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.

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

BACKGROUND AND OBJECTIVE: 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. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

Psychobiological responses to drug cues before and after methadone intake in heroin-dependent patients: A pilot study

Craving and stress frequently drive compulsive heroin use. Although methadone attenuates craving, drug-conditioned stimuli can trigger craving and possibly stress arousal in heroin-dependent patients receiving methadone maintenance. This study investigated drug cue-related craving, affectivity, and cortisol reactivity in 16 methadone-maintained patients before and after daily methadone. Unexpectedly, drug cues significantly increased craving after (t[15]=-4.27, p=0.001), but not before methadone intake. Patients displayed blunted cortisol response after post-methadone drug cues (t[15]=3.05, p=0.008) suggesting dissociated craving and cortisol reactivity after methadone intake of possible clinical relevance.

Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers

Steady-state blood concentrations of (R)- methadone (i.e., the active form), (S)-methadone, and (R,S)-methadone were measured before and after introduction of paroxetine 20 mg/day during a mean period of 12 days in 10 addict patients in methadone maintenance treatment. Eight patients were genotyped as CYP2D6 homozygous extensive metabolizers (EMs) and two patients as poor metabolizers (PMs). Paroxetine significantly increased concentrations of both enantiomers of methadone in the whole group (mean increase for (R)-methadone +/- SD, 26 +/- 32%; range, -14% to +83%, p = 0.032; for (S)-methadone, 49 +/- 51%; range, -29% to +137%, p = 0.028; for (R,S)-methadone, 35 +/- 41%; range, -20% to +112%, p = 0.032) and in the group of eight EMs (mean increase, 32%, p = 0.036; 53%, p = 0.028; and 42%, p = 0.036, for (R)-methadone, (S)-methadone, and (R,S)-methadone, respectively). On the other hand, in the two PMs, (S)-methadone but not (R)-methadone concentrations were increased by paroxetine (mean increases of 36% and 3%, respectively). Paroxetine is a strong CYP2D6 inhibitor, and these results confirm previous studies showing an involvement of CYP2D6 in methadone metabolism with a stereoselectivity toward the (R)-enantiomer. Because paroxetine is a mild inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, increase of (S)-methadone concentrations in both EMs and PMs could be mediated by inhibition of any of these isozymes.

Opioid maintenance therapy in Switzerland: an overview of the Swiss IMPROVE study

BACKGROUND/AIMS: Switzerland’s drug policy model has always been unique and progressive, but there is a Need to reassess this system in a rapidly changing world. The IMPROVE study was conducted to gain understanding of the attitudes and beliefs towards opioid maintenance therapy (OMT) in Switzerland with regards to quality and Access to treatment. To obtain a “real-world” view on OMT, the study approached its goals from two different angles: from the perspectives of the OMT patients and of the physicians who treat patients with maintenance therapy. The IMPROVE study collected a large body of data on OMT in Switzerland. This paper presents a small subset of the dataset, focusing on the research design and methodology, the profile of the participants and the responses to several key questions addressed by the questionnaires. METHODS: IMPROVE was an observational, questionnaire-based cross-sectional study on OMT conducted in Switzerland. Respondents consisted of OMT patients and treating physicians from various regions of the country. Data were collected using questionnaires in German and French. Physicians were interviewed by phone with a computer-based questionnaire. Patients self-completed a paper-based questionnaire at the physicians’ Offices or OMT treatment centres. RESULTS: A total of 200 physicians and 207 patients participated in the study. Liquid methadone and methadone tablets or capsules were the medications most commonly prescribed by physicians (60% and 20% of patient load, respectively) whereas buprenorphine use was less frequent. Patients (88%) and physicians (83%) were generally satisfied with the OMT currently offered. The current political framework and lack of training or information were cited as determining factors that deter physicians from engaging in OMT. About 31% of OMT physicians interviewed were ≥60 years old, indicating an ageing population. Diversion and misuse were considered a significant problem in Switzerland by 45% of the physicians. CONCLUSION: The subset of IMPROVE data presented gives a present-day, real-life overview of the OMT landscape in Switzerland. It represents a valuable resource for policy makers, key opinion leaders and drug addiction researchers and will be a useful basis for improving the current Swiss OMT model.

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.

Mandibular implant overdentures followed for over 10 years: patient compliance and prosthetic maintenance

PURPOSE: The mandibular implant overdenture is a popular treatment modality and is well documented in the literature. Follow-up studies with a long observation period are difficult to perform due to the increasing age of patients. The present data summarize a long-term clinical observation of patients with implant overdentures. MATERIALS AND METHODS: Between 1984 and 1997, edentulous patients were consecutively admitted for treatment with an implant overdenture. The dentures were connected to the implants by means of bars or ball anchors. Regular maintenance was provided with at least one or two scheduled visits per year. Recall attendance and reasons for dropout were analyzed based on the specific history of the patient. Denture maintenance service, relining, repair, and fabrication of new dentures were identified, and complications with the retention devices specified separately. RESULTS: In the time period from 1984 to 2008, 147 patients with a total of 314 implants had completed a follow-up period of >10 years. One hundred one patients were still available in 2008, while 46 patients were not reexamined for various reasons. Compliance was high, with a regular recall attendance of >90%. More than 80% of dentures remained in continuous service. Although major prosthetic maintenance was rather low in relation to the long observation period, visits to a dental hygienist and dentist resulted in an annual visit rate of 1.5 and 2.4, respectively. If new dentures became necessary, these were made in student courses, which increased the treatment time and number of appointments needed. Complications with the retention devices consisted mostly of the mounting of new female retainers, the repair of bars, and the changing of ball anchors. The average number of events and the rate of prosthetic service with ball anchors were significantly higher than those with bars. Twenty-two patients changed from ball anchors to bars; 9 patients switched from a clip bar to a rigid U-shaped bar. CONCLUSIONS: This long-term follow-up study demonstrates that implant overdentures are a favorable solution for edentulous patients with regular maintenance. In spite of specific circumstances in an aging population, it is possible to provide long-term care, resulting in a good prognosis and low risk for this treatment modality. For various reasons the dropout rate can be considerable in elderly patients and prosthetic service must be provided regularly.

Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma

Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma.

EEG correlation and power during maintenance of wakefulness test after sleep-deprivation

To investigate whether there are any objective EEG characteristics that change significantly between specific time periods during maintenance of wakefulness test (MWT) and whether such changes are associated with the ability to appropriately communicate sleepiness.

Maintenance of implant-supported maxillary prostheses: a 2-year controlled clinical trial

To analyze maintenance service of fixed maxillary prostheses and overdentures based on conventional gold bars or titanium bars and frameworks fabricated with computer-aided design/computer-assisted manufacture (CAD/CAM) technology.

Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis

BACKROUND ; AIMS: Topical corticosteroids are effective in inducing clinical and histologic remission in patients with eosinophilic esophagitis (EoE). However, the best long-term management strategy for this chronic inflammatory disease has not been determined.