Second meeting of the French CEIP (Centres d'Evaluation et d'Information sur la Pharmacodépendance). Part I: how to evaluate and prevent the abuse and dependence on hypnotic/anxiolytic drugs?

The second meeting of the French CEIP (Centres d'Evaluation et d'Information sur la Pharmacodépendance) was organized during the annual congress of the French Society of Pharmacology Therapeutics and Physiology in 2008. The aim of this meeting was to update the knowledge on abuse and dependence of the anxiolytics and hypnotics from different points of view (pharmacoepidemiology, epidemiology and treatment). The first part of this meeting summarized the pharmacological data obtained by the pharmacoepidemiological tools developed by the CEIP network. Even if the abuse liability of these agents is not a new problem, it remains always present and characterized by differences of misuse between drugs in real-life settings. The second part targeted to a subtype of consumers, the elderly population, because older patients are more likely to be prescribed with multiple prescriptions and also more at risk for prescription abuse. Despite this evidence, there is a scarcity of information on the factors associated with a such behaviour and its screening, assessment, diagnosis and treatment.

Dopaminergic modulation of amygdala activity during emotion recognition in patients with Parkinson disease.

Variable findings have been reported for emotional processing in patients with Parkinson disease (PD). These contradictions could be due to differences in the progression of dopamine (DA) depletion. Levodopa treatment could have either beneficial or detrimental effects on brain functions modulated by DA according to disease progression. In healthy subjects, levodopa administration leads to a decreased amygdala activation in response to emotional tasks. Because it is known that there is a link between DA loss in mesolimbic system and depression, we hypothesized that PD patients without depression would have spared limbic DA projections. Consequently, levodopa medication could overdose limbic regions relative to severe dorsal striatal denervation. To evaluate the effect of levodopa on amygdala activation, we conducted a functional magnetic resonance imaging study in nondemented, nondepressed PD patients compared with healthy volunteers. Patients with PD and healthy subjects received either levodopa or placebo in 2 functional magnetic resonance imaging sessions. Amygdala activation was evaluated during a facial emotion recognition task. A similar right-amygdala activity was seen in both healthy subjects and PD patients in the placebo session. After levodopa administration, activity was reduced in both groups. In the patients, the levodopa dose used significantly improved motor dysfunction. Nondemented, nondepressed PD patients thus seem to have relatively preserved DA mesolimbic projections, and consequently, the same dose of levodopa needed to correct the lack of DA in the severely depleted putamen (motor part of striatum) would incidentally overdose the mesolimbic projections toward the amygdala.

Comparison of chronic analgesic drugs prevalence in Parkinson's disease, other chronic diseases and the general population.

Patients with Parkinson's disease (PD) frequently experienced pain. Nevertheless, there are no epidemiological data about frequency of pain in PD. We compare pain prevalence using analgesic prescription in PD patients, in the general population and in two samples of painful patients: diabetics and osteoarthritis patients in France. Data were obtained from the French System of Health Insurance for the year 2005. Medications (antiparkinsonian, antidiabetics drugs and osteoarthritis drugs) were used for identification of PD, diabetic and osteoarthritis patients. We estimated the prevalence of analgesic drugs prescription (at least one analgesic drug) and the prevalence of chronic analgesic drugs prescription (more than 90 DDD of analgesic drug). The study included 11,466 PD patients. PD patients significantly received more prescription of analgesics than the general population (82% versus 77%,) and fewer than patients with osteoarthritis (82% versus 90%). No significant difference was found between PD and diabetic patients. The chronic prescription of analgesic drugs was more prevalent in PD patients (33%) than in the general population (20%) and in diabetic patients (26%) and similar to that in osteoarthritis patients. PD patients were more exposed than the general population and diabetics to opiates, acetaminophen, and adjuvant analgesics chronic use.

Second Meeting of the French CEIP (Centres d'Évaluation et d'Information sur la Pharmacodépendance). Part I: How to Evaluate and Prevent the Abuse and Dependence on Hypnotic/Anxiolytic Drugs?

Les deuxièmes journées de Pharmacodépendances organisées par le réseau français des CEIP Addictovigilance (Centres d'Évaluation et d'Information sur la Pharmacodépendance) se sont tenues lors du congrès annuel de la Société Française de Pharmacologie et de Thérapeutique en 2008. Elles avaient pour thème l'abus et la pharmacodépendance des anxiolytiques et hypnotiques en combinant plusieurs approches pharmacoépidémiologiques, épidémiologiques et thérapeutiques. Les données présentées en première partie ont synthétisé l'apport des outils pharmacoépidémiologiques développés par les CEIP et ont souligné les différences en terme d'abus et de dépendance au sein de cette classe des anxiolytiques et hypnotiques. La deuxième partie a porté sur les caractéristiques de cette consommation a sein de la population âgée et a souligné le peu d'informations disponibles sur les facteurs associés à ce comportement, son dépistage, son évaluation, son diagnostic et son traitement.

Amygdala activation modulated by levodopa during emotional recognition processing in healthy volunteers: a double-blind, placebo-controlled study.

A critical role of dopaminergic systems in emotional processing has been revealed by several animal and clinical studies in Parkinson disease and schizophrenia. We conducted a study with functional magnetic resonance imaging (fMRI) in 13 healthy volunteers to test the dopaminergic modulation on amygdala response to emotional processing and to evaluate if it was the result of a direct action on amygdalar nuclei or indirect modulation via medial prefrontal cortex projecting on amygdala.A placebo-controlled crossover experimental design was used. Subjects received either levodopa (100 mg) or placebo in 2 fMRI sessions. Amygdala activation was evaluated during a facial emotion recognition test.The statistical comparison between placebo versus levodopa situations revealed a significant reduction in activation of right amygdala during the levodopa fMRI session. The functional connectivity analysis revealed only a change of correlated activations between right and left amygdala, and not medial prefrontal cortex, after levodopa administration. Our results suggest that administration of levodopa to healthy volunteers impairs the amygdalar activation. It supports the hypothesis that amygdala activation follows an inverted U-shaped curve in relation to dopamine (DA) concentration. The results of the functional connectivity seem to suggest a dopaminergic action on amygdalar nuclei rather than a modulation of medial prefrontal cortex on amygdala.

Effect of levodopa on healthy volunteers' facial emotion perception: an FMRI study.

OBJECTIVE: A link between the brain dopaminergic (DA) system and emotional processing seems to be supported by the DA nature of neural systems surrounding emotional recognition, the occurrence of emotional deficits in medical disorders involving a DA dysfunction, and the effect of DA agonists or antagonists on emotional processing. The authors tested the influence of levodopa administration on emotional processing in a functional MRI (fMRI) study of 10 elderly volunteers. METHODS: A placebo-controlled, cross-over experimental design was used. Subjects received either levodopa (100 mg) or placebo in 2 fMRI sessions. Performance was evaluated with a passive facial emotion perception test. RESULTS: During the placebo situation, the region-of-interest (ROI) analysis showed that emotional processing activated the bilateral amygdala. In levodopa volunteers, this activation was missing. The statistical comparison between the 2 situations (emotional vs control condition) revealed a highly significant reduction in activation of the bilateral amygdala for the levodopa fMRI session (P corrected <0.0001 in the left and P = 0.002 in the right amygdala). CONCLUSION: These results suggest that administration of levodopa to healthy volunteers directly or indirectly impairs the amygdalar activation during the emotional perception task. The authors hypothesized that amygdala activation may conform to an inverted U-shaped function in relation to changing dopamine levels.

An electromyographic analysis of the effect of levodopa on the response time of healthy subjects.

RATIONALE: Recently, we have shown that oral absorption of levodopa shortens reaction time (RT), measured as the interval between the response signal and the onset of voluntary electromyographic (EMG) activity. The motor time (MT) interval that elapses from the EMG activity to the mechanical response was not analysed. OBJECTIVE: The purpose of the present study was to analyse the effect of the dose of levodopa administrated in our previous study on the MT. Eight healthy adults (aged 21-28, mean=25), performed a two-choice visual RT task after oral absorption of a single dose of levodopa (200 mg) or a placebo (randomized, double-blind, cross-over design). RESULTS: Like RT, MT was shorter under levodopa than under placebo. Statistical analyses demonstrated that this effect was present for all deciles of the RT and MT distributions. CONCLUSION: Levodopa shortens not only RT but also MT, which points at the implication of the dopaminergic system in both premotor and motor processes.

Dopamine and human information processing: a reaction-time analysis of the effect of levodopa in healthy subjects.

RATIONALE: Dopamine is involved in a variety of motor and non-motor information-processing operations. One way to determine its contribution to human information processing is to study reaction time (RT) performance after oral absorption of its precursor, levodopa, which increases its concentration in the nervous system. OBJECTIVE: The purpose of the present study was to investigate the effect of a single dose of levodopa on information processing in healthy human subjects using the additive-factor method. After oral absorption of a single dose of levodopa (200 mg) or a placebo (randomized, double-blind, cross-over design), eight adults (aged 21-28 years, mean 25 years) performed a two-choice visual RT task. Signal intensity, stimulus-response mapping and foreperiod duration were manipulated. RESULTS: The effects of these three variables were found additive on RT, indicating that that three independent stages - namely, stimulus preprocessing, response selection and motor adjustment - were manipulated. Levodopa improved RT performance in a specific way: it interacted with signal intensity but its effect was additive with those of stimulus-response mapping and foreperiod duration. CONCLUSION: These results show that levodopa specifically affects the stimulus preprocessing stage, which suggests that the dopaminergic system plays a role in sensory processing, possibly by acting on the level of arousal.