A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial of Naltrexone in the Treatment of Alcohol Dependence or Abuse

Amphetamine abuse and dependence is a global health concern with a collateral increase in medical and social problems. Although some of the neurobiological mechanisms underlying amphetamine dependence and its devastating effects in humans are known, the development of rational and evidence-based treatment is lagging. There is evidence from preclinical studies suggesting that the endogenous opioid system plays a role in mediating some of the behavioral and neurochemical effects of amphetamine in a variety of controlled settings. In the present study we assessed the effects of naltrexone, an opioid antagonist (50 mg) on the subjective physiological and biochemical response to dexamphetamine (30 mg) in 20 amphetamine-dependent patients. Patients received naltrexone/amphetamine followed by placebo/amphetamine, 1 week apart in a randomized double-blind placebo-controlled design. The primary objective of the study was to evaluate the effect of pretreatment with naltrexone on the subjective response to amphetamine, using a Visual Analog Scale. The secondary objective was to investigate the effects of naltrexone on physiological and biochemical responses to amphetamine, as measured by changes in blood pressure, heart rate, skin conductance, and cortisol. Naltrexone significantly attenuated the subjective effects produced by dexamphetamine in dependent patients (po0.001). Pretreatment with naltrexone also significantly blocked the craving for dexamphetamine (po0.001). There was no difference between the groups on the physiological measures. The results suggest that the subjective effects of amphetamine could be modulated via the endogenous opioid system. The potential of naltrexone as an adjunct pharmaceutical for amphetamine dependence is promising.

Section: Resultssupporting

confidence: 90%

Naltrexone Attenuates the Subjective Effects of Amphetamine in Patients with Amphetamine Dependence

Jayaram‐Lindström

Konstenius

Eksborg

et al. 2007

“…therapeutic efficacy of NTX in treating alcoholism (O'Malley et al, 1992(O'Malley et al, , 1996Volpicelli et al, 1992Volpicelli et al, , 1997Anton et al, 1999;Chick et al, 2000;Johnson and Ait-Daoud, 2000;Heinala et al, 2001;Krystal et al, 2001;Morris et al, 2001;Guardia et al, 2002), identifying factors that predict therapeutic response to NTX is a critical goal of alcoholism research. Although the cognitive effects of acute and chronic NTX may differ, recent data supports equivalent or greater efficacy of acute NTX dosing, relative to daily maintenance, in reducing excessive alcohol intake (Hernandez-Avila et al, 2006).…”

Section: Discussion Ntx Effects On Impulsive Choicementioning

confidence: 99%

Endogenous Opioid Blockade and Impulsive Responding in Alcoholics and Healthy Controls

Mitchell

Fields

et al. 2006

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.

“…The beneficial effect of naltrexone observed by these investigators was independently replicated (O'Malley et al, 1992), leading to approval of the medication by the US Food and Drug Administration for treatment of alcohol dependence. Since that time, the majority of clinical trials have established the benefits of naltrexone in the treatment of alcoholism (Oslin et al, 1997;Chick et al, 2000;Anton et al, 2001;Monterosso et al, 2001;Monti et al, 2001;Morris et al, 2001). The use of naltrexone is based on an endorphin compensation model, suggesting that some alcohol-dependent individuals sustain a relative deficiency in endogenous opioids after experiencing a stressful event (Volpicelli, 1987;Volpicelli et al, 1990;Kreek, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…Although the majority of samples studied have shown a significant advantage of naltrexone over placebo (O'Malley et al, 1992;Volpicelli et al, 1992;Oslin et al, 1997;Chick et al, 2000;Anton et al, 2001;Monti et al, 2001;Morris et al, 2001), other studies have failed to show a significant drugplacebo difference (Kranzler et al, 2000;Krystal et al, 2001). Clearly, naltrexone does not help all alcohol-dependent adults and not all persons who drink alcohol show evidence of a 'high' (King et al, 1997) or an increase in endogenous opioids induced by alcohol consumption.…”

Section: Introductionmentioning

confidence: 99%

A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

Oslin

Berrettini

Kranzler

et al. 2003

552

399

This study examined the association between two specific polymorphisms of the gene encoding the m-opioid receptor and treatment outcomes in alcohol-dependent patients who were prescribed naltrexone or placebo. A total of 82 patients (71 of European descent) who were randomized to naltrexone and 59 who were randomized to placebo (all of European descent) in one of three randomized, placebo-controlled clinical trials of naltrexone were genotyped at the A +118 G (Asn40Asp) and C +17 T (Ala6Val) SNPs in the gene encoding the m-opioid receptor (OPRM1). The association between genotype and drinking outcomes was measured over 12 weeks of treatment. In subjects of European descent, individuals with one or two copies of the Asp40 allele treated with naltrexone had significantly lower rates of relapse (p ¼ 0.044) and a longer time to return to heavy drinking (p ¼ 0.040) than those homozygous for the Asn40 allele. There were no differences in overall abstinence rates (p ¼ 0.611), nor were there differences in relapse rates or abstinence rates between the two genotype groups among those assigned to placebo. These preliminary results are consistent with prior literature demonstrating that the opioid system is involved in the reinforcing properties of alcohol and that allelic variation at OPRM1 is associated with differential response to a m-receptor antagonist. If replicated, these results would help to identify alcohol-dependent individuals who may be most likely to respond to treatment with naltrexone.