Transcript Document

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  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 defensivesounding 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