Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence

Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n = 95 group A, n = 103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.

Noxious stimulation response index: a novel anesthetic state index based on hypnotic-opioid interaction

The noxious stimulation response index (NSRI) is a novel anesthetic depth index ranging between 100 and 0, computed from hypnotic and opioid effect-site concentrations using a hierarchical interaction model. The authors validated the NSRI on previously published data.

Optimizing heroin-assisted treatment (HAT): Assessment of the contribution of direct ethanol metabolites in identifying hazardous and harmful alcohol use

Heavy alcohol consumption may accelerate the progression of hepatitis C-related liver disease and/or limit efforts at antiviral treatment in opioid-dependent patients receiving heroin-assisted treatment (HAT). Our study aims to assess alcohol intake among HAT patients by self-reports compared to direct ethanol metabolites.

Strategies for evaluating the economic value of drugs in alcohol dependence treatment

To assess existing health economic strategies, which are used to evaluate the economic value of drugs to treat alcohol dependence (AD) such as acamprosate, naltrexone and any other pharmaceuticals.

Nonrandomness, nonlinear dependence, and nonstationarity of electroencephalographic recordings from epilepsy patients

To derive tests for randomness, nonlinear-independence, and stationarity, we combine surrogates with a nonlinear prediction error, a nonlinear interdependence measure, and linear variability measures, respectively. We apply these tests to intracranial electroencephalographic recordings (EEG) from patients suffering from pharmacoresistant focal-onset epilepsy. These recordings had been performed prior to and independent from our study as part of the epilepsy diagnostics. The clinical purpose of these recordings was to delineate the brain areas to be surgically removed in each individual patient in order to achieve seizure control. This allowed us to define two distinct sets of signals: One set of signals recorded from brain areas where the first ictal EEG signal changes were detected as judged by expert visual inspection ("focal signals") and one set of signals recorded from brain areas that were not involved at seizure onset ("nonfocal signals"). We find more rejections for both the randomness and the nonlinear-independence test for focal versus nonfocal signals. In contrast more rejections of the stationarity test are found for nonfocal signals. Furthermore, while for nonfocal signals the rejection of the stationarity test increases the rejection probability of the randomness and nonlinear-independence test substantially, we find a much weaker influence for the focal signals. In consequence, the contrast between the focal and nonfocal signals obtained from the randomness and nonlinear-independence test is further enhanced when we exclude signals for which the stationarity test is rejected. To study the dependence between the randomness and nonlinear-independence test we include only focal signals for which the stationarity test is not rejected. We show that the rejection of these two tests correlates across signals. The rejection of either test is, however, neither necessary nor sufficient for the rejection of the other test. Thus, our results suggest that EEG signals from epileptogenic brain areas are less random, more nonlinear-dependent, and more stationary compared to signals recorded from nonepileptogenic brain areas. We provide the data, source code, and detailed results in the public domain.

Pharmacogenomic considerations in opioid analgesia

Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration.

Acute effects of intravenous heroin on the hypothalamic-pituitary-adrenal axis response: a controlled trial

Heroin dependence is associated with a stressful environment and with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The present study examined the acute effects of intravenous heroin versus placebo on the HPA axis response in heroin-dependent patients. Twenty-eight heroin-dependent patients in heroin-assisted treatment and 20 age- and sex-matched healthy participants were included in a controlled trial in which patients were twice administered heroin or saline in a crossover design, and healthy controls were only administered saline. The HPA axis response was measured by adrenocorticotropic hormone (ACTH) levels and by cortisol levels in serum and saliva before and 20 and 60 minutes after substance administration. Craving, withdrawal, and anxiety levels were measured before and 60 minutes after substance application. Plasma concentrations of heroin and its main metabolites were assessed using high-performance liquid chromatography. Heroin administration reduces craving, withdrawal, and anxiety levels and leads to significant decreases in ACTH and cortisol concentrations (P < 0.01). After heroin administration, cortisol concentrations did not differ from healthy controls, and ACTH levels were significantly lower (P < 0.01). In contrast, when patients receive saline, all hormone levels were significantly higher in patients than in healthy controls (P < 0.01). Heroin-dependent patients showed a normalized HPA axis response compared to healthy controls when they receive their regular heroin dose. These findings indicate that regular opioid administration protects addicts from stress and underscore the clinical significance of heroin-assisted treatment for heroin-dependent patients.

Self-efficacy as a predictor of outcome after residential treatment programs for alcohol dependence: simply ask the patient one question!

Self-efficacy has been identified as one of the most consistent variables that predict the outcome of alcohol treatment. However, many previous studies in this field failed to control for other important predictors (e.g., dependences severity, psychiatric symptoms, and treatment goal). Our study's first goal was to evaluate the predictive value of self-efficacy when most other relevant variables were statistically controlled. The second goal was to compare the predictive values of self-efficacy assessed with the Situational Confidence Questionnaire (SCQ), and general self-efficacy assessed with a single question.

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 D(2) 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.

From the chiral magnetic wave to the charge dependence of elliptic flow

The quark-gluon plasma formed in heavy ion collisions contains charged chiral fermions evolving in an external magnetic field. At finite density of electric charge or baryon number (resulting either from nuclear stopping or from fluctuations), the triangle anomaly induces in the plasma the Chiral Magnetic Wave (CMW). The CMW first induces a separation of the right and left chiral charges along the magnetic field; the resulting dipolar axial charge density in turn induces the oppositely directed vector charge currents leading to an electric quadrupole moment of the quark-gluon plasma. Boosted by the strong collective flow, the electric quadrupole moment translates into the charge dependence of the elliptic flow coefficients, so that $v_2(\pi^+) < v_2(\pi^-)$ (at positive net charge). Using the latest quantitative simulations of the produced magnetic field and solving the CMW equation, we make further quantitative estimates of the produced $v_2$ splitting and its centrality dependence. We compare the results with the available experimental data.