Jacques Besson

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.

The in vivo implication of various cytochrome P450 (CYP) isoforms and of P‐glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment.

Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment

Recent in vitro studies have suggested an important role of cytochrome P450 (CYP) 2B6 and CYP2C19 in methadone metabolism. We aimed to determine the influence of CYP2B6, CYP2C9, and CYP2C19 genetic polymorphism on methadone pharmacokinetics and on the response to treatment.

Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers

Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)‐methadone. Whole‐cell patch‐clamp experiments using cells expressing hERG showed that (S)‐methadone blocked the hERG current 3.5‐fold more potently than (R)‐methadone (IC50s (half‐maximal inhibitory concentrations) at 37°C: 2 and 7 μM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)‐methadone, electrocardiograms, CYP2B6 genotypes, and (R)‐ and (S)‐methadone plasma concentrations were obtained for 179 patients receiving (R,S)‐methadone. The mean heart‐rate‐corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439±25 ms; n=11) than in extensive metabolizers (non *6/*6; 421±25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2–17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)‐methadone.

Association of dopamine and opioid receptor genetic polymorphisms with response to methadone maintenance treatment

BACKGROUND Genetic variations of the dopamine and opioid receptors could influence the response to methadone maintenance treatment (MMT). METHODS We included 238 MMT patients according to their response to treatment and methadone dosing, along with 217 subjects without substance dependence. All were genotyped for polymorphisms of the dopamine D1, D2, micro-opioid and delta-opioid receptor genes. RESULTS The polymorphisms of the micro-opioid (118A>G), delta-opioid (921T>C), dopamine D1 (DdeI) and D2 (TaqI A) receptor genes were not associated with response to MMT and methadone dosing, whereas an association was found with the dopamine D2 receptor (DRD2) 957C>T polymorphism. The 957CC carriers were more frequently non-responders to treatment (OR=2.4; p=0.02) and presented a fourfold shorter period of negative urine screening (p=0.02). No significant differences in allele frequencies were observed between the MMT patients and the control group, suggesting no association of the analyzed polymorphisms with opioid dependence. CONCLUSIONS These results suggest that DRD2 genotype may contribute to the understanding of the interindividual variability to the response to MMT.

A French Translation of the Obsessive-Compulsive Drinking Scale for Craving in Alcohol-Dependent Patients: A Validation Study in Belgium, France, and Switzerland

The Obsessive-Compulsive Drinking Scale (OCDS) is an instrument developed to measure cognitive aspects of alcohol craving. The aim of this study was to validate the French translation of the OCDS according to the international methodology as published by Hunt and coworkers (see text), including forward-backward translations, patient interviews (9 patients), patient’s perception of acceptability (15 patients), and final validation within a treatment program (50 patients). All 74 patients were native French-speaking alcohol-dependent patients from Belgium, France, and Switzerland. The derived aggregated total (TOT) score and both subscores corresponding to the obsessive (OB) and compulsive (CP) dimensions were shown to be asymptomatically normal. Good internal consistencies were found, with Cronbach α: TOT = 0.88; OB = 0.82; CP = 0.79. The test-retest procedure was used to examine intrarater reliability (r = 0.81). The construct validity was examined with linear correlation of the two main components: r(OB, CP) = 0.62; r(OB, TOT) = 0.86; r(CP, TOT) = 0.92. Principal-components analysis revealed two main factors: the first factor representing the total scale score, while the obsessive and compulsive subscale scores were distributed along factor two. The translated scale seems to be psychometrically as valid as the original English scale and confirms the psychometric properties of the OCDS.

Stage of Change of Cigarette Smoking in Alcohol-Dependent Patients

Despite the heavy burden of tobacco-related problems in alcohol-dependent patients, little effort has been directed toward reducing the prevalence of smoking in these patients. It seems reasonable to develop nicotine addiction treatments for alcohol-dependent patients based on the smoker’s stage of change. To assess the stage of change for tobacco consumption and possible quitting barriers in alcohol-dependent patients, 88 consecutively admitted inpatients of a Swiss university-affiliated alcohol withdrawal clinic were interviewed with a semistructured schedule. More than half of the alcohol-dependent smokers (50.7%) considered the possibility of smoking cessation or had already decided to stop, although the majority (83.1%) were highly dependent smokers. Positive reinforcers were factors influencing motivation both to stop smoking as well as to continue smoking, whereas negative reinforcers had no influence. As recovering alcoholic patients are often interested in smoking cessation and the introduction of nicotine treatment interventions has been shown not to jeopardize the outcome of alcohol treatment, alcohol treatment programs should include counseling for smoking cessation. Education and training for staff is essential, as their beliefs and habits remain an important barrier.

Topiramate in opiate withdrawal.

The alpha2-adrenergic agonist clonidine is the mainly used drug for the opiate withdrawal. Its efficacy and tolerance in treating withdrawal symptoms is, however, suboptimal. The pharmacological profile of topiramate suggests it could be rather valuable for opiate withdrawal, as there is some evidence that topiramate acts, among others, through inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, which play an important role in the withdrawal-induced activation of the locus coeruleus (LC) by glutamate. Three patients undergoing an inpatient opiate detoxification program were treated with topiramate, which achieved a nearly complete control of withdrawal symptoms.

Motivational Intervention to Reduce Cannabis Use in Young People with Psychosis: A Randomized Controlled Trial

Background: Cannabis use has a negative impact on psychosis. Studies are needed to explore the efficacy of psychological interventions to reduce cannabis use in psychosis. Our aim is to study the efficacy of a specific motivational intervention on young cannabis users suffering from psychosis. Methods: Participants (aged less than 35 years) were randomly assigned to treatment as usual (TAU) alone, or treatment as usual plus motivational intervention (MI + TAU). TAU was comprehensive and included case management, early intervention and mobile team when needed. Assessments were completed at baseline and at 3, 6 and12 months follow-up. Results: Sixty-two participants (32 TAU and 30 MI + TAU) were included in the study. Cannabis use decreased in both groups at follow-up. Participants who received MI in addition to TAU displayed both a greater reduction in number of joints smoked per week and greater confidence to change cannabis use at 3 and 6 months follow-up, but differences between groups were nonsignificant at 12 months. Conclusions: MI is well accepted by patients suffering from psychosis and has a short-term impact on cannabis use when added to standard care. However, the differential effect was not maintained at 1-year follow-up. MI appears to be a useful active component to reduce cannabis use which should be integrated in routine clinical practice.

β-Arrestin2 influences the response to methadone in opioid-dependent patients

β-Arrestin2 (ARRB2) is a component of the G-protein-coupled receptor complex and is involved in μ-opioid and dopamine D2 receptor signaling, two central processes in methadone signal transduction. We analyzed 238 patients in methadone maintenance treatment (MMT) and identified a haplotype block (rs34230287, rs3786047, rs1045280 and rs2036657) spanning almost the entire ARRB2 locus. Although none of these single nucleotide polymorphisms (SNPs) leads to a change in amino-acid sequence, we found that for all the SNPs analyzed, with exception of rs34230287, homozygosity for the variant allele confers a nonresponding phenotype (n=73; rs1045280C and rs2036657G: OR=3.1, 95% CI=1.5–6.3, P=0.004; rs3786047A: OR=2.5, 95% CI=1.2–5.1, P=0.02) also illustrated by a 12-fold shorter period of negative urine screening (P=0.01). The ARRB2 genotype may thus contribute to the interindividual variability in the response to MMT and help to predict response to treatment.

No Influence of ABCB1 Haplotypes on Methadone Dosage Requirement

processed EEG as a pharmacodynamic end point of opioid sedation because these indices are very insensitive to the clinical sedation produced by opioids and correlate poorly with opioid plasma concentration. In fact, in order to produce a bispectral index of 50, the remifentanil effect site concentration must be 38.02+2.57 ng/ml, equivalent to a fentanyl effect site concentration of 15.8 ng/ml. This high effect site concentration of fentanyl can be achieved with a 16 mg/kg fentanyl bolus—well above the usual dose for spontaneously ventilating volunteers. As the clinical pharmacology community embraces the use of processed EEG as a pharmacodynamic end point to explore the factors that alter pharmacodynamic responses, it is important to choose a metric that is responsive to the drug of interest in the concentration range being studied. Therefore, I would advocate that the bispectral index and other processed EEG indices be utilized to study the pharmacodynamics of only sedative/ hypnotic drugs. To investigate the phenomena of opioid-induced sedation, we should advocate the use of clinical sedation scales, such as the modified Observer’s Assessment of Alertness/Sedation. By choosing the correct pharmacodynamic measurement, we investigators can avoid type II errors that come about from choosing an insensitive pharmacometric. This will allow future investigations to clearly define the genetic factors associated with altered pharmacodynamic sensitivity and improve safe administration of these potent drugs.