Hair morphine concentrations of fatal heroin overdose cases and living heroin users

Aims To compare heroin and other opiate use of heroin overdose fatalities, current street heroin users and drug-free therapeutic community clients. Design Hair morphine concentrations that assess heroin use and other opiate use in the 2 months preceding interview or death were compared between heroin overdose fatalities diagnosed by forensic pathologists (fOD) (n = 42), current street heroin users (CU) (n = 100) and presumably abstinent heroin users in a drug-free therapeutic community (TC) (n = 50). Setting Sydney, Australia. Findings The mean age and gender breakdown of the three samples were 32.3 years, 83% male (FOD), 28.7 years, 58% male (CU) and 28.6 years, 60% male (TC). The median blood morphine concentration among the FOD cases was 0.35 mg/l, and 82% also had other drugs detected. There were large differences between the three groups in hair morphine concentrations, with the CU group (2.10 ng/mg) having concentration approximately four times that of the FOD group (0.53 ng/mg), which in turn had a concentration approximately six times that of the TC group (0.09 ng/mg). There were no significant differences between males and females in hair concentrations within any of the groups. Hair morphine concentrations were correlated significantly with blood morphine concentrations among FOD cases (r = 0.54), and self-reported heroin use among living participants (r = 0.57). Conclusions The results indicate that fatal cases had a lower degree of chronic opiate intake than the active street users, but they were not abstinent during this period.

Systemic coadministration of chloramphenicol with intravenous but not intracerebroventricular morphine markedly increases morphine antinociception and delays development of antinociceptive tolerance in rats

Chloramphenicol, an in vitro inhibitor of the glucuronidation of morphine to its putative antianalgesic metabolite, morphine-3-glucuronide (M3G), was coadministered with morphine in adult male Sprague-Dawley rats to determine whether it inhibited the in vivo metabolism of morphine to M3G, thereby enhancing morphine antinociception and/or delaying the development of antinociceptive tolerance. Parenteral chloramphenicol was given acutely (3-h studies) or chronically (48-h studies). Morphine was administered by the i.v. or i.c.v. route. Control rats received chloramphenicol and/or vehicle. Antinociception was quantified using the hotplate latency test. Coadministration of chloramphenicol with i.v. but not i.cv. morphine increased the extent and duration of morphine antinociception by approximate to 5.5-fold relative to rats that received i.v. morphine alone. Thus, the mechanism through which chloramphenicol enhances i.v. morphine antinociception in the rat does not directly involve supraspinal opioid receptors. Acutely, parenteral coadministration of chloramphenicol and morphine resulted in an approximate to 75% increase in the mean area under the serum morphine concentration-time curve but for chronic dosing there was no significant change in this curve, indicating that factors other than morphine concentrations contribute significantly to antinociception. Antinociceptive tolerance to morphine developed more slowly in rats coadministered chloramphenicol, consistent with our proposal that in vivo inhibition of M3G formation would result in increased antinociception and delayed development of tolerance. However, our data also indicate that chloramphenicol inhibited the biliary secretion of M3G. Whether chloramphenicol altered the passage of M3G and morphine across the blood-brain barrier remains to be investigated.

Alfaxalone-butorphanol versus alfaxalone-morphine combination for immersion anaesthesia in oriental fire-bellied toads (Bombina orientalis)

Oriental fire-bellied toads (Bombina orientalis) are small semi-aquatic anuran species popular as both pets and laboratory animals. Although they are commonly anaesthetized to undergo clinical and experimental procedures, very little is known about their anaesthetic management. The aims of this prospective, randomized, cross-over experimental trial were to establish effective butorphanol and morphine concentrations to be added to alfaxalone for immersion anaesthesia (pilot study), and to compare the anaesthetic and antinociceptive effects of the two drug mixtures (alfaxalone-butorphanol and alfaxalone-morphine), in Bombina orientalis toads. For the actual trial, the toads were randomly assigned to one of two treatment groups: AB and AM, with seven animals in each group, which received alfaxalone-butorphanol and alfaxalone-morphine combinations, respectively, at the concentrations established during the pilot study. Heart rate, respiratory rate, von Frey filament threshold and response to nociceptive withdrawal (NWR), righting and myotactic reflexes were measured at 5 min intervals until return of righting reflex was observed. The investigator who carried out all the measurements was blinded to the treatment. Any undesired effect or complication was noted and recorded. The two treatments were found to be comparable in terms of onset and duration of anaesthesia, and occurrence of undesired effects. However, group AM resulted in lower NWR scores and higher von Frey filament thresholds than group AB. It is concluded that, at the investigated concentrations and in combination with alfaxalone by immersion, morphine provides better antinociception than butorphanol in oriental fire-bellied toads.

Heroin overdose: causes and consequences

Over the past decade fatal opioid overdose has emerged as a major public health issue internationally. This paper examines the risk factors for overdose from a biomedical perspective. while significant risk factors for opioid overdose fatality are well recognized, the mechanism of fatal overdose remains unclear. Losses of tolerance and concomitant use of alcohol and other CNS depressants clearly play a major role in fatality; howeve, such risk factors do not account for the strong age and gender patterns observed consistently among victims of overdose. There is evidence that systemic disease may be more prevalent in users at greatest risk of overdose. We hypothesize that pulmonary and hepatic dysfunction resulting from such disease may increase susceptibility to both fatal and non-fatal overdose. Sequelae of non-fatal overdose are recognized in the clinical literature but few epidemiological data exist describing the burden of morbidity arising from such sequelae. The potential for overdose to cause persisting morbidity is reviewed.

Heroin overdose: Research and evidence-based intervention

Drug overdose is a major cause of Premature death and morbidity among heroin users. This article examines recent research into heroin overdose to inform interventions that will reduce the rate of overdose death. The demographic characteristics of overdose cases are discussed, including factors associated with overdose: polydrug use, drug purity, drug tolerance, routes of administration, and suicide. Responses by heroin users at overdoses are also examined. Potential interventions to reduce the rate of overdose and overdose-related morbidity are examined in light of the emerging data in this field.

Codeine and breastfeeding: cases and STIS position

Codeine is commonly used in North America in the postpartum period for pain associated with episotomyand caesarean section. Analgesic properties of codeine are mainly due to its metabolisation intomorphine (5-10%) via CYP2D6. This enzyme is subject to genetic variability, which can alter theamount of active narcotic excreted into breastmilk. A recent case report highlighted this issue, reportingfatal consequences in a newborn whose mother was taking codeine for episiotomy-related pain (1-2). New-born's blood (post-mortem) and mother's milk showed high morphine concentrations. Genotypeanalysis classified the mother as a CYP2D6 ultrarapid metabolizer, a genotype associated withenhanced formation of morphine from codeine. The authors concluded "clinical and laboratory picturewas consistent with opioid toxicity leading to neonatal death". Subsequent comments expressed reasonnabledoubts on this conclusion, though (3-4). Since, anxiety increased about the safety of codeineduring breastfeeding and genetic screening was proposed as a prevention strategy.STIS position:? Codeine with paracetamol is not a usual pain prescription in the postpartum period in Switzerland.This markedly reduces codeine use during lactation in our country, and may partly explain why webarely collected 3 codeine exposures through breastmilk in 15 years at the STIS (all reported afterabove case's publication and without side effects).? Other centrally acting analgesics are not considered safer (5) than codeine during lactation andrequire close observation for somnolence in both the mother and the infant in case of repeated maternaldosage. A lack of monitoring was salient in the case reported above (1).? If the incidence of CYP2D6 polymorphism (1-10% of individuals in Western Europe) (6) can beconsidered of clinical significance, it is not the exclusive predisposing factor to toxic effects. Healthynewborns can be particularly sensitive to even usual doses of narcotic analgesics because of immaturedrug disposition (7). Conditions leading to impaired clearance or increased susceptibility inthe infant (e.g. preterm birth, metabolic diseases) represent further risk factors for opioid toxicity,regardless of the molecule.In conclusion, when prescribed on a large scale, codein can be rarely associated with adverse drugreactions in breastfed infants (8-9). However, other central acting analgesics cannot be considered asinvariably safer. Therefore, paracetamol and well documented NSAID should be used in 1st choiceduring lactation. In case of severe pain, codeine (with paracetamol) remains an acceptable choice butrequires close monitoring, and breastfeeding mothers should be educated regarding risks related toaccumulation in the newborn. Finally, it is doubtful whether CYP2D6 genetic screening would preventall toxic effects, as other risk factors exist for opioids toxicity

Determination of Opiates in Whole Blood and Vitreous Humor: A Study of the Matrix Effect and an Experimental Design to Optimize Conditions for the Enzymatic Hydrolysis of Glucuronides

Faculty of Medicine University of Sao Paulo

Cerebrospinal fluid and plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in patients before and after initiation of intracerebroventricular morphine for cancer pain management

Twenty-three patients treated with intracerebroventricular (ICV) morphine in this study not only obtained excellent pain relief without rapid increases in dose, but also experienced a reduction in morphine-related side effects. By 24 h after initiation of ICV morphine, the mean trough cerebrospinal fluid (CSF) morphine concentration (approximately 20 mu M) was 50-fold higher than the baseline concentration (approximately 0.4 mu M), and the CSF concentration of morphine-6-glucuronide (M6G) was undetectable (

Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment.

Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NTX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions. Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca(2+)-dependent component of the action potential duration (APD) elicited by picomolar-nanomolar morphine and unmasks inhibitory APD shortening. The present study provides a cellular mechanism to account for previous reports that low doses of NLX and NTX paradoxically enhance, instead of attenuate, the analgesic effects of morphine and other opioid agonists. Furthermore, chronic cotreatment of DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents the development of (i) tolerance to the inhibitory APD-shortening effects of high concentrations of morphine and (ii) supersensitivity to the excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low (femtomolar-picomolar) concentrations of morphine and other opioid agonists. These in vitro studies suggested that ultra-low doses of NLX or NTX that selectively block the excitatory effects of morphine may not only enhance the analgesic potency of morphine and other bimodally acting opioid agonists but also markedly attenuate their dependence liability. Subsequent correlative studies have now demonstrated that cotreatment of mice with morphine plus ultra-low-dose NTX does, in fact, enhance the antinociceptive potency of morphine in tail-flick assays and attenuate development of withdrawal symptoms in chronic, as well as acute, physical dependence assays.

Simultaneous determination of morphine, oxycodone, morphine-3-glucuronide, and noroxycodone concentrations in rat serum by high performance liquid chromatography-electrospray ionization-tandem mass spectrometry

An assay using high performance liquid chromatography (HPLC)-electrospray ionization-tandem mass spectrometry (ESI-MS-MS) was developed for simultaneously determining concentrations of morphine, oxycodone, morphine-3-glucuronide, and noroxycodone, in 50 mul samples of rat serum. Deuterated (d(3)) analogues of each compound were used as internal standards. Samples were treated with acetonitrile to precipitate plasma proteins: acetonitrile was removed from the supernatant by centrifugal evaporation before analysis. Limits of quantitation (ng/ml) and their between-day accuracy and precision (%deviation and %CV) were-morphine, 3.8 (4.3% and 7.6%); morphine-3-glucuronide, 5.0 (4.5% and 2.9%); oxycodone, 4.5 (0.4% and 9.3%); noroxycodone, 5.0 (8.5% and 4.6%). (C) 2004 Elsevier B.V. All rights reserved.

Morphine has a dual concentration-dependent effect on K+-evoked substance P release from rat peripheral airways

Our previous investigations of possible lung mechanisms underlying the effectiveness of nebulized morphine for the relief of dyspnoea, have shown a high density of non-conventional opioid binding sites in rat airways with similar binding characteristics (opioid alkaloid-sensitive, opioid peptide-insensitive) to that of putative mu(3)-opioid receptors on immune cells. To investigate whether these lung opioid binding sites are functional receptors, this study was designed to determine (using superfusion) whether morphine modulates the K+-evoked release of the pro-inflammatory neuropeptide, substance P (SP), from rat peripheral airways. Importantly, K+-evoked SP release was Ca2+-dependent, consistent with vesicular release. Submicromolar concentrations of morphine (1 and 200 nM) inhibited K+-evoked SP release from rat peripheral airways in a naloxone (1 mu M) reversible manner. By contrast, 1 mu M morphine enhanced K+-evoked SP release and this effect was not reversed by 1 mu M naloxone. However, 100 mu M naloxone not only antagonized the facilitatory effect of 1 mu M morphine on K+-evoked SP release from rat peripheral airways but it inhibited release to a similar extent as 200 nM morphine. It is possible that these latter effects are mediated by non-conventional opioid receptors located on mast cells, activation of which causes naloxone-reversible histamine release that in turn augments the release of SP from sensory nerve terminals in the peripheral airways. Clearly, further studies are required to investigate this possibility. (C) 1997 Academic Press Limited.

Comparison of the effects of tramadol, codeine, and ketoprofen alone or in combination on postoperative pain and on concentrations of blood glucose, serum cortisol, and serum interleukin-6 in dogs undergoing maxillectomy or mandibulectomy

Objective-To compare analgesic effects of tramadol, codeine, and ketoprofen administered alone and in combination and their effects on concentrations of blood glucose, serum cortisol, and serum interleukin (IL)-6 in dogs undergoing maxillectomy or mandibulectomy. Animals-42 dogs with oral neoplasms. Procedures-30 minutes before the end of surgery, dogs received SC injections of tramadol (2 mg/kg), codeine (2 mg/kg), ketoprofen (2 mg/kg), tramadol + ketoprofen, or codeine + ketoprofen (at the aforementioned dosages). Physiologic variables, analgesia, and sedation were measured before (baseline) and 1, 2, 3, 4, 5, and 24 hours after surgery. Blood glucose, serum cortisol, and serum IL-6 concentrations were measured 1, 3, 5, and 24 hours after administration of analgesics. Results-All treatments provided adequate postoperative analgesia. Significant increases in mean +/- SD blood glucose concentrations were detected in dogs receiving tramadol (96 +/- 14 mg/dL), codeine (120 +/- 66 mg/dL and 96 +/- 21 mg/dL), ketoprofen (105 +/- 22 mg/dL), and codeine + ketoprofen (104 +/- 16 mg/dL) at 5, 1 and 3, 5, and 3 hours after analgesic administration, respectively, compared with preoperative (baseline) values. There were no significant changes in physiologic variables, serum IL-6 concentrations, or serum cortisol concentrations. Dogs administered codeine + ketoprofen had light but significant sedation at 4, 5, and 24 hours. Conclusions and Clinical Relevance-Opioids alone or in combination with an NSAID promoted analgesia without adverse effects during the 24-hour postoperative period in dogs undergoing maxillectomy or mandibulectomy for removal of oral neoplasms. (Am J Vet Res 2010;71:1019-1026)

Therapeutic concentration of morphine reduces oxidative stress in glioma cell line

Morphine is a potent analgesic opioid used extensively for pain treatment. During the last decade, global consumption grew more than 4-fold. However, molecular mechanisms elicited by morphine are not totally understood. Thus, a growing literature indicates that there are additional actions to the analgesic effect. Previous studies about morphine and oxidative stress are controversial and used concentrations outside the range of clinical practice. Therefore, in this study, we hypothesized that a therapeutic concentration of morphine (1 μM) would show a protective effect in a traditional model of oxidative stress. We exposed the C6 glioma cell line to hydrogen peroxide (H2O2) and/or morphine for 24 h and evaluated cell viability, lipid peroxidation, and levels of sulfhydryl groups (an indicator of the redox state of the cell). Morphine did not prevent the decrease in cell viability provoked by H2O2 but partially prevented lipid peroxidation caused by 0.0025% H2O2 (a concentration allowing more than 90% cell viability). Interestingly, this opioid did not alter the increased levels of sulfhydryl groups produced by exposure to 0.0025% H2O2, opening the possibility that alternative molecular mechanisms (a direct scavenging activity or the inhibition of NAPDH oxidase) may explain the protective effect registered in the lipid peroxidation assay. Our results demonstrate, for the first time, that morphine in usual analgesic doses may contribute to minimizing oxidative stress in cells of glial origin. This study supports the importance of employing concentrations similar to those used in clinical practice for a better approximation between experimental models and the clinical setting.