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Naltrexone Vs. Nefazodone for Treatment of Alcohol Dependence a Placebo-Controlled Trial Henry R

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Naltrexone Vs. Nefazodone for Treatment of Alcohol Dependence a Placebo-Controlled Trial Henry R Naltrexone vs. Nefazodone for Treatment of Alcohol Dependence A Placebo-Controlled Trial Henry R. Kranzler, M.D., Vania Modesto-Lowe, M.D., M.P.H., and Jeffrey Van Kirk, J.D., M.S. This study compared the effects of nefazodone, a rate of treatment attrition. There were no reliable between- serotonergic antidepressant, with the opioid antagonist group differences in drinking behavior. These results naltrexone, and an inactive placebo in 183 alcohol- indicate that nefazodone is not efficacious for treatment of dependent subjects receiving weekly relapse prevention alcohol dependence. Furthermore, the clinical utility of psychotherapy. Following a single-blind, placebo lead-in naltrexone seems to be limited by its adverse effects, a period, subjects were randomly assigned to receive study finding that has important implications for efforts to medication, which they took under double-blind conditions develop medications to treat alcohol dependence. for 11 weeks. Naltrexone treatment was associated with [Neuropsychopharmacology 22:493–503, 2000] significantly more adverse neuropsychiatric and © 2000 American College of Neuropsychopharmacology. gastrointestinal effects, poorer compliance, and a greater Published by Elsevier Science Inc. KEY WORDS: Naltrexone; Nefazodone; Alcohol dependence; cerebrospinal fluid levels of ␤-endorphin in alcoholics Alcoholism; Randomized control trial; Alcohol treatment as compared with controls (Aguirre et al. 1990; Genaz- zani et al. 1981). Furthermore, unaffected adult children Psychosocial interventions, such as psychotherapy and of alcoholics have basal levels of ␤-endorphin compara- referral to self-help groups (e.g., Alcoholics Anony- ble to those of abstinent alcoholics and significantly mous), are the standard treatments for alcohol depen- lower than those of unaffected adults without a paren- dence. However, the past decade has witnessed re- tal history of alcoholism (Gianoulakis et al. 1989, 1996). newed interest in medications to treat alcoholism When given alcohol, adult children of alcoholics also (Kranzler and Jaffe 1998; Litten and Allen 1998). The showed a significantly greater increase (i.e., a “normal- most intensively studied pharmacological treatments ization”) of ␤-endorphin levels (Gianoulakis et al. 1989, for alcohol dependence include opioid antagonists, se- 1996). rotonergic agonists, and acamprosate (Kranzler and Two double-blind placebo-controlled trials of the Jaffe 1998; Litten and Allen 1998). opioid antagonist naltrexone (NTX) showed it to de- Evidence supporting a role for the opioid system in crease risk of relapse to heavy drinking in alcoholics alcohol dependence includes lower basal plasma and (Volpicelli et al. 1992; O’Malley et al. 1992). These were the basis for approval of the drug by the U.S. Food and Drug Administration for the treatment of alcohol de- From the Alcohol Research Center, Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT. pendence. Subsequently, Oslin et al. (1997) found that Address correspondence to: Henry R. Kranzler, M.D., Depart- NTX was superior to placebo in reducing the risk of re- ment of Psychiatry, MC2103, University of Connecticut Health Cen- lapse in a study of older veterans. However, Volpicelli ter, Farmington, CT 06030-2103. Received June 16, 1999; revised September 29, 1999; accepted et al. (1997) found that NTX was superior to placebo October 8, 1999. (PLA) only among alcoholics who were highly compli- NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 5 © 2000 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/00/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(99)00135-9 494 H.R. Kranzler et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 5 ant with study visits and medication. Hersh et al. (1998) more than PLA. A similar lack of effects was observed failed to show an advantage for NTX over PLA on mea- when a variety of other variables, including family his- sures of substance use or craving among subjects with tory of alcoholism, were examined in combination with co-morbid alcohol and cocaine use disorders. In a pre- medication treatment. Similarly, Kabel and Petty (1996) liminary study of a sustained-release preparation of showed no effect of fluoxetine, compared with PLA, NTX, Kranzler et al. (1998) found that the active formu- among alcoholic veterans. lation was superior to PLA in reducing the frequency of We chose to study nefazodone (NEF) in light of the heavy drinking. variable results from studies of SSRI treatment of alco- The indoleamine neurotransmitter serotonin (5-HT) hol dependence. Although NEF has a moderate inhibi- also seems to play a role in the pathophysiology of alco- tory effect on reuptake of serotonin and norepineph- hol dependence (Gorelick 1989; Roy et al. 1990). Com- rine, it potently and selectively blocks the postsynaptic pared to controls, alcoholics have low CSF levels of 5-HT2 receptor (Taylor et al. 1995). Based on preclinical 5-hydroxyindoleacetic acid (5-HIAA), the major metab- findings implicating this receptor in alcohol drinking olite of 5-HT (Gorelick 1989; Roy et al. 1990). Further- behavior (Meert et al. 1991; Myers et al. 1993), we hy- more, an inverse relationship between CSF 5-HIAA lev- pothesized that the potent activity of NEF at the 5-HT2 els and the time elapsed since alcohol was last receptor would enhance the serotonin reuptake inhibit- consumed has been observed in alcoholics (Banki 1981). ing effect of the drug. Consequently, the present study These findings suggest that drinking in alcoholics may compared the effects of NTX, NEF, and an inactive PLA serve to increase low 5-HT activity. on risk and severity of relapse in alcohol-dependent However, studies of the effect of serotonergic medi- subjects. cations on human drinking behavior have yielded mixed results. The selective serotonin reuptake inhibi- tors (SSRIs) zimelidine, citalopram, viqualine, and flu- METHODS oxetine were shown to produce modest decreases in al- cohol consumption in nondepressed heavy drinkers Subjects (Naranjo et al. 1984, 1987, 1989, 1990). However, when One hundred ninety-four subjects with DSM-III-R alco- fluvoxamine was combined with cognitive-behavioral hol dependence (American Psychiatric Association therapy to treat alcohol dependence, the medication 1987) were recruited through advertisements in local was poorly tolerated and seemed to be unsuitable for news media and referrals from area clinicians. The re- use among patients with this disorder (Kranzler et al. cruitment procedure and the study protocol were ap- 1993). proved by the Institutional Review Board of the Uni- Of the SSRIs, fluoxetine’s effects on human alcohol versity of Connecticut Health Center. All subjects gave consumption have been most studied. Among alcohol- written, informed consent before participation. ics given access to alcohol on a research ward, fluoxe- tine reduced alcohol consumption by 14% during the Inclusion/Exclusion Criteria. Subjects were included first week, a significant advantage over PLA. The effect, in the study if they: (1) expressed a desire to maintain however, did not persist (Gorelick and Paredes 1992). abstinence from alcohol for the 12-week treatment pe- Naranjo et al. (1990) found that fluoxetine 60 mg/day riod; (2) were willing to be randomly assigned to one of decreased daily alcohol consumption by 17% from the treatment conditions and to receive weekly counsel- baseline in a group of early-stage problem drinkers, an ing; (3) were 18 to 60 years old; (4) were abstinent from effect that was not observed with fluoxetine 40 mg/day alcohol for at least 3 days before the baseline research or PLA. Subsequently, Naranjo et al. (1994) found that, assessment (as evidenced by self-report and two breath although fluoxetine 60 mg/day reduced the desire for alcohol measurements); (5) were able to read English alcohol, both in an experimental bar setting and when and complete study evaluations; and (6) if female, compared with PLA in an outpatient trial, it did not sig- lacked reproductive potential. Subjects were excluded if nificantly reduce alcohol consumption. Using a cross- they: (1) were homeless; (2) were currently dependent over design, Gerra et al. (1992) compared the effects of on a psychoactive substance other than alcohol or nico- fluoxetine 40 mg/day, acamprosate, and PLA for treat- tine; (3) had a past diagnosis of opioid dependence; (4) ment of alcoholism. These investigators found that al- regularly used psychoactive medications or disulfiram; though both active medications were superior to PLA (5) were currently suicidal, manic, or psychotic; (6) had in reducing the number of drinks consumed, the effect significant, uncontrolled medical illness; or (7) were ab- of fluoxetine was significant only among patients with a stinent longer than 28 days before randomization. Psy- parental history of alcoholism. chiatric disorders that did not require acute interven- Kranzler et al. (1995) found that fluoxetine treatment tion, such as mild major depression, were not in conjunction with cognitive-behavioral psychother- exclusionary. When disorders that were potentially apy in ambulatory alcoholics did not decrease drinking amenable to pharmacotherapy were identified, subjects NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 5 Nefazodone vs. Naltrexone for Alcoholism 495 were informed of the availability of a potentially effec- quences were conducted at baseline and at the end of tive treatment and were given
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