Francina Fonseca

Prevalence of long QTc interval in methadone maintenance patients.

BACKGROUND There is a concern about cardiac rhythm disorders related to QTc interval prolongation induced by methadone. A cross-sectional study was designed to evaluate the prevalence of long QTc (LQTc) interval in patients in methadone maintenance treatment (MMT) and risk factors for LQTc. METHODS The study population included 109 subjects (74 males, median age 43 years). Socio-demographic and toxicological variables were recorded, as well as concomitant use of drugs related with QT prolongation, history of heart diseases, and corrected QT interval by heart rate (QTc) in the ECG. Plasma concentrations of (R)-methadone and (S)-methadone enantiomers were determined in 69 subjects. RESULTS Ten patients (9.2%) presented a QTc above 440 ms but a QTc above 500 ms was observed in only 2 (1.8%). Patients with QTc above 440 ms compared with the remaining subjects were older (median [25th-75th percentile range]: 49 [39-56] years vs. 37 [33-43]; Wilcoxons W=217.5, p=0.002) and took a higher daily dose of methadone (median [25th-75th percentile range]: 120 [66-228] mg/day vs. 60 [40-110] mg/day; W=298.5, p=0.037). Methadone dose correlated with QTc interval (Pearsons r(2)=0.291, p=0.002). Patients with and without long QTc showed no differences in plasma concentrations of (R)-methadone and (S)-methadone enantiomers. CONCLUSIONS The prevalence of LQTc was 9.2%. An association between LQTc and methadone doses was observed but the relationship with plasma concentrations of methadone enantiomers is unclear.

BDNF variability in opioid addicts and response to methadone treatment: preliminary findings

Brain‐derived neurotrophic factor (BDNF) signaling pathways have been shown to be essential for opioid‐induced plasticity. We conducted an exploratory study to evaluate BDNF variability in opioid addict responders and nonresponders to methadone maintenance treatment (MMT). We analyzed 21 single nucleotide polymorphisms (SNPs) across the BDNF genomic region. Responders and nonresponders were classified by means of illicit opioid consumption detected in random urinalysis. Patients were assessed by a structured interview (Psychiatric Research Interview for Substance and Mental Disorders (PRISM)‐DSM‐IV) and personality was evaluated by the Cloninger’s Temperament and Character Inventory. No clinical, environmental and treatment characteristics were different between the groups, except for the Cooperativeness dimension (P < 0.001). Haplotype block analysis showed a low‐frequency (2.7%) haplotype (13 SNPs) in block 1, which was more frequent in the nonresponder group than in the responder group (4/42 vs. 1/135; Pcorrected = 0.023). Fine mapping in block 1 allows us to identify a haplotype subset formed by only six SNPs (rs7127507, rs1967554, rs11030118, rs988748, rs2030324 and rs11030119) associated with differential response to MMT (global P sim = 0.011). Carriers of the CCGCCG haplotype had an increased risk of poorer response, even after adjusting for Cooperativeness score (OR = 20.25 95% CI 1.46–280.50, P = 0.025). These preliminary results might suggest the involvement of BDNF as a factor to be taken into account in the response to MMT independently of personality traits, environmental cues, methadone dosage and psychiatric comorbidity.

Methadone maintenance treatment in Spain: the success of a harm reduction approach

PROBLEM During the 1980s, Spain had very strict laws limiting access to opioid agonist maintenance treatment (OAMT). Because of this, mortality among people who used illicit opioids and other illicit drugs was high. Spain was also the European country with the highest number of cases of acquired immunodeficiency syndrome transmitted through illicit drug injection. APPROACH The rapid spread of human immunodeficiency virus (HIV) infection among people using heroin led to a shift from a drug-free approach to the treatment of opioid dependence to one focused on harm reduction. A substantial change in legislation made it possible to meet public health needs and offer OAMT as part of harm reduction programmes in the public health system, including prisons. LOCAL SETTING Legislative changes were made throughout the country, although at a different pace in different regions. RELEVANT CHANGES Legal changes facilitated the expansion of OAMT, which has achieved a coverage of 60%. A parallel reduction in the annual incidence of HIV infection has been reported. Reductions in morbidity and mortality and improved health-related quality of life have been described in patients undergoing OAMT. LESSONS LEARNT The treatment of opioid dependence has been more heavily influenced by moral concepts and prejudices that hinder legislation and interfere with the implementation of OAMT than by scientific evidence. To fulfil public health needs, OAMT should be integrated in harm reduction programmes offered primarily in public facilities, including prisons. Longitudinal studies are needed to detect unmet needs and evaluate programme impact and suitability.

Functional alteration in frontolimbic systems relevant to moral judgment in cocaine-dependent subjects

Cocaine addiction is characterized by persistent decision‐making deficits, which are linked to structural and functional abnormalities in frontolimbic systems. Moral judgment is as a special instance of decision making, in which both cognitive and emotional signals must be adequately integrated to decide how to resolve moral dilemmas. Here, we employed a moral dilemmas functional magnetic resonance imaging (fMRI) task to explore possible alterations of frontolimbic systems in cocaine‐dependent subjects. We also explored if these alterations relate to more basic deficits in functional connectivity within these systems during spontaneous resting‐state activation. Ten cocaine‐dependent subjects and 14 non‐drug‐using controls participated in the study. Cocaine‐dependent subjects were carefully selected to discard potentially confounding co‐morbidities, and they underwent a uniform supervised abstinence period of 10 days. Both groups were scanned, and fMRI maps were generated to identify (1) brain response to moral dilemmas; and (2) the strength of functional connectivity within frontolimbic systems during resting‐state. During the moral dilemmas task, cocaine‐dependent subjects showed reduced activation involving frontolimbic structures as the anterior cingulate cortex (ACC), left insula and brain stem. Connectivity analyses showed that cocaine users had less resting‐state functional connectivity between ACC, thalamus, insula and brain stem. These results demonstrate that cocaine‐dependent subjects have functional alterations in the frontolimbic systems that support moral judgment and social decision making.

Response to Methadone Maintenance Treatment is Associated with the MYOCD and GRM6 Genes

AbstractBackground: There is increasing interest in the pharmacogenetic basis for explaining differences between patients in treatment outcome among methadone-treated subjects. Most studies have focused on genetic polymorphisms related to methadone pharmacokinetics and, to a lesser extent, those genes implicated in the pharmacodynamics of methadone. Objective: This study aimed to investigate the associations between response to methadone maintenance treatment (MMT) and polymorphisms in genes coding for the OPRM1 opioid receptor, the metabotropic glutamate receptors GRM6 and GRM8, the nuclear receptor NR4A2, the photolyase enzyme cryptochrome 1 (CRY1), and the transcription factor myocardin (MYOCD), which have previously been associated with the risk of opioid dependence disorder. Methods: The study used an association, case-control design, conducted in the setting of an MMT program in a drug abuse outpatient center in Barcelona, Spain. We recruited 169 opioid-dependent patients (diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders [4th Edition] criteria) receiving MMT. The inclusion criteria included Caucasian ethnicity, being enrolled in MMT for at least 6 months, and receiving a stable methadone dose for the previous 2 months. The exclusion criteria included language-related barriers, severe cognitive impairment, or any medical disorder that would interfere with the research assessments.Single nucleotide polymorphism (SNP) variants in several candidate genes and regions were genotyped: MYOCD (rs1714984), GRM8 (rs1034576), CRY1 (rs1861591), GRM6 (rs953741), OPRM1 (rs1074287), NR4A2 (rs1405735), and the intergenic variants rs965972 (1q31.2) and rs1867898 (2q21.2).MMT response status was assessed by the number of opioid-positive controls detected by random urinalysis in the previous 2 months. We used the chi-squared test and p-value for the allele frequencies of the eight SNPs in responders versus nonresponders, and multivariate logistic regression analyses to examine associations between genotypes in the responder and ronresponder groups under codominant, dominant, and recessive models of inheritance. Results: A final sample of 116 opioid-dependent patients were included and classified as methadone responders (n = 83) and nonresponders (n = 33), according to illicit opioid use detection in random urinalysis. The responders and nonresponders showed similar demographic and clinical characteristics. All SNPs were in Hardy-Weinberg equilibrium. Subjects carrying the AA genotype at rs1861591 CRY1; Chr 12: 105941056 G>A) had a higher risk of being nonresponders (odds ratio [OR] = 2.99; 95% CI 1.14, 7.85; = 0.035), although this difference disappeared with multiple testing corrections. Patients carrying the A allele at rs1714984 MYOCD; Chr 17: 12558425 G>A) had an increased risk of being nonresponders only if they were also carriers of the AG genotype at rs953741 GRM6; Chr5: 178262451 A>G) [OR= 10.83; 95% CI 2.52, 46.66; p = 0.006]. Conclusions: A positive association was observed between response to methadone and two variants in the genes MYOCD and GRM6. A pharmacogenetic epistatic effect between SNPs in MYOCD and GRM6 appears to modulate inter-individual variations in MMT response.

Human Pharmacology of Mephedrone in Comparison with MDMA.

Mephedrone (4-methylmethcathinone) is a novel psychoactive substance popular among drug users because it displays similar effects to MDMA (3,4-methylenedioxymethamphetamine, ecstasy). Mephedrone consumption has been associated with undesirable effects and fatal intoxications. At present, there is no research available on its pharmacological effects in humans under controlled and experimental administration. This study aims to evaluate the clinical pharmacology of mephedrone and its relative abuse liability compared with MDMA. Twelve male volunteers participated in a randomized, double-blind, crossover, and placebo-controlled trial. The single oral dose conditions were: mephedrone 200 mg, MDMA 100 mg, and placebo. Outcome variables included physiological, subjective, and psychomotor effects, and pharmacokinetic parameters. The protocol was registered in ClinicalTrials.gov (NCT02232789). Mephedrone produced a significant increase in systolic and diastolic blood pressure, heart rate, and pupillary diameter. It elicited stimulant-like effects, euphoria, and well-being, and induced mild changes in perceptions with similar ratings to those observed after MDMA administration although effects peaked earlier and were shorter in duration. Maximal plasma concentration values for mephedrone and MDMA peaked at 1.25 h and 2.00 h, respectively. The elimination half-life for mephedrone was 2.15 h and 7.89 h for MDMA. In a similar manner to MDMA, mephedrone exhibits high abuse liability. Its earlier onset and shorter duration of effects, probably related to its short elimination half-life, could explain a more compulsive pattern of use as described by the users.

Anticonvulsant drugs in cocaine dependence: A systematic review and meta-analysis

A systematic review and meta-analysis according to the methodology developed by the Cochrane Collaboration and the Quality of Reporting of Meta-Analyses statement based on randomized controlled trials to evaluate the efficacy of anticonvulsants in subjects with cocaine dependence were performed. Fifteen randomized, double-blind, placebo-controlled clinical trials involving 1,236 patients were included. Two outcome measures were evaluated: retention in the anticonvulsant treatment (compared to the placebo treatment) and the subsequent cocaine use, measured by urinalysis results. The efficacy of the seven anticonvulsant drugs analyzed was not homogenous. On average, 50% of the enrolled participants were lost to follow-up. Treatments did not show an improvement in subject retention compared to placebo. Overall, the number of cocaine-positive urine samples was close to statistical significance (95% confidence interval = 0.85-1.06) compared to placebo. Available clinical trials indicate that there is insufficient evidence to justify the use of anticonvulsant drugs in treating cocaine dependence.

Risk of QTc prolongation in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy

BACKGROUND Concern regarding the QTc interval in human immunodeficiency virus (HIV)-infected patients has been growing in recent years, and cases of prolonged QTc interval and torsades de pointes have been described in HIV-infected patients on methadone therapy. This study aimed to determine the prevalence and factors associated with long QTc interval in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy. METHODS A cross-sectional study was conducted in opioid-dependent HIV-infected patients on methadone maintenance therapy at a drug abuse outpatient center. Patients with any cardiac disease, drug-positive urine test, electrolyte abnormalities, and changes in their antiretroviral therapy (ART) or methadone doses in the last 2 months were excluded. Heart rate and QT interval in lead II were measured using the Bazett formula. RESULTS Ninety-one patients were included: 58 (63.7%) were men with a median age of 44.5 years and 68 of 91 (74.7%) were on ART. Median methadone dose was 70 mg/day (range 15-250 mg/day) and mean QTc interval was 438 ± 34 ms. Prolonged QTc interval (>450 ms) was documented in 33 of 91(36.3%) patients, and 3 of 91 (3.2%) had QTc >500 ms. On multiple linear regression analysis, methadone doses (P = .005), chronic hepatitis C-induced cirrhosis (P = .008), and being ART-naive (P = .036) were predictive of prolonged QTc. CONCLUSIONS The prevalence of prolonged QTc interval in opioid-dependent HIV-infected patients on methadone maintenance therapy is high. Risk factors for prolongation of the QTc interval are chronic hepatitis C-induced cirrhosis, higher methadone doses, and being ART-naive. Thus, electrocardiographic monitoring is required to minimize cardiovascular morbidity and mortality in this specific HIV group.

ALDH5A1 variability in opioid dependent patients could influence response to methadone treatment

Methadone maintenance treatment is the most widely-used therapy in opioid dependence, but some patients relapse or drop out from treatment. We genotyped a genetic variant in the succinic semialdehyde dehydrogenase enzyme gene, ALDH5A1, and found that subjects carrying the T variant allele have a higher risk to be nonresponders to methadone treatment (OR=3.16; 95% CI [1.48-6.73], P=0.0024). This could be due to a reduction in the ALDH5A1 enzyme activity, that would increase endogenous gamma-hydroxbutyric acid (GHB) and gamma-aminobutyric acid (GABA) levels and therefore, inducing symptoms such as sedation and impaired pschomotor performance. These neuropsychological effects related with the reduction in enzyme activity could be responsible for a higher propensity to relapse in these genetically predisposed patients.

Something New about Something Old: A 10-Year Follow-Up on Classical and New Psychoactive Tryptamines and Results of Analysis

ABSTRACT New psychoactive tryptamines may be a public health risk since they intend to mimic the hallucinogenic effects of regulated psychoactive drugs. Few studies describe uses and clinical effects of unregulated new psychoactive tryptamines. This study aims (1) to explore the presence of tryptamines classified as NPS among the substances delivered for analysis to a harm-reduction organization; (2) to describe the substances found in the samples after analysis; and (3) to compare analytical results of regulated vs. non-regulated tryptamines. Samples delivered and analyzed by gas chromatography-mass spectrometry from 2006 to 2015 were included. A descriptive study of results was conducted. From 25,296 samples that were delivered, 436 were tryptamines; from these 232 (53.21%) were non-regulated. The most delivered non-regulated tryptamine was 4-AcO-DMT. A search of the PubMed database in July 2016 revealed that no studies in humans have ever been carried out with 4-AcO-DMT. Unregulated tryptamines likely contained one unadulterated substance (p ≤ 0.001). The number of samples submitted which contained tryptamines increased during the course of the study, with significant differences in client expectations vs. analysis results between the controlled and uncontrolled groups. There is a need for further research in order to prevent the potential health risks associated with their use.