Drinking Levels and Profiles of Alcohol Addicted Rats Predict Response to Nalmefene
Jerome C. FooValentina VengelieneHamid R. NooriIkuhiro YamaguchiKenji MoritaTôru NakamuraYoshiharu YamamotoRainer Spanagel
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Abstract:
Background: Pharmacotherapeutic options supporting the treatment of alcohol dependence are recommended and available but underutilized, partly due to questions about efficacy. Nalmefene, a μ-opioid receptor antagonist and partial kappa receptor agonist, is recommended for reduction of alcohol consumption, but evidence about its effectiveness has been equivocal; identifying factors which predict response will help optimize treatment. Methods: The alcohol deprivation effect paradigm is a tightly controlled procedure comprising repeated deprivation and reintroduction phases, leading to increased preference for alcohol; reintroduction approximates relapse. Using a digital drinkometer system measuring high-resolution drinking behavior, we examined the effects of nalmefene on relapse drinking behavior in alcohol addicted rats. We also tested whether drinking behavior in the relapse phase prior to nalmefene administration predicted treatment response. We further examined whether longitudinal drinking behavior and locomotor activity predicted treatment response. Results: Our results showed that nalmefene (0.3 mg/kg) reduced relapse-like consumption significantly (∼20%) compared to vehicle on the first 2 days of alcohol reintroduction. Examining the first 6 h of a preceded treatment-free relapse episode revealed drinking patterns clustering the rats into responders (reduction of >40%, n = 17) and non-responders (reduction of <40%, n = 7) to subsequent nalmefene treatment. During the first 6 h of the preceding relapse phase, responders consumed more alcohol than non-responders; the amount of alcohol consumed during each drinking approach was larger but frequency of drinking did not differ. Longitudinal drinking behavior and locomotor activity did not significantly predict response. Conclusion: Our results suggest that nalmefene reduces alcohol intake during a relapse-like situation but effectiveness can differ greatly at the individual level. However, who responds may be informed by examining drinking profiles and rats that show high drinking levels prior to treatment are more likely to respond to nalmefene.Keywords:
Nalmefene
Objectives: On the basis of the recent advances in drug therapy of alcoholism, we conducted a review on opioid receptor antagonist drugs with approved indication for the treatment of alcoholism, such as naltrexone and nalmefene. Methods: We reviewed over 100 publications on peptides and opioid receptors, as well as studies conducted in experimental animals and in humans on the effect of opioid receptor antagonists on alcohol consumption in the treatment of alcoholism. We also reviewed the pharmacological characteristics of naltrexone and nalmefene, and the usefulness of these drugs in clinical practice. Results: Much evidence has demonstrated the efficacy of naltrexone and nalmefene for the reduction of alcohol consumption, in experimental animals as well as in humans examined under experimental bar conditions; however, due to its different receptor profile, nalmefene has been associated with higher efficacy levels in reducing alcohol consumption in alcohol-dependent rats. In addition, a great number of controlled clinical trials have demonstrated the efficacy of naltrexone for relapse prevention in patients with an alcohol dependence disorder. Recent controlled clinical trials have demonstrated the efficacy of nalmefene “as-needed” in the reduction of alcohol consumption in subjects with mild alcohol dependence. Conclusions: Both naltrexone and nalmefene have proved to be safe, well tolerated, easy to manage, and efficient drugs for the treatment of alcohol dependence disorder
Nalmefene
Alcohol Dependence
Narcotic antagonists
Opioid antagonist
Alcohol use disorder
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Objectives: On the basis of the recent advances in drug therapy of alcoholism, we conducted a review on opioid receptor antagonist drugs with approved indication for the treatment of alcoholism, such as naltrexone and nalmefene. Methods: We reviewed over 100 publications on peptides and opioid receptors, as well as studies conducted in experimental animals and in humans on the effect of opioid receptor antagonists on alcohol consumption in the treatment of alcoholism. We also reviewed the pharmacological characteristics of naltrexone and nalmefene, and the usefulness of these drugs in clinical practice. Results: Much evidence has demonstrated the efficacy of naltrexone and nalmefene for the reduction of alcohol consumption, in experimental animals as well as in humans examined under experimental bar conditions; however, due to its different receptor profile, nalmefene has been associated with higher efficacy levels in reducing alcohol consumption in alcohol-dependent rats. In addition, a great number of controlled clinical trials have demonstrated the efficacy of naltrexone for relapse prevention in patients with an alcohol dependence disorder. Recent controlled clinical trials have demonstrated the efficacy of nalmefene “as-needed” in the reduction of alcohol consumption in subjects with mild alcohol dependence. Conclusions: Both naltrexone and nalmefene have proved to be safe, well tolerated, easy to manage, and efficient drugs for the treatment of alcohol dependence disorder (currently known as alcohol use disorder). On the basis of recent controlled clinical trials, nalmefene has been shown to result in a significant reduction of alcohol consumption, thereby representing a new objective that extends the therapeutic possibilities for those patients who do not wish for a continuous abstinence, but rather a reduction of alcohol consumption.
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Alcohol Dependence
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Opioid antagonist treatments reduce alcohol drinking in rodent models and in alcohol-dependent patients, with variable efficacy across different studies. These treatments may suffer from the development of tolerance and opioid receptor supersensitivity, as suggested by preclinical models showing activation of these processes during and after subchronic high-dose administration of the short-acting opioid antagonist naloxone. In the present study, we compared equipotent low and moderate daily doses of naltrexone and nalmefene, two opioid antagonists in the clinical practice for treatment of alcoholism. The antagonists were given here subcutaneously for 7 days either as daily injections or continuous osmotic minipump-driven infusions to alcohol-preferring AA rats having trained to drink 10% alcohol in a limited access protocol. One day after stopping the antagonist treatment, [35 S]GTPγS autoradiography on brain cryostat sections was carried out to examine the coupling of receptors to G protein activation. The results prove the efficacy of repeated injections over infused opioid antagonists in reducing alcohol drinking. Tolerance to the reducing effect on alcohol drinking and to the enhancement of G protein coupling to μ-opioid receptors in various brain regions were consistently detected only after infused antagonists. Supersensitivity of κ-opioid receptors was seen in the ventral and dorsal striatal regions especially by infused nalmefene. Nalmefene showed no clear agonistic activity in rat brain sections or at human recombinant κ-opioid receptors. The findings support the as-needed dosing practice, rather than the standard continual dosing, in the treatment of alcoholism with opioid receptor antagonists.
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Abstract Objective Naltrexone and nalmefene are approved for the treatment of alcohol use disorders, in different countries. Naltrexone is also approved for the treatment for opioid use disorders, most recently in a depot formulation. These compounds target primarily μ(mu)‐ and κ(kappa)‐opioid receptor systems, which are involved in the downstream neurobiological effects of alcohol and in the modulation of neuroendocrine stress systems. The study objective was to compare the neuroendocrine effects of naltrexone and nalmefene on adrenocorticotropic hormone (ACTH), cortisol, and prolactin, in normal volunteers. Method Adult normal volunteers ( n = 11 male and n = 9 female) were studied in a stress‐minimized inpatient setting on three consecutive days, after intravenous saline, naltrexone HCl (10 mg), or nalmefene HCl (10 mg), in fixed order. ACTH, cortisol, and prolactin were analyzed pre‐injection and up to 180 min post‐injection. Results Naltrexone and nalmefene caused elevations in ACTH and cortisol compared with saline. Nalmefene had a greater effect on ACTH and cortisol, compared with naltrexone. Both compounds also caused elevations in prolactin in males (females were not examined, due to the influence of menstrual cycle on prolactin). Conclusions This study suggests that both nalmefene and naltrexone have effects potentially due to κ‐partial agonism in humans, as well as antagonist effects at μ‐receptors.
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Background: The mu-opioid antagonist naltrexone is one of the few approved pharmacotherapies for the treatment of alcohol dependence. Recently, the mu-opioid antagonist and partial kappa agonist nalmefene was approved by the European Medicines Agency for the reduction of alcohol consumption in adult patients with alcohol dependence. To date, no head-to-head studies have compared the efficacy and safety of naltrexone and nalmefene in reducing alcohol consumption. Methods: An indirect meta-analysis of randomized controlled studies on these 2 medications was conducted. A random effects model was used to measure effects and compare the 2 medications. 4 placebo-controlled studies with nalmefene and 13 with naltrexone were included. Results: A statistically significant advantage of nalmefene towards naltrexone in the 2 patient-relevant outcome efficacy criteria, quantity and frequency of drinking, was found. Both drugs had a benign safety profile. Conclusions: This indirect meta-analysis indicates an advantage of nalmefene over naltrexone. Nalmefene is an effective and well-tolerated medication for the reduction of alcohol consumption. Additional data are necessary to demonstrate possible advantages of nalmefene over naltrexone in the treatment of alcohol dependence.
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Narcotic antagonists
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Florian Naudet has drawn up a letter to the editor [1] to comment on our paper “Comparing Nalmefene and Naltrexone in Alcohol Dependence: Are there any Differences? Results from an Indirect Meta-analysis” [2] in this journal. We would like to comment on this manuscript.
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On the basis of the recent advances in drug therapy of alcoholism, we conducted a review on opioid receptor antagonist drugs with approved indication for the treatment of alcoholism, such as naltrexone and nalmefene.We reviewed over 100 publications on peptides and opioid receptors, as well as studies conducted in experimental animals and in humans on the effect of opioid receptor antagonists on alcohol consumption in the treatment of alcoholism. We also reviewed the pharmacological characteristics of naltrexone and nalmefene, and the usefulness of these drugs in clinical practice.Much evidence has demonstrated the efficacy of naltrexone and nalmefene for the reduction of alcohol consumption, in experimental animals as well as in humans examined under experimental bar conditions; however, due to its different receptor profile, nalmefene has been associated with higher efficacy levels in reducing alcohol consumption in alcohol-dependent rats. In addition, a great number of controlled clinical trials have demonstrated the efficacy of naltrexone for relapse prevention in patients with an alcohol dependence disorder. Recent controlled clinical trials have demonstrated the efficacy of nalmefene "as-needed" in the reduction of alcohol consumption in subjects with mild alcohol dependence.Both naltrexone and nalmefene have proved to be safe, well tolerated, easy to manage, and efficient drugs for the treatment of alcohol dependence disorder (currently known as alcohol use disorder). On the basis of recent controlled clinical trials, nalmefene has been shown to result in a significant reduction of alcohol consumption, thereby representing a new objective that extends the therapeutic possibilities for those patients who do not wish for a continuous abstinence, but rather a reduction of alcohol consumption.Objetivos: A partir de los recientes progresos en la farmacoterapia del alcoholismo, hemos efectuado una revisión sobre los fármacos antagonistas de los receptores opioides, que tienen aprobada la indicación para el tratamiento del alcoholismo, como son naltrexona y nalmefeno. Metodología: Hemos revisado más de 100 publicaciones sobre péptidos y receptores opioides, el efecto de los fármacos antagonistas de los receptores opioides sobre el consumo de alcohol, tanto en animales como en humanos, tanto en el laboratorio como para el tratamiento del alcoholismo. También se describen las características farmacológicas de naltrexona y de nalmefeno y su utilidad en la práctica clínica. Resultados: Múltiples evidencias han demostrado la eficacia de naltrexona y nalmefeno para reducir el consumo de alcohol, tanto en animales de laboratorio como también en personas estudiadas en situación de bar experimental, aunque debido al diferente perfil receptorial, nalmefeno ha sido relacionado con una mayor eficacia para la reducción del consumo de alcohol, en ratas que presentan dependencia del alcohol. Además, un gran número de ensayos clínicos controlados han demostrado la eficacia de naltrexona para la prevención de recaídas, en personas que presentan un trastorno por dependencia del alcohol. Ensayos clínicos controlados recientes han demostrado la eficacia de nalmefeno “a demanda” para reducir el consumo de alcohol, en personas que presentan un trastorno por dependencia del alcohol de baja gravedad. Conclusiones: Tanto naltrexona como nalmefeno han demostrado ser fármacos seguros, bien tolerados, de manejo sencillo, y eficaces para el tratamiento del trastorno por dependencia del alcohol, (actualmente llamado trastorno por consumo de alcohol). A partir de recientes ensayos clínicos controlados se ha comprobado que nalmefeno produce una reducción significativa del consumo de alcohol, lo cual supone un nuevo objetivo que amplía las posibilidades de tratamiento para los pacientes que no desean la abstención continuada, sino una reducción de su consumo de alcohol.
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Alcohol Dependence
Alcohol use disorder
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