Opioid System Modulator Research Articles

Nalmefene combined noninvasive positive-pressure ventilation in Chinese patients with chronic obstructive pulmonary disease coupled with type II respiratory failure: A meta-analysis.

Nalmefene is an opioid system modulator with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor. Previous studies have suggested that nalmefene could improve respiratory function in patients with chronic obstructive pulmonary disease (COPD). However, there is no comprehensive systematic review published regarding the clinical efficacy of nalmefene. We explored the following electronic bibliographic databases: EMBASE, Web of Science, PubMed, Wanfang, and Chinese national knowledge infrastructure. To collect data from randomized controlled trials on the therapy of COPD coupled with type II respiratory failure and nalmefene + noninvasive ventilator treatment. The retrieved articles were screened to determine the final inclusion criteria and to extract relevant data, such as the clinical efficacy rate, pulmonary function, blood gas analysis, and adverse reactions. In our study, we used relative risk and weighted mean deviation, as well as a 95% confidence interval for describing nalmefene effectiveness and safety while treating COPD with type II respiratory failure. The outcomes of the meta-analysis demonstrated that the clinical efficacy rate of the nalmefene + noninvasive ventilation group was higher than that of the naloxone + noninvasive ventilation and noninvasive ventilation groups. Moreover, the improvement indices of pH value, partial pressure and saturation of blood oxygen, partial pressure of carbon dioxide, and pulmonary function of the nalmefene + noninvasive ventilation group were better than those of the noninvasive ventilation group, and there was no increase in the occurrence of adverse drug reactions. Nalmefene combined with noninvasive ventilation can significantly improve the blood gas index and lung function in patients with COPD combined with type II respiratory failure.

Opioid Mechanisms and the Treatment of Depression.

Opioid receptors are widely expressed in the brain, and the opioid system has a key role in modulating mood, reward processing and stress responsivity. There is mounting evidence that the endogenous opioid system may be dysregulated in depression and that drug treatments targeting mu, delta and kappa opioid receptors may show antidepressant potential. The mechanisms underlying the therapeutic effects of opioid system engagement are complex and likely multi-factorial. This chapter explores various pathways through which the modulation of the opioid system may influence depression. These include impacts on monoaminergic systems, the regulation of stress and the hypothalamic-pituitary-adrenal axis, the immune system and inflammation, brain-derived neurotrophic factors, neurogenesis and neuroplasticity, social pain and social reward, as well as expectancy and placebo effects. A greater understanding of the diverse mechanisms through which opioid system modulation may improve depressive symptoms could ultimately aid in the development of safe and effective alternative treatments for individuals with difficult-to-treat depression.

Electroacupuncture Attenuates Surgical Stress-Induced Reduction of T Lymphocytes through Modulation of Peripheral Opioid System.

To investigate the action mechanisms of electroacupuncture (EA) on postoperative immunosuppression. Male C57BL/6 mice (5`-7 weeks old) were randomly divided into: the sham injury group, the surgical trauma stressed group, the EA group [surgery + 2/100 Hz EA at Neiguan (PC 6)], and the EA+ Nal (surgery + EA + intraperitoneal injection of naloxone). Abdominal surgical trauma stress mice model was established. EA was performed on bilateral PC 6 acupoints by an EA apparatus (2/100 Hz) for 20 min once a day for 3 days. The mRNA expressions of MOR, DOR, and KOR in thymus and L3`-L5 dorsal root ganglions (DRG) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and the protein expressions of MOR, DOR, and KOR in thymus were measured by Western blot. Flow cytometry assay was used to detect the levels of T lymphocyte subtypes in the peripheral blood. Surgical trauma induced decreased the mRNA expression level of MOR in both thymus (P<0.01) and L3`-L5 DRGs (P<0.05). Moreover, EA treatment not only significantly attenuated the MOR protein and mRNA expression in the thymus (both P<0.05), but also markedly increased expression of DOR and KOR opioid receptor in thymus (P<0.01). However, the mRNA expressions of opioid receptors were not regulated by EA in the DRG (all P>0.05). Furthermore, T lymphocyte population of CD3+ and CD4+ was decreased in the peripheral blood after surgical trauma (both P<0.01). EA treatment can significantly elevate the population of CD3+ (P<0.01), CD4+ (P<0.05) and CD8+ T cells (P<0.01). Intraperitoneal injection of the non-selective opioid receptor antagonist naloxone blocked the up-regulation of T lymphocytes by EA. EA may improve postoperative immunosuppression through the peripheral opioid system.

Opioid system modulation of cognitive affective bias: implications for the treatment of mood disorders

A significant number of patients (30%) do not adequately respond to commonly prescribed antidepressants (e.g. SSRIs, SNRIs, and TCAs). Opioid receptors and their endogenous peptides have demonstrated a clear role in the regulation of mood in animal models and may offer an alternative approach to augment existing therapies. Nevertheless, there is an urgent need to find better ways to predict a patient's response to drug treatment, to improve overall drug responding, and to reduce the time to symptom remission using novel diagnostic and efficacy biomarkers. Cognitive processes, such as perception, attention, memory, and learning, are impaired in patients with mood disorders. These processes can be altered by emotions, a phenomenon called cognitive affective bias. Negative affective biases are a key feature of major depressive disorder (MDD) and may present concurrently with other cognitive deficits. Importantly, a significant percentage of patients report residual cognitive impairments even after effective drug treatment. This approach offers a new opportunity to predict patient treatment responses, potentially improving residual cognitive symptoms and patient outcomes. This review will (1) describe the underlying neurocircuitry of affective cognition and propose how negative biases may occur, (2) outline the role of opioid receptors in affective cognition, executive function, and MDD, and (3) present evidence from the published literature supporting a modulatory role for opioid drugs on negative affective bias, with a focus on kappa-opioid receptor antagonists, currently in development for clinical use for treatment-resistant MDD.

Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder

Buprenorphine/samidorphan (BUP/SAM; ALKS 5461) is an investigational opioid system modulator for the adjunctive treatment of patients with major depressive disorder (MDD), who did not respond adequately to prior antidepressant therapy (ADT). FORWARD-2, an open-label extension study, assessed long-term safety and tolerability of adjunctive BUP/SAM treatment in these patients. Patients from four short-term trials and de novo patients were enrolled; all had confirmed MDD and a current major depressive episode lasting 2–24 months. Patients were treated with an established ADT for ≥8 weeks before receiving sublingual, adjunctive BUP/SAM 2 mg/2 mg for up to 52 weeks. Safety (primary objective) was assessed via adverse events (AEs), the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale (COWS). Exploratory evaluation of efficacy was done using the Montgomery–Åsberg Depression Rating Scale (MADRS). Of 1485 patients, 50% completed the study and 11% discontinued due to AEs. AEs of nausea, headache, constipation, dizziness, and somnolence, each occurred in ≥10% of patients. There was no evidence of increased suicidal ideation or behavior. Euphoria-related AEs were uncommon (1.2%). Following abrupt BUP/SAM discontinuation, “drug withdrawal” AEs were infrequent (0.4%), and the incidence of COWS categorical worsening after abrupt drug discontinuation was low (6.5%). Improvements in mean MADRS scores were maintained until study end, suggesting durability of antidepressant effect in patients continuing treatment. BUP/SAM was generally well tolerated, with a low risk of abuse and an AE profile consistent with those seen in placebo-controlled studies. Withdrawal reports were uncommon and of limited clinical impact.

Buprenorphine/samidorphan combination for the adjunctive treatment of major depressive disorder: results of a phase III clinical trial (FORWARD-3).

BackgroundThe endogenous opioid system is a fundamental regulator of mood in humans. Previously reported clinical trials have demonstrated the efficacy of the investigational agent buprenorphine/samidorphan (BUP/SAM) combination, an opioid-system modulator, for the adjunctive treatment of major depressive disorder. We present here a third phase III study of different design.MethodsAdult patients with major depressive disorder and inadequate response to antidepressant therapy were enrolled in this double-blind, placebo-controlled, placebo run-in study to evaluate the efficacy, safety, and tolerability of adjunctive BUP/SAM 2 mg/2 mg. Patients with baseline Hamilton Depression Rating Scale score $20 received double-blind placebo in addition to background antidepressant therapy for 4 weeks. Nonresponders were randomized to receive adjunctive BUP/SAM 2 mg/2 mg or placebo for 6 weeks. The primary end point was change in Montgomery–Åsberg Depression Rating Scale (MADRS)-10 total score from randomization at baseline to the end of the 6-week treatment period.ResultsLeast-squares mean change in MADRS-10 score at end of treatment was -4.8 (SE 0.67) in the BUP/SAM 2 mg/2 mg group and -4.6 (SE 0.66) in the placebo group (mean difference -0.3 [SE 0.95], P=0.782). There were no differences in MADRS-based response or remission rates. Overall, 42.9% of the BUP/SAM 2 mg/2 mg group and 34.5% of the placebo group experienced at least one treatment-emergent adverse event during the 6-week treatment period, most of which were mild or moderate in severity. There were no clinically important changes in laboratory parameters, weight, or vital signs and no evidence of abuse potential during treatment or opiate-withdrawal symptoms post treatment.ConclusionEfficacy results in FORWARD-3 measured by change in MADRS-10 score did not meet the primary end point, but postbaseline improvement in MADRS-10 in the BUP/SAM 2 mg/2 mg group was consistent with that seen in previously reported trials. BUP/SAM 2 mg/2 mg was well tolerated.

Opioid system modulators buprenorphine and samidorphan alter behavior and extracellular neurotransmitter concentrations in the Wistar Kyoto rat

Approximately two-thirds of major depressive disorder (MDD) patients do not respond adequately to current therapies. BUP/SAM (ALKS 5461), a combination of buprenorphine (BUP) and samidorphan (SAM), is a novel opioid system modulator in development as an adjunct treatment for MDD. Using a rat strain (Wistar Kyoto rat) that is predisposed to stress and has an inadequate response to selective serotonin reuptake inhibitors (SSRIs), we investigated the effect of BUP and SAM, individually and in combination, in established nonclinical assays used to study antidepressants (the forced swim test, FST) and anxiolytics (marble burying test). As opioids and their receptors are expressed in mesocorticolimbic regions of the brain, we analyzed extracellular concentrations of dopamine, serotonin, and/or their metabolites in brain areas associated with mood and motivation. BUP alone and in combination with SAM significantly reduced immobility in the FST. Similarly, the BUP/SAM combination significantly reduced immobility in SSRI (escitalopram)-treated rats. BUP/SAM also decreased burying behavior. SAM attenuated BUP-induced changes of extracellular levels of serotonin and dopamine in the medial prefrontal cortex and nucleus accumbens shell. The latter suggests that the addition of SAM to BUP may limit activation of the mesolimbic dopamine reward pathway and thereby reduce BUP's reinforcing properties. SAM alone had no effect on neurochemistry or immobility in the FST. Collectively, these data indicate that opioid system modulation may offer an alternative mechanism that does not rely on enhanced serotonergic neurotransmission in neurocircuits associated with antidepressant and anxiolytic activity in nonclinical models.

Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies

The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design. Efficacy was measured using the Montgomery–Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and −10 versus placebo: −1.5, P = 0.018; −1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: –1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (–1.8, P = 0.010; –1.8, P = 0.004, respectively). The overall effect size (Hedges’ g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.

Pharmacokinetics and Short-term Safety of ALKS 3831, a Fixed-dose Combination of Olanzapine and Samidorphan, in Adult Subjects with Schizophrenia

PurposeALKS 3831 is composed of a flexible dose of olanzapine and a fixed dose of 10-mg samidorphan (a novel opioid system modulator), designed to provide the established antipsychotic efficacy of olanzapine and to mitigate olanzapine-induced weight gain. To support clinical development of ALKS 3831, we conducted a multicenter, randomized, open-label, Phase I study to obtain steady-state exposure for olanzapine and samidorphan and short-term safety at the intended therapeutic dose range of ALKS 3831 10/10 (10-mg olanzapine/10-mg samidorphan) to ALKS 3831 20/10 (20-mg olanzapine/10-mg samidorphan) in subjects with schizophrenia. MethodsAfter a 1-week olanzapine lead-in period, 42 subjects (14 women) with schizophrenia were randomly assigned (1:1) to receive ALKS 3831 10/10 or ALKS 3831 20/10 bilayer oral tablets once daily for 14 days. Plasma concentrations of olanzapine and samidorphan were quantified by using an LC-MS/MS method. Pharmacokinetic parameters were calculated according to noncompartmental analysis. Safety was monitored throughout the study. FindingsAfter a 1-week olanzapine lead-in phase with titration of olanzapine dose up to 15 mg/d, the steady-state concentration of olanzapine was reached in 3–4 days and that of samidorphan was reached in 5 days after initiation of once-daily oral administration of ALKS 3831 10/10 or ALKS 3831 20/10. At steady state, exposure to olanzapine increased dose proportionally from 10 mg (ALKS 3831 10/10) to 20 mg (ALKS 3831 20/10), and exposure to samidorphan was similar between the 2 ALKS 3831 dose groups, indicating that different dose levels of olanzapine in ALKS 3831 had no impact on the pharmacokinetic profile of samidorphan. ALKS 3831 was well tolerated, and no safety concerns unique to ALKS 3831 compared with olanzapine monotherapy were identified. ImplicationsIn the present study, samidorphan exposure was not affected by different dose levels of olanzapine in ALKS 3831. In addition, olanzapine exposure as a component of ALKS 3831 was comparable with previously published data for olanzapine monotherapy. The present data indicate that combining olanzapine with samidorphan does not affect the pharmacokinetic profile of either drug and support continued clinical evaluation of ALKS 3831. ClinicalTrials.gov identifier: NCT02804568.

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial

Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as adjunctive treatment for major depressive disorder. BUP/SAM is a fixed-dose combination of buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor antagonist, and samidorphan, a μ-opioid receptor antagonist added to address the abuse and dependence potential of buprenorphine. In this study, we assessed the effect of samidorphan on the abuse potential of buprenorphine in the BUP/SAM combination in nondependent, recreational, adult opioid users (ClinicalTrials.gov ID: NCT02413281). Participants were randomized to 6 treatments in a blinded, Williams crossover design: placebo, BUP/SAM at the intended therapeutic dose (2mg/2mg), at 4-fold (8mg/8mg) and 8-fold (16mg/16mg) the therapeutic dose, and buprenorphine alone (8mg and 16mg). The primary end point was maximum effect (Emax ) on the visual analog scale for "at the moment" Drug Liking. Emax of Drug Liking for the BUP/SAM 2mg/2mg dose was similar to that for placebo (median within-subject difference [90% confidence interval]: 2.5 [0.0-9.0]). The supratherapeutic doses of BUP/SAM showed differences of small magnitude on Drug Liking Emax compared to placebo. Drug Liking Emax for all BUP/SAM doses were significantly lower than those observed for either buprenorphine dose alone. Fewer participants reported adverse events associated with abuse potential with BUP/SAM than with buprenorphine alone, and the overall safety profile of BUP/SAM was consistent with prior reports in healthy volunteers. These findings indicate that samidorphan substantially reduces the abuse potential of buprenorphine in the BUP/SAM combination.

S171. Samidorphan in Combination With Buprenorphine Improves Behavioral Deficits in Non-Clinical Tests of Depression and Anxiety Using SSRI Insensitive Rats

ALKS 5461, a combination of buprenorphine (BUP) and samidorphan (SAM), is an opioid system modulator under development as an adjunct treatment for MDD patients with inadequate response to conventional antidepressants. Here, we study the behavioral effects of the combination of BUP and SAM, alone and together, with a selective serotonin reuptake inhibitor (SSRI) in the Wistar Kyoto (WKY) rat strain, a model that mimics some aspects of depression and anxiety and is reportedly insensitive to SSRI treatment.

F172. Clinical Evaluation of Abuse Potential of ALKS 5461

ALKS 5461 is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD) comprised of buprenorphine (BUP) and samidorphan (SAM), a μ-opioid receptor antagonist added to address the abuse/dependence potential of BUP. The ability of SAM to address the abuse potential of BUP in the ALKS 5461 combination was explored.

Role of Estradiol in the Regulation of Prolactin Secretion During Late Pregnancy.

Estrogen action is necessary for evidencing the stimulatory action of mifepristone and naloxone on prolactin (PRL) secretion during late pregnancy. Our aim is to determine the mechanism mediating this facilitator action of estrogens. To investigate the hypothalamic mechanisms involved in estrogen actions in PRL secretion at the end of pregnancy, we measured the effect of pretreatment with the estrogen antagonist tamoxifen on the expression of tyrosine hydroxylase (TH), hormone receptors (ERα and β, PRs, PRLR(long)), and μ- and κ- opioid receptors (ORs) at mRNA (by semiquantitative RT-PCR) and protein (by western blot for TH, PRLR(long), ERα, PRs, μ- and ORs) levels in extracts of medial basal hypothalamus (MBH) and serum PRL, E2 and P4 levels (by RIA) in mifepristone- and naloxone-treated rats. Tamoxifen administration partially prevented PRL release induced by the combined treatment. TH expression diminished and ERα expression increased in mifepristone-treated rats at mRNA and protein levels and tamoxifen partially prevented these changes with no effect on PRs expression. Mifepristone increased PRLR(long) mRNA levels; this increase was blocked by tamoxifen. Combined tamoxifen and mifepristone treatment decreased μ- and k-ORs mRNA but not protein levels. In conclusion, E2 induces neuroadaptive mechanisms necessary to facilitate PRL release preceding delivery. Acting through ERα, E2 modulates hypothalamic dopaminergic neurons activity, regulating TH, μ- and κ-ORs and PRLR(long) expression, and is necessary for evidencing the effects of P4 withdrawal. Its presence on days 14 and 15 of pregnancy is crucial to facilitate the opioid system modulation of PRL secretion at the end of pregnancy in the rat.

Memory-enhancing effect of aspirin is mediated through opioid system modulation in an AlCl3-induced neurotoxicity mouse model.

Neurodegenerative disorders such as Alzheimers disease (AD) are multifaceted and there are currently a limited number of therapeutic strategies available to treat them. Aspirin is known to act on multiple therapeutic targets and is a successful anti-inflammatory agent in various tissues. The present study aimed to ascertain the performance of aspirin when employed as a therapeutic agent to treat neurodegeneration on novel targets, including opioid system genes, in an AlCl3-induced neurotoxicity mouse model. The effects of two doses of aspirin (5 and 20 mg/kg aspirin for 12 days) were investigated in an AlCl3-induced neurotoxicity mouse model (150 mg/kg AlCl3 for 12 days). Neurological improvements were assessed through different behavioral tests and the effects of aspirin on opioid system gene expression levels were assessed by reverse transcription-polymerase chain reaction. Both doses resulted in improvements in cognitive behavior. A 5 mg/kg dose of aspirin was revealed to be effective for spatial memory improvement (7.14±0.84 sec), whilst a 20 mg/kg dose was superior for improving extinction learning (7.63±4.04%). Aspirin (5 mg/kg) also significantly improved contextual memory (48.05±10.6%) when compared with the AlCl3-treated group (1.49±0.62%; P<0.001). Aspirin was also observed to significantly decrease δ-opioid receptor expression in the cortex (1.09±0.08 and 1.27±0.08, respectively) at both doses (5 and 20 mg/kg) when compared with the AlCl3-treated group (3.69±1.43; P<0.05). Furthermore, aspirin at 5 mg/kg significantly reduced expression of prodynorphin in the cortex (0.57±0.20) when compared with the AlCl3-treated group (1.95±0.84; P<0.05). Notably, the effect of aspirin was significant in the cortex but not in the hippocampus. In summary, aspirin was effective in ameliorating the AD-like symptoms via the modulation of opioid systems. However, additional studies are required to determine the long term effects of aspirin on such conditions.

Before and after nalmefene, a case report

IntroductionClinical and social improvement after treatment with nalmefene in an alcoholic 41-year-old male, with history of dependence during 20 years.Case reportOur patient had been abusing alcohol for almost 20 years with short breaks of abstinence (one month). Before treatment he made a consumption of 105 g of alcohol per day. Serological examination showed hepatic alterations (GGT 2115, ALT 229) and a low amount of platelets (61,000). He also had no other relevant medical history and other possible clinical diagnoses were excluded. After a week detoxification program and alcohol consumption cessation during one month, the analytical values drastically changed: ALT 35, GGT 275, platelets 222,000.DiscussionNalmefene is an opioid system modulator with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor. Nalmefene as-needed has been shown to reduce the total amount of alcohol consumption and number of heavy drinking days and to improve liver function. The aim of this treatment is centered in decreasing consumption rather than achieving a total abstinence.ConclusionsAgainst other pharmacologic approaches such as disulfiram an acamprosate, the options that allow acute consumption help patients in controlling drinking rampage and make them realize they will be able to afford alcohol cessation.Disclosure of interestThe authors have not supplied their declaration of competing interest.

P-81SECONDARY BENEFITS OF ALCOHOL REDUCTION WITH NALMEFENE

The opioid system modulator nalmefene reduce average daily total alcohol consumption, number of heavy drinking days, and improve liver function and clinical status in alcohol-dependent patients. We investigated the effect of alcohol reduction with nalmefene 18 mg on alcohol dependence features, drinking consequences, and mood in two 6-month randomized, double-blind, placebo-controlled, studies (NCT00811720; NCT00812461) in alcohol-dependent patients. …

Alcohol Dependence and Alcoholic Liver Disease

Alcohol dependence is a disabling condition that has a high prevalence, but in Europe only a small fraction of the people diagnosed with alcohol abuse and dependence are treated, representing the widest treatment gap, as compared with other mental disorders. Early diagnosis and monitoring of alcoholic liver disease (ALD) is still insufficiently solved. Although ALD is the most common cause for liver disease in the Western world, it largely remains underestimated and underdiagnosed for many reasons. The recent introduction of non-invasive elastographic techniques such as transient elastography (TE) has significantly improved the early diagnosis of alcoholic liver cirrhosis (ALC). As demonstrated in the literature, inflammation-associated liver stiffness (LS) rapidly decreases during alcohol detoxification, and is also directly correlated to change in LS in both abstinent and relapsing patients. Newly published data show that LS could be used to monitor and validate hepatoprotective effects during nalmefene usage. Nalmefene is an opioid system modulator that diminishes the reinforcing effects of alcohol, helping the patient to reduce drinking. Three randomised, multicentre, double-blind, placebo-controlled, parallelgroup Phase III studies were designed to assess the efficacy and safety of nalmefene in reducing alcohol consumption. Patients with a high or very high drinking risk level (DRL) at baseline and randomisation show a clinically significant effect from nalmefene treatment, which is generally well tolerated. Moreover, reduced alcohol consumption supported by nalmefene in combination with psychosocial support may indeed help to reduce the alcohol-related burden and the large treatment gap.

EPA-0255 – Clinical relevance of as-needed treatment with nalmefene in alcohol dependent patients

The opioid system modulator nalmefeneis the first pharmacological therapy approved in the European Union for reduction of alcohol consumption. To evaluate the clinical relevance of the reduction of alcohol consumption in patients with at least high drinking risk level at screening and randomisation from the two, identically designed, randomised controlled 6-month studies ESENSE1 (NCT00811720) and ESENSE2 (NCT00812461) of nalmefene versus placebo. Study medication was taken as-needed. All patients received a motivational and adherence-enhancing intervention (BRENDA). Response criteria were based on alcohol consumption at month 6 and Clinical Global Impression – Severity of Illness/Improvement (CGI-S/I), Short Form Health Survey version 2 (SF-36) mental component summary(MCS) scores at week 24. Clinical relevance was also studied using the Drinker Inventory of Consequences (DrInC), Alcohol Dependence Scale (ADS), and liver function variables. Pooled study population: 667 patients (placebo N=332; nalmefene N=335). The proportion of responders was higher in the nalmefene group than in the placebo group with odds ratios for response consistently significantly (p<0.05) in favour of nalmefene. The difference in the proportions of responders translated to numbers-needed-to-treat ranging from 6 to 10. Significant differences to placebo (p<0.05) in the SF-36 MCS and physical component summary score, ADS, DrInC, CGI-I/S and liver enzymes further supported the clinical relevance of the treatment effect. In view of the immense alcohol-related burden to society, the harm to the individual and the large treatment gap partly due to a reluctance to engage in abstinence, the effect of nalmefene is clearly clinically relevant.

Nalmefene: a guide to its use in alcohol dependence

The opioid system modulator nalmefene (Selincro®) is the first pharmacological therapy to be approved in the EU to reduce alcohol consumption in adults with alcohol dependence and a high drinking risk level. In the target population (i.e. alcohol-dependent patients with at least a high drinking risk level at screening and randomization), as-needed oral nalmefene 18 mg reduced both the number of heavy drinking days and total alcohol consumption to a significantly greater extent than placebo at 6 and 13 months. Oral nalmefene was generally well tolerated in patients with alcohol dependence. Thus, as-needed nalmefene provides an important new option for use in the treatment of alcohol dependence.

Nalmefene: A Review of Its Use in the Treatment of Alcohol Dependence

The opioid system modulator nalmefene (Selincro®) is approved in the EU for as-needed use to reduce alcohol consumption in alcohol-dependent adults with a high drinking risk level. This article reviews the efficacy and tolerability of as-needed oral nalmefene in the treatment of alcohol dependence, as well as summarizing its pharmacological properties. In two randomized, double-blind, multinational trials (ESENSE 1 and ESENSE 2), as-needed nalmefene significantly reduced the number of heavy drinking days (in both trials) and total alcohol consumption (in ESENSE 1) at month 6. In the randomized, double-blind, multinational SENSE trial, as-needed nalmefene significantly improved both of these endpoints at month 13, but not at month 6. As-needed nalmefene had a greater beneficial effect in the target population (i.e. alcohol-dependent patients with at least a high drinking risk level at screening and randomization), with post hoc analyses revealing significant reductions in both the number of heavy drinking days and total alcohol consumption at month 6 (in ESENSE 1 and ESENSE 2) and at month 13 (in SENSE). Oral nalmefene was generally well tolerated in patients with alcohol dependence, with the most commonly occurring adverse events including nausea, insomnia and dizziness. In conclusion, as-needed nalmefene provides an important new option for use in the treatment of alcohol dependence.