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Nalmefeno en el tratamiento de la dependencia alcohólica: revisión de su farmacología, mecanismo de acción y metaanálisis de su eficacia clínica

Eur Neuropsychopharmacol. 2016. doi: 10.1016/j.euroneuro.2016.10.008

Resumen

Nalmefeno es un antagonista de los receptores opioides mu y delta (MOR, DOR) y agonista parcial de los receptores kappa (KOR) que ha sido autorizado en la Unión Europea y otros países para la reducción del consumo de alcohol en pacientes con dependencia alcohólica y un consumo de riesgo elevado según la OMS ("población diana"). En esta revisión se presenta una visión general de la farmacología de nalmefeno, de su mecanismo de acción, y un metaanálisis de su eficacia en la reducción del consumo de alcohol.

La revisión se basó en una búsqueda bibliográfica sistemática. Se realizaron metaanálisis de efectos aleatorios con los ensayos publicados y no publicados que evaluaron la reducción del consumo, mediante el empleo del cambio en el número de días de consumo intenso (DCI) y en el consumo total de alcohol (CTA) respecto a la situación basal como variable de valoración principal. Para cada estudio incluido y para cada dosis, se utilizó la g de Hedges como estimador no sesgado de las diferencias medias estandarizadas entre nalmefeno y placebo.

Los datos preclínicos sugieren que nalmefeno contrarresta la disregulación del sistema de MOR/endorfina y de KOR/dinorfina inducida por el alcohol. La evidencia existente sugiere también que la reducción del consumo de alcohol es una estrategia terapéutica efectiva que puede aplicarse en los pacientes que no están preparados para llegar a la abstinencia. Por último, los metaanálisis confirmaron la eficacia de 20 mg de nalmefeno para reducir los DCI en la población de análisis ITT (g de Hedge=−0,20; IC del 95% −0,30 a −0,09) y en la población diana (g de Hedge=−0,33; IC del 95% −0,48 a −0,18).

Se observaron resultados similares en cuanto al CTA.

Varios metaanálisis, incluido el nuevo que se presenta aquí, respaldan la eficacia de nalmefeno para reducir el consumo de alcohol. En conclusión, dado que no requiere una abstinencia, este tratamiento brinda la posibilidad de motivar a más pacientes para su uso y, por lo tanto, facilita el abordaje de un importante problema de salud pública.

Palabras clave: Nalmefeno, Alcohol, Dependencia de alcohol, Preclinico, Clinico, Metaanálisis.

1. Introducción

El objetivo de esta revisión de nalmefeno es triple: (1) una visión general de su farmacología; (2) una visión general de su mecanismo de acción; y  (3) un metaanálisis de los ensayos controlados y aleatorizados (ECA) sobre su eficacia en el tratamiento de pacientes con dependencia del alcohol. En la visión general de la farmacología preclínica y clínica de nalmefeno resaltamos sus semejanzas y diferencias con otros antagonistas opioides, como naltrexona. Nalmefeno es un antagonista de los receptores opioides mu y delta y, a diferencia de naltrexona, es un agonista parcial del receptor opioide kappa. La evidencia existente sugiere que este perfil diferente de acción sobre el receptor kappa (KOR) puede proporcionar a nalmefeno unas propiedades terapéuticas específicas, además del bloqueo del refuerzo positivo que tiene en común con los antagonistas opioides clásicos. Nalmefeno es en la actualidad el único tratamiento farmacológico autorizado para la reducción del consumo de alcohol (y no para la abstinencia) en pacientes con dependencia alcohólica en la Unión Europea y en otros varios países como Suiza, Australia, Turquía, Rusia, Israel y Hong Kong. En consecuencia, el segundo objetivo de esta revisión es analizar el fundamento de la reducción del daño/consumo controlado como resultado clínicamente favorable. Por lo que respecta al tercer objetivo, describimos los resultados de una revisión sistemática y metaanálisis que se realizaron con los datos de los ensayos clínicos en los que se ha examinado la eficacia de nalmefeno en la reducción del consumo de alcohol, con la inclusión de datos tanto publicados como no publicados. Por lo que respecta al perfil de seguridad de nalmefeno, nos remitimos a un artículo recientemente publicado sobre este tema (van den Brink et al., 2015) y a un metaanálisis reciente en el que se han examinado los riesgos y beneficios de nalmefeno (Palpacuer et al., 2015). En dicho metaanálisis no se aborda la población de pacientes  para los que se ha autorizado el uso de nalmefeno (población diana: pacientes con dependencia alcohólica y un consumo de riesgo como mínimo alto según la Organización Mundial de la Salud (OMS) (2000) que constituye en cambio el centro de interés de nuestra revisión.

2. Neuropsicofarmacología preclínica de nalmefeno

Nalmefeno es un ligando de los receptores opioides que tienen una afinidad mayor para los receptores opioides μ y κ (MOR y KOR) que para los receptores opioides δ (DOR) (Bart et al, 2005 y Michel et al, 1985), y muestra un efecto antagonista en el MOR y el DOR, pero en cambio un efecto agonista parcial en el KOR (Bart et al., 2005). El sistema opioide endógeno ha sido ampliamente estudiado en relación con el refuerzo del alcohol, la recompensa y la recaída, ya que uno de los primeros tratamientos que fueron autorizados para la dependencia alcohólica fue un antagonista de los receptores de opioides  (es decir, naltrexona; véase la revisión de Heilig and Egli, 2006). Se ha demostrado que el bloqueo de la señalización del sistema opioide con antagonistas selectivos del MOR y el DOR reduce la autoadministración de alcohol (AAA) en roedores sin dependencia (Stromberg et al., 1998); (Hyytia and Kiianmaa, 2001); (Kissler et al., 2014), mientras que los antagonistas selectivos del KOR no muestran generalmente efecto alguno sobre la AAA en ausencia de dependencia  (véase la revisión de Walker et al., 2012). Por consiguiente, los MOR y los DOR, pero no así los KOR, se consideran dianas viables para reducir los efectos de refuerzo positivo del alcohol. En las ratas sin dependencia, nalmefeno reduce la AAA de manera dosis-dependiente, presumiblemente a causa de un antagonismo de los MOR (June et al, 1998, June et al, 2004, Nealey et al, 2011, y Kissler et al, 2014) de un modo que se ha demostrado que es equipotente con la acción de naltrexona (Walker and Koob, 2008). Sin embargo, cada vez es mayor la evidencia que sugiere que, en animales con dependencia o retirada del alcohol, el aumento de la expresión de la dinorfina A (DIN), el ligando endógeno de los KOR (Chavkin et al., 1982) y/o la amplificación de la señalización de los KOR contribuyen a producir los efectos de refuerzo negativo del alcohol al fomentar estados de disforia que pueden conducir a un consumo de alcohol excesivo y fomentar la recaída en el consumo de alcohol durante la abstinencia (Markou et al, 1998, Koob, 2009, y Walker, 2012). En condiciones de consumo crónico de alcohol, la señalización de los MOR está atenuada y la actividad del sistema DIN/KOR está exacerbada (véase, por ejemplo, Walker et al., 2012 y Kissler et al., 2014). La observación de que nalmefeno fue significativamente más eficaz que naltrexona para reducir la AAA elevada en las ratas con dependencia se atribuyó supuestamente a un mecanismo del KOR y esto se confirmó con la observación de que un antagonismo selectivo del KOR reducía la AAA excesiva durante la retirada del alcohol (Walker and Koob, 2008). Subsequent investigations into KOR-mediated behaviors in alcohol dependence have established DYN/KOR system contributions to multiple phenotypes of alcohol dependence in humans and animals, including deficits in motivation, affect and executive function (Bazov et al, 2013, Berger et al, 2013, Walker and Kissler, 2013, and Kissler and Walker, 2016). Recent findings highlight the differences in the effects of MOR/DOR and KOR antagonists on non-dependent and alcohol-dependent ASA (Kissler et al., 2014): intra-amygdalar infusion of MOR/DOR antagonists dose-dependently reduced non-dependent ASA but not escalated ASA in dependent animals, whereas KOR antagonists reduced escalated ASA in dependent animals without altering non-dependent use. Owing to the combined MOR antagonist/KOR partial agonist properties, nalmefene was shown to reduce ASA in both alcohol non-dependent and alcohol-dependent conditions. Noteworthy is that KOR antagonism, including the functional antagonism that nalmefene could provide under heightened DYN tone in dependence (Kissler et al., 2014), reduces escalated ASA to pre-dependent ‘social’ levels of drinking in rats during acute withdrawal (Walker et al., 2011) and protracted abstinence (Kissler and Walker, 2016), which is consistent with reduced-risk drinking in humans.

3. Clinical pharmacology of nalmefene

Nalmefene is rapidly absorbed following administration of a single dose (18 mg free base), with a peak plasma concentration (Cmax) of 16.5 ng/ml achieved within 1.5 h (time to peak plasma concentration, Tmax) and a total exposure (area under the curve, AUC) of 131 ng h/ml. Nalmefene has an absolute bioavailability of 41%, and shows plasma binding of approximately 30%, with an estimated volume of distribution of 3200 L. Nalmefene has an oral clearance of 169 L/h and a terminal half-life (T1/2) of approximately 12.5 h. Based on in vitro studies, no clinically relevant interactions are anticipated with alcohol or with drugs metabolized by the most common CYP450 and UGT enzymes (Selincro Product Characteristic 2013). A positron emission tomography (PET) study has shown that, following rapid absorption, nalmefene attained very high receptor occupancy at μ-opioid receptors (87–100%) 3 h after dosing, which persisted 26 h after dosing (83–100%), (Ingman et al., 2005). The decline in receptor occupancy occurred more slowly than the decline in the plasma concentrations of nalmefene and its metabolites (Ingman et al., 2005). Since nalmefene is a mu-opioid antagonist, it will block the effect of opioid analgesics, and may precipitate opioid withdrawal in patients chronically taking opioids (Donnerstag et al., 2015).

4. Reducción del consumo de alcohol como objetivo alternativo

Abstinence from alcohol has (until recently) been the prevailing goal in the treatment of alcohol dependence. Although this approach has been challenged repeatedly, abstinence remains the primary treatment goal in most countries around the world. Empirical research into controlled drinking (reduced alcohol consumption), a harm-reduction strategy, started with a landmark study by Sobell and Sobell (1973). Using cognitive behavioral therapy, they showed the feasibility of reduced drinking; a finding replicated by an independent controlled study (Sanchez-Craig et al., 1984). Nevertheless, much controversy remained on controlled drinking as an acceptable approach when treating (severely) alcohol dependent patients (Sobell and Sobell, 1995, Sobell and Sobell, 2011, and van Amsterdam and van den Brink, 2013).

Meanwhile, the clinical benefits of reducing heavy drinking to moderate drinking was supported by longitudinal studies demonstrating that patients could sustain moderate drinking over time and had reduced alcohol problems compared to heavy drinkers (Gual et al., 2013); In the US, Project MATCH showed that those drinking moderately at the end of the 4 month psychosocial treatment maintained moderate drinking and showed good clinical outcomes one or more years later (Maisto et al., 2007). Based on initial work by Sinclair and colleagues (reviewed in 2001) placebo controlled medication trials in actively drinking patients were undertaken. Some of the early proof-of-concept studies used the opioid antagonist naltrexone (Heinälä et al., 1999) and the anti-epileptic medication topiramate (Johnson et al, 2007 and Johnson et al, 2007) and showed a consistent reduction of alcohol consumption in the active medication group and to some extent in the placebo group. Along these lines a recent meta-analysis of medications used in alcohol treatment found that opioid antagonists showed better efficacy for reducing alcohol consumption than for maintaining abstinence (Jonas et al., 2014).

Alcohol dependence has the widest treatment gap (82%) in mental health care (Kohn et al., 2004), mainly because patients are reluctant to endorse abstinence (Marlatt and Witkiewitz, 2002; National Survey on Drug Use & Health, SMA 2013). About half of alcohol-dependent individuals who eventually seek treatment mention reduction of consumption over abstinence as their preferred treatment goal (Heather et al, 2010 and Hodgins et al, 1997). In their guideline, the European Medicines Agency (EMA, 2010) acknowledges the value of a harm reduction treatment strategy of fewer heavy drinking days and lower total alcohol consumption as an interim step towards abstinence (EMA, 2010). Similarly, the US Food and Drug Administration (FDA) recently identified reduced heavy drinking as a beneficial clinical outcome in their published draft guidance on preferred clinical outcomes for alcohol dependence treatment studies (FDA, 2015).

5. Revisión sistemática de la literatura y metaanálisis de la eficacia de nalmefenoe

5.1. Métodos experimentales

5.1.1. Selección de los estudios

A systematic literature review was conducted to identify studies evaluating nalmefene for the reduction of alcohol consumption in adult, alcohol-dependent patients and to evaluate efficacy. The following databases were searched concatenated: Medline (incl. Medline In-Process), EMBASE, PsychInfo via the provider ProQuest and the clinical study reports available for nalmefene manufacturer-sponsored studies (European Public Assessment Report 2012). The search was not limited by date. The search was conducted using a combination of search terms and keywords for alcoholism, nalmefene, and terms related to the study design (e.g., randomized controlled trial [RCT]). The full search strategy is presented in supplementary materials. The PICOS (population/patients, intervention, comparison, outcomes, study design) inclusion and exclusion criteria strategy was used to assess titles and abstracts for the systematic review at screening level 1 and full-text assessment at screening level 2. The level 2 study selection was divided in two parts: 2a intention-to-treat (ITT) (or modified ITT if used in the original publication) population analyses; and 2b patient population and intervention according to the nalmefene label as defined by the EMA (target population: alcohol dependent patients with at least high drinking risk levels according to the World Health Organization (WHO, 2000). Furthermore, at level 2 the selection was restricted to studies reporting change from baseline in alcohol consumption. Studies only reporting alcohol consumption at endpoint (i.e. not change from baseline) were excluded for methodological reasons as these should not be combined with change from baseline values when analyzing standardized mean differences (Higgins & Green, 2011). Studies designed to prevent relapse to (heavy) drinking and therefore did not report on reduction of alcohol consumption were excluded.

5.1.2. Outcomes and data extraction

The outcome analysed was the change from baseline in the number of HDDs to the primary endpoint assessment (if defined in the study protocol) or to the final assessment. The endpoint varied between studies from month 3 to month 7 after randomization. The definition of a HDD (for men, a day with alcohol consumption ≥ 60 g or ≥ 64 g; for women, a day with alcohol consumption ≥ 40 g or ≥ 48 g) differed slightly between studies.

For identified studies, data was extracted from the publication or from the clinical study report. As the Mixed Model for Repeated Measures (MMRM) approach was used as primary analysis in the majority of studies, and because this methodology appropriately handles missing data, results based on MMRM analysis was preferred. In the absence of MMRM results, observed case data was used because analysis results based on a single imputation method (e.g. ANCOVA-BOCF) tend to underestimate the variance of the treatment effect and Witkiewitz et al. (2014) has illustrated how single imputation led to biased estimates of the treatment effect for continuous heavy drinking outcomes in alcohol clinical trials.

The subgroup of patients with at least high drinking risk levels according to the WHO at both screening and randomisation was of special interest, as it corresponds to the target patient population to be treated with nalmefene according to the nalmefene label (European Summary of Product Characteristics, Selincro; European Medicines Agency, 2013). For the studies that could evaluate the efficacy in this patient population, the change from baseline in the number of HDDs was analysed using the definition of HDDs as reported in the pivotal trials of Nalmefene (Mann et al, 2013, Gual et al, 2013, and van den Brink et al, 2014). Data for this subgroup of patients was extracted from the publications or was available from re-analyses in case the subgroup was not considered in the publication. In accordance with the European Medicine Agency guideline on alcohol dependence (EMA, 2010), the pivotal trials of nalmefene were designed to include reductions in HDD and in total alcohol consumption (TAC) as co-primary endpoints for the target population. Therefore we will also briefly describe the meta-analysis results for change in TAC in the target population.

5.1.3. Statistical analysis

For each study identified, the mean difference between each nalmefene dose and placebo was standardised using the pooled within-groups standard deviation in the study. Hedges’ g was used as an unbiased estimator of the standardised mean difference. Random-effects meta-analyses were performed to estimate the combined difference between each nalmefene dose and placebo using study level data, thus the standardised outcome for each treatment in each study (using the pooled within-groups standard deviation in the study) was used as the dependent variable in the analyses. Random-effects models were used as they allow for between-study heterogeneity and provide more conservative estimates in the presence of heterogeneity. All analyses were performed in SAS version 9.4 using PROC MIXED.

6. Results from the systematic literature and meta-analysis

6.1. Estudios seleccionados

The literature search yielded 232 relevant citations. A total of 77 records were excluded at level 1 screening of titles/abstracts, and a further 148 and 151 articles were respectively excluded at the level 2a and 2b full-text article screening stage (see flow diagram Figure 1). After applying the screening criteria for level 2a, 7 records describing 7 studies were included. Four records describing 5 studies were included after applying screening criteria for level 2b. Two single-site, (relatively) small randomized placebo controlled studies on nalmefene were excluded at level 2b because the reported (positive) outcomes did not include reduction in the number of heavy drinking days (Mason et al., 1994;Mason et al 1999). Details on study characteristics, data source and data extracted for statistical analyses are provided in the Supplementary material Tables S1a and S1b.

Fig. 1

Figure 1

Flow Diagram for Identification Process in the Systematic Review of nalmefene studies.

 

6.2. Meta-analyses results

ITT population (see Figure 2): The 5 mg and 10 mg doses of nalmefene were only included in one study each, of limited sample size. Based on the individual study results, the effect size (Hedges’ g) for the change from baseline in the number of HDDs was −0.06 and 0.10 for the 5 mg and 10 mg dose of nalmefene, respectively, whereas for the 20 mg and 40 mg dose of nalmefene, Hedges’ g ranged from −0.07 to −0.30 and −0.06 to −0.28, respectively. The random effects meta-analyses estimated the overall effect size as −0.20 (95% CI: −0.30 to −0.09) and −0.16 (95% CI: −0.47 to 0.14) for the 20 mg and 40 mg dose of nalmefene, respectively. The between-studies variance was estimated to be zero in both meta-analyses, indicating that there was no heterogeneity in the treatment effect between studies, thus study results were very consistent.

Fig. 2

Figure 2

Meta-analysis of change from baseline in monthly HDDs; nalmefene versus placebo – ITT population. N: The number of patients at endpoint assessment.

 

Target population (see Figure 3): The effect size for the change from baseline in the number of HDDs was consistent across the individual study results (ranging from −0.22 to −0.43) and the estimate of the overall effect size from the random effects meta-analysis was −0.33 (95% CI: −0.48 to −0.18) for 20 mg dose versus placebo. The random effects meta-analysis on the change from baseline in TAC was consistent with the results for HDDs and led to a similar estimate of the treatment effect for the 20 mg dose versus placebo in the target population: (−0.35; 95% CI: −0.51 to −0.20) (data on file).

Fig. 3

Figure 3

Meta-analysis of change from baseline in monthly HDDs; nalmefene versus placebo – Target Population. N: The number of patients at endpoint assessment.

 

7. Discussion

This review provides an overview of the pharmacology, mechanisms of action and clinical efficacy of nalmefene in reducing alcohol consumption in the treatment of alcohol dependence. Nalmefene shares mu and delta opioid antagonism with naltrexone, but has a different profile at the kappa-opioid receptor. Preclinical studies with nalmefene suggest that kappa-opioid properties of the drug may normalize a chronically dysregulated KOR-dynorphine system. The review also shows that reduction strategies can be successful in reducing the risk of harm due to excessive alcohol use in alcohol dependent patients. Finally, the systematic literature review identified 7 placebo-controlled studies testing the effect of nalmefene in alcohol dependent patients and the meta-analysis estimated the efficacy of 20 mg nalmefene for reducing HDDs: overall effect size in ITT population: Hedge׳s g=−0.20; 95% CI −0.30 to −0.09; overall effect size in target population: Hedge׳s g=−0.33; 95% CI −0.48 to −0.18. This overall effect size for reducing HDDs in the ITT population is similar to the one in the primary analysis of the meta-analysis by Palpacuer et al. (2015). The main difference between our results and those from Palpacuer et al. (2015) is that we also report the results for the nalmefene target population as it was approved by the EMA and thus essential for those who want to prescribe nalmefene according to the registered indication.

Our meta-analysis has some limitations. First, the evidence for efficacy at the 5 and 10 mg dose is weak, as each dose was included in only one study with a small sample size. Second, the included studies differed considerably in study characteristics (e.g. treatment duration, dose); however patient characteristics were similar in terms of age, sex and baseline drinking as illustrated in Supplementary material Tables S1a and S1b. Moreover, the treatment effect (nalmefene versus placebo) for individual studies was generally consistent throughout the treatment period, thus the between-study differences in endpoint of analysis are unlikely to have influenced the results of the meta-analyses. Third, this meta-analysis has a focus on reduction in alcohol consumption, endpoints that are recognized by the EMA guideline as appropriate endpoints to address intermediate harm reduction. This differs from the meta-analysis by Palpacuer et al. (2015) that also addressed health outcomes, including mortality. However, as pointed out by Roerecke et al. (2015), the clinical relevance in terms of reduced mortality cannot be established based on time-limited efficacy and/or safety trials lasting up to 12–15 months. Moreover, several health outcomes have already been published for the nalmefene target population in Aubin et al. (2015). Fourth, there are results on the nalmefene patient population approved by EMA which was defined post-hoc. The credibility and interpretation of the results based on a subgroup of patients depend on the plausibility of the findings and replication of evidence across studies (Hemmings, 2014). It is well-known that non-specific treatment effects prior to randomisation can introduce heterogeneity (Johnson et al, 2003 and Mann et al, 2012) and this provides a plausible explanation for the heterogeneity observed, within each study in the ITT population, which led to the identification of the nalmefene target population (see European Public Assessment Report 2012 and van den Brink et al., 2013). Moreover, there was no imbalance in baseline characteristics between treatment groups in the target population in each of the studies and the evidence for efficacy in the target population was replicated consistently across studies, thus concluding based on results from the target population meta-analysis is justified. A frequently mentioned barrier for the use of medications in alcohol dependence treatment has been a perceived low efficacy of pharmacotherapy (Thomas et al., 2003). However the effect sizes reported in the target population are well in the range for approved medicinal products in general medicine and psychiatry, including alcohol dependence (Leucht et al, 2012 and Aubin et al, 2015). In addition, Aubin et al. performed various responder analyses based on drinking variables, physician and patient reported outcomes from the nalmefene pivotal trials to provide a better insight into the clinical relevance of nalmefene treatment in patients with alcohol dependence. Across the various responder definitions, odds ratios (OR) ranged from 1.79 to 2.44 and numbers-needed-to-treat (NNT) ranged from 6 to 10 (Aubin et al., 2015).

Despite these positive results, the EMA approval of nalmefene has recently kindled vivid criticism. Fitzgerald et al. (2016) have questioned nalmefene׳s approval based on a post-hoc analysis of patients with high or very high drinking levels and without alcohol reduction prior to randomization (“target population”). EMA has taken note of this critique and discussed their decision again in July 2016 at the Committee for Medicinal Products for Human Use (CHMP). Their conclusion reads as follows: “The Committee discussed the data and having taken into account the divergent position at time of positive opinion, concluded that the recent literature reports do not contain new information that would necessitate a re-evaluation of the benefit/risk ratio of Selincro” (European Medicines Agency, 2016).

Finally, nalmefene-related reductions in alcohol consumption are likely to be paralleled by decreases in mortality risk (Roerecke et al., 2015) and improvements in mental health (Francois et al., 2015). One may speculate that these expected improvements in mental health are caused by an amelioration of alcohol-related dysregulations of the KOR/Dynorphin system (Berger et al., 2013) by the partial KOR-agonist nalmefene, which in turn may have led to a (further) reduction of alcohol consumption. In addition, recent evidence has expanded the treatment potential of KOR-directed pharmacotherapy, because it was found that KOR/Dynorphin dysregulation produced by alcohol dependence seems to persist into protracted abstinence (Kissler and Walker, 2016) and that cues associated with KOR activation in non-dependent animals could drive escalated alcohol self-administration in a KOR antagonist-sensitive manner (Berger et al., 2013). Taken together, integrating the protracted-abstinence with the negative-affective cue-induced data, there is growing evidence supporting KOR-directed therapeutics that do not exclusively involve ׳alcohol-dependent׳ populations, but also pre- and post-dependent populations and expand the potential utility of ligands with a KOR mechanism of action, from acute withdrawal to protracted abstinence.

8. Conclusion

Both preclinical and clinical evidence supports the efficacy of nalmefene in reducing alcohol consumption. This alcohol reduction strategy has the potential to diminish the current treatment gap and thus to help address a major public health concern.

Fuente de financiación

There was no funding for this article.

Contributors

Karl Mann, Wim van den Brink and Robert Swift drafted the manuscript. Brendan Walker provided the parts on preclinical research, Per Sørensen, Lars Torup and Antoni Gual did the meta-analysis. All authors provided important intellectual content.

Financial disclosures

Karl Mann is a consultant to Abbvie, D&A Pharma, Lundbeck, Novartis, and Pfizer. He has received speaker fees from Lundbeck. Lars Torup was employed by Lundbeck at the time of the conduct of this research. Per Sørensen is employed by Lundbeck. Antoni Gual has received honoraria and travel grants from Abbvie, Lundbeck, D&A Pharma, and Servier.

Robert Swift has received research grant funding and consulting fees from Farmaceutico CT, consulting fees and travel reimbursements from D&A Pharma, and travel reimbursements and honoraria from Lundbeck. Brendan Walker is a consultant for Lundbeck and within the last three years, has received honoraria from Lundbeck for speaking at Lundbeck-hosted scientific meetings. Wim van den Brink has received honoraria from Eli Lilly, Indivior, Lundbeck, Merck Serono, Mundipharma, Pfizer, as well as speaker fees from Lundbeck. He has also received investigator-initiated industry grants from Alkermes, and Neurotech, is a consultant to D&A Pharma, Kinnov Therapeutics, Bioproject, Indivior, Lundbeck, Merck Serono, Novartis and Mundipharma, and has received renumeration for expert testimony provided to Indivior and Mundipharma.

Acknowledgements

The authors take public responsibility for the content of the manuscript; have made substantive intellectual contributions to, and given final approval of, the submitted work.

Appendix A. Supplementary material

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Supplementary material

 

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Footnotes

a Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany

b Novo Nordisk Foundation, Copenhagen, Denmark

c H. Lundbeck A/S, Valby, Denmark

d Neurosciences Institute, Hospital Clinic, IDIBAPS, Barcelona, Spain

e Center for Alcohol and Addiction Studies, Brown University, and the Providence VA Medical Center, Providence, RI, USA

f Laboratory of Alcoholism and Addictions Neuroscience, Washington State University, WA, USA

g Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Correspondence to: Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Central Institute of Mental Health, Square J5, 68159 Mannheim, Germany.

Título y publicación originales:

“Nalmefene for the management of alcohol dependence: review on its pharmacology, mechanism of action and meta-analysis on its clinical efficacy”, Karl Mann, Lars Torup, Per Sørensen, Antoni Guald, Robert Swift, Brendan Walker, Wim van den Brink, European Neuropsychopharmacology, 2016. doi: 10.1016/j.euroneuro.2016.10.008.

© de la traducción al español: 2016 Elsevier España, S.L.U.

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