By Arline Kaplan ©2002
(All Rights Reserved)
In the wake of the Sept. 11,
2001, many recovering alcoholics relapsed and problem drinking has been
increasing.
According to a survey from
the National Center on Addiction and Substance Abuse (CASA) at Columbia
University, 23 states, five cities and Washington, D.C. have detected an
increased demand for alcohol and drug treatment since the attacks on the World
Trade Center and Pentagon.
The telephone survey of
offices of substance abuse services in 50 states, the 10 largest U.S. cities
and Washington, D.C. is a follow up to one conducted in December of 2001.
Joseph A. Califano, Jr., CASA
president and former U.S. Secretary of Health, Education and Welfare, in a
April 2 (2002) press statement said that Òthe rubble may be almost cleared
away, but the lingering effects of Sept. 11 and its aftermath are far from
over. It is imperative to provide
treatment for individuals who have turned to alcohol and drugs to cope or have
relapsed from sobriety, so that they do not become the second wave of victims
of our national tragedy.Ó
The states detecting an
increase in demand for substance abuse treatment since Sept. 11 include Alabama,
Alaska, Arizona, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii,
Idaho, Illinois, Kansas, Kentucky, Maine, Massachusetts, Nebraska, Nevada, New
Hampshire, New Jersey, New York, Pennsylvania, Tennessee and Virginia. Cities reporting increased demand for
treatment include Detroit, Houston, New York, Philadelphia and Phoenix.
While Califano and others are
raising public awareness about the links between stress and alcoholism,
researchers are studying biological mechanisms that may underlie drinking
behavior. And such mechanisms include the hypothalamic-pituitary-adrenal (HPA)
axis, which plays a pivotal role in stress.
Ray Litten, Ph.D., chief of
the Treatment Research Branch at the National Institute on Alcohol Abuse and
Alcoholism (NIAAA), said researchers are identifying pathways that are involved
in alcohol drinking behavior, studying genes that may be involved, looking at
intracellular signaling processes within the cell, and integrating all of
this. The goal is Òto develop a
new generation of medications that are more potent than we have now.Ó
From a neuroscience
perspective, drinking behavior is complex.
ÒAbout 10 years ago, many
people thought that just one neurotransmitter would be involved in alcohol
drinking behavior, but it is really driven by numerous neurotransmitter
systems,Ó Litten said.
In addition to the opioid
system, preclinical studies have shown that alcohol affects neurotransmitters
in the brain, including dopamine, serotonin, glutamate, γ-aminobutyric
acid and norepinephrine (Fuller and Gordis, 2001).
Hormonal systems, such as the
HPA axis, are involved as well, Litten said. Some researchers, for example,
have found alcohol dependence is associated with long-lasting alterations in
HPA-axis (Anthenelli et al., 2001), and NIAAA-funded preclinical studies have
shown that stressed animals will increase their drinking.
A chemical that may play a
key role in producing arousal, anxiety and other emotional responses to stress
is corticotropin-releasing factor, secreted by the hypothalamus. NIAAA-funded investigators are looking
at CRF-antagonists that block CRF receptors in the brain. CRF-antagonists have
been promising in reducing drinking behavior in animals, Litten said. He added
that NIAAA hopes to test the efficacy and safety of CRF-antagonists in humans
soon. Several pharmaceutical companies also are working on developing
CRF-antagonists.
In preclinical studies,
several other compounds have shown efficacy in reducing alcohol consumption in
animals including an N-methyl-D-aspartate agonist; and a compound that is both
a serotonin 1A-receptor agonist and a serotonin 2-receptor
antagonist (Fuller and Gordis, 2001).
Major advances in
pharmacological treatment of alcoholism have occurred within the last decade,
according to Litten.
ÒNaltrexone [ReVia] was
approved in 1994 and ushered in a new generation of medications to treat
alcoholism. It is the first
medication approved in over 50 years. The previous medication was disulfiram
(Antabuse),Ó Litten said. ÒNaltrexone represents a new type of medication, one
that reduces oneÕs desire or urge to drink or perhaps even craving. We are
still trying to investigate exactly how it does this.Ó
NIAAA is funding several
studies to determine naltrexoneÕs full clinical potential as well as its
limitations. Some researchers are studying the efficacy of naltrexone for early
problem drinkers, for relapse prevention, for alcohol dependence, for
maintenance treatment and for treatment of alcoholism and posttraumatic stress
disorder. Other researchers are assessing safety issues and appropriate
dosages. For instance, 100 mg/day of naltrexone may be more effective than 50
mg/day, Litten said. Researchers are also investigating whether any differences
exist in twice versus once-a-day dosing.
ÒNaltrexone is not a magic
bullet. There have about a dozen studies published on it and more are coming
out. Overall, it has small to medium effect. It can help many but not all
alcoholics,Ó Litten said.
In a review of naltrexone and
other pharmacological studies, Anton (2001) wrote, ÒThe weight of the evidence
suggests that naltrexone not only reduces risk for relapse but also promotes
abstinence.Ó
One recent study produced a
negative finding. Krystal et al. (2001) conducted a multicenter, double-blind,
placebo-controlled evaluation of the efficacy for naltrexone when administered
for three or 12 months as an adjunct to standardized psychosocial treatment
(12-step facilitation counseling). The authors concluded, Òour findings do not
support the use of naltrexone for the treatment of men with chronic, severe
alcohol dependence.Ó
Litten said the study focused
on a specialized populationÑveterans. The VA patients were generally 10 years
older than most patients in previously published naltrexone studies, they had
been drinking longer and some were more treatment resistant. Additionally,
patients in the VA study received 50 mg/day of naltrexone. Perhaps if they had
taken dosage up to 100 mg/day, he said, they might have seen an effect.
Krystal et al. acknowledged,
ÒThe results may not be generalizable to patients with less chronic and severe
alcohol dependence, non-Veterans Affairs settings or women.Ó The investigators did find evidence
that patients who were more compliant with prescribed medication, attended more
counseling sessions and participated in more Alcoholics Anonymous meetings had
better outcomes.
Recent studies have suggested
that patient compliance plays a significant role in the efficacy of naltrexone
(Chick 2000; Volpicelli et al., 1997) have shown that with highly compliant
patients you get more of a pharmacological effect than those who were less than
highly compliant.
Acamprosate (Cambral), a
derivative of the naturally occurring amino acid taurine, has been studied
extensively in Europe (i.e., 16 trials and 4,600 subjects), Litten said. It is
approved for alcoholism treatment in 37 countries. Acamprosate acts at
different sites of the brain than naltrexone.
ÒNaltrexone blocks the opioid
receptors whereas acamprosate appears to interact with the glutamate receptor.
Now, how it interacts with the glutamate receptor is still unclear at this
juncture,Ó Litten said in an interview.
Some double-blind,
placebo-controlled trials in Europe found that acamprosate increases the time
to first drink and the number of abstinent days when compared with placebo
treatments (Anton, 2001). The acamprosate studies generally lasted six to 12
months.
A 21-site trial of
acamprosate has recently been completed in the United States with 601
alcohol-dependent patients. Results of this trial are being submitted to the
Food and Drug Administration as part of a New Drug Application to obtain U.S.
approval, Litten said.
Stephanie OÕMalley at the
University of Connecticut currently is conducting a study on whether
acamprosate lessens the intensity of acute withdrawal from alcohol.
There is another compound
that isnÕt as far along as naltrexone or acamprosate called ondansetron
(Zofran), a drug that affects the serotonin system, Litten said. It is a 5-HT3
blocker.
Johnson et al. (2000)
conducted a 12-week dosage trial of ondansetron in early-onset alcoholics and
late-onset alcoholics. The main outcome measures were self-reported alcohol
consumption, days abstinent, and plasma carbohydrate deficient transferring
(CDT) level, a marker of transient alcohol consumption.
Ò[They] did find an effect
for this compound in early-onset alcoholics but not late-onset alcoholics. In
fact we are funding a couple studies to see if [they] can reproduce this and
better understand why it is effective for early-onset alcoholics, but not
late-onset alcoholics,Ó Litten said.
ÒAnother area that we are
interested in is using these medications in combinationÉthese [medications] are
acting on different sites of the brain. The question would be, if you use them
in combination, would they have an enhanced effect. It is a strategy that is
commonly used in other medical disorders, such as blood pressure regulation and
treatment of cancer or AIDs,Ó he said.
NIAAA is funding about a half
dozen studies of various combinations in different populations of alcoholics.
One study is a combination of ondansetron with naltrexone. In 2001, Johnson and
colleagues (Ait-Daoud et al.) published preliminary findings that the
combination of ondansetron and naltrexone reduced alcohol craving and enhanced
drinking outcome to a greater extent than had each demonstrated alone. In one
trial to be completed in 2005, Johnson and colleagues will compare the
effectiveness of ondansetron and naltrexone both alone and in combination in
treating early-onset alcoholics versus late-onset alcoholics. Follow-up
assessments will be completed at one, three, six and nine months after
treatment. All patients will receive cognitive behavioral therapy.
Most of the treatments
available in the United States for alcoholism have been behavioral in nature,
according to NIAAA. A large number of clinical trials conducted over the past
15 have demonstrated effectiveness for several types of behavioral therapies,
including cognitive behavioral therapy, motivation enhancement therapy, marital
family therapy, brief interventions and community reinforcement approach
(Fuller and Hiller-Sturmhofel, 1999; National Institute on Alcohol Abuse and
Alcoholism, 2000).
The results of the studies on
brief intervention therapy have surprised Litten. The therapy consists of
providing brief counseling to patients by a physician or nursing staff in five
or less office visits. It has proven very successful in reducing drinking
levels in patients who are experiencing alcohol-related problems.
Motivation enhancement
therapy used in Project MATCH, is a form of brief intervention but of higher
intensity, Litten said. It involves strategies to motivate patients to stop or
reduce their drinking and proved nearly as effective as cognitive behavioral
and 12-step facilitation therapies in reducing the frequency and amount of
drinking in alcohol-dependent patients (Project MATCH Research Group, 1998).
NIAAA has issued two program
announcements to further improve behavioral therapies and to identify the
active process or components of treatments and how they result in positive
outcomes
ÒIdeally, if you could
identify the active components and get rid of the components that arenÕt
useful, you could develop a more efficient and more efficacious therapy,Ó he
said.
NIAAA also has launched the
COMBINE study (Combining Medications and Behavioral Interventions). COMBINE is
the first national study to evaluate the effectiveness of behavioral treatments
alone and in combination with medications. The study is at 11 sites. Plans are to recruit and randomize
1,375 people who meet current diagnostic criteria for alcohol dependence.
Richard K. Fuller, M.D., director of NIAAAÕs Division of Clinical and
Prevention Research, is the project officer.
In the study, we are looking
at naltrexone and acamprosate, and the combination of naltrexone and
acamprosate, Litten said. Two
kinds of behavioral therapy also are included. One is a medication management,
a low intensity therapy that can be used in primary care settings, where
patients get compliance enhancement techniques, are encouraged to remain
abstinent and receive information about alcoholism and the medication side effects.
The more intense therapy, multicomponent behavioral intervention, is conducted
in a specialized alcoholism treatment setting. That therapy incorporates
elements of three therapies that were shown to increase abstinent days and
reduce heavy drinking―cognitive behavioral therapy, motivational
enhancement therapy and also the 12-step facilitation.
ÒWe are taking the best of the three therapies that were used in NIAAAÕs Project MATCH,Ó Litten said. ÒBasically, a patient will either get acamprosate or naltrexone, a combination, or placebo and they will receive one of the two behavioral therapies. So far we have recruited 500 patients. It will still be a couple of years before we will know the results of that study. Ò
Litten believes medications
and behavioral therapies should be viewed as a team.
ÒAlcoholism is a complex
disease, it is not a homogeneous disease,Ó he said. ÒThe more weapons you have
to treat alcoholism, the better chance you have to cure it.Ó
Ait-Daoud N, Johnson BA,
Prihoda TJ, Hargita ID (2001), Combining ondansetron and naltrexone reduces
craving among biologically predisposed alcoholics: preliminary clinical
evidence. Psychopharmacology (Berl) 154(1):23-27.
Anthenelli RM, Maxwell RA,
Geracioti TD Jr. Hauger R (2001), Stress hormone dysregulation at rest and
after serotonergic stimulation among alcohol-dependent men with extended
abstinence and controls. Alcohol Clin Exp Res 25(5):692-703.
Anton RF (2001),
Pharmacologic approaches in the management of alcoholism. J Clin Psychiatry
62(suppl 20): 11-17.
Chick J, Anton R, Checinski K
et al. (2000), A multicentre, randomized, double-blind, placebo-controlled
trial of naltrexone in the treatment of alcohol dependence or abuse. J Alcohol
Alcoholism 35(6):587-593.
Fuller RK, Gordis E (2001),
Naltrexone treatment for alcohol dependence. N Engl J Med 345:24:1770-1771.
Fuller RK, Hiller-Sturmhofel
S (1999), Alcoholism treatment in the United States: an overview. Alcohol
Research & Health 23:69-77.
Johnson BA, Roache JD, Javors
MA et al. (2000), Ondansetron for reduction of drinking among biologically
predisposed alcoholic patients: a randomized controlled trial. JAMA
284(8):963-971 [see comments].
Krystal JH, Cramer JA, Krol
WF et al. (2001), Naltrexone in the treatment of alcohol dependence. N Engl J
Med 345(24):1734-1739.
National Institute on Alcohol
Abuse and Alcoholism (2000), New advances in alcoholism treatment. Alcohol
Alert 49:1-4.
Project MATCH Research Group
(1998), Matching patients with alcohol disorders to treatments; clinical
implications from Project MATCH. J Mental Health 7:589-602.
Volpicelli JR, Rhines KC,
Rhines JS et al. (1997), Naltrexone and alcohol dependence. Role of Subject
compliance. Arch Gen Psychiatry 54(8):737-742 [see comment].
(PT 0402 updated)
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