The Use of Very High-Doses of Baclofen for the Treatment of Alcohol-Dependence: A Case Series

Baclofen, particularly high-dose baclofen, has recently emerged as a treatment of major interest for alcohol-dependence. However, baclofen has many potentially dangerous side effects, and the maximal dose of baclofen that may be used is a matter of discussion. Here, the author analyses the medical charts of the last 100 patients seen in his clinic, 17 of whom have been taking a very high dose of baclofen, that is to say, more than 300mg per day. The analysis of the charts shows that the very high doses baclofen were justified in almost all the cases. Side effects are analyzed

A Review of the Potential Mechanisms of Action of Baclofen in Alcohol Use Disorder

Baclofen, a GABA-B receptor agonist, is a promising treatment for alcohol use disorder (AUD). Its mechanism of action in this condition is unknown. GABA-B receptors interact with many biological systems potentially involved in AUD, including transduction pathways and neurotransmitter systems. Preclinical studies have shown that GABA-B receptors are involved in memory storage and retrieval, reward, motivation, mood and anxiety; neuroimaging studies in humans show that baclofen produces region-specific alterations in cerebral activity; GABA-B receptor activation may have neuroprotective effects; baclofen also has anti-inflammatory properties that may be of interest in the context of addiction. However, none of these biological effects fully explain the mechanism of action of baclofen in AUD. Data from clinical studies have provided a certain number of elements which may be useful for the comprehension of its mechanism of action: baclofen typically induces a state of indifference toward alcohol; the effective dose of baclofen in AUD is extremely variable from one patient to another; higher treatment doses correlate with the severity of the addiction; many of the side effects of baclofen resemble those of alcohol, raising the possibility that baclofen acts as a substitution drug; usually, however, there is no tolerance to the effects of baclofen during long-term AUD treatment. In the present article, the biological effects of baclofen are reviewed in the light of its clinical effects in AUD, assuming that, in many instances, clinical effects can be reliable indicators of underlying biological processes. In conclusion, it is proposed that baclofen may suppress the Pavlovian association between cues and rewards through an action in a critical part of the dopaminergic network (the amygdala), thereby normalizing the functional connectivity in the reward network. It is also proposed that this action of baclofen is made possible by the fact that baclofen and alcohol act on similar brain systems in certain regions of the brain

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30–80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an “off-label” prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD

Étude électrophysiologique des effets du tabac, de sa fumée et de la nicotine sur des neurones dopaminergiques de l aire tegmentale ventrale in vivo chez le rat, la souris sauvage et la souris ß2 KO

La nicotine est considérée comme étant la molécule addictogène de la cigarette et du tabac. Mais différentes études cliniques, utilisant notamment des substituts nicotiniques, débouchent pratiquement toutes sur une même conclusion : efficacité ne dépassant que de peu celle d un placebo, et très limitée dans le temps, contrastant avec le pouvoir hautement addictif du tabac, qu'il soit chiqué, prisé ou fumé. Dans ce travail de thèse, nous avons essayé de mettre en évidence le rôle que pourraient avoir certains des autres composés présents dans le tabac ou produits par pyrolyse. Nous avons d abord utilisé des extraits aqueux de fumée et de tabac pour approcher un aspect global de ce que les fumeurs absorbent chaque fois qu ils fument une cigarette, nous rapprochant ainsi des conditions physiologiques du fumeur. Puis nous avons choisi un certain nombre de substances. La cotinine, métabolite de la nicotine. L harmane, une ß-carboline, synthétisée au cours de la combustion et dans l organisme des fumeurs. La norharmane, une ß-carboline, présente en partie dans le tabac et synthétisée dans la fumée par pyrolyse. La technique utilisée tout au long de ce travail est l enregistrement électrophysiologique. Cette technique s applique très bien à l étude in vivo de différents systèmes neuronaux y compris le système dopaminergique. Nous l avons utilisée chez le rat, la souris WT et la souris Knockout ß2 (ß2KO). Nous nous sommes intéressés à deux aspects de l activité cellulaire des neurones dopaminergiques de l aire tegmentale ventrale : la fréquence de décharge (le firing) et les bouffées (bursts). En parallèle, nous avons conduit des expériences de liaison (binding) sur des cultures de cellules exprimant le récepteur nicotinique a4ß2. Nos résultats les plus significatifs ont montré que : Les bursts sont le plus souvent absents après les injections d extraits de tabac et de fumée. Cela pourrait, entre autres, impliquer qu il existe dans le tabac et la fumée des composés autres que la nicotine qui bloquent les effets de la nicotine sur les bursts. Les effets des extraits de tabac et de fumée sur le firing et les bursts ne sont plus présents chez les souris ß2 KO, ce qui implique que l ensemble des composés du tabac agit essentiellement sur les récepteurs nicotiniques porteurs de la chaine ß2, même si des hypothèses alternatives existent. L harmane a des effets activateurs très puissants sur le firing des neurones dopaminergiques, et ces effets sont bloqués à 80% par la mécamylamine, ce qui démontre qu un des principaux composés du tabac et de la fumée autre que la nicotine agit par un mécanisme essentiellement nicotinique. Les expériences de binding confirment que les effets du tabac et de la fumée impliquent les récepteurs nicotiniques d une façon majeure, mais d une façon qui diffère légèrement de celle de la nicotine.Les résultats que nous avons obtenus montrent que les effets pharmacologiques du tabac ne se résument pas à ceux de la seule nicotine. Ils peuvent constituer un point de départ pour d autres travaux, notamment pour étudier de plus près les effets des ß-carbolines. Il est nécessaire d identifier les types de récepteurs sur lesquels elles se fixent, en utilisant des agonistes et antagonistes de récepteurs aux neurotransmetteurs contrôlant l activité des neurones dopaminergiques. Des expériences sur des souris transgéniques chez lesquelles différents types de sous-unités de récepteurs nicotiniques ont été supprimés doivent également être envisagées, pour déterminer les mécanismes d action des composants autres que la nicotine contenus dans le tabac et sa fumée sur les neurones dopaminergiquesNicotine is generally considered as the sole tobacco addictive compound. However, nicotine replacement therapy studies almost all end with the same conclusion: the effectiveness of nicotine replacement is very limited on the short-term, and hardly exceeds that of placebo on the long-term. In addition, studies dealing with the effects of denicotinized cigarettes have provided evidence that these cigarettes have an addictive potential. In the present work, we tried to determine the behavioral role of some tobacco or smoke compounds other than nicotine at the neuronal level. We first compared the effects of nicotine with those of whole tobacco and smoke extracts, given that these preparations closer mimic the smoking situation than nicotine alone. We then examined the effects of a number of selected tobacco or smoke compounds. Cotinine, a major nicotine metabolite. Harmane and norharmane, two ß-carbolines synthesized in smoke as well as in the body of smokers. The technique used consists in the in vivo recording of the firing rate and bursts of dopamine neurons in the ventral tegmental area after intravenous injections of compounds in rats and mice. This electrophysiological technique is known to be a useful way to investigate the properties of selected compounds. In the case of mice, we used wild type and ß2 KO mice. We also made a series of in vitro experiments investigating the binding properties of the compounds on cells expressing high densities of a4ß2 nicotinic receptors. The main results of our studies are the following: Bursts are absent most of the times after the injection of the extracts. These results suggest that tobacco and smoke extracts contain compounds that inhibit the burst-promoting effects of nicotine. Increased firing is no longer present in ß2 KO mice treated with tobacco or smoke extracts, indicating that tobacco and smoke components, as a whole, primarily acts on nicotinic receptors that carry the ß2 chain, although alternative hypotheses may exist. Harmane very strongly activates the firing of dopaminergic neurons. Up to 80% of this effect is blocked by mecamylamine, demonstrating that that a major component of tobacco and smoke other than nicotine acts primarily through a nicotinic mechanism. The binding experiments confirm that the effects of tobacco and smoke involve nicotinic receptors in a major way, but in a way that slightly differs from that of nicotine. Our results may constitute a new starting point for further work, especially for a closer look at the effects of ß-carbolines. Attempts to identify the types of receptors involved in these effects are needed, using agonists and antagonists of neurotransmitter receptors that control the activity of dopamine neurons. Experiments on transgenic mice with deletion of different types of subunits of nicotinic receptors should also be made, to determine the different mechanisms of action of tobacco and smoke compounds other than nicotine on dopaminergic neuronsPARIS-EST-Université (770839901) / SudocSudocFranceF

Etude fonctionnelle des récepteurs dopaminergiques D3. Comparaison des effets comportementaux de microinjections intracérébrales de ligands dopaminergiques

CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

Étude des effets du tabac et de composants du tabac sur les neurones sérotoninergiques in vivo chez le rat

Il existe des liens entre consommation chronique de tabac et troubles anxio-dépressifs, et le tabagisme maternel augmente la fréquence des dépressions chez les enfants devenus adultes. Le système sérotoninergique (5-HT) est le système de neurotransmetteurs cérébraux le plus impliqué dans la dépression et son traitement. L'objectif de ce travail était d'étudier les effets du tabac et de ses principaux composants sur la neurotransmission 5-HT en utilisant comme modèle l'activité électrophysiologique des neurones 5-HT du noyau du raphé dorsal enregistrés in vivo sous anesthésie. Les résultats montrent que : - En aigu : la nicotine, ainsi que d'autres composants de tabac, l'harmane, la nornicotine et l'anabasine, inhibent l'activité des neurones 5-HT. L'harmane est un inhibiteur de la monoamine oxydase de type A (IMAO-A) et son effet inhibiteur ne serait pas lié à cette propriété IMAO-A, et c'est un effet différent de celui de la nicotine. Les effets de la nicotine, de la nornicotine et de l'anabasine se ressemblent, avec un mécanisme impliquant les récepteurs nicotiniques. La répétition des injections de nicotine désensibilise les neurones. Les extraits globaux du tabac et de fumée ont un effet nicotine-like mais plus intense que celui de la nicotine seule. - En chronique : la nicotine modifie de façon dos-dépendante la sensibilité des neurones 5-HT au citalopram (inhibiteur de la recapture de sérotonine), sans changement de l'activité basale de ces neurones. - En traitement prénatal : chez les rats devenus adultes, on observe une augmentation de l'activité de base des neurones 5-HT et une disparition de leur désensibilisation aux injections aiguës répétées de nicotine.Studies have shown relationships between tobacco consumption and depression. It has also been shown that offspring of smoking mothers show greater tendency towards mood alterations as adults. The serotonergic (5-HT) systems is the brain neurotransmitter system most strongly implicated in depression and its treatment. The aim of the present work was to evaluate the effects of nicotine and other major tobacco components on 5-HT neurotransmission by using an electrophysiological model : the firing of dorsal raphe nucleus 5-HT neurons captured in vivo in anaesthetised rats. The results show that : - Acute administration of : nicotine, harmane, nornicotine and anabasine inhibit the firing of 5-HT neurons. Although harmane is a monoamine oxidase-A inhibitor, its inhibiting effects on 5-HT neurons is unrelated to this fact. The effects of harmane on 5-HT neurons differ from those of nicotine. Nicotine, nornicotine and anabasine effects were similar and involve nicotinic receptors. Repeated nicotine injections desensitize neurons. Tobacco extracts and smoke extracts have a nicotine-like effect but one much more marked than the effects of nicotine alone. - Chronic nicotine administration dose-dependently afters the sensitivity of 5-HT neurons to citalopram (a selective serotonin recapture inhibitor), without modifying the basal firing of neurons. - Adult offspring of female rats pretreated with nicotine during gestation show an increase of basal firing of 5-HT neurons and an absence of desensitization of neurons during repeated acute injections of nicotine.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Prescriptions hors autorisation de mise sur le marché en psychiatrie publique hospitalière

Objectif. Analyser les prescriptions en psychiatrie publique hospitalière. Méthodes. Analyse un jour donné des prescriptions psychiatriques et somatiques pour l’indication, la posologie, la durée de traitement et le schéma thérapeutique. Interrogation individuelle des prescripteurs pour les prescriptions hors autorisation de mise sur le marché (hors-AMM). Résultats. Cinq mille quatre-vingt-six lignes de prescription relevées pour 495 patients, avec globalement 34 % de prescriptions hors-AMM (médicaments psychiatriques : 43,5 % ; médicaments somatiques : 22,7 %). Médicaments psychiatriques : 22,3 % de prescriptions hors-AMM pour l’indication, 13,1 % pour la posologie, 4,5 % pour la durée de traitement et 6,2 % pour le schéma thérapeutique (les prescriptions hors-AMM pour l’indication tombent à 12,1 % quand on enlève le clonazépam – dont les conditions de prescription ont été restreintes fin 2011). Médicaments somatiques : respectivement 4,5 %, 14,9 %, 4,8 % et 12,5 %. Conclusions. Les pourcentages se rapportant aux indications des médicaments psychiatriques sont nettement inférieurs à ceux publiés dans la littérature (les autres chiffres sont nouveaux). Certaines prescriptions hors-AMM apparaissent potentiellement justifiées au vu des données de la littérature, d’autres non

Electrophysiological characterization of harmane-induced activation of mesolimbic dopamine neurons.

International audienceIt has been suggested that the beta-carbolines harmane and norharmane may be involved in the pathophysiology of Parkinson's disease, psychosis and addiction, but the mechanisms of these possible effects remain to be elucidated. In the present study, the effects of the two compounds were examined by using in vivo extracellular recordings of ventral tegmental dopamine neurons. The effects of harmane (2mg/kg) and norharmane (2mg/kg), were compared to those of nicotine (11microg/kg), of cotinine (0.5mg/kg), of the monoamine-oxidase-A inhibitor befloxatone (0.12mg/kg), and of the monoamine-oxidase-B inhibitor selegiline (0.5mg/kg). The effects of harmane were also tested after pre-treatment with the nicotine receptor antagonist mecamylamine. The results show that all substances, except befloxatone, activate the firing and/or burst activity of dopamine neurons. The increase in firing rate produced by harmane was approximately 18 times greater than that produced by nicotine. Such powerful excitation of dopamine neurons by harmane may in part explain its involvement in neurotoxicity, psychosis and addiction. The absence of effect of befloxatone supports the hypothesis that the effect of harmane is not related to its monoamine-oxidase-A inhibitory properties. Mecamylamine inhibited by approximately 80% the activity of harmane, indicating that the activating effect of harmane on dopamine neurons involves several mechanisms, among which activation of nicotinic receptors likely has a prominent importance. The results of the present study support the hypothesis that harmane could be a tobacco (or smoke) component other than nicotine involved in tobacco dependence