Treatment Of Opioid-dependent Patients Research Articles

MATERNAL AND FETAL BUPRENORPHINE PHARMACOKINETICS IN PREGNANT SHEEP DURING TRANSDERMAL PATCH DOSING: Buprenorphine pharmacokinetics in pregnant sheep

BackgroundBuprenorphine is used in the opioid maintenance treatment for opioid dependent patients, including pregnant women. Despite the wide use, limited data exists on buprenorphine pharmacokinetics and fetal exposure during pregnancy. The aim of our study was to determine the buprenorphine pharmacokinetics during transdermal patch dosing to pregnant sheep and, to determine the extent of transplacental transfer of buprenorphine to the fetus. MethodsPregnant sheep in late gestation (n=50) received 20, 25 or 40 µg/h of buprenorphine as a 7-day extended-release transdermal patch. Plasma samples were collected from the ewe and the fetus on days 1 – 6, and buprenorphine and norbuprenorphine concentrations were determined. During the exposure period the sheep had a surgical procedure on the second day, a recovery phase, and an experimental procedure on the sixth day. In the experiment, hypoxia was induced under anesthesia for 18 sheep to investigate if decreased fetal pH would cause ion-trapping of buprenorphine in the fetus. The fetal/maternal plasma concentration ratio was determined on the second and on the sixth exposure day at baseline and during hypoxia. Maternal pharmacokinetics were modelled with a population pharmacokinetic method using the data from this study and our previous intravenous administration study. ResultsThe transdermal patch provided an extended release of buprenorphine throughout the exposure period, but the release rate declined approximately 20 h after patch placement. The median fetal/maternal plasma concentration ratio was 13 – 27 % throughout the exposure period at baseline. A ratio over 100 % was observed for four sheep on the sixth exposure day (102 – 269 %). A minor increase was seen in the median fetal/maternal-ratios during maternal hypoxia. Norbuprenorphine was undetected in all plasma samples. ConclusionsThe low transplacental passage of less than one fourth of the ewe's exposure supports buprenorphine as an alternative to methadone in opioid maintenance therapy during pregnancy.

Efficacy and Tolerability of Long-Acting Injectable Formulation of Nalmefene (Nalmefene Consta 393.1 mg) for Opioid Relapse Prevention: A Multicentre, Open-Label, Randomised Controlled Trial

Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) for the treatment of opioid-dependent patients. Design, Setting, and Participants: A 12 weeks, open-label, randomised controlled trial conducted between June 2009-July 2011, at 14 Hospital-based drug clinics, in the 12 countries. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder. Of the 3200 individuals screened, 3000 (93.7%) adults were randomized 1500 participants to receive injections of Long-acting depot formulations ofNalmefene (Nalmefene Consta 393.1 mg) given intramuscularly once in 12 weeks and 1500participants to receive extended-release Naltrexone (Vivitrol 380 mg), administered intramuscularly every fourth week for 12 weeks. Main Outcomes and Measures: The primary endpoints (protocol) were: Confirmed Opioid abstinence (percentage i.e. the number of patients who achieved complete abstinence during week 12). Confirmed abstinence or “opioid-free” was defined as a negative urine drug test for opioids and no self-reported opioid use. Weeks 1 - 4 were omitted from this endpoint to allow for stabilization of abstinence. Secondary end points included a number of days in treatment, treatment retention and craving. The study also investigated, on 275 participants, degree and time course of mu-opioid receptor occupancy following single doses of Nalmefene extended-release injection (Nalmefene Consta 393.1 mg) as well as the plasma concentration of Nalmefene and Nalmefene-3-O-glucuronide. Safety was assessed by adverse event reporting. Results: Of 3000 participants, mean (SD) age was 27.1 (±4.8) years and 831 (27.7%) were women. 1500 individuals were randomized to receive injections of Long-acting depot formulations of Nalmefene (Nalmefene Consta 393.1 mg) and 1500 to receive injections of extended-release Naltrexone (Vivitrol 380 mg); 2088 participants (69.6.0%) completed the trial. Primary endpoints: Confirmed Opioid Abstinence: Complete abstinence was sustained by 86% (n = 1290) of Nalmefene patients (patients treated with Nalmefene Consta 393.1 mg, long-acting depot formulations) compared with 43% (n = 645) of patients treated with extended-release Naltrexone 380 mg (Vivitrol), during weeks 5 - 12 (χ2 = 672.34, P < 0.0001). Secondary Endpoint: Craving: A statistically and clinically significant reduction in opioid craving was observed with Nalmefene (Nalmefene Consta 393.1 mg, long-acting depot formulations) vs. Naltrexone (extended-release Naltrexone, Vivitrol 380 mg) by week 4 (P =0.0048), which persisted every week through 12 (P < 0.0001). Patients given Nalmefene (Nalmefene Consta 393.1 mg, long-acting depot formulations) had a 75% decrease in craving from baseline to week 12. Patients given a Naltrexone (extended-release Naltrexone, Vivitrol 380 mg) had a 3% increase in craving from baseline to week 12 (Mean change in self-reporting craving). Secondary Endpoint: Treatment Retention: Long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) helped significantly more patients complete 12 weeks treatment (n = 1245, 83%) compared with extended-release Naltrexone (Vivitrol 380 mg) (n = 570, 38%) (χ2 = 635.53, P < 0.0001). Patients on long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) had longer treatment retention than patients on extended-release Naltrexone (Vivitrol 380 mg). Concentrations of Nalmefene and Nalmefene-3-O-Glucuronide in Plasma: Analyses were made of 275 study sample. There was no statistically significant difference for plasma nalmefene concentrations between days 2 and 84 (p = 0.416). The plasma concentration of Nalmefene were 20.3 and 28.5 ng/ml and concentrations of nalmefene-3-O-glucuronide were 2.1 and 4.1 ng/ml, respectively. Plasma levels of Nalmefene remained above 20 ng/ml for approximately 12 weeks after administration of Nalmefene, long-acting depot formulations (Nalmefene Consta 393.1 mg). PET Assessments: Very high mu-opioid receptor occupancy by Nalmefene was detected 1 day after treatments at which time point the occupancy was 100.0% after Nalmefene injection (Nalmefene Consta 393.1 mg). Nalmefene Consta 393.1 mg injection (long-acting intramuscular formulation of Nalmefene) led to a very high occupancy ofmu-opioid receptors in all brain areas examined; the thalamus, caudate nucleus, and frontal cortex. Depending on the brain area mu-opioid receptor occupancy varied between 83.0% and 85.8% 84 days after dosing. Adverse Reactions: Adverse events were similar in opioid-dependent patients treated with long-acting intramuscular formulation of Nalmefene (Nalmefene Consta 393.1 mg) vs. patients treated with extended-release Naltrexone (Vivitrol 380 mg). Conclusions and Relevance: Long-acting depot formulations of Nalmefene (Nalmefene Consta 393.1 mg) was more effective then extended-release Naltrexone (Vivitrol 380 mg) in maintaining short-term abstinence from heroin and should be considered as a treatment option for opioid-dependent individuals.

Anxiety Treatment of Opioid Dependent Patients with Buprenorphine: A Randomized, Double-blind, Clinical Trial.

Objective:The objective of this study is to examine the impact of vary doses of buprenorphine on anxiety symptoms in opioid-dependent inpatients over a 7 days period, using a randomized controlled trial design.Design:Patients were randomized to three groups.Patients and Methods:Fourteen men who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for both opioid use disorder and generalized anxiety disorder and were seeking for treatment.Intervention:Patients obtain dosages of 32 mg or 64 mg or 96 mg of buprenorphine as a single dose only and were treated in a psychiatric inpatient unit. Of 14 subjects; 5 (35.7%) obtained 32 mg, 4 (28.6%) obtained 64 mg, and 5 (35.7%) obtained 96 mg of buprenorphine.Measurements:Administering daily Hamilton Anxiety Rating Scale and interview.Results:All the patients ended the 7-day treatment time. The results showed a significant reduction in anxiety symptoms within each of the three groups (P = 0.00), but no difference in outcome between the groups (P = 0.605).Conclusions:The outcome suggests a single high dose of buprenorphine can supply a speedy, safe, simple, and suitable means of anxiety treatment. The single high dose of buprenorphine could be a novel mechanism medication that provides a rapid and sustained improvement for generalized anxiety disorder in opioid dependent patients. Placebo-controlled trials of longer duration are needed to evaluate ability, safety, and psychological and physiological influence of extended exposure to this medication.

Safety, Effectiveness and Tolerance of Buprenorphine-Naloxone in the Treatment of Opioid Dependence: Results from a Nationwide Non-Interventional Study in Routine Care

Buprenorphine is well known in the treatment of opioid dependence. Despite a high safety profile and good tolerance buprenorphine has been subject to misuse and diversion. To reduce misuse the antagonist naloxone was added and the 4:1 combination of buprenorphine-naloxone was launched in Germany in March 2007. On the basis of the results from international clinical trials a non-interventional study was conducted to gather data on safety, effectiveness, retention and acceptability of buprenorphine-naloxone in the treatment of opioid dependent patients in routine care. A nationwide multicentre 12-month prospective, non-interventional, post-marketing, surveillance study was carried out with 12 assessment points in N=384 opioid dependent patients currently in maintenance treatment from N=69 general practitioners, clinics and outpatient clinics in Germany. N=337 data sets were eligible for analysis. The rates of patients with serious and non-serious adverse events were low with 1.2% and 17.5%, respectively. No deaths occurred during the observational period and only one hospitalization was documented. Concomitant drug use decreased for all illicit substances. Mental health and quality of life measured with standardized self-assessment questionnaires improved significantly. The 12-month retention rate was 57.1%. Of the n=181 patients still in treatment at the end of the observation period, 96.7% continued treatment with buprenorphine-naloxone. The findings of the non-interventional study indicate high effectiveness and safety of buprenorphine-naloxone in the treatment of opioid dependence. The medication was well accepted by opioid dependent patients in long-term substitution treatment with substantial reductions of concomitant drug use and measurable improvement in quality of life.

Switching From Methadone to Diamorphine—2-Year Results of the German Heroin-Assisted Treatment Trial

Background: Several international clinical studies have found diamorphine treatment for opioid-dependent patients to show significantly better effects compared with methadone maintenance treatment. Aims: This analysis of the German trial of heroin-assisted treatment investigates the effects on patients’ health and drug use after switching from 12-month methadone to 12-month diamorphine treatment under similar study conditions. Methods: For a period of 24 months, the state of health was explored using the Opiate Treatment Index (OTI) health scale and the Symptom Checklist-90-R (SCL-90-R), while drug use and social situation by an extended version of the European Addiction Severity Index (EuropASI) every 6 months. Changes in these criteria were tested for significance by repeated measures analyses. Of the 434 patients, who started the 2nd year of study treatment, 90 were methadone–diamorphine switchers, and 344 received diamorphine for 2 years. Results: In the 2nd year, the methadone–diamorphine switchers succeed in catching up with the diamorphine patients. After switching to diamorphine, significant improvements in health and use of street heroin and cocaine were achieved during 1 year of diamorphine treatment. Conclusions: The results of the course of methadone–diamorphine switchers are a methodologically independent contribution toward confirming the positive effects of diamorphine treatment for difficult-to-treat opioid-dependent patients. This study supports the hypothesis that changing from optimized methadone treatment under the conditions of the clinical trial to diamorphine treatment is associated with improvements in health and drug use behavior. The study's limitations are noted.

Effectiveness of Neurofeedback Training as a Treatment for Opioid-Dependent Patients

Neurofeedback (NF) training has been employed as a therapeutic method in substance-dependence disorder over the last three decades. The purpose of the present study was to examine the effectiveness of this method on improvement of comorbid neuro-psychological syndromes in opioid-dependence disorder. Psychopathological and craving dimensions and brain activity signals of 20 opioid dependent patients were measured using Symptom Checklist-90-Revised (SCL-90-R), Heroin Craving Questionnaire (HCQ), and Quantitative Electroencephalography (QEEG). All the patients were undergoing pharmacotherapy. They were assigned to two groups that were matched based on SCL-90-R scores, education and age. The experimental group received 30 sessions of NF training in addition to their medicine. The control group received only the usual pharmacotherapy. The probable changes were monitored by reappraisal of all the patients after the treatment. We hypothesized that patients in the experimental group would show more reduction in their comorbid syndromes. The Multivariate Analysis of Covariance (MANCOVA) showed that the experimental group, in comparison with control group, showed significantly more improvement in all three outcome measures. In the SCL-90-R, improvement was noted with the hypochondriacs, obsession, interpersonal sensitivity, aggression, psychosis, and general symptomatic indexes. In the HCQ, improvement was found in the anticipation of positive outcome, desire to use substance, and total average score. Finally, the QEEG showed positive changes in frontal, central and parietal delta, frontal and central theta, parietal alpha and frontal and central Sensory Motor Rhythm (SMR) amplitudes. This study suggests that NF can be used as a therapeutic method to ameliorate abnormalities related to opioid-dependence disorders. The results emphasize the importance of neuropsychological interventions in treatment of substance-dependence disorders.

Integrated Opioid Use Disorder and HIV Treatment: Rationale, Clinical Guidelines for Addiction Treatment, and Review of Interactions of Antiretroviral Agents and Opioid Agonist Therapies

Injection drug use (IDU) is an important vector of HIV infection in the United States. Many patients with HIV infection have comorbid substance use disorders. Integrated treatment for HIV and substance use disorders has been shown to improve HIV and other health outcomes, but significant barriers to integrated treatment exist. For individuals who are dependent on injection opioid drugs, agonist therapies of methadone or buprenorphine maintenance are available as part of a treatment program. Patients who are infected with HIV and require antiretroviral therapy (ART) are at risk for drug-drug interaction between ART and methadone or buprenorphine. We present a programmatic approach to the evaluation and treatment of opioid use disorders for HIV care providers, as well as a summary of the available knowledge of interactions of methadone and buprenorphine with ART, along with the level of evidence for each actual or potential interaction. Based on the available information of practice and the level of clinical significance of drug-drug interactions, we conclude that buprenorphine-based maintenance treatment for opioid dependent patients is the preferred maintenance therapy for integrated treatment systems.

Methadone Restores Local and Remote Eeg Functional Connectivity in Opioid-Dependent Patients

Currently it has been proposed that normal brain function is critically dependent upon a dynamical balance between functions of local neuronal assemblies and global integrative processes. A loss of such metastable balance in favor of either independent or hyper-ordered processing is considered as the reflection of a brain disease. It has been shown that opioid dependence can be characterized as a disease of brain metastable balance, wherein local functional connectivity (synchronicity within neuronal assemblies) increased and remote functional connectivity (synchronicity between neuronal assemblies) decreased. Since methadone may be used as a maintenance treatment for opioid-dependent patients, the aim of this research was to study how methadone would influence the temporal and metastable cortical organization through the measures of local and remote electroencephalogram (EEG) functional connectivity in six opioid-depended patients who manage to complete at least six-month methadone treatment. The present study demonstrated that average parameters of temporal and metastable organization of the cortical dynamics (indexed by local and remote EEG functional connectivity) in such opioid-dependent patients did not differ from normal values of healthy subjects. We interpret these findings as a capability of the methadone to restore a normal temporal and metastable structure of brain activity in opioid-dependent patients after many months of methadone treatment. To our knowledge, present preliminary study is the first where the influence of methadone on temporal and metastable structure of EEG activity is demonstrated.

Opioid treatment programs in the Clinical Trials Network: Representativeness and buprenorphine adoption

As the Clinical Trials Network (CTN) begins to focus efforts on disseminating the results of its research studies to the addiction treatment field, it is important to begin to assess the capacity of programs outside the CTN to integrate with fidelity these endorsed treatment practices. To date, no data exist to assess the representativeness of opioid treatment programs (OTPs) participating in the CTN, nor potential barriers to the effective diffusion of practices aimed at the treatment of opioid-dependent patients, including buprenorphine. Using data obtained from OTPs within the CTN ( n = 49) and a sample drawn from the population of U.S. OTPs ( n = 50), this study compares the two groups on their organizational, clinical, and client characteristics, as well as their adoption of buprenorphine. The study finds that the populations differ significantly on numerous variables but that structural characteristics appear more predictive of buprenorphine adoption than either staff or caseload differences. Implications for studying the diffusion and implementation of evidence-based research findings are discussed.

Validation and development of a self-report outcome measure (MAP-sc) in opiate addiction

Aims and MethodTo develop and assess the viability of a self-completion version of the Maudsley Addiction Profile for assessing and monitoring the functioning of opioid-dependent patients. A total of 206 treatment-seeking opioid-dependent patients completed the Maudsley Addiction Profile interview and a self-completion version at a single clinic appointment at a substance misuse facility. Scores from both formats were compared using correlation coefficients.ResultsNon-parametric correlation coefficients between interview and self-completion version for alcohol, drug, psychiatric, family and legal problems correlated in excess of 0.7 for the majority of the 20 items that were compared.Clinical ImplicationsA short, self-administered questionnaire version of the Maudsley Addiction Profile is a feasible alternative to the interview for assessing and monitoring treatment of opioid-dependent patients. The questionnaires were usually completed by clients within 15 min. These would be particularly useful in services with very limited staffing time, such as primary care.

Provider Satisfaction with Office-Based Treatment of Opioid Dependence

Purpose: New federal regulations allow for office-based treatment of opioid dependent patients with opioid agonist medication (e.g., buprenorphine). We sought to evaluate the literature on office-based physicians' acceptance of this practice. Methods: We searched the MEDLINE database for original research examining office-based providers' acceptance or satisfaction with office-based treatment. Articles included in the analysis met the following criteria: (1) discussed the treatment of patients with substance abuse disorders, (2) focused on the treatment of opioid dependent patients, (3) discussed treatment with opioid agonist therapy, (4) discussed treatment by office-based physicians, (5) presented original research, and (6) provided data examining physician acceptance or satisfaction. Results: Eight studies met the criteria. Their heterogeneity precluded aggregate analysis. Four of 8 studies revealed that providers had a positive perception concerning the efficacy of opioid agonist treatment, 4/8 indicated that providers believed that opioid dependent patients were more complex than others in their practices, and 3/8 studies indicated the need for additional support services. Conclusions: There are few studies of provider satisfaction with office-based treatment of opioid dependence. This literature reveals overall provider acceptance of this practice but highlights the need for support services. Further research, designed to identify the barriers to provider satisfaction with office-based opioid agonist therapy, is needed to ensure that these barriers do not limit expansion of this practice.

Management of opioid dependence

Purpose of the review The present review provides an overview of the most recent developments in the treatment of opioid-dependent patients, using a chronic disease model as a starting point, and taking crisis intervention, cure (detoxification, relapse prevention), care (stabilization and harm reduction) and palliation as the major treatment goals. Recent findings The various high-quality studies, systematic literature reviews and formal meta-analyses clearly demonstrate that, currently, many proven effective interventions are available for crisis intervention, detoxification, stabilization and harm reduction. Interventions directed at relapse prevention are still problematic and only effective in motivated patients in stable living conditions and with adequate social support. Treatment innovations are primarily based on experimental animal studies. Newly developed cannabinoid receptor antagonists and cortisol synthesis inhibitors show great promise. Summary Opioid dependence is a chronic relapsing disease that is difficult to cure, but stabilization and harm reduction can greatly increase the life expectancy and quality of life of patients, their direct environment and society as a whole