1. Practical Applications Of Neuroscience Research February 16, 2007 Charles P. O’Brien, MD, PhD University of Pennsylvania Philadelphia VA Medical Center

2. Search: Non-addicting med for severe pain NIH (NIDA) Opiate Receptors 1973 Endogenous opioids “endorphins” Enkephalin 1975 ∂ B-Endorphin µ Dynorphin k Nociceptin OFQ/NOC 1990’s

3. Post-Synaptic Neuron Kappa Mu Delta Affinity for Opiate Receptor TX TX TX TX Opiate Receptors Kappa Mu Delta Naltrexone 406 108 54 Naltrexone 406 108 54 Morphine 1 1 1 Morphine 1 1 1 MOR MOR MOR MOR.. NOC N

4. New Concepts: agonist antagonist partial agonist inverse agonist

5. Opiate receptor antagonists 1970s Naloxone reverse opiate analgesia treat opiate overdose Naltrexone block heroin relapse (FDA 1984) treat babies born with excess endorphins treat form of infertility by stimulating gonadotrophins

6. Naltrexone treatment of opiate addiction Little use for heroin addiction Treatment of choice for physicians and other “white collar” addicts Successful treatment of parolees and probationers Block revolving door: heroin-prison-heroin

7. SubstanceOral Nltx Control Sig. (N=34) (N=17) (N=34) (N=17) Opiate8%30%p<.05 Cocaine33%49%NS Amphetamine0%1%NS Benzodiazepine2%6%NS Marijuana13%19%NS Alcohol2%4%NS Parolees Mean Percent Positive Urines

8. Re-Incarceration at 6 months NaltrexoneControl Percent subjects 26% 56% P<.05

9. Study in Parolees with History of Opiate Addiction Six sites Providence, RI NYC (Columbia) NYC (NYU) Philadelphia Baltimore Richmond Relapse Rate to Heroin Addiction Re-incarceration Rate

10. Alcohol stimulates endogenous opioids Unexpected finding from animal models Monkeys 1979 Rats 1980s First study in human alcoholics, Philadelphia VAMC 1983-90 Family history positive alcoholics Opiate-like euphoria from alcohol High craving for alcohol

11. Subjective “high” in Naltrexone and Placebo Subjects Subjective “high” in Naltrexone and Placebo Subjects Naltrexone Placebo mean “high” rating 0.1 0 - 0.1 - 0.2 - 0.3 - 0.4 - 0.5 * * p<.05

12. Non-relapse “Survival” Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880 No. of Weeks Receiving Medication 1023456789101112 0.0 0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.3 Naltrexone HCL (N=35) Placebo (N=35) Cummulative Proportion with No Relapse

13. Rates of Never Relapsing According to Treatment Group (n=97) O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992 Naltrexone/coping skills Naltrexone/supportive therapy Placebo/coping skills Placebo/supportive therapy Days 0 20 40 60 80 100 n=97 020408060

14. Naltrexone treatment of alcoholism Philadelphia VA results replicated 1992 FDA approval 1994 Naltrexone used throughout the world for alcoholism Does not work for all alcoholics

15. Genetics of alcoholism Genetic variant of µ opiate receptor “G allele” Increased euphoria from alcohol Euphoria blocked by Naltrexone Increased risk of opiate addiction Increased risk of alcoholism G allele: 20-25% of European-Americans Poor outcome randomized to placebo treatment & counseling Excellent results with naltrexone & counseling

16. Relapse Rate by Genotype

17. Replication study Nalt A/G, GG95%N = 28 Nalt A/A73%N = 86 Plac. A/G, GG63%N = 60 Plac. A/A65%N = 205 Odds ratio, nalt good regs, GVA = 10.25 (95% CI 1.31 - 80.0 P=.03) “Good” Results

18. New delivery system One injection each month Slow release Blocks opiates and endogenous opioids for one month Alcoholism: FDA approved 2006 Opiate addiction: in clinical trial

19. Summary Search for non-addicting pain reliever Discovery of opiate receptors Discovery of endogenous opioids Development of opiate antagonists New treatment for opiate addiction New treatment for alcoholism Endophenotype of alcoholism ? Reduced re-incarceration of heroin addicts

20. Institutionalization in the United States (per 100,000 adults) Total RatePrison RateMental Hospital Rate ___ Total Rate __ __ __ Prison Rate _ _ _ Mental Hospital Rate