BDNF receptor antagonism during the induction of morphine dependence exacerbates the severity of physical dependence and ameliorates psychological dependence in rats.

This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) during induction of morphine dependence on the severity of physical and psychological dependence and the cerebrospinal fluid (CSF) BDNF levels in morphine-dependent and withdrawn rats. Rats became morphine-dependent by increasing daily doses of morphine for 7 days, along with ANA-12 injection. Then, rats were tested for the severity of physical dependence on morphine (spontaneous withdrawal signs), anxiety-like (the elevated plus maze), depressive-like (sucrose preference test) behaviors after spontaneous morphine withdrawal. Also, the CSF BDNF levels were assessed 2 h after the last dose of morphine and day 13 after morphine withdrawal in morphine-dependent and withdrawn rats. We found that the morphine withdrawal signs were significantly higher in morphine dependent rats receiving ANA-12 on days of 5-7 after morphine withdrawal, also ANA-12 exacerbated overall dependence severity. While, the percentage of time spent in the open arms and sucrose preference were higher in morphine-dependent rats receiving ANA-12 than morphine-dependent rats receiving saline. Also, the ANA-12 injection decreased the CSF BDNF levels following morphine dependence, while increased it after morphine withdrawal. We conclude that the ANA-12 exacerbated the severity of physical morphine dependence but attenuated the anxiety/depressive-like behaviors in morphine-dependent and withdrawn rats. Also, ANA-12 injection was able to reverse the changes in the CSF BDNF levels. Therefore, ANA-12 is not more likely to complete treatment for opiate addiction.

Adolescent chronic escalating morphine administration induces long lasting changes in tolerance and dependence to morphine in rats.

Adolescence is a gradual period of transition from childhood to adulthood. It is considered as a sensitive developmental time point that long lasting changes occur in the brain. The present study examined adolescent chronic escalating morphine administration on morphine tolerance and dependence in adulthood. Adolescent male Wistar rats (30days old) were administered increasing doses of morphine (2.5 to 25mg/kg, s.c.) every 12h, for 10days. Control rats received saline according to the same protocol. Thereafter, during adulthood (65-75days old), tolerance to antinociceptive effect of morphine was induced by subcutaneous injection of 3mg/kg morphine, once a day for 7days. Morphine analgesia was measured in the animals by tail flick test every two days, 10min before and 30min after morphine administration. Also, in another test, adult rats were administered morphine (10mg/kg, s.c.) twice a day for 9days to become morphine dependent. On day 10, naloxone (2mg/kg, i.p.) was injected 2h after morphine administration. Somatic signs of morphine withdrawal were then recorded in a clear Plexiglas test chamber for 25min. Results showed that adolescent morphine treatment significantly facilitates the development of tolerance to the analgesic effect of morphine and increases morphine withdrawal signs (grooming, head tremor, sniffing, scratching and teeth chattering) in adulthood compared to the saline group. Facilitation of morphine tolerance and potentiation of withdrawal signs suggests that chronic escalating morphine treatment during adolescence causes long-lasting effects on development of morphine tolerance and dependence in adulthood.

Opioid agonist doses for oxycodone and morphine dependence: Findings from a retrospective case series.

INTRODUCTION: Use of opioid agonist treatments for prescription opioid (PO) dependence is rapidly increasing. Current guidelines are based on research with heroin users. This study aimed to examine methadone and buprenorphine dose requirements for PO-dependent people. DESIGN AND METHODS: A retrospective case series of PO-dependent patients entering methadone and buprenorphine treatment. Daily oral morphine equivalent (OME) doses at baseline were calculated using standard dose conversion calculations. Dose conversion tables were used to estimate opioid agonist doses, based on starting dose of PO. Baseline methadone and buprenorphine dose at days 7 and 28 were examined. Linear models were fit to the data. RESULTS: Participants (n = 44) were 67% male, mean age 41 years (SD 10 years); 69% reported a pain condition. The methadone group (n = 21) had a mean PO dose of 704.5 mg OME (SD 783.5 mg) prior to treatment, and mean methadone dose of 45.3 mg (SD 13.1 mg) at day 7 and 61.6 mg (SD 20.8 mg) at day 28. The buprenorphine group (n = 23) had a mean PO dose of 771.7 mg OME (SD 867.7 mg) prior to treatment, with a mean dose of 14.6 mg (SD 8.3 mg) at day 7 and 18.1 (SD 8.9 mg) at day 28. Linear relationships were not found between OME and opioid agonist dose. CONCLUSIONS: Opioid agonist dosages varied substantially between individuals, and from predicted dosages based on dose conversion tables. Use of conversion tables to guide selection of opioid agonist dosage may compromise patient safety. [Nielsen S, Bruno R, Degenhardt L, Demirkol A, Lintzeris N. Opioid agonist doses for oxycodone and morphine dependence: Findings from a retrospective case series Drug Alcohol Rev 2017;36:311-316].

Evidence of slow-release morphine sulfate abuse and diversion: epidemiological approaches in a French administrative area.

Slow-release oral morphine sulfate (SM) is one of the most abused prescription opioids in France. However, the regional feature of the abuse of morphine is poorly documented. To investigate the abuse of SM in a French administrative region, a multisource approach was applied. The first approach was based on SM exposition at national and regional level using the OPPIDUM survey. In a second approach, we analyzed a drug reimbursement database to assess the magnitude of SM abuse in Languedoc-Roussillon (LR) region. A clustering method was applied to classify patients and to describe the profile of deviant patients. The third approach was based on a self-administered anonymous questionnaire, proposed to patients seen in addiction care centers in the LR region and consuming oral SM. The OPPIDUM study showed that in most regions, where the prevalence of heroin use is higher than the national average of 9.1%, SM consumers were fewer. With the clustering method, three subgroups were identified. One of them gathered 35 users (3.2%) with a deviant behavior characterized by significantly more dispensations, dispensing pharmacies, and prescribers. These subjects were mainly men, younger, and more consumers of benzodiazepines and opioid maintenance therapy than the others. The third study allowed specifying that SM was mainly injected (93.7%), bought in the street (80%), and used because of unavailability and the poor quality of heroin (33.9%). The three proposed approaches are complementary and help to clarify the abuse of oral SM, while assessing the motivations of this abuse.

[The morphofunctional features of the heart associated with acute morphine poisoning during the period of chronic drug intoxication].

The objective of the present study was to improve forensic medical diagnostics of the cases of death associated with morphine poisoning based on the investigation into the biochemical changes in blood and pericardial fluid as well as morphological changes in the myocardial structures. The studies were carried out with the use of thin-layer chromatography, colorimetric and morphological methods including hematoxylin and eosin, Lee's methylene blue, and van Gieson's picrofuscin staining. These techniques were supplemented by light and polarization microscopy. The study has demonstrated the presence of morphine in 99.16% of the blood and pericardial samples obtained in the cases of poisoning. The comparison of the results of biochemical and pathomorphological studies of the myocardium made it possible to evaluate the functional and morphological conditions of the heart in the case of acute morphine poisoning during the period of chronic drug intoxication.

Hair testing in postmortem diagnosis of substance abuse: An unusual case of slow-release oral morphine abuse in an adolescent.

Morphine sulfate misuse is essentially observed among regular heroin injectors. To our knowledge, primary addiction to morphine sulfate is exceptional, especially among young adolescents. A 13-year-old girl, with no history of addiction, was found dead with three empty blisters of Skenan(®) LP 30 mg at her side. Opiates were detected in biological fluids and hair by chromatographic methods. Blood analyses confirmed morphine overdose (free morphine: 428 ng/mL; total morphine: 584 ng/mL) and segmental hair analysis confirmed regular exposure over several months (maximum morphine concentration 250 pg/mg). Suspecting the victim's mother of recreational use of Skenan(®), the magistrate ordered analysis of her hair, with negative results. From an epidemiological viewpoint, this case of oral morphine sulfate abuse in an adolescent with no previous history suggests the emergence of a new trend of morphine sulfate consumption. From a toxicological viewpoint, it demonstrates the value of hair testing, which documented the victim's regular exposure and made an important contribution to the police investigation.

Codeine to morphine concentration ratios in samples from living subjects and autopsy cases after incubation.

The codeine to morphine concentration ratio is used in forensic toxicology to assess if codeine has been ingested alone or if morphine and/or heroin have been ingested in addition. In our experience, this interpretation is more difficult in autopsy cases compared with samples from living persons, since high morphine concentrations are observed in cases where only codeine is assumed to have been ingested. We have investigated if codeine and morphine glucuronides are subject to cleavage to the same extent in living and autopsy cases in vitro. We included whole blood samples from eight living subjects and nine forensic autopsy cases, where only codeine ingestion was suspected. All samples were incubated for 2 weeks at 37°C and analyzed for codeine and six codeine metabolites using liquid chromatography tandem mass spectrometry. A reduction in the codeine to morphine concentration ratio was found, both in samples from living subjects (mean 33%, range 22-50%) and autopsy cases (mean 37%, range 13-54%). The increase in the morphine concentrations was greater in the autopsy cases (mean 85%, max 200%) compared with that of the living cases (mean 51%, max 87%). No changes were seen for codeine or codeine-6-glucuronide concentrations. The altered ratios might mislead the forensic toxicologist to suspect morphine or heroin consumption in cases where only codeine has been ingested.

Adicción, impulsividad y curvas temporales de deseo / Addiction, impulsivity and temporal curves of desire

En este estudio se aborda desde las teorías del aprendizaje, el rol de la impulsividad y el deseo de consumo en pacientes con diagnóstico de dependencia de sustancias en abstinencia, consumo habitual y recaída. Para ello, se presenta un nuevo método de valoración del deseo basado en las “curvas de descuento”, en el que los pacientes deben describir como perciben la evolución temporal e intensidad de su deseo. Al mismo tiempo, a través de un breve cuestionario sobre emoción y deseo elaborado por los autores y de la Escala de Impulsividad de Plutchik, se pretende comprobar si las emociones positivas o negativas aumentan, disminuyen o no están implicadas en los cambios de deseo e impulsividad. La percepción de la evolución del deseo de los pacientes pertenecientes a los grupos Recaída y Consumo Habitual es similar y presenta una forma hiperbólica, sin embargo, el grupo Recaída presentaba una mayor impulsividad. Además, se halla relación en pacientes de este grupo Recaída entre incremento del deseo de forma hiperbólica, estados placenteros e impulsividad. La mayor puntuación en impulsividad y la evolución hiperbólica del deseo en pacientes que han sufrido recientemente una recaída muestra la necesidad de tener en cuenta y tratar específicamente estos aspectos como relevantes en terapia psicológica y/o farmacológica (AU)

This study addresses, from theories of associative learning, the impulsivity and craving in patients with a diagnosis of substance dependence in abstinence, habitual use and relapse. We present a new method for the assessment of desire based on discount curve self description, in which patients describe how they perceive the temporal evolution and intensity of their desire. At the same time, through a brief questionnaire about emotion and desire –developed by the authors–and the Plutchik Impulsivity Scale, we set out to check whether positive or negative emotions increase, decrease, or are uninvolved in changes of desire and impulsivity. Perception of the evolution of desire in patients from the Relapse and Habitual Use groups is similar and presents a hyperbolic curve, but the Relapse group presented greater impulsivity. Moreover, a relationship is found in patients from the Relapse group between the hyperbolic increase of desire, the pleasurable states and impulsivity. The higher scores on impulsivity and the hyperbolic evolution of desire in patients who have recently suffered a relapse indicate the need to consider and specifically address these aspects as relevant to psychotherapy and/or pharmacological therapy (AU)

Biomarkers of opiate use.

The interpretation of toxicological findings is critical for the thorough investigation of the use and abuse of psychoactive substances. A positive analytical result for a sample taken could usually result in criminal proceedings and a punitive outcome for the defendant whose sample was analysed. The detection of markers of illicit opiate misuse is important both in the management of substance misuse and in the postmortem identification of illicit opiate use. The aim of this study was to emphasise the role of opiate biomarkers available at the laboratory and in the clinical environment. Urine remains the biological tool of choice for qualitative detection of illicit drug use in a clinical setting, while quantitative accuracy remains strictly the domain of blood. Accurate interpretation of the screening tests within a clinical setting alongside other relevant information remains the key to the usefulness of any test. Moreover, the finding of a morphine/codeine concentration ratio in blood exceeding unity is a strong evidence that the person had used heroin, as opposed to having taken a prescription analgesic drug containing codeine.

Urine drug test interpretation: what do physicians know?

OBJECTIVE: To determine the level of urine drug test (UDT) interpretive knowledge of physicians who use these instruments to monitor adherence in their patients on chronic opioid therapy. METHODS: A seven-question instrument consisting of six five-option, single-best-answer multiple choice questions and one yes/no question was completed by 114 physicians (77 who employ UDT and 37 who do not) attending one of three regional opioid education conferences. We calculated frequencies and performed chi2 analyses to examine bivariate associations between UDT utilization and interpretive knowledge. RESULTS: The instrument was completed by 80 percent of eligible respondents. None of the physicians who employ UDT answered all seven questions correctly, and only 30 percent answered more than half correctly. Physicians who employ UDT performed no better on any of the questions than physicians who do not employ UDT. CONCLUSIONS: Physicians who employ UDT to monitor patients receiving chronic opioid therapy are not proficient in test interpretation. This study highlights the need for improved physician education; it is imperative for physicians to work closely with certified laboratory professionals when ordering and interpreting these tests.

Hair analysis by LC-MS as evidence of nalbuphine abuse by a nurse.

Individuals in any profession can succumb to chemical abuse. Among the healthcare profession, nurses represent a specific group because of their ease of access to drugs, particularly narcotics. Opioids, potentially highly addictive agents, are usually their drug of choice. Nalbuphine, a synthetic opioid analgesic, is prescribed for moderate-to-severe acute pain, for chronic pain syndromes, and in obstetrics to decrease the adverse respiratory effect of opioid epidural administration. The case of a nurse who was suspected of drug misuse after the disappearance of two nalbuphine ampules in an obstetrics service is described. Because of discrepancies in the results of her blood and urine samples, a sample of head hair was subsequently collected from the nurse. A hair analysis of nalbuphine by liquid chromatography-mass spectrometry has not been previously described. Following decontamination and grinding, hair was mixed with a Söerensen buffer, then subjected to ultrasonic treatment (1 h), and extracted with ethyl acetate. A quantitative analysis was performed with two channels (30 and 45 V), and it is based on a m/z 358 for nalbuphine and a m/z 330 for methylclonazepam as an internal standard. The method was linear from 0.020 to 12 ng/mg of hair (R(2) = 0.972), and the limit of detection and limit of quantitation are 0.020 ng/mg. Accuracy (CV), assessed at 0.4 and 1.6 ng/mg of hair, was 6.18% and 5.77%, respectively, for intraday assays and 4.5% and 10.9% for interday assays. Recovery efficiency at 1.6 ng/mg and 8 ng/mg of hair was 100% and 97.4%, respectively. The hair specimen from the nurse (6 cm) was cut into three equal lengths. Nalbuphine, venlafaxine, and nordiazepam were detected. The concentration of nalbuphine was similar in the three hair locks: 5.07, 7.06, and 5.70 ng/mg of hair. A hair analysis revealed the repeated intake of nalbuphine by the nurse. This person was treated for depression for several months with Effexor (venlafaxine) and Nordaz (nordiazepam) prior to the investigation. Hair appears to be a unique matrix to provide evidence for chronic drug exposure by establishing a historic record that is not possible by blood or urine analysis.

[Comparative evaluation of clinical symptoms and status of bone metabolism in patients with heroin and buprenorphine addiction in the period of withdrawal].

The purpose of this study was the evaluation of clinical heroin symptoms and buprenorphine drug addiction in the withdrawal period with the purpose of their comparison, study of parameters of bone metabolism in the both groups. In the study group were included 40 patients with heroin and 27 with buprenorphine addiction in the period of abstinence. Our investigations have shown, that in the both groups, among clinical symptoms ossalgias, arthralgias and mialgias attributes to the expressed dysfunction of vegetative system, were most prominent. Decrease of sexual functions was found in half of inspected patients. Biochemical investigations have shown intensive clearance of calcium with the urine that indicates intensifying resorbtion processes in the bone tissue. Symptoms of hypogonadism were accompanied by the decrease of the level of testosterone in the blood. Parameters of mineral consistency of the bone tissue was decreased both in patients with heroin and buprenorphine addiction.

Prescription pain medications: frequently asked questions and answers for health care professionals, and law enforcement personnel.

A consensus document on frequently asked questions, answers and references relating to the use and abuse o f prescription analgesics was released to the public in August 2004 by the Drug Enforcement Administration, Last Acts Partnership, and the Pain & Policies Study Group of the University of Wisconsin. This document provides clear answers to common questions and is intended for primary care clinicians and drug enforcement and regulatory personnel. It clearly states that police and regulatory personnel should not interfere with medical practice and that clinicians have an obligation to practice in a legal manner. Topics addressed include risk assessment, how opioid treatment works, patient behavior, abuse, addiction, rules and laws, and clear descriptions of how and why the DEA may prosecute a clinician.

Novel assay format permitting the prolonged use of regeneration-based sensor chip technology.

A polyclonal antibody raised against morphine-3-glucuronide (M3G, the main metabolite of heroin and morphine) was used in the development of a novel assay format using a surface plasmon resonance (SPR)-based biosensor. Previously developed assays have generated calibration curves based on differences in the quantity of response units binding to the surface of a chip coated with the analyte. The novel assay described here was based on the development of a standard curve using the slope of a series of consecutive binding interactions. Using this format, regeneration between each assay cycle was no longer required. This increased the useable life span of the chip surface and, as a result, decreased the cost associated with the assay. Thus, at least 15 binding interactions could be carried out before the saturation of antibody on the surface of the chip caused the response to deviate significantly from linearity. After 15 nonregenerated binding interactions, the slope still remained within 1.5% of the slope after a single binding event. Analysis time, and the sample volumes required were also markedly decreased while sensitivity was enhanced. The inhibition assay developed had a detection range of 270 to 17,500 pg ml(-1).

[Pregnancy and drug abuse]. / Graviditet og misbrug af narkotiske stoffer.

The antenatal care of pregnant women with drug abuse is very complex and costly both in money and in time. The women often live under different circumstances than non-abusing women, and their personal and social resources are often very small. Collaboration between the hospital and the social system is essential in order to obtain a positive outcome of the pregnancy. Retrospective records of pregnancy, outcome and follow-up on 18 morphine-abusing women referred for delivery at Glostrup hospital in Copenhagen county over the three year period 1992-1994 are reported here. The study show the children are born in relatively good condition, although almost all needed postnatal detoxification, since their mothers was not able to stop their drug abuse during pregnancy. The pregnancy was with few complications because of tight antenatal care for these women. The study also shows a need for defining a common goal for the care of these women and their children and binding political commitments in order to obtain this goal.

[Verification and determination of opiates in the urine and blood with thin-layer chromatography followed by densitometry in fatal cases of drug abuse]. / Dôkaz a stanovenie opiátov v moci a v krvi pri ich zneuzívaní v letálnych prípadoch metódou tenkovrstvovej chromatografie s následnou denzitometriou.

Urine and blood concentrations of free and total morphin or 6-monoacetylmorphin were presented in fatal cases of morphin type opiates abuse. A solid phase extraction method was developed for isolation of drugs and their metabolities from biological material which used Separcol small columns with non-polar contents SI C 18T. Thin layer chromatography with densitometry anabled screening for quality evaluations. Resultes were compared with those obtained by fluoropolarizing immunodetection on Abbotts TDxFLx device. Possibility and cause of false positive results were discussed when using initial, screening, commercially available immunotests.