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The RINCA Study On the Reduction of Negative Consequences associated with heavy drinking

Explore the impact of opioid system in heavy drinking and the Deprivation Effect leading to relapse. Learn about the RINCA Study and how Naltrexone and Nalmefene can mitigate these effects.

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The RINCA Study On the Reduction of Negative Consequences associated with heavy drinking

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  1. The RINCA StudyOn the Reduction of Negative Consequences associated with heavy drinking Dr. Josep Guardia-Serecigni Vicepresident of SOCIDROGALCOHOL Senior Consultant in Psychiatry Addictive Behavior Unit Departement of Psychiatry Hospital de la Santa Creu y Sant Pau BARCELONA (SPAIN) jguardia@santpau.cat

  2. INDEX • Opioid system and heavy drinking. • Deprivation Effect and Relapse to heavy drinking. • Treatment of Alcoholism. • The RINCA Study. • Conclusions Dr. Josep Guardia-Serecigni

  3. Opioids and Alcohol • Acute alcohol induces beta-endorphin release in the the midbrain VTA. (Jarjour, Bai and Gianoulakis, 2009) • The activation of opioid receptors (in VTA GABA neurons), by beta-endorphin, increases the release of mesolimbic dopamine. (Gessa et al., 1985; Imperato y Di Chiara, 1986; Marinelli et al., 2003;Chefer et al., 2005; Ford et al., 2006) • Mesolimbic dopamine increase is related to: • POSITIVE REINFORCING EFFECT of alcohol and to • LOSS of CONTROL over drinking. • Opioid receptor antagonists, such as naltrexone or nalmefene, may attenuate both: • The alcohol reinforcing effect and • The loss of control over drinking. (Volpicelli et al., 1986; Hyytia and Sinclair, 1993; Froehlich et al., 1990) Dr. Josep Guardia-Serecigni

  4. ACUTE ETHANOL ADMINISTRATION (Clapp et al., 2008) Beta-endorfin release  Decrease of GABA transmission  Disinhibition of DA neurons in the VTA  Increase dopamine release in de N. Accumbens  LOSS of CONTROL Dr. Josep Guardia-Serecigni

  5. ACUTE ETHANOL ADMINISTRATION Release of Beta-endorfins  Block opioid receptors  STOP the chain Decrease of GABA transmission Desinhibition of DA neurons in the VTA Increase in dopamine release in de N. Accumbens (Clapp et al., 2008) NALTREXONE NALMEFENE Dr. Josep Guardia-Serecigni

  6. Deprivation Effect andRELAPSE to heavy drinking Dr. Josep Guardia-Serecigni

  7. The Deprivation Effect • After many days of sobriety, the person who has developed an alcohol addiction, is more likely to lose control on drinking, the day he/she tries to have a drink again. • This is not only a psychological effect, but a neurobiological evidence, repeatedly tested in the laboratory, with rats, monkeys and people addicted to alcohol. • The relapse consequences can be serious, because a relapse may induce: • Big emotional disorders. • Severe behavioral disruptions (self- or hetero-aggressiveness). • And even overdose or sudden death, due to heart rhythm disturbances. Dr. Josep Guardia-Serecigni

  8. RECOVERY and RELAPSE • Simple CONTINUED SOBRIETY does NOT EXTINGUISHES the ADDICTIVE CONDITIONING to alcohol. • Either treatment with Disulfiram or long term sobriety DO NOT PROTECT from the DEPRIVATION EFFECT. • Probably the patient will have a drink (sooner or later): • The “fantasy” of the patient (and also his relatives) is that, after a non-drinking period, he will be able to control drinking again. • And his usual demand for help is to drink "normally", "as other people do." • However, due to the DEPRIVATION EFFECT: • When the addicted patient will have a new drink it will reappear the: • Loss of control over drinking => behavioral disorders (associated) • Negative consequences => "PROBLEMS" . Dr. Josep Guardia-Serecigni

  9. Opioid antagonists block the Deprivation Effect • NALMEFENE and NALTREXONE: • Can block the Deprivation Effect, • thus making easier self-control on drinking. • Studies performed in the laboratory (experimental bar) have checked that NALMEFENE and NALTREXONE produce (from the first day of treatment) a decrease in: • alcohol consumption per occasion (people end up drinking less) • speed of alcohol consumption (they drink slower) • alcohol-reinforcing effect (it is not so pleasant) • an increase in satiety effect (they stop drinking alcohol) • unpleasant symptoms of intoxication (headache, dizziness, .....) (Davidson et al., 1999; Drobes, Anton, Thomas and Voropnin, 2004) • Studies performed with “as needed” NALMEFENE or "targeted" NALTREXONE have shown that in addition, they may decrease (in the long term): • alcohol craving ("obsession" for drinking, "need" to enter the bar and need to have an alcoholic drink) • total alcohol consumption. Dr. Josep Guardia-Serecigni

  10. Drinking REDUCTION as a goal of treatment • The majority of alcoholic patients: • Say that they want to stop drinking, but not forever. • Think that in a near future they will develop moderate drinking. • And what they really want, and they ask for, is to get back to the control over drinking. • When an addicted person remains sober for a long time, he usually develops some wrong tihinking, such as: • He no longer has an alcohol problem. • “Maybe the doctors have been wrong with the diagnosis of alcohol addiction”, and • “Therefore, now it’s no longer a problem to have a dink”. • Instead, the person who maintains the "struggle" for drinking just a few dinks per occasion, helped by nalmefene: • He develops a more realistic knowledge of his Addictive Disease, • He remains more alert, given the "PERSISTENT" risk to LOSE his CONTROL over drinking. • And his LONG TERM RECOVERY, becomes more STABLE. Dr. Josep Guardia-Serecigni

  11. Treatment of Alcoholism Dr. Josep Guardia-Serecigni

  12. Treatament outcome variables • The FDA(Food & Drug Administration) considers both as a treatment success : • Continued sobriety • Low-risk drinking. • Clinical trials, like COMBINE study: • use the outcome variable “Percentage of subjects with no heavy drinking days” (PSNHDDs), during treatment. (Anton et al., 2004) • They have foound a clear relationship between: • The number of days that the patient exceeds the limit of 5 drinks/occasion (4 in women), and • The amount of negative consequences of heavy drinking. (Falk et al., 2010) Dr. Josep Guardia-Serecigni

  13. Naltrexone Treatment Outome (Falk et al., COMBINE study, 2006) Dr. Josep Guardia-Serecigni

  14. Time to Relapse to Heavy Drinkingª (N=202)(Guardia-Serecigni et al., 2002) Dr. Josep Guardia-Serecigni a Más de cinco UBE/día para los hombres (>4 en las mujeres) b Kaplan-Meier Log Rank estadístico=4, df=1, p<0.05

  15. Dr. Josep Guardia-Serecigni

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  17. Clinical Remission Criteria • The COMBINE study, conducted in the United States (Anton et al., 2006): • Compare several pharmacological and psychosocial treatments of alcoholism, and • It concludes that one of the most useful criteria of treatment outcome is the number of heavy drinking days along the treatment, • Because this outcome criteria has a good correlation with the number of negative consequences (related to heavy drinking) that has suffered each patient, during the treatment, and even during its subsequent follow-up. (Falk et al., 2010) • It would be like saying: • Not drinking alcohol every day and • Not reaching the limit of heavy drinking in any occasion of drinking, • It is associated with not having negative consequences and • It is considered as CLINICAL REMISSION. Dr. Josep Guardia-Serecigni

  18. Drinker Inventory of Consequences (DrinC) Negative Consequences number of heavy drinking days Dr. Josep Guardia-Serecigni

  19. Risk drinking levels(WHO,2004) Dr. Josep Guardia-Serecigni

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  21. Ideal patient profile for Nalmefene • ESENSE studies show that nalmefene is effective in reducing alcohol consumption for: • Low severity alcoholism patients • Without an alcohol withdrawal syndrome • Without other unestabilitzed psychiatric disorders. • And asking for REDUCING alcohol consumption. Dr. Josep Guardia-Serecigni

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  23. The RINCA study Reduction of Negative Consequences associated with Heavy Drinking Dr. Josep Guardia-Serecigni

  24. The RINCA study • Is a treatment study: • with nalmefene • for the REDUCTION of alcohol drinking • in low severity alcohol dependent people. • The hypothesis is that: • having one pill of nalmefene on each occasion of drinking => • low risk drinking => • not having negative consequences (assessed by DrinC Inventory) => • clinical remission of the alcohol dependence disorder. Dr. Josep Guardia-Serecigni

  25. Reduction of negative consequences associated with heavy drinking • The cardinal symptom of alcohol addiction is the LOSS of CONTROL over drinking. • But what are really visible are the NEGATIVE CONSEQUENCES or “PROBLEMS” associated to HEAVY DRINKING. • The DrInc Inventory of Consequences (DRINC): • Assess the number of "PROBLEMS“, • that are negative consequence of heavy drinking. • Hypothesis: • If the patient reduces substantially their alcohol consumption, • the scores of DrInC inventory will show also a significant decrease. • Expected Outcome: • If treatment with Nalmefene • is associated with a significant reduction or even the complete disappearance of the Negative Consequences, • The patient will reach the clinical REMISSION of his Alcoholism. Dr. Josep Guardia-Serecigni

  26. RINCA study Preliminary results Dr. Josep Guardia-Serecigni

  27. AGE Dr. Josep Guardia-Serecigni

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  30. Baseline scores of DrinC inventory Dr. Josep Guardia-Serecigni

  31. Total baseline alcohol consumption (grams)last 28 days Dr. Josep Guardia-Serecigni

  32. Baseline average of daily alcohol consumption (grams) Dr. Josep Guardia-Serecigni

  33. Baseline GGT values Dr. Josep Guardia-Serecigni

  34. Baseline MCV (mean corpuscular volume) Dr. Josep Guardia-Serecigni

  35. Comparisons between Baseline and 4th week of treatment Dr. Josep Guardia-Serecigni

  36. Comparisons between Baseline and 8th week of treatment Dr. Josep Guardia-Serecigni

  37. Comparisons between Baseline and 12th week of treatment Dr. Josep Guardia-Serecigni

  38. DrinC score comparison between baseline, 4th week, 8th week, and 12th week of treatment Dr. Josep Guardia-Serecigni

  39. Total alcohol consumption comparison between baseline, 4th, 8th, and 12th week of treatment Dr. Josep Guardia-Serecigni

  40. Average daily alcohol consumption comparison between basal, 4th, 8th, and 12th week of treatment Dr. Josep Guardia-Serecigni

  41. baseline and final GGT p<.001 Dr. Josep Guardia-Serecigni

  42. Baseline and final MCV p<.001 Dr. Josep Guardia-Serecigni

  43. CONCLUSIONS • The person who has developed an alcohol use disorder shows: • DIFFICULTY to CONTROL DRINKING which leads to REPEATED “PROBLEMS”. • Even if he has stopped drinking for a wile, the day he will try to have a drink again, he will suffer the • DEPRIVATION Effect => Uncontrolled drinking => Negative Consequences (or PROBLEMS associated). • NALMEFENE: • Neutralize the Deprivation Effect, and • It helps to REDUCE alcohol consumption. • The person who reduces and maintains a low risk drinking level: • He stops showing Negative Consequences of their drinking. • He reaches the CLINICAL REMISSION of his Alcoholism. • Therefore, low-severity alcoholic patients: • Well trained for REDUCING alcohol consumption, and • Helped with NALMEFENE. • They can get the REMISSION of their ALCOHOLISM. • Just by maintaining a LOW RISK DRINKING level, in all drinking occasions. Dr. Josep Guardia-Serecigni

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