Preliminary investigations into tris(2,2'-bipyridyl) ruthenium (III) as a chemiluminescent reagent for the detection of 3,6-diacetylmorphine (heroin) on surfaces

The use of tris(2,2'-bipyridyl) ruthenium (III) as a chemiluminescent spray reagent spot-test for heroin is discussed. Two forms of the reagent are investigated an aqueous and an anhydrous where both were found to give vastly different results. The aqueous reagent giving slow, low intensity chemiluminescence whilst the anhydrous reagent gave a fast, bright response in the presence of 3,6-diacetylmorphine. The anhydrous reagent is less sensitive the slow, intensity response is characteristic of only two opiates tested 3,6-diacetylmorphine and 3-monoacetylmorphine.

An improved process for the N-demethylation of opiate alkaloids using an iron(II) catalyst in acetate buffer

An improved process to N-demethylate opiate alkaloids utilising a solution of the ferrous porphyrin, tetrasodium 5,10,15,20-tetra(4-sulfophenyl)porphyrinatoiron(II) [=Fe(II)-TPPS (8)], in acetate buffer is described. This method provided the corresponding N-demethylated opiates in good yield with high reproducibility.

Disciplinary proceedings against doctors who abuse controlled substances

Study examined 27 reports from disciplinary tribunals against medical practitioners who abused narcotic analgesics (often combined with other drugs of addiction) between 2010 and 2015. The study covered all States and Territories except Tasmania (no reports were accessible for this jurisdiction. The reports revealed that 12 medical practitioners were in their 40s; five in their 30s; and one person still in the 20s. Although majority were General Practitioners (15 out of 27), other medical specialties were also represented. Self-administered Pethidine was the most prevalent opioid (11 out of 27), and was the only drug used alone. Morphine was self-administered by six doctors; the same number used high doses of Panadeine Forte, Codeine and Codeine Phosphate, and Fentanyl was abused by five doctors. Surprisingly, fewer medical practitioners appear to use such opiates such as Propofol, Tramadol and Tramol, Oxycodone and Endone. The examination of cases suggests lack of consistency in the imposition of professional sanctions and penalties by the relevant tribunals. The study concludes that disciplinary tribunals should apply the test of proportionality in the form of ‘reasonable necessity’ when deciding whether to remove or suspend the addicted medical practitioner from the Register.

Opioid mu-receptors in the rostral medullary raphe modulate hypoxia-induced hyperpnea in unanesthetized rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ropivacaína isolada e associada ao fentanil ou ao tramadol administrados pela via peridural em cães

A anestesia peridural é amplamente difundida no meio veterinário, utilizando-se o anestésico local isolado ou associado aos opióides, capazes de promover aumento do efeito analgésico. O objetivo deste estudo foi avaliar a função cardiorrespiratória e analgésica da ropivacaína isolada ou associada ao fentanil ou tramadol. Para tanto, oito cães foram tranqüilizados com acepromazina, submetidos à anestesia peridural com um dos seguintes protocolos: GR (ropivacaína), GRF (ropivacaína + fentanil), GRT (ropivacaína + tramadol), em volume total de 0,25ml kg-1, e foram avaliados os parâmetros: freqüência cardíaca e respiratória, temperatura retal, pressão arterial sistólica, e gasometria do sangue arterial, os bloqueios sensitivo e motor, o grau de sedação e a ocorrência de possíveis efeitos indesejáveis. A diminuição da freqüência cardíaca nos grupos GRF e GRT foi mais intensa e ocorreu hipotermia significativa no GRF. Foi evidenciada sedação severa em GRF e GRT. O período de recuperação foi mais curto nos animais de GRT. O GRT foi o grupo que apresentou bloqueio mais cranial. Foram observadas bradicardia, hipotermia e síndrome de Shiff-Sherrington no período trans-anestésico em animais de todos os grupos. Nas 24 horas de período pós-anestésico, não foram evidenciados efeitos indesejáveis nos grupos. O GRF apresentou maior duração de anestesia e analgesia, enquanto que o GRT apresentou a menor duração de anestesia com analgesia intermediária e o GR apresentou duração intermediária, com menor analgesia. Não foram encontradas alterações respiratórias e hemogasométricas, porém, bradicardia, hipotermia e síndrome de Schiff-Sherrington, alterações trans-anestésicas comuns na anestesia peridural foram encontradas.

Opiate activation suppresses the drinking, pressor and natriuretic responses induced by cholinergic stimulation of the medial septal area

The present study investigates the participation and interaction between cholinergic and opiate receptors of the medial septal area (MSA) in the regulation of Na+, K+ and water excretion, drinking and blood pressure regulation. Male Holtzman rats were implanted with stainless steel cannulae opening into the MSA. Na+, K+ and water excretion, water intake and blood pressure were measured after injection of carbachol (cholinergic agonist), FK-33824 (an opiate agonist) + carbachol or naloxone (an opiate antagonist) + carbachol into MSA. Carbachol (0.5 or 2.0 nmol) induced an increase in Na+ and K+ excretion, water intake and blood pressure and reduced the urinary volume. FK-33824 reduced the urinary volume and Na+ and K+ excretion. Previous injection of FK-33824 (100 ng) into the MSA blocked the increases in Na+ and K+ excretion, water intake and blood pressure induced by carbachol. Naloxone (10 μg) produced no changes in the effect of 2.0 nmol carbachol, but potentiated the natriuretic effect induced by 0.5 nmol dose of carbachol. These data show an inhibitory effect of opiate receptors on the changes in cardiovascular, fluid and electrolyte balance induced by cholinergic stimulation of the MSA in rats. © 1992.

Avaliação cardiorrespiratória e analgésica da ropivacaína isolada e associada ao fentanil ou ao tramadol, administrados pela via peridural em cães

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Opioid mu-receptors in the rostral medullary raphe modulate hypoxia-induced hyperpnea in unanesthetized rats

Aim: It has been suggested that the medullary raphe (MR) plays a key role in the physiological responses to hypoxia. As opioid mu-receptors have been found in the MR, we studied the putative role of opioid mu-receptors in the rostral MR (rMR) region on ventilation in normal and 7% hypoxic conditions. Methods: We measured pulmonary ventilation ((V) over dotE) and the body temperatures (Tb) of male Wistar rats before and after the selective opioid l-receptor antagonist CTAP ( d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2, cyclic, 0.1 mu g per 0.1 mu L) was microinjected into the rMR during normoxia or after 60 min of hypoxia. Results: The animals treated with intra-rMR CTAP exhibited an attenuation of the ventilatory response to hypoxia ( 430 +/- 86 mL kg) 1 min) 1) compared with the control group ( 790 +/- 82 mL kg) 1 min) 1) ( P < 0.05). No differences in the Tb were observed between groups during hypoxia. Conclusion: These data suggest that opioids acting on l-receptors in the rMR exert an excitatory modulation of hyperventilation induced by hypoxia.

Effects of high-dose heroin versus morphine in intravenous drug users: a randomised double-blind crossover study

The purpose of this study is to evaluate the effects of high doses of injected opiates as prescribed maintenance in intravenous drugs users. This was accomplished via a randomised double-blind study with crossover at an outpatient clinic in Bern, Switzerland. The subjects were 39 patients with a long history of intravenous opioid use and persistent abuse despite treatment; they were randomly allocated to two groups. Group A was started on controlled injection of graduated doses of morphine up to a satisfying individual dose and was then switched as a double blind to heroin at a randomly determined day between week three and four. Subsequently this group was given heroin for the remaining two to three weeks of the study. Group B was started on heroin and was then switched to morphine in the same manner. Equipotent solutions of 3% morphine and 2% heroin were administered. The main outcome measures were clinical observations, structural interviews and self report of subjective experiences to assess the effects of the drugs. In 16 cases, the study had to be discontinued owing to severe morphine-induced histamine reactions. Thirteen participants in Group B presented these adverse reactions on the day of the switch-over. Full data were thus only obtainable for 17 participants. Average daily doses were 491 mg for heroin and 597 mg for morphine. The findings indicate that heroin significantly produced a lower grade of itching, flushing, urticaria and pain/nausea. A negative correlation between dose and euphoria was observed for both heroin and morphine. The authors concluded that as heroin produces fewer side effects it is the preferred high-dose maintenance prescription to morphine. The perceived euphoric effects are limited in both substances.

Characteristics and experiences of past participants in the Texas Peer Assistance Program for Nurses

There are nearly 200,000 licensed practicing nurses in the state of Texas, representing one-tenth of the nations' workforce. The prevalence of substance abuse among nurses is estimated to range between six and 20 percent in this professional group.^ Since March 1987, the Texas Peer Assistance Program for Nurses (TPAPN) has offered intervention, education, support and monitoring to nurses in Texas whose practice has become impaired due to substance abuse and/or mental illness. Since then approximately 44 percent of nurses who voluntarily signed participation agreements successfully completed the program; fifty-six percent have not. One determinant of completion for those nurses identified as chemically dependent is abstinence from mood altering substances. Other helping professions report higher rates of abstinence two years following treatment.^ The purpose of this study was to investigate the relationship between relapse, demographics, treatment variables, work setting, "stress" indicators and support factors for nurses who participated in TPAPN. A questionnaire was mailed to 1000 randomly selected nurses who had signed agreements since 1987 and were no longer active in the program. More than 41% of the questionnaires were returned undeliverable.^ Recipients of the questionnaire were known only to TPAPN, never to the investigator. All information was received anonymously except when the participant chose to sign the questionnaire. A cover letter explaining the study and inviting participation was enclosed. Completion and return of the questionnaire was considered consent to participate.^ Findings demonstrated a significant relationship between relapse and opiates as the drug of choice for past participants in the Texas Peer Assistance Program for Nurses. Significant associations were found among factors such as control at work, support, physical complaints, job security, self-esteem and employment in this sample. Respondents shared copious written comments about their experiences in TPAPN. These data were analyzed using qualitative methods and compared with similar studies of recovering nurses. Further research with nurses whose practice has been affected by abuse of chemical and mental illness is warranted. ^

Association between ethnicity and treatment status in opioid dependence therapy using methadone and suboxone drugs

Opioids are drugs with opium-like qualities that are either derived from opiates (drugs created from opium, such as morphine or codeine) or chemically produced. In the U.S. opiate abuse and related deaths have been increasing and traditional maintenance treatment has been Methadone with variable success. However, since 2003 synthetic Buprenorphine has been used since it is prescribed daily by physicians in pill form and should improve outcomes. Comparative studies are limited and the effect of ethnicity on treatment outcome is unknown. ^ Data collected at one clinic from December 2005 through May 2009 were used to compare the association between ethnicity and other socioeconomic variables with treatment status, and to identify factors associated with the dropout among participants. Descriptive tables and multiple logistic regression models were used to examine the data on 1,295 total participants. Of the total, 875 participants (68%) were from the Methadone subsample and 420 participants (32%) from the Buprenorphine subsample; only about 15% stayed in treatment. ^ This study showed that with either Methadone or Buprenorphine maintenance therapy, only about 15% participants stay active over 3.5 years. Methadone treated patients that stayed active in treatment were associated with Caucasian ethnicity and were more likely to be employed. With Buprenorphine maintenance treatment only age over 40 years was associated with continuing activity in the program. Further studies that examine the reasons for the high dropout status and the implication of the socioeconomic and ethnic associations found in this data may help to improve treatment outcomes.^

Abolition of morphine-immunosuppression in mice lacking the μ-opioid receptor gene

Opiates are potent analgesic and addictive compounds. They also act on immune responses, and morphine, the prototypic opiate, has been repeatedly described as an immunosuppressive drug. Pharmacological studies have suggested that the inhibitory action of opiates on immunity is mediated by multiple opioid receptor sites but molecular evidence has remained elusive. Recently, three genes encoding μ- (MOR), δ-, and κ-opioid receptors have been cloned. To investigate whether the μ-opioid receptor is functionally implicated in morphine immunosuppression in vivo, we have examined immune responses of mice with a genetic disruption of the MOR gene. In the absence of drug, there was no difference between wild-type and mutant mice with regard to a large number of immunological endpoints, suggesting that the lack of MOR-encoded protein has little consequence on immune status. Chronic morphine administration induced lymphoid organ atrophy, diminished the ratio of CD4+CD8+ cells in the thymus and strongly reduced natural killer activity in wild-type mice. None of these effects was observed in MOR-deficient mice after morphine treatment. This demonstrates that the MOR gene product represents a major molecular target for morphine action on the immune system. Because our previous studies of MOR-deficient mice have shown that this receptor protein is also responsible for morphine analgesia, reward, and physical dependence, the present results imply that MOR-targeted therapeutic drugs that are developed for the treatment of pain or opiate addiction may concomitantly influence immune responses.

Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons.

The mesolimbic dopamine system, which arises in the ventral tegmental area (VTA), is an important neural substrate for opiate reinforcement and addiction. Chronic exposure to opiates is known to produce biochemical adaptations in this brain region. We now show that these adaptations are associated with structural changes in VTA dopamine neurons. Individual VTA neurons in paraformaldehyde-fixed brain sections from control or morphine-treated rats were injected with the fluorescent dye Lucifer yellow. The identity of the injected cells as dopaminergic or nondopaminergic was determined by immunohistochemical labeling of the sections for tyrosine hydroxylase. Chronic morphine treatment resulted in a mean approximately 25% reduction in the area and perimeter of VTA dopamine neurons. This reduction in cell size was prevented by concomitant treatment of rats with naltrexone, an opioid receptor antagonist, as well as by intra-VTA infusion of brain-derived neurotrophic factor. In contrast, chronic morphine treatment did not alter the size of nondopaminergic neurons in the VTA, nor did it affect the total number of dopaminergic neurons in this brain region. The results of these studies provide direct evidence for structural alterations in VTA dopamine neurons as a consequence of chronic opiate exposure, which could contribute to changes in mesolimbic dopamine function associated with addiction.

Dual signal transduction through delta opioid receptors in a transfected human T-cell line.

Opiates are known to function as immunomodulators, in part by effects on T cells. However, the signal transduction pathways mediating the effects of opiates on T cells are largely undefined. To determine whether pathways that regulate free intracellular calcium ([Ca2+]i) and/or cAMP are affected by opiates acting through delta-type opioid receptors (DORs), a cDNA encoding the neuronal DOR was expressed in a stably transfected Jurkat T-cell line. The DOR agonists, deltorphin and [D-Ala2, D-Leu5]-enkephalin (DADLE), elevated [Ca2+]i, measured by flow cytofluorometry using the calcium-sensitive dye, Fluo-3. At concentrations from 10(-11)-10(-7) M, both agonists increased [Ca2+]i from 60 nM to peak concentrations of 400 nM in a dose-dependent manner within 30 sec (ED50 of approximately 5 x 10(-9) M). Naltrindole, a selective DOR antagonist, abolished the increase in [Ca2+]i, and pretreatment with pertussis toxin was also effective. To assess the role of extracellular calcium, cells were pretreated with EGTA, which reduced the initial deltorphin-induced elevation of [Ca2+]i by more than 50% and eliminated the second phase of calcium mobilization. Additionally, the effect of DADLE on forskolin-stimulated cAMP production was determined. DADLE reduced cAMP production by 70% (IC50 of approximately equal to 10(-11) M), and pertussis toxin inhibited the action of DADLE. Thus, the DOR expressed by a transfected Jurkat T-cell line is positively coupled to pathways leading to calcium mobilization and negatively coupled to adenylate cyclase. These studies identify two pertussis toxin-sensitive, G protein-mediated signaling pathways through which DOR agonists regulate the levels of intracellular messengers that modulate T-cell activation.

Decreased brain reward produced by ethanol withdrawal.

Abstinence from chronic administration of various drugs of abuse such as ethanol, opiates, and psychostimulants results in withdrawal syndromes largely unique to each drug class. However, one symptom that appears common to these withdrawal syndromes in humans is a negative affective/motivational state. Prior work in rodents has shown that elevations in intracranial self-stimulation (ICSS) reward thresholds provide a quantitative index that serves as a model for the negative affective state during withdrawal from psychostimulants and opiates. The current study sought to determine whether ICSS threshold elevations also accompany abstinence from chronic ethanol exposure sufficient to induce physical dependence. Rats prepared with stimulating electrodes in the lateral hypothalamus were trained in a discrete-trial current-intensity ICSS threshold procedure; subsequently they were subjected to chronic ethanol administration in ethanol vapor chambers (average blood alcohol level of 197 mg/dl). A time-dependent elevation in ICSS thresholds was observed following removal from the ethanol, but not the control, chambers. Thresholds were significantly elevated for 48 hr after cessation of ethanol exposure, with peak elevations observed at 6-8 hr. Blood alcohol levels were directly correlated with the magnitude of peak threshold elevation. Ratings of traditional overt signs of withdrawal showed a similar time course of expression and resolution. The results suggest that decreased function of reward systems (elevations in reward thresholds) is a common element of withdrawal from chronic administration of several diverse classes of abused drugs.