Effects Of Naltrexone Research Articles

Stabilization of remission in patients with opioid depen dence: pharmacological and pharmacogenetic aspects

Modern narcology demonstrates a problem of insufficient effectiveness of pharmacotherapy for stabilization of remission in patients with opioid dependence. Effectiveness of the existing pharmacological approaches to solving this problem varies from patient to patient. In Russia, naltrexone is a medication mainly used for stabilization of remission in patients with opioid dependence. The main course of inefficient effectiveness of naltrexone in treatment of opioid dependence could be explained by poor compliance. The effectiveness can be improved by three ways: 1) using extendedrelease formulations of naltrexone; 2) using naltrexone combined with other medications to reduce symptoms resulting in relapse; 3) conducting a pharmacogenetic analysis to provide patients’ stratification by the effectiveness of pharmacotherapy. The main objective of this review is to analyze opportunities for improving pharmacological treatment methods in stabilization of remission in patients with opioid dependence using the combined pharmacotherapy and pharmacogenetic analysis in order to develop individualized pharmacological treatment approach.

A pharmacogenetic analysis of dopaminergic and opioidergic genes in opioid addicts treated with the combination of naltrexone and guanfacine

To evaluate an effect of opioid receptor and dopamine system gene polymorphisms on the efficacy of combined treatment with oral naltrexone and guanfacine in a randomized double blinded double dummy placebo controlled clinical trial. Three hundred and one patients with opioid dependence were randomized into 4 treatment groups: naltrexone 50 mg/day + guanfacine 1 mg/day (N+G); naltrexone + placebo guanfacine (N+GP); placebo naltrexone + guanfacine (NP+G); double placebo (NP+GP). The primary outcome was treatment retention. All enrolled participants were genotyped for polymorphisms in the following genes: mu- (OPRM1), kappa-opioid receptors (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (SLC6A3, DAT1) and alpha-2-adrenoreceptor (ADRA2A) a pharmacological target of guanfacine. The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone monotherapy. Regardless of treatment, several gene polymorphisms were associated with higher chance to complete the treatment program: allele Т DRD4 - 521 С/Т (rs1800955) (р=0.039; OR (95% CI)=3.7 (1.1-12.7); log-rank test: р=0.01); allele С DRD2 С957Т (rs6277) (р=0.03; HR=0.6 (0.34-0.95); genotype combination: DRD4 VNTR (LL) + OPRM1 A118G (rs1799971) (AA), р=0.051; DRD2 C957T (ТТ) + OPRM1 (rs1074287) (СС), р=0.025; DRD2 - 141С (II) + OPRM1 (rs510769) (АА), р=0.035; DBH Fau(СС) + OPRM1 (rs1074287) (СС), р=0.0497. Regardless of treatment several polymorphisms were associated with high risk of relapse: allele Т (rs510769) OPRM1 (р=0.053), allele А (rs1799971, A118G) OPRM1 (р=0.056), allele S exon III 48 bp DRD4 VNTR (р=0.001; HR=3.1 (ДИ 95% 1.57-6.18); genotype combinations: DRD4 - 521 С/Т (ТТ) + DRD2 Nco I (TT), р=0.026; DRD4 -521 С/Т (ТТ) + DRD2 -141 С (II), р=0.011; DRD4 - 521 С/Т (ТТ) + OPRM1 A118G (rs1799971) (AA), р=0.011; DRD2 Nco I(ТТ) + ADRA2A (СС), р=0.012; DRD2 Nco I(ТТ) + OPRM1 A118G (AA), р=0.02. The effects dependent on the treatment group were as follows: 1) in the N+G group, patients with the DRD4 -521 С/Т TT genotype had higher probability of completion of treatment program in comparison with other genotypes (CC and CT) (log-rank test: p=0.002); 2) in NP + GP group, patients with the OPRM1 rs510769 T allele had higher risk of relapse compared to the genotype GG (p=0.008) (FDR p<0.0125). The additive effect of opioid receptor genes and dopaminergic system genes on outcomes of treatment opioid dependence with oral naltrexone and guanfacine was shown. Pharmacological effects of naltrexone and guanfacine were associated with genetic variants of the DRD4 - 521C/T polymorphism, since its effect was shown only in the N+G group. The effect of the OPRM1 rs510769 polymorphism was demonstrated in the double placebo group that was associated with personality traits (temperament, character) and determined compliance. Genetic analysis is useful for determining potential responders to treatment of opioid dependence; genotyping can increase the efficacy of pharmacotherapy.

Supplier-dependent differences in intermittent voluntary alcohol intake and response to naltrexone in Wistar rats

Alcohol use disorder (AUD) is a worldwide public health problem and a polygenetic disorder displaying substantial individual variation. This work aimed to study individual differences in behavior and its association to voluntary alcohol intake and subsequent response to naltrexone in a seamless heterogenic group of animals. Thus, by this approach the aim was to more accurately recapitulate the existing heterogeneity within the human population. Male Wistar rats from three different suppliers (Harlan Laboratories B.V., RccHan™:WI; Taconic Farms A/S, HanTac:WH; and Charles River GmbH, Crl:WI) were used to create a heterogenic group for studies of individual differences in behavior, associations to intermittent voluntary alcohol intake and subsequent response to naltrexone. The rats were tested in the open field prior to the Y-maze and then given voluntary intermittent access to alcohol or water in the home cage for 6 weeks, where after, naltrexone in three different doses or saline was administered in a Latin square design over 4 weeks and alcohol intake and preference was measured. However, supplier-dependent differences and concomitant skew subgroup formations, primarily in open field behavior and intermittent alcohol intake, resulted in a shifted focus to instead study voluntary alcohol intake and preference, and the ensuing response to naltrexone in Wistar rats from three different suppliers. The results showed that outbred Wistar rats are diverse with regard to voluntary alcohol intake and preference in a supplier-dependent manner; higher in RccHan™:WI relative to HanTac:WH and Crl:WI. The results also revealed supplier-dependent differences in the effect of naltrexone that were dose- and time-dependent; evident differences in high-drinking RccHan™:WI rats relative to HanTac:WH and Crl:WI rats. Overall these findings render RccHan™:WI rats more suitable for studies of individual differences in voluntary alcohol intake and response to naltrexone and further highlight the inherent heterogeneity of the Wistar strain. The overall results put focus on the importance of thoroughly considering the animals used to aid in study design and for comparison of reported results.

Effect of Naltrexone on photoperiodic regulation of testicular steroidogenesis in adult golden hamster, Mesocricetus auratus

Photoperiodic regulation of testicular steroidogenesis through modulation of MT1R expression and local melatonin content is well established. However, additional mediators besides local melatonergic system in photoperiodic control of testicular steroidogenesis in golden hamster have not been studied in detail. Endogenous opioid peptides (EOP) are known to regulate reproduction via acting at multiple levels of the hypothalamus–pituitary–gonadal (HPG) axis. The presence of β-endorphin, a naturally occurring opioid peptide, and its receptor (μ-opioid receptor, μOR) has been reported in rat testes; however the functional significance of photoperiodic regulation μOR in testicular steroidogenesis is not clear. In the present study, we assessed the effect of Naltrexone (Nal), a μOR antagonist, in photoperiodic regulation of testicular steroidogenesis. Immunohistochemical (IHC) localization and expression of μOR along with the expression of steroidogenic markers in testes was analyzed through western blot analyses. IHC suggest immunoreactivity for μOR in Leydig cells with strong immunoreactivity under SD (short-day) condition, whereas weak immunoreactivity was observed under LD (long-day). The expression of μOR was significantly decreased following Nal administration in both the photoperiodic conditions. The localization and differential photoperiodic regulation of μOR in Leydig cells suggests its involvement in testicular steroidogenesis. Further, Nal administration significantly increased the expression of steroidogenic markers (AR, StAR, P450SCC, LH-R, 3β-HSD and 17-HSD) and plasma testosterone concentration under SD condition as compared to SD-control. We may therefore suggest that photoperiod differentially regulates the expression of μOR which thereby mediates the inhibitory effect of melatonin on testicular steroidogenesis.

Putting the brakes on the “drive to eat”: Pilot effects of naltrexone and reward-based eating on food cravings among obese women

PurposeObese individuals vary in their experience of food cravings and tendency to engage in reward-driven eating, both of which can be modulated by the neural reward system rather than physiological hunger. We examined two predictions in a sample of obese women: (1) whether opioidergic blockade reduced food-craving intensity, and (2) whether opioidergic blockade reduced an association between food-craving intensity and reward-driven eating, which is a trait-like index of three factors (lack of control over eating, lack of satiation, preoccupation with food). MethodsForty-four obese, pre-menopausal women completed the Reward-Based Eating Drive (RED) scale at study start and daily food-craving intensity on 5days on which they ingested either a pill-placebo (2days), a 25mg naltrexone dose (1day), or a standard 50mg naltrexone dose (2days). ResultsCraving intensity was similar under naltrexone and placebo doses. The association between food-craving intensity and reward-driven eating significantly differed between placebo and 50mg naltrexone doses. Reward-driven eating and craving intensity were significantly positively associated under both placebo doses. As predicted, opioidergic blockade (for both doses 25mg and 50mg naltrexone) reduced the positive association between reward-driven eating and craving intensity to non-significance. ConclusionsOpioidergic blockade did not reduce craving intensity; however, blockade reduced an association between trait-like reward-driven eating and daily food-craving intensity, and may help identify an important endophenotype within obesity.

The Effect of CRH, Dexamethasone and Naltrexone on the Mu, Delta and Kappa Opioid Receptor Agonist Binding in Lamb Hypothalamic-Pituitary-Adrenal Axis.

The aim of the study was to evaluate changes in the opioid receptor binding (mu, delta and kappa) in the hypothalamus, anterior pituitary and adrenal cortex (HPA) of lambs treated in vivo with corticotrophin releasing hormone (CRH), naltrexone, an opioid receptor antagonist (NAL), and dexamethasone, a potent cortisol analog (DEX). Experiment was carried out on 3 months old female lambs of polish mountain strain. Lambs received a single i.v. injection of NaCl (control), CRH (alone or in combination with naltrexone), naltrexone or dexamethasone. One hour later animals were decapitated under anaesthesia, tissues were dissected out and receptor binding assays were performed with radioligands for each type of opioid receptors--3H-DAGO, 3H-DPDPE and 3H-EKC for mu, delta and kappa receptor, respectively. Coexistence of specific binding sites for each type of opioid receptor was demonstrated in all levels of HPA axis of control lambs, however their distribution was uneven. Acute treatment with CRH, DEX and NAL caused downregulation or upregulation of mu, delta, kappa receptor binding in each level of HPA axis. CRH effects on mu, delta and kappa opioid receptor binding varied within the HPA axis and were modulated by naltrexone. Treatment with naltrexone increased in vitro mu, delta and kappa receptor binding in most tested structures except delta receptor binding in adrenal (decrease by 52%) and kappa receptor binding in pituitary (decrease by 41%). Dexamethasone significantly decreased the mu, delta and kappa opioid receptor binding in adrenal cortex but differentially affected opioid receptor binding in hypothalamus and pituitary. It seems probable that endogenous opioid peptides acting through mu, delta and kappa receptors interact with the hormones released from the hypothalamic-pituitary-adrenal axis in physiological and pathophysiological situations.

The Novel μ-Opioid Receptor Antagonist GSK1521498 Decreases Both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking.

Distinct environmental and conditioned stimuli influencing ethanol-associated appetitive and consummatory behaviors may jointly contribute to alcohol addiction. To develop an effective translational animal model that illuminates this interaction, daily seeking responses, maintained by alcohol-associated conditioned stimuli (CSs), need to be dissociated from alcohol drinking behavior. For this, we established a procedure whereby alcohol seeking maintained by alcohol-associated CSs is followed by a period during which rats have the opportunity to drink alcohol. This cue-controlled alcohol-seeking procedure was used to compare the effects of naltrexone and GSK1521498, a novel selective μ-opioid receptor antagonist, on both voluntary alcohol-intake and alcohol-seeking behaviors. Rederived alcohol-preferring, alcohol-nonpreferring, and high-alcohol-drinking replicate 1 line of rats (Indiana University) first received 18 sessions of 24 h home cage access to 10% alcohol and water under a 2-bottle choice procedure. They were trained subsequently to respond instrumentally for access to 15% alcohol under a second-order schedule of reinforcement, in which a prolonged period of alcohol-seeking behavior was maintained by contingent presentations of an alcohol-associated CS acting as a conditioned reinforcer. This seeking period was terminated by 20 min of free alcohol drinking access that achieved significant blood alcohol concentrations. The influence of pretreatment with either naltrexone (0.1-1-3 mg/kg) or GSK1521498 (0.1-1-3 mg/kg) before instrumental sessions was measured on both seeking and drinking behaviors, as well as on drinking in the 2-bottle choice procedure. Naltrexone and GSK1521498 dose-dependently reduced both cue-controlled alcohol seeking and alcohol intake in the instrumental context as well as alcohol intake in the choice procedure. However, GSK1521498 showed significantly greater effectiveness than naltrexone, supporting its potential use for promoting abstinence and preventing relapse in alcohol addiction.

Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion

BackgroundThe opioid antagonists naloxone/naltrexone are involved in improving learning and memory, but their cellular and molecular mechanisms remain unknown. We investigated the effect of naloxone/naltrexone on hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) trafficking, a molecular substrate of learning and memory, as a probable mechanism for the antagonists activity. MethodsTo measure naloxone/naltrexone-regulated AMPAR trafficking, pHluorin-GluA1 imaging and biochemical analyses were performed on primary hippocampal neurons. To establish the in vivo role of GluA1-Serine 845 (S845) phosphorylation on the behavioral effect induced by inhibition of the endogenous μ-opioid receptor (MOR) by naltrexone, MOR knockout, and GluA1-S845A mutant (in which Ser845 was mutated to Ala) mice were tested in a water maze after chronic naltrexone administration. Behavioral responses and GluA1 levels in the hippocampal postsynaptic density in wild-type and GluA1-S845A mutant mice were compared using western blot analysis. ResultsIn vitro prolonged naloxone/naltrexone exposure significantly increased synaptic and extrasynaptic GluA1 membrane expression as well as GluA1-S845 phosphorylation. In the MOR knockout and GluA1-S845A mutant mice, naltrexone did not improve learning, which suggests that naltrexone acts via inhibition of endogenous MOR action and alteration of GluA1 phosphorylation. Naltrexone-treated wild-type mice had significantly increased phosphorylated GluA1-S845 and GluA1 levels in their hippocampal postsynaptic density on the third day of acquisition, which is the time when naltrexone significantly improved learning. ConclusionsThe beneficial effect of naltrexone on spatial learning and memory under normal conditions appears to be the result of increasing GluA1-S845 phosphorylation-dependent AMPAR trafficking. These results can be further explored in a mouse model of memory loss.

Naltrexone vs Placebo for the Treatment of Alcohol Dependence: A Randomized Clinical Trial.

Alcohol use disorder is one of the leading causes of disability worldwide. While effective pharmacological treatments exist, they are efficacious only in certain individuals, contributing to their limited use. Secondary analysis of clinical trial data suggests that a functional polymorphism (rs1799971, Asn40Asp) of the µ-opioid receptor gene (OPRM1) is associated with the risk of relapse to heavy drinking following treatment with the opioid antagonist naltrexone. To prospectively examine whether rs1799971 is predictive of naltrexone treatment response. We conducted a 12-week, double-blind, randomized clinical trial of naltrexone vs placebo in individuals with alcohol dependence (intent-to-treat analysis). Participants were randomly assigned to study treatment based on the presence of 1 or 2 copies of the Asp40 allele compared with those homozygous for the Asn40 allele (2 × 2 cell design). Recruitment occurred between January 2009 and September 2013. All participants were seen in an outpatient clinical setting. A convenience sample of participants (n = 221) was recruited from 5 sites. All participants met DSM-IV criteria for alcohol dependence, with no concurrent psychotic or manic symptoms, no use of concurrent psychotropic medications, and no current dependence on illicit substances. The study drug was naltrexone (50 mg) given once daily or corresponding placebo. The primary study outcome measure was relapse to heavy drinking measured using the timeline follow-back method. There was no evidence of a genotype × treatment interaction on the primary outcome of heavy drinking (P = .32). In the Asn40 group, the observed effect of naltrexone was similar to that in previous trials (odds ratio, 0.69; 95% CI, 0.41-1.18; P = .17), with a very small naltrexone effect in the Asp40 group (odds ratio, 1.10; 95% CI, 0.52-2.31; P = .80), contrary to the pattern expected a priori. A significant reduction in heavy drinking occurred across all groups (P = .001). Other drinking outcomes, and all secondary outcomes, demonstrated similar time effects, with no genotype × treatment interaction. The results of this study do not support the hypothesis that the Asp40 allele moderates the response to naltrexone treatment. It is premature to use the Asn40Asp polymorphism as a biomarker to predict the response to naltrexone treatment of alcohol dependence. clinicaltrials.gov Identifier: NCT00831272.

Placebo-Controlled, Double-Blind, Randomized Pilot Study to Evaluate the Effects of Low-Dose Naltrexone on Quality of Life and Fatigue in Newly Diagnosed High-Grade Glioma (P4.210)

Placebo-Controlled, Double-Blind, Randomized Pilot Study to Evaluate the Effects of Low-Dose Naltrexone on Quality of Life and Fatigue in Newly Diagnosed High-Grade Glioma (P4.210)

Opioid treatment at release from jail using extended-release naltrexone: a pilot proof-of-concept randomized effectiveness trial.

Relapse to addiction following incarceration is common. We estimated the feasibility and effectiveness of extended-release naltrexone (XR-NTX) as relapse prevention among opioid-dependent male adults leaving a large urban jail. Eight-week, proof-of-concept, open-label, non-blinded randomized effectiveness trial. New York City jails and Bellevue Hospital Center Adult Primary Care clinics, USA. From January 2010 to July 2013, 34 opioid-dependent adult males with no stated interest in agonist treatments (methadone, buprenorphine) received a counseling and referral intervention and were randomized to XR-NTX (n = 17) versus no medication (n = 17) within one week prior to jail release. XR-NTX (Vivitrol(®) ; Alkermes Inc.), a long-acting injectable mu opioid receptor antagonist. The primary intent-to-treat outcome was post-release opioid relapse at week 4, defined as ≥10 days of opioid misuse by self-report and urine toxicologies. Secondary outcomes were proportion of urine samples negative for opioids and rates of opioid abstinence, intravenous drug use (IVDU), cocaine use, community treatment participation, re-incarceration and overdose. Acceptance of XR-NTX was high; 15 of 17 initiated treatment. Rates of the primary outcome of week 4 opioid relapse were lower among XR-NTX participants: 38 versus 88% [P<0.004; odds ratio (OR) = 0.08, 95% confidence interval (CI) = 0.01-0.48]; more XR-NTX urine samples were negative for opioids, 59 versus 29% (P<0.009; OR = 3.5, 95% CI = 1.4-8.5). There were no significant differences in the remaining secondary outcomes, including rates of IVDU, cocaine use, re-incarceration and overdose. Extended-release naltrexone is associated with significantly lower rates of opioid relapse among men in the United States following release from jail when compared with a no medication treatment-as-usual condition.

Discriminative Stimulus Effects of Naltrexone in Rats with Limited Access to Sucrose

In most operant paradigms, large doses of naloxone are typically required to establish naloxone as a discriminative stimulus in opioid‐naïve subjects. Chronic, but limited access to sucrose increases endorphin and dopamine function in rats. We wondered if rats given limited access to sucrose could be trained to recognize doses of naltrexone (NTX) that are typically not discriminable in operant paradigms. Prior to discrimination training, rats were trained to lever press and were then given access to sucrose (25% or 32%) for 12 hours a day for two weeks. Rats were then given daily injections of either saline or NTX (3.2 mg/kg, 15 min PT) 1 hour after sucrose access. After the training session subjects were returned to their home cage for the remainder of the 12 hour sucrose‐access period. Subjects learned to discriminate NTX from saline in a mean of 72 sessions (Md = 63, range 27‐135 sessions). No significant differences in acquisition of the NTX‐saline discrimination or initial NTX dose‐effect functions were noted between sucrose concentrations. These results provide further support for the notion that chronic sucrose consumption increases endogenous endorphin function.

(405) A potential anti-inflammatory effect of low-dose naltrexone in fibromyalgia

(405) A potential anti-inflammatory effect of low-dose naltrexone in fibromyalgia

The Effects of Naltrexone on Subjective Response to Methamphetamine in a Clinical Sample: a Double-Blind, Placebo-Controlled Laboratory Study.

Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of 'crave drug,' 'stimulated,' and 'would like drug access,' decreased the the post-MA administration timecourse of 'anxious' and increased ratings of 'bad drug effects,' as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA.

Whose mu fared better? The effect of extended-release naltrexone (XR-NTX) on treatment outcomes for opioid and alcohol users

Background In 2010, Los Angeles County made the decision to offer publicly funded patients receiving treatment for substance use disorders extended-release naltrexone (XR-NTX, brand name “Vivitrol”). Since 2010, over 1200 patients have received at least one dose of extended-release naltrexone. Little is known concerning the differential impact of the medication on those who use it for alcohol use disorders (AUDs) when compared to patients who take the medication for opioid use disorders (OUDs).

Subchronic administration of short-acting naltrexone has no effect on striatal dopamine transporter availability, food intake or body weight gain in rats.

The opioid receptor antagonist naltrexone is successfully used in the treatment of opioid and alcohol dependence. However, questions have been raised about possible anhedonic side effects, because the opioid system is directly involved in hedonic responses to natural rewarding activities, possibly due to its indirect effects on the striatal dopamine transporter (DAT). In order to test this hypothesis, 30 rats were randomized to either a 10-day treatment with 3 mg/kg short-acting naltrexone or vehicle. No significant differences between the groups were found in striatal DAT availability, cumulative food intake (for 48 or 72 h), body weight gain and abdominal fatpad weight. Thus, the results of this study suggest that (sub)chronic treatment with short-acting naltrexone does not induce possible anhedonic effects. However, it cannot be ruled out the anhedonic effect of naltrexone is only short-lived and thus not detected in the current study. Therefore, future studies are needed to study possible acute anhedonic effects at several time points shortly after short-acting naltrexone administration and to directly compare the possible anhedonic effects of long-acting with those of short-acting opioid antagonists.

Social network moderators of naltrexone and behavioral treatment effects on heavy drinking in the COMBINE study.

Oral naltrexone is an efficacious medication for treatment of alcohol dependence, but small effect sizes and variability in outcomes suggest the presence of person-level moderators of naltrexone response. Identification of contextual or psychosocial moderators may assist in guiding clinical recommendations. Given the established importance of social networks in drinking outcomes, as well as the potential effects of naltrexone in reducing cue reactivity which may be especially important among those with more heavy drinkers and more alcohol cues in their networks, we examined pretreatment social network variables as potential moderators of naltrexone treatment effects in the COMBINE study. The sample included all COMBINE study participants in medication conditions with full data on the Important People Inventory (IPI) and covariates at intake (N=1,197). The intake IPI assessed whether participants had any frequent drinkers in their network and the average frequency of contact with these drinkers. The effects of treatment condition, pretreatment network variables, and their interactions on percent heavy drinking days were tested in hierarchical linear models, controlling for demographics and baseline clinical covariates. In treatment conditions involving medical management and combined behavioral intervention (CBI), the effects of active naltrexone on heavy drinking were significantly greater for individuals with frequent drinkers in their network (z=-2.66, p<0.01) and greater frequency of contact with those drinkers (z=-3.19, p<0.01). These network variables did not moderate the effects of active naltrexone without CBI. When delivered in conjunction with behavioral interventions, naltrexone can be more potent for alcohol-dependent adults who have greater contact with frequent drinkers prior to treatment, which may indicate patterns of environmental exposure to alcohol. Contextual, social risk factors are a potential avenue to guide personalized treatment of alcohol dependence.

Effect of naltrexone on neuropathic pain in mice locally transfected with the mutant μ-opioid receptor gene in spinal cord.

Opioid antagonists, such as naloxone and naltrexone, exhibit agonistic properties at the mutated μ receptor, MOR-S196ACSTA. In our previous study, systemic naloxone (10 mg·kg(-1) , s.c.) elicited antinociceptive effect without the induction of tolerance, dependence or rewarding effect in mice 2 weeks after intrathecal administration of double-stranded adeno-associated virus-MOR-S196ACSTA-eGFP. Here, we have investigated if this antinociceptive paradigm would be effective in a mouse model of neuropathic pain. Spinal nerves were ligated in male C57BL/6 mice 3 or 4 weeks after intrathecal injection of the lentivirus encoding the construct of MOR-S196ACSTA-eGFP (LV-MOR-S196ACSTA). Anti-allodynic effects of daily s.c.injections of saline, naltrexone (10 mg·kg(-1) ) or morphine (10 mg·kg(-1) ) were assessed by the von Frey test. After 14 days of treatment with saline, naltrexone or morphine, signs of natural withdrawal were measured at 22 and 46 h after the last injection. To determine the rewarding effects induced by morphine or naltrexone, the conditioned place preference test was carried out. Anti-allodynic effects, as measured by von Frey test, increased after naltrexone or morphine treatment in mice transfected with LV-MOR-S196ACSTA in the spinal cord. Cessation of treatment with morphine, but not naltrexone, induced natural withdrawal and rewarding effects. Systemic injection of naltrexone after the expression of a mutant μ opioid receptor, MOR-S196ACSTA, in the spinal cord may have therapeutic potential for chronic neuropathic pain, without the development of dependence or addiction. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Abuse potential of eslicarbazepine acetate in recreational sedative users

Aims: Naltrexone is a ffJ-opioid receptor antagonist that blocks the euphoric effects of heroin and opioids. Opioid craving, depression, anxiety, and anhedonia are triggers for relapse and dropping out of treatment. It is important to evaluate the effect of implantable and oral naltrexone on craving, depression, anxiety and anhedonia. Methods: 306 patients with opioid dependence were enrolled into three cell (102ss/cell) randomized, double-blind, placebocontrolled, 6 month trial and received implantable ntx, oral ntx (50mg/day), or placebo. Psychiatric evaluations were performed using the Visual Analog Scale of Craving for opiates, Beck Depression Inventory, Spielberger State-Trait Anxiety Test, and Chapman Scale of Physical and Social Anhedonia. Psychometric variables were analyzed using ANOVA repeated measures with Tukey test for between group post hoc comparisons. Results: The percentage of patients that completed 6months of tx without relapse was: 52.9% in the ntx-implant group, 15.7% in oral ntx (survival analysis, log-rank test, P< .001), and 10.8% in the placebo group (P< .001). Therewas a significant decrease of craving over the course of tx from 3 to 3.5 on a 10-point scale at baseline to 0.5–1.1 at 6 months among those who were retained in treatment (F5,1095=21.2; P<0.001). Psychiatric symptoms including depression, anxiety, and anhedonia were moderately elevated at baseline and gradually decreased to normal levels within the first 1–2 months among all patients who remained in tx and did not relapse, with no differences between groups. Conclusions: The improvements in heroin craving, depression, anxiety, and anhedonia among those who were retained in treatment and did not relapse are most likely an effect of treatment success and not specifically related to naltrexone since they occurred regardless of medication group. Long-term blockade of opiate receptors with naltrexone did not induce anhedonia or depression. Financial support: National Institute on Drug Abuse (1-R01DA-017317 and KO5 DA-17009).

HCV genotype distribution among injection drug users in Taiwan

naltrexone in opioid dependent patients, including both datadriven and addressing commonly asked topics on safety (e.g., hepatic health, anhedonia/depression, post treatment overdose risk). Methods: Per-subject urine data was solicited from all RCT authors and subjected to statistical analysis in accordance with Cochrane requirements. Subjective measures of opioid agonist use and other substances were also analyzed. For safety outcomes, a qualitative assessment was conducted of all relevant RCT and non-RCT contributions. Seven databases were searched, producing n=1104 abstracts, of which n=43 were relevant articles and n=6 were RCTs. Risk of bias was assessed for all studies in accordance with Cochrane principles. Results: Meta-analysis found a main effect of sustained release naltrexone on illicit opioid use (Z=5.2, p< .01) on both urine and subjective measures. On safety outcomes, sustained release naltrexone was generally well tolerated with some variations in site reactions due to the type of administration method used. Risk of biaswas generally consideredmoderate to high, especially for nonrandomized studies. Conclusions: Sustained releasenaltrexone increases abstinence from opioids in opioid dependent patients who volunteered for this type of medication-assisted abstinence and was generally safe in use. While no larger studies have yet compared sustained release naltrexone to maintenance treatment with methadone or buprenorphine, this review indicates that sustained release naltrexone can be considered an effective an safe treatment option for opioid dependence. Note: Results & Conclusions are subject to final approval by the Cochrane Drugs & Alcohol Group editorial review board Financial Support: The University of Oslo The Research Council of Norway.