Naltrexone Alters Subjective and Psychomotor Responses to Alcohol in Heavy Drinking Subjects

McCaul, Mary E.; Wand, Gary S.; Eissenberg, Thomas; Rohde, Charles A.; Cheskin, Lawrence J.

doi:10.1016/s0893-133x(99)00147-5

Cited by 110 publications

(80 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These data are consistent with naltrexone metabolism previously reported in heavy drinkers and in opioid dependent subjects (McCaul et al, 2000b;Verebey et al, 1976). It has been suggested that increasing the dose of naltrexone to increase levels of naltrexone and 6-b-naltrexol in blood may be needed to achieve successful treatment in some individuals (McCaul et al, 2000a;Rohsenow, 2004). Previous studies in our laboratory have shown that doubling the dose of naltrexone from 50 to 100 mg was more effective in reducing subjective effects of alcohol (ie ratings of alcohol 'liking' and 'best effects') in heavy drinkers and also doubled the serum levels of 6-b-naltrexol (McCaul et al, 2000b).…”

Section: Discussionsupporting

confidence: 90%

Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Weerts

Kim

Wand

et al. 2007

Neuropsychopharmacol

138

147

View full text Add to dashboard Cite

Blockade of brain m-opioid receptor (m-OR) and d-opioid receptor (d-OR) was investigated in recently abstinent alcohol-dependent subjects (N ¼ 21) maintained on naltrexone. Subjects completed a 19-day inpatient protocol, which included alcohol abstinence followed by naltrexone treatment (50 mg) on days 15-19. Blood samples were collected after the first administration of naltrexone to evaluate serum levels of naltrexone and 6-b-naltrexol. Regional brain m-OR binding potential (BP) and d-OR K i was measured using [ 11 C]carfentanil (CAR) positron emission tomography (PET) and [11 C]methyl naltrindole ([ 11 C]MeNTI) PET, respectively, before (day 5) and during naltrexone treatment (day 18). Naltrexone inhibition of [ 11 C]CAR BP was near maximal across all brain regions of interest with little variability across subjects (mean + SD% inhibition ¼ 94.9 + 4.9%). Naltrexone only partially inhibited the [ 11 C]MeNTI K i and there was more variability across subjects (mean + SD% inhibition ¼ 21.1 + 14.49%). Peak serum levels of naltrexone were positively correlated with % inhibition of d-OR K i in neocortex and basal ganglia. Peak serum levels of naltrexone were not correlated with % inhibition of m-OR BP. Peak levels of 6-b-naltrexol were not significantly correlated with % inhibition of m-OR BP or d-OR K i . Thus, the FDA recommended therapeutic dose of naltrexone was sufficient to produce near complete inhibition of the m-OR in recently abstinent alcohol dependent subjects. The lower percent inhibition of d-OR and greater variability in d-OR blockade by naltrexone across subjects may contribute to individual differences in treatment outcomes to naltrexone. Further investigations on the relationship between individual differences in d-OR blockade by naltrexone and clinical outcomes should be explored.

show abstract

Section: Discussionsupporting

confidence: 90%

Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Weerts

Kim

Wand

et al. 2007

Neuropsychopharmacol

138

147

View full text Add to dashboard Cite

show abstract

“…that demonstrated a naltrexone-alcohol interaction in earlier analyses of combined male and female subjects (McCaul et al 2000a); current findings are based on male subjects only. Using a joystick, subjects were instructed to rate liking at the current time on a horizontal line anchored with "Not at all" on the left and "Extremely" on the right.…”

Section: Subjective Responsesmentioning

confidence: 46%

“…Psychomotor and subjective responses of male and female subjects have been reported previously (McCaul et al 2000a). …”

Section: Dependent Measuresmentioning

confidence: 95%

Naltrexone Dampens Ethanol-Induced Cardiovascular and Hypothalamic- Pituitary-Adrenal Axis Activation

McCaul

2001

Neuropsychopharmacology

Self Cite

View full text Add to dashboard Cite

Alcohol ingestion activates the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. This study examined naltrexone effects on alcohol-induced increases in physiological responses and their association with alcohol liking. Using a within-subjects design, heavy drinking men (N ϭ 19) were maintained on each of three naltrexone doses (0, 50, and 100 mg, p.o.) over an 8-day inpatient stay. Within each naltrexone dose, subjects had three alcohol challenge sessions (none, moderate, high) The brain opioid system has been proposed to be part of the neurocircuitry involved in alcohol reward and heavy alcohol drinking (Froehlich and Wand 1997;Gianoulakis and deWaele 1994;Reid et al. 1991). Pharmacological studies indicate that opioid receptor antagonists, such as naloxone hydrochloride and naltrexone, decrease alcohol self-administration in animal models (Altshuler et al. 1980;Froehlich et al. 1990;Hubbell et al. 1986Hubbell et al. , 1991Marfaing-Jallat et al. 1983;Samson and Doyle 1985;Weiss et al. 1990). Clinical trials demonstrated that naltrexone reduces alcohol drinking and self-reported "high," alcohol craving, as well as relapse rates in recently abstinent outpatient alcohol-dependent patients (O'Malley et al. 1992;Volpicelli et al. 1992Volpicelli et al. , 1995 . These findings led to naltrexone's approval by the Food and Drug Administration as a pharmacotherapeutic agent for the treatment of alcohol dependence. Naltrexone is thought to reduce alcohol-induced high and relapse by binding to opioid receptors in discrete brain regions associated with reward and craving, and to prevent receptor activation by alcohol-induced release of endogenous opioid peptides.Alcohol induces a variety of acute physiological responses when consumed in moderate-to-high doses. It is well established that intoxicating doses of alcohol increase heart rate (Docter et al. 1966;Iwase et al. 1995 McCaul et al. 1989;Sellers et al. 1972;Turkkan et al. 1988;van de Borne et al. 1997). These heart rate increases are hypothesized to be positively associated with the reinforcing or appetitive motivational effects of alcohol (Peterson et al. 1996) . Alcohol has less predictable effects on blood pressure, with reports of blood pressure increases (Iwase et al. 1995;Sellers et al. 1972) and no effects following alcohol ingestion (Turkkan et al. 1988;van de Borne et al. 1997). Finally, alcoholinduced peripheral vasodilation and associated skin temperature increases have been consistently reported (Iwase et al. 1995;Turkkan et al. 1988) and is thought to be one explanation for the lack of a consistent rise in blood pressure after alcohol consumption.Acute administration of intoxicating doses of alcohol also activates the hypothalamic-pituitary-adrenal (HPA) axis thereby increasing ACTH and glucocorticoid levels (Inder et al. 1995;Rivier et al. 1984;Waltman et al. 1993). It remains unclear whether alcohol-induced activation of the HPA axis has any relationship to its reinforcing properties. Rodent studies show that alcohol increases pla...

show abstract

“…One possibility is that NTX decreases the rewarding effect of alcohol intake (Swift et al, 1994;Volpicelli et al, 1995;Sinclair, 2001). Another possibility is that NTX reduces drinking by generating aversive side effects, such as nausea, when ethanol is consumed (Davidson et al, 1999;de Wit et al, 1999;McCaul et al, 2000;Mitchell et al, 2005a). However, there is also evidence that NTX significantly reduces alcohol craving in alcoholics during abstinence (Monti et al, 1999;Rohsenow et al, 2000;O'Malley et al, 2002), and improves resistance to thoughts, urges, and behaviors associated with drinking (Anton et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Endogenous Opioid Blockade and Impulsive Responding in Alcoholics and Healthy Controls

Mitchell

Fields

et al. 2006

Neuropsychopharmacol

View full text Add to dashboard Cite

The opioid receptor antagonist naltrexone (NTX) is one of few approved treatments for alcoholism, yet the mechanism by which it reduces drinking remains unclear. In rats, NTX reduces morphine-induced impulsive choice bias; however, nothing is known about the drug's effect on discrete aspects of impulsive behavior in humans, such as decision-making and inhibitory control. Here, we used a modified delay discounting procedure to investigate whether NTX improves decision-making or inhibitory control in humans. We measured the effect of acute NTX (50 mg) on choice between smaller sooner (SS) and larger later monetary rewards and on response errors (motor mismatch) in a high conflict condition in a group of abstinent alcoholics (AA) and healthy control subjects (CS). We previously reported that AA selected the SS option significantly more often than did CS in this paradigm. If the choice bias of AA is due to enhanced endogenous opioid signaling in response to potential reward, NTX should reduce such bias in the AA group. We found that NTX did not reliably reduce impulsive choice in the AA group; however, NTX's effect on choice bias across individuals was robustly predictable. NTX's effect on choice bias was significantly correlated with scores on Rotter's Locus of Control (LOC) scale; increasingly internal LOC scores predicted increasing likelihood of impulsive choices on NTX. In addition, we found that NTX significantly enhanced control of motor responses, particularly within the CS group. These results suggest that endogenous opioids may impair response selection during decision-making under conflict, and that NTX's effects on explicit decision-making are personality-dependent. Determining the biological basis of this dependence could have important implications for effective alcoholism treatment.

show abstract

Naltrexone Alters Subjective and Psychomotor Responses to Alcohol in Heavy Drinking Subjects

Cited by 110 publications

References 36 publications

Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Naltrexone Dampens Ethanol-Induced Cardiovascular and Hypothalamic- Pituitary-Adrenal Axis Activation

Endogenous Opioid Blockade and Impulsive Responding in Alcoholics and Healthy Controls

Contact Info

Product

Resources

About