinking

Percent of Subjects

Naltrexone Placebo

slide17

Days Drinking

Average Drinking Days

per week

Naltrexone Placebo

slide18

Subjective “high” in Naltrexone and Placebo Subjects

0.1

0

- 0.1

- 0.2

- 0.3

- 0.4

- 0.5

mean “high” rating

*

Naltrexone Placebo

* p<.05

slide19

Pharmacological Treatments for Alcoholism

Craving Scores by Week

Mean (SEM) Craving Score (0-9)

0 1 2 3 4 5 6 7 8 9 10 11 12

Weeks on Medication

slide20

Alcohol Relapse

coming to treatment appointment with a blood alcohol concentration

> 100 mg%

or

B. self report of drinking five or more days within one week

or

C. self report of five or more drinks during one drinking occasion

non relapse survival
Non-relapse “Survival”

1.0

0.9

0.8

0.7

Cummulative Proportion with No Relapse

0.6

0.5

0.4

0.3

Naltrexone HCL (N=35)

Placebo (N=35)

0.2

0.1

0.0

0

1

2

3

4

5

6

7

8

9

10

11

12

No. of Weeks Receiving Medication

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

series of lucky coincidences22
Series of Lucky Coincidences
  • 1. Altshuler poster at CPDD
  • 2. Joe Volpicelli decides on Fellowship
  • 3. Roger Meyer joins Penn Advisory Bd
  • 4. Lilly rescinds permission to study Prozac in alcoholics
slide23

Rates of Never Relapsing According to Treatment Group (n=97)

Naltrexone/coping skills

Naltrexone/supportive therapy

Placebo/coping skills

Placebo/supportive therapy

100

80

60

40

n=97

20

0

0

20

40

60

80

Days

O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992

series of coincidences
Series of Coincidences
  • 1. Altshuler poster at CPDD
  • 2. Joe Volpicelli decides on Fellowship
  • 3. Roger Meyer joins Penn Advisory Bd
  • 4. Lilly rescinds permission to study Prozac in alcoholics
  • 5. Len Cook, PhD retires from Dup-Merck
  • 6. President wants good publicity
  • 7. Curtis Wright at FDA
  • 8. Obesity studies with 350 mg
results heavy drinking days
Results: Heavy Drinking Days

Baseline

Placebo

Vivitrol190 mg

Vivitrol380 mg

75th Percentile

30

25th Percentile

25

21.5

19.3

19.3

20

15

Median Heavy Drinking Days per Month

10

7.0

5.9

5.6

5.4

4.9

4.4

4.0

5

3.1

2.1

0

Overall

Male

Female

slide28
Assumption: alcohol causes the release of endogenous opioids which are “required” for DA release in response to alcohol?
opioid antagonism

Alcohol

Opioid Antagonism

Dopamine

Dopamine

Nucleus Accumbens

GABA

-EndorphinNeuron

Ventral Tegmental Area

Arcuate Nucleus

Gianoulakis. Alcohol-Seeking Behavior: The Roles of the Hypothalamic-Pituitary-Adrenal Axis and the Endogenous Opioid System. Alcohol Health and Research World. 1998;22(3).

naltrexone concurrently antagonizes etoh induced accumbal da release and etoh self administration
Naltrexone Concurrently Antagonizes EtOH-Induced Accumbal DA Release and EtOH Self-Administration

Gonzales & Weiss (2002) J Neurosci 18:10663-10671

variable response to alcohol
Variable response to alcohol

Alcohol seeking

10 of 22 Rhesus (Altshuler)

15% Vervets

10-15% H. sapiens

Less variable in rodents

µ receptor knock outs will not self administer alcohol

slide32

Opiate Receptors

Post-Synaptic

Neuron

N

NOC

Kappa Mu Delta

..

..

..

..

NX

MOR

MOR

NX

MOR

NX

MOR

Affinity for Opiate Receptor

KappaMuDelta

Naltrexone 406 108 54

Morphine 1 1 1

which opioid receptors
Which opioid receptors?

Stromberg, M.F., Casale, M., Volpicelli, L, Volpicelli, J.R. and O’Brien, C.P.: A

comparison of the effects of the opioid antagonists naltrexone, naltrindole, and b-

funaltrexamineon ethanol consumption in the rat. Alcohol, 15(4):281-289, 1998.

slide34

Individual Variation: two patients who both meet DSM-IV criteria for “alcohol dependence” but by a totally different neurophysiological mechanism.

slide35

Nalmephene: probably equal to naltrexone, comparisons not done

Intermittent nalmephene: to be approved in Europe

Blocking opioid receptors is key, but not certain which one:m, k, d

slide36
Alcohol effects become conditioned to environmental cuesNaltrexone blocks cue induced relapse better than stress induced(F. Weiss et al)
slide39

**

**

*

Bmax/Kd

Cocaine Craving

2.5

2.0

1.5

1.0

0.50

0.0

-0.50

2.5

2.0

1.5

1.0

0.50

0.0

-0.50

Change in Craving (Post-Pre)

Change in Craving (Post-Pre)

30 20 10 0 -10 -20 -30 -40

30 20 10 0 -10 -20 -30 -40

% Change Bmax/kd

% Change Bmax/kd

Caudate

Putamen

slide40

Satisfy craving

- agonists

methadone, bup - Heroin

methylphenidate - Cocaine, Meth

- Cognitive craving decision

Naltrexone alcoholism

Naltrex Heroin

Naltrex Boetiger

slide41

Pharmacological Treatments for Alcoholism

Craving Scores by Week

Mean (SEM) Craving Score (0-9)

0 1 2 3 4 5 6 7 8 9 10 11 12

Weeks on Medication

slide42

Opioid craving VAS scores: Change from baseline

OCS Mean Change from Baseline

P=0.0002

BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Visit Week

addiction therapy may be related to activation of frontal cortex
Addiction Therapy may be related to activation of Frontal Cortex

(Boettiger, et.al. 2009)

(Crews and Boettiger et.al. 2009)

slide45

(PACS < 5) (PACS 6-15) (PACS > 15)

Baseline Craving Scores

16

n = 57

14

12

% Days Heavy Drinking

10

NTX

n = 44

8

PLA

n = 72

6

4

2

0

Low Crave

Mod Crave

High Crave

PACS = Penn Alcohol Craving Scale

family history and naltrexone efficacy
Family History and Naltrexone Efficacy

16

n = 29

14

12

NXT

10

% Days Heavy Drinking

n = 73

n = 77

PLA

8

6

4

2

0

< 25% Alc Problem 25%-50% Alc Problem > 50% Alc Problem

Density of Familial Alcohol Problems

slide47

Change in b- Endorphin Levels after Alcohol Consumption

% change in plasma b-endorphin levels

Minutes after alcohol consumption

slide48

BAES Stimulation Scores

Among FH+ and FH Subjects

Placebo

Naltrexone

Base 2 30 min 60 min 120 min

Base 2 30 min 60 min 120 min

slide49

Key effect: Sensitivity of Endogenous Opioid system to alcoholOne source of individual variability in response to ethyl alcohol

slide50

Conclusion: Opioid system modulates alcohol reward.This can be useful in rehabilitation program, but blocking opioid receptors is not a “cure”A genetic variant shows greater endorphin response

slide51

A Double-Blind, Placebo-Controlled Trial Combining Sertraline and Naltrexone for Treating Co-Occurring Depression and Alcohol Dependence

Helen M. Pettinati, Ph.D.

David W. Oslin, M.D.

Kyle M. Kampman, M.D.

William D. Dundon, Ph.D.

HuXie, M.S.

Thea L. Gallis, B.A.

Charles A. Dackis, M.D.

Charles P. O’Brien, M.D., Ph.D.

how prevalent are co occurring depression and alcohol dependence and what is the prognosis
How Prevalent are Co-Occurring Depression and Alcohol Dependence, and What is the Prognosis?
  • Prevalence of major depression in alcoholism
    • 10 - 20% of clinical patients with an alcohol disorder have a current depressive disorder dx; 50% have a lifetime depressive disorder dx.
  • Prognosis of alcohol dependent patients with co-occurring psychiatric dxs
    • Psychiatric diagnosis (e.g. major depression) by history or structured interview is usually associated with poor drinking outcomes.
slide53
Status over the Last Decade of Using Antidepressants to Treat Comorbid Depression and Alcohol Dependence (1993-2006)

+True only under certain circumstances

slide54

Time to First Heavy Drinking Day and Time to First Drinking Day in Depressed Alcohol-Dependent Patients Randomly Assigned to Medication Treatment or Placebo

slide56

CNN Special

Addiction: Life on the edge

  • 5 patients followed for one year
  • Different parts of country
  • Admissions
  • Graduations
  • Relapses
  • Interviews with counselors at famous programs
slide57

Sanjay Gupta, MD

  • Interviews, patients, families, reasons for relapses
  • Last show:
  • Tall patient from Brown University
  • Not one of the 5 index patients
  • Interviewed near end of series
  • Apparently only patient treated with medication
slide58

GUPTA: And so he tried again. He checked himself into an experimental program run by Brown University. This time he got counseling once a week and a daily pill, a medicine called naltrexone. About two months into it, Walter Kent suddenly noticed the world around him looked and felt different.

KENT: And I had just turned around and I said, this is really something for the first time in my life that I never had this sensation where I didn’t want a drink. And this, to me, was like a godsend because of the fact that for someone who had to have a drink, now all of a sudden I don't need that -- I don't have that feeling anymore.

GUPTA: He hasn’t had a drink in more than eight years. Even after his doctor stopped the medication. He’s healthy, back at work, fixing up carburetors.. And now he's part of a running debate. Is addiction an illness you can treat with a pill or a character flaw to be tackled with therapy and self-help?

Addiction: Life on the Edge – CNN Correspondent Dr. Sanjay Gupta aired April 19, 2009

slide59

GUPTA: Despite the evidence, most fancy rehab centers use medication only rarely, if at all. The focus is much more on therapy.

Head Counselor Minnesota: With the health care professional staff here at Hazelden, our experience tells us having that network of support in recovery is what really makes the difference.

GUPTA: More so than medication?

CLARK: More so than just medication, exactly.

GUPTA: And that's the conventional wisdom.

Addiction: Life on the Edge – CNN Correspondent Dr. Sanjay Gupta aired April 19, 2009

slide60

California Program

GUPTA: What about medications?

Head Counselor California Program: We do not use them at the Betty Ford Center.

No comment from the interviewer, no follow up questions.

Addiction: Life on the Edge – CNN Correspondent Dr. Sanjay Gupta aired April 19, 2009

slide61

FOR MORE INFORMATION

http://www.med.upenn.edu/csa/or

obrien@mail.trc.upenn.edu

slide62

Psychopharmacology: the Fourth Generation of Progress, edited by Floyd E. Bloom and David J. Kupfer.

Raven Press, Ltd., New York 1995.

Chapter 149

Pharmacotherapy of Alcoholism

Charles P. O’Brien, Michael J. Eckardt, and V. Markku I. Linnoila