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- An Unusual Case of Death Probably Triggered by the Association of Buprenorphine at Therapeutic Dose with Ethanol and Benzodiazepines and with Very Low Norbuprenorphine Level. [JOURNAL ARTICLE]
- J Forensic Sci 2014 Oct 27.
Buprenorphine is largely prescribed for maintenance treatment in opioid dependence due to its safety profile. Nevertheless, fatalities at therapeutic dose have been described when associated with other central nervous system depressants, such as ethanol or benzodiazepines. Here, we report a case of death due to association of buprenorphine at therapeutic dose with benzodiazepines and ethanol. Although toxicity has been often attributed to its metabolite norbuprenorphine rather than to buprenorphine itself, in our case, norbuprenorphine was not detected in urine and bile and only in traces in blood. Moreover, the presence in blood of free buprenorphine but not of glucuronide metabolites argues for an unusual early death, at the beginning of buprenorphine metabolism. We propose that in the context of prior toxic impregnation, buprenorphine directly (and not via its metabolite norbuprenorphine) acted as a triggering factor by blocking the ventilatory response, rapidly leading to fatal respiratory depression.
- Association of Opioid Agonist Therapy With Lower Incidence of Hepatitis C Virus Infection in Young Adult Injection Drug Users. [JOURNAL ARTICLE]
- JAMA Intern Med 2014 Oct 27.
Injection drug use is the primary mode of transmission for hepatitis C virus (HCV) infection. Prior studies suggest opioid agonist therapy may reduce the incidence of HCV infection among injection drug users; however, little is known about the effects of this therapy in younger users.To evaluate whether opioid agonist therapy was associated with a lower incidence of HCV infection in a cohort of young adult injection drug users.Observational cohort study conducted from January 3, 2000, through August 21, 2013, with quarterly interviews and blood sampling. We recruited young adult (younger than 30 years) injection drug users who were negative for anti-HCV antibody and/or HCV RNA.Substance use treatment within the past 3 months, including non-opioid agonist forms of treatment, opioid agonist (methadone hydrochloride or buprenorphine hydrochloride) detoxification or maintenance therapy, or no treatment.Incident HCV infection documented with a new positive result for HCV RNA and/or HCV antibodies. Cumulative incidence rates (95% CI) of HCV infection were calculated assuming a Poisson distribution. Cox proportional hazards regression models were fit adjusting for age, sex, race, years of injection drug use, homelessness, and incarceration.Baseline characteristics of the sample (n = 552) included median age of 23 (interquartile range, 20-26) years; 31.9% female; 73.1% white; 39.7% who did not graduate from high school; and 69.2% who were homeless. During the observation period of 680 person-years, 171 incident cases of HCV infection occurred (incidence rate, 25.1 [95% CI, 21.6-29.2] per 100 person-years). The rate ratio was significantly lower for participants who reported recent maintenance opioid agonist therapy (0.31 [95% CI, 0.14-0.65]; P = .001) but not for those who reported recent non-opioid agonist forms of treatment (0.63 [95% CI, 0.37-1.08]; P = .09) or opioid agonist detoxification (1.45 [95% CI, 0.80-2.69]; P = .23). After adjustment for other covariates, maintenance opioid agonist therapy was associated with lower relative hazards for acquiring HCV infection over time (adjusted hazard ratio, 0.39 [95% CI, 0.18-0.87]; P = .02).In this cohort of young adult injection drug users, recent maintenance opioid agonist therapy was associated with a lower incidence of HCV infection. Maintenance treatment with methadone or buprenorphine for opioid use disorders may be an important strategy to prevent the spread of HCV infection among young injection drug users.
- [Pharmacotherapy of heroin addiction.] [JOURNAL ARTICLE]
- Neuropsychopharmacol Hung 2014 Sep; 16(3):127-140.
Heroin addiction is one of the most devastating and expensive of public health problems. The most effective treatment for this epidemic is opioid replacement therapy. Replacement of heroin, a short-acting euphoriant with methadone or other opioids that have significantly longer durations of action provides a number of therapeutic benefits. Opioid detoxification has a role in both preventing acute withdrawal and maintaining long-term abstinence. Opioid-based detoxification is based on the principle of cross-tolerance, in which one opioid is replaced which another that is slowly tapered. For the treatment of heroin addicts a wide range of psychosocial and pharmacotherapeutic treatments is available; of these, methadone maintenance treatment has the most evidence of benefit. Methadone maintenance reduces and/or eliminates the use of heroin, reduces the death rates and criminality associated with heroin use, and allows patients to improve their health and social productivity. In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with heroin injection, such as hepatitis and HIV. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with heroin. There is growing interest in expanding treatment into primary care, allowing opioid addiction to be managed like other chronic illnesses. Buprenorphine which is a long-acting partial agonist was also approved as pharmacotherapy for opioid dependence. Opioid antagonists can reduce heroin self-administration and opioid craving in detoxified addicts. Naltrexone, which is a long-acting competitive antagonist at the opioid receptors, blocks the subjective and objective responses produced by intravenous opioids. Naltrexone is employed to accelerate opioid detoxification by displacing heroin and as a maintenance agent for detoxified formerly heroin-dependent patients who want to remain opioid-free.
- Recovery of Drugs of Abuse from Dräger DCD5000 Oral Fluid Collection Device in Australia. [JOURNAL ARTICLE]
- J Anal Toxicol 2014 Oct 22.
In Australia, it is a requirement of workplace oral fluid (OF) drugs of abuse testing that drug recovery from collection devices be verified by an accredited laboratory. Recovery data are used in conjunction with collection volume imprecision data and uncertainty of measurement to provide an estimation of drug concentration in neat OF. The manufacturer's product information for the DCD5000 collection device indicates that the collection volume of the swab is 380 µL. Recovery data for the swab when used with the isopropanol provided by the manufacturer are not available. A series of experiments using fortified drug-free OF were performed to assess the collection volume imprecision of the Dräger DCD5000 swab and the recovery of drugs from the swab using isopropanol. The fortified OF was collected with the swabs (n = 16), and swabs were discharged into vials of isopropanol as per the manufacturer's instructions. The mean collection volume of the DCD5000 swab was 487 µL with an imprecision of 1.3%. Recovery of drug from the device ranged from 86 to 98% for drugs listed in the Australian OF workplace testing standard. Recovery of methadone, buprenorphine and norbuprenorphine ranged from 93 to 102%. Recovery of 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene was 45%, suggesting that urine is more suitable sample if methadone therapy is being monitored. Overall, drug recovery from the device using isopropanol was acceptable when the increased collection volume of the swab was taken into account.
- Preclinical Modeling of Primal Emotional Affects (SEEKING, PANIC and PLAY): Gateways to the Development of New Treatments for Depression. [JOURNAL ARTICLE]
- Psychopathology 2014 Oct 22.
Mammalian brains contain at least 7 primal emotional systems - SEEKING, RAGE, FEAR, LUST, CARE, PANIC and PLAY (capitalization reflects a proposed primary-process terminology, to minimize semantic confusions and mereological fallacies). These systems help organisms feel affectively balanced (e.g. euthymic) and unbalanced (e.g. depressive, irritable, manic), providing novel insights for understanding human psychopathologies. Three systems are especially important for understanding depression: The separation distress (PANIC) system mediates the psychic pain of separation distress (i.e. excessive sadness and grief), which can be counteracted by minimizing PANIC arousals (as with low-dose opioids). Depressive dysphoria also arises from reduced brain reward-seeking and related play urges (namely diminished enthusiasm (SEEKING) and joyful exuberance (PLAY) which promote sustained amotivational states). We describe how an understanding of these fundamental emotional circuits can promote the development of novel antidepressive therapeutics - (i) low-dose buprenorphine to counteract depression and suicidal ideation emanating from too much psychic pain (PANIC overarousal), (ii) direct stimulation of the SEEKING system to counteract amotivational dysphoria, and (iii) the discovery and initial clinical testing of social-joy-promoting molecules derived from the analysis of the PLAY system. © 2014 S. Karger AG, Basel.
- Multimodal Perineural Analgesia with Combined Bupivacaine-Clonidine-Buprenorphine-Dexamethasone: Safe In Vivo and Chemically Compatible in Solution. [JOURNAL ARTICLE]
- Pain Med 2014 Oct 23.
The use of adjuvants in regional anesthesia has increased. However, there are knowledge gaps pertaining to 1) in vivo local tissue effects of these adjuvants; and 2) chemical compatibility and solubility of these drugs in solution with each other and with local anesthetics. This study addresses these gaps in knowledge.In vivo rat safety/toxicopathology study and analytical chemistry study.Collaborating Good Laboratory Practice laboratories under the direction of the university-based principal investigator.Single-injection formulations of clonidine, buprenorphine, and dexamethasone were combined with either bupivacaine or midazolam, and were administered to groups of rats. Post-injection behavior was monitored to assess changes related to the block. A continuous infusion of bupivacaine, clonidine, and dexamethasone was administered to another group of rats, and behavioral effects were recorded. After 15 days, rats were sacrificed and their nerves/dorsal root ganglia were examined by the pathologist. Samples of combined drug solutions were processed at an analytical chemistry laboratory for compatibility, solubility, and stability.Each of the single-injection formulations produced reversible sensory and/or motor block. None of the study drugs caused damage to any of the nerve segments or related tissue. The text describes the concentrations at which compatibility and solubility of the combined drug solutions were achieved.Four-drug single-injection formulations are described that 1) had compatible and stable concentrations in solution; and 2) produced reversible nerve block without causing long-term motor or sensory deficits or damage to sciatic nerves/dorsal root ganglia.
- Investigation of cross-species translatability of pharmacological MRI in awake nonhuman primate - a buprenorphine challenge study. [Journal Article]
- PLoS One 2014; 9(10):e110432.
Pharmacological MRI (phMRI) is a neuroimaging technique where drug-induced hemodynamic responses can represent a pharmacodynamic biomarker to delineate underlying biological consequences of drug actions. In most preclinical studies, animals are anesthetized during image acquisition to minimize movement. However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns. Significant efforts have been made to establish awake imaging in rodents and nonhuman primates (NHP). Whilst various platforms have been developed for imaging awake NHP, comparison and validation of phMRI data as translational biomarkers across species remain to be explored.We have established an awake NHP imaging model that encompasses comprehensive acclimation procedures with a dedicated animal restrainer. Using a cerebral blood volume (CBV)-based phMRI approach, we have determined differential responses of brain activation elicited by the systemic administration of buprenorphine (0.03 mg/kg i.v.), a partial µ-opioid receptor agonist, in the same animal under awake and anesthetized conditions. Additionally, region-of-interest analyses were performed to determine regional drug-induced CBV time-course data and corresponding area-under-curve (AUC) values from brain areas with high density of µ-opioid receptors.In awake NHPs, group-level analyses revealed buprenorphine significantly activated brain regions including, thalamus, striatum, frontal and cingulate cortices (paired t-test, versus saline vehicle, p<0.05, n = 4). This observation is strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[11C]methyl]buprenorphine ([11C]BPN) positron emission tomography imaging study in baboons. Furthermore, our findings are consistent with previous buprenorphine phMRI studies in humans and conscious rats which collectively demonstrate the cross-species translatability of awake imaging. Conversely, no significant change in activated brain regions was found in the same animals imaged under the anesthetized condition.Our data highlight the utility and importance of awake NHP imaging as a translational imaging biomarker for drug research.
- Long-term agonist and antagonist therapy for adolescent opioid dependence: a description of two cases. [Journal Article]
- Indian J Psychol Med 2014 Oct; 36(4):439-43.
Adolescents constitute only a small percentage of treatment seekers in drug dependence treatment settings. Little research evidence is available for pharmacological treatment of adolescent opioid dependence and no prior case report is available from India. We discuss two adolescent patients with opioid (heroin) dependence visiting a tertiary care center who have been stabilized on agonist (sublingual buprenorphine-naloxone) and antagonist (oral naltrexone) respectively for a substantial period of time. A comprehensive management approach, including intensive psychosocial interventions and family involvement, was followed in addition to pharmacotherapies. More research is needed on the efficacy of pharmacological treatment in adolescent opioid users.
- Sexual dysfunction in patients with alcohol and opioid dependence. [Journal Article, Review]
- Indian J Psychol Med 2014 Oct; 36(4):355-65.
There are limited numbers of studies which have evaluated the sexual dysfunction (SD) in patients with alcohol and opioids dependence. This article reviews the existing literature. Electronic searches were carried out using the PubMed, Google Scholar, and ScienceDirect to locate the relevant literature. Subjects addicted to heroin or on methadone maintenance treatment (MMT) or buprenorphine maintenance treatment (BMT) show higher rates of SD in comparison to the general population. SD rates have ranged 34-85% for heroin addicts, 14-81% for MMT, 36-83% for BMT, and 90% for naltrexone maintenance. The rates of SD in alcohol-dependent population have ranged 40-95.2%, with rates being consistently much higher in alcohol-dependent population than in the healthy controls or social drinkers. The common SDs reported have been erectile dysfunction followed by premature ejaculation, retarded ejaculation and decreased sexual desire among men, and dyspareunia and vaginal dryness among women. This review suggests that long-term use of alcohol and opioids are associated with SD in almost all domains of sexual functioning. There is a need to increase the awareness of clinicians about this association as many times SD in patients with substance abuse lead to poor treatment compliance and relapse. Further, there is a need to carry out more number of studies to understand the relationship in a better way.
- Primary Care-Based Buprenorphine Taper vs Maintenance Therapy for Prescription Opioid Dependence: A Randomized Clinical Trial. [JOURNAL ARTICLE]
- JAMA Intern Med 2014 Oct 20.
Prescription opioid dependence is increasing and creates a significant public health burden, but primary care physicians lack evidence-based guidelines to decide between tapering doses followed by discontinuation of buprenorphine hydrochloride and naloxone hydrochloride therapy (hereinafter referred to as buprenorphine therapy) or ongoing maintenance therapy.To determine the efficacy of buprenorphine taper vs ongoing maintenance therapy in primary care-based treatment for prescription opioid dependence.We conducted a 14-week randomized clinical trial that enrolled 113 patients with prescription opioid dependence from February 17, 2009, through February 1, 2013, in a single primary care site.Patients were randomized to buprenorphine taper (taper condition) or ongoing buprenorphine maintenance therapy (maintenance condition). The buprenorphine taper was initiated after 6 weeks of stabilization, lasted for 3 weeks, and included medications for opioid withdrawal, after which patients were offered naltrexone treatment. The maintenance group received ongoing buprenorphine therapy. All patients received physician and nurse support and drug counseling.Illicit opioid use via results of urinanalysis and patient report, treatment retention, and reinitiation of buprenorphine therapy (taper group only).During the trial, the mean percentage of urine samples negative for opioids was lower for patients in the taper group (35.2% [95% CI, 26.2%-44.2%]) compared with those in the maintenance group (53.2% [95% CI, 44.3%-62.0%]). Patients in the taper group reported more days per week of illicit opioid use than those in the maintenance group once they were no longer receiving buprenorphine (mean use, 1.27 [95% CI, 0.60-1.94] vs 0.47 [95% CI, 0.19-0.74] days). Patients in the taper group had fewer maximum consecutive weeks of opioid abstinence compared with those in the maintenance group (mean abstinence, 2.70 [95% CI, 1.72-3.75] vs 5.20 [95% CI, 4.16-6.20] weeks). Patients in the taper group were less likely to complete the trial (6 of 57 [11%] vs 37 of 56 [66%]; P < .001). Sixteen patients in the taper group reinitiated buprenorphine treatment after the taper owing to relapse.Tapering is less efficacious than ongoing maintenance treatment in patients with prescription opioid dependence who receive buprenorphine therapy in primary care.clinicaltrials.gov Identifier: NCT00555425.