Preclinical research on endogenous opioid system involvement in alcohol reinforcement has led to studies of the effectiveness of the opioid antagonist naltrexone for treatment of alcohol dependence. In two clinical trials, naltrexone decreased alcohol craving and drinking in alcohol dependent subjects. Recently, naltrexone has been studied under more diverse conditions, including heterogeneous subject populations, longer medication periods, different dose levels and different therapy conditions. Results have been more variable than those of the original clinical trials and it is now clear that many alcohol dependent patients do not benefit from naltrexone as administered under current practice standards. These recent studies highlight the need for research to identify predictors of naltrexone treatment response. Our research has identified a negative relationship between serum 6-beta naltrexol level (naltrexone's major metabolite) and alcohol consumption in patients on 50 or 100 mg naltrexone. Above a level of 40 ng/ml 6-beta-naltrexol, alcohol consumption was fully suppressed; however, as reported in earlier studies on naltrexone metabolism, 6-beta-naltrexol levels were highly variable across patients. The proposed research will examine the effectiveness of several opioid-related variables as predictors of naltrexone treatment outcomes. First, we will measure endogenous opioid system activity by naloxone challenge test as a marker of opioid system dysfunction resulting from chronic drinking. Second, we will measure unblocked mu opioid receptor binding at the 24-hr nadir of steady-state naltrexone levels using Positron Emission Tomography (PET). Third, we will obtain daily serum 6-beta-naltrexol levels during naltrexone induction as a marker of individual differences in naltrexone bioavailability. Fourth, we will measure self-reported alcohol craving, withdrawal and mood. Alcohol-dependent subjects (N= 192) with no other substance abuse or psychiatric disorders will be randomized to: placebo, once daily naltrexone 100 mg, or twice daily naltrexone 50 mg. All subjects will undergo a 2-week inpatient protocol, including alcohol withdrawal, naloxone challenge test, naltrexone induction according to dose condition, and PET imaging. After discharge, subjects will participate in a 12-week outpatient clinical trial with regular measurement of drinking, craving and mood, and 6-beta-naltrexol. Follow-up will be conducted 6 and 12 months post-enrollment. Results will provide new scientific and clinical knowledge on predictors of naltrexone treatment response and the interrelationships of endogenous opioid activity, mu opioid receptor blockade by naltrexone, serum 6-beta-naltrexol levels and alcohol craving and mood.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011855-03
Application #
6168673
Study Section
Special Emphasis Panel (ZAA1-FF (02))
Program Officer
Fertig, Joanne
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
3
Fiscal Year
2000
Total Cost
$504,215
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Weerts, Elise M; Wand, Gary S; Kuwabara, Hiroto et al. (2014) Association of smoking with ?-opioid receptor availability before and during naltrexone blockade in alcohol-dependent subjects. Addict Biol 19:733-42
Wand, Gary S; Weerts, Elise M; Kuwabara, Hiroto et al. (2013) The relationship between naloxone-induced cortisol and delta opioid receptor availability in mesolimbic structures is disrupted in alcohol-dependent subjects. Addict Biol 18:181-92
Weerts, Elise M; McCaul, Mary E; Kuwabara, Hiroto et al. (2013) Influence of OPRM1 Asn40Asp variant (A118G) on [11C]carfentanil binding potential: preliminary findings in human subjects. Int J Neuropsychopharmacol 16:47-53
Wand, Gary S; Weerts, Elise M; Kuwabara, Hiroto et al. (2012) The relationship between naloxone-induced cortisol and mu opioid receptor availability in mesolimbic structures is disrupted in alcohol dependent subjects. Alcohol 46:511-7
Stephens, Mary Ann C; McCaul, Mary E; Weerts, Elise M et al. (2012) Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype is associated with cortisol responsivity to naloxone challenge. Psychopharmacology (Berl) 224:223-30
Weerts, Elise M; Wand, Gary S; Kuwabara, Hiroto et al. (2011) Positron emission tomography imaging of mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjects. Alcohol Clin Exp Res 35:2162-73
Wand, Gary S; Weerts, Elise M; Kuwabara, Hiroto et al. (2011) Naloxone-induced cortisol predicts mu opioid receptor binding potential in specific brain regions of healthy subjects. Psychoneuroendocrinology 36:1453-9
Tang, Jing; Kuwabara, Hiroto; Wong, Dean F et al. (2010) Direct 4D reconstruction of parametric images incorporating anato-functional joint entropy. Phys Med Biol 55:4261-72
Weerts, Elise M; Kim, Yu Kyeong; Wand, Gary S et al. (2008) Differences in delta- and mu-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects. Neuropsychopharmacology 33:653-65
Bencherif, Badreddine; Stumpf, Martin J; Links, Jonathan M et al. (2004) Application of MRI-based partial-volume correction to the analysis of PET images of mu-opioid receptors using statistical parametric mapping. J Nucl Med 45:402-8

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