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Alcohol Abuse vs. Dependence, & the Evolving Role of Naltrexone as Adjunctive Pharmacotherapy Alexander DeLuca, M.D., FASAM Presentation to the Department of Medicine of St. Luke’s / Roosevelt Hospital Center, New York City 2/12/2002 http://www.doctordeluca.com/

Alcohol Abuse vs. Dependence Traditionally, there has been an assumption on the part of clinicians in the field that these entities are part of a continuum of illness We call substance abuse disorders “chronic, relapsing and progressive” We have thought (and taught) that if a person destined for alcohol dependence had 1-3 alcohol-related problems today, that number would increase over time

Substance Abuse Treatment in the U.S. Roots not in medicine or psychiatry, but in the self-help movement as epitomized by Alcoholics Anonymous. Focus on complete (‘radical’) abstinence While the NIH and any textbook will tell you that the first line treatment for alcohol abuse is decreased alcohol intake and an attempt to regain control, this is not an option on the menu of the average treatment center

Abuse vs. Dependence in Clinical Practice Alcohol abuse is rarely identified and treated as such except in special populations If abuse = ‘dependence early on the curve,’ then the tendency to treat all patients presenting for treatment in the same setting and with the same modalities is somewhat rational Controlled drinking and moderation remain highly contentious concepts within the treatment community

Recent Articles and Implications Schuckitt, 2001: Prospective study of over 1300 DSM-IV diagnosis of alcohol dependence predicts a chronic disorder with a relatively severe course DSM-IV diagnosis of abuse predicts a milder, less persistent disorder that does not usually progress to dependence Krystal, 2001: “Our findings do not support the use of naltrexone for the treatment of… chronic, severe alcohol dependence.” Sinclair, 2001: No benefit of NAL over placebo when combined with support for abstinence. “Naltrexone is most effective when paired with drinking but ineffective when given during abstinence…”

Krystal, NEJM, December 2001 Krystal ’01: Multi-center DBPC study of NAL as adjunctive Tx to individual 12-step facilitation therapy and encouragement to attend AA. 627 vets, almost all male, with chronic, severe alcohol dependence Three groups: 12 month NAL daily; 3 months NAL à 9 months placebo; 12 months placebo. At 13 weeks, no significant difference between NAL and placebo in days to relapse. At 52 weeks, no differences in % of drinking days or # drinks per day. Unfortunately, this lead article in the NEJM will be misunderstood as proving that ‘NAL doesn’t work,’ which was not helped, IMO, by the defensive-sounding Fuller / Gordis letter in the same issue.

Naltrexone; Determinants of Efficacy There are two different hypotheses about how naltrexone (NAL) works in the treatment of alcohol disorders Abstinence protocol – hypothesis: craving and/or reinforcing properties of alcohol mediated by opioid system and are blocked by NAL Extinction protocol – hypothesis: opioidergic activity reinforces drinking and NAL blocks the reinforcement Type of adjunctive psychosocial treatment “Supportive” aka 12 Step Facilitation therapy Cognitive Behavioral Therapy Coping Skills Therapy is variant most studied in association with NAL

Naltrexone and Psychotherapy Balldin ’97 - NAL is effective when paired with CBT, otherwise not. O’Malley ’96 – Relapse to heavy drinking prevented in Coping Skills group and not in the abstinence oriented “supportive” psychotherapy group.

A Closer Look at Naltrexone Efficacy Sinclair 2000: Review of 8 double blind placebo controlled studies. Three trials tested NAL in two ways: 1)  ‘supportive,’ (abstinence-oriented) psychotherapy 2)  with therapy acknowledging that relapse occurs and teaching how to cope including how to control drinking once it has begun All found benefits with NAL + Coping Skills; none with NAL + abstinence

The Abstinence Protocol Detoxification Period of abstinence without medication Usually one to three weeks Naltrexone daily in association with individual or group psychotherapy Usually three to six months Usually 50 mg per day Naltrexone discontinued

The Extinction Protocol Based on extensive preclinical research using animal models Naltrexone causes extinction of alcohol drinking Naltrexone causes extinction of responding for alcohol Naltrexone is started without requiring prior detoxification or abstinence Usually 50 mg daily Variant: naltrexone taken only in drinking situations; drug is carried indefinitely.

Abstinence Protocols Dominate the Literature in the U.S. Used in Volpicelli ’92 and O’Malley ’92 Double blind, placebo controlled studies of approximately 100 patients each Significantly decreased craving, fewer drinking days, fewer patient meeting relapse criteria, higher abstention rates, of those who drank – fewer relapsed Consequently, similar protocol used in subsequent clinical trials and in most clinical practice

Survival to First Drink If NAL helps patients abstain longer compared to placebo, this would justify requirement of detox and abstinence. Overwhelmingly, the clinical trial literature shows no significant difference between NAL and placebo conditions prior to the onset of drinking Only study to contrary with significant positive NAL effect in abstinent condition is Volpicelli ’97 after excluding non-compliant patients and non-completers. Literature generally does demonstrate beneficial NAL effects after some drinking has resumed

Re-Examination of Abstinence Literature Volpicelli ’92: “[NTX Tx] did not appear to prevent subjects from sampling alcohol…The primary effect…was seen in patients who drank any alcohol while attending outpatient treatment.” Moncrieff ’97 on O’Malley ’92: “Two survival analysis are presented, one with any drinking and one with relapse as the criterion of failure. The latter but not the former demonstrate significant overall effect of medication.” Chick 2000: “[A] statistically significant advantage in the… time to first drinking, was not seen, although there was a trend… although patients were advised to abstain, < 20% did so.”

Problems with the Abstinence Protocol With only weak (not statistically significant) positive effects for NTX demonstrated, can detox and radical abstinence be justified considering: The rebound effect, probably secondary to receptor upregulation by NTX, causing increased drinking after period of NTX & abstention in animal models If it is unethical to tell a successfully abstinent alcoholic to resume drinking, is it not also “… unethical to tell patients to abstain while on NTX, knowing that they will receive the major benefits only if they disobey…”

A Public Health Perspective Only a small percentage of problem drinkers seek help Understandable fear and loathing of diagnosis and treatment is likely a significant part of the reason Presenting for treatment will almost surely net you a “diagnosis” (label) of “alcoholism” and a prescription for lifelong radical abstinence Detoxification can be uncomfortable and dangerous, and is always expensive A subset of patients are unable to abstain for the requisite period prior to NAL initiation and this waiting period is not supported by research Many problem drinkers would likely appreciate the option of controlled drinking and NAL