Blood Morphine Concentration Research Articles

Determination of morphine in postmortem rabbit bone marrow and comparison with blood morphine concentrations

The aim of this study is to predict how long after time of death a buried body could be analyzed for opiates in soft tissues and to show the accessibility and suitability of bone marrow as a useful toxicological specimen from buried bodies. Morphine solutions were injected in nine albino rabbits. Doses ranged from 0.3 to 1.1 mg/kg with 0.1 mg/kg increments. One hour after the injections, the rabbits were sacrificed. Blood, urine and bone marrow samples were collected for analysis. After the whole bodies were buried, femur bone marrow specimens were collected on the seventh and fourteenth days. CEDIA ® was used to monitor morphine contents of the collected samples. All experimental cases showed that the increase in the given morphine doses correlated with the increase in blood and bone marrow morphine concentrations. High morphine concentrations were detected in urine samples, but there was no correlation between the urine and blood or urine and bone marrow morphine concentrations. Statistically meaningful increases in bone marrow morphine concentrations were found parallel to increase of blood morphine concentrations. Seventh and fourteenth day postmortem morphine concentrations also followed this correlation. Morphine concentrations in bone marrow at 7 and 14 day postmortem decreased consistently when compared with bone marrow morphine concentrations collected immediately after death. We conclude that in sudden death when other specimens are unavailable due to degradation, bone marrow can be a most useful specimen. Further experimental research in this area is required to validate bone marrow as an alternative tissue.

Postmortem Morphine Concentrations Following Use of a Continuous Infusion Pump

We report a case involving unusually high postmortem morphine concentrations in a 44-year-old male with end-stage pancreatic cancer. He was receiving morphine for pain control via a single subclavian intravenous catheter. Allegations of foul play were made by family members at the time of death, so a full autopsy was performed. Comprehensive toxicology on autopsy samples indicated that morphine was the only drug present. Quantitative analysis of free and total morphine revealed extraordinarily high concentrations of the drug. Free morphine concentrations in heart blood, vitreous fluid, brain, liver, stomach contents, and urine were 96 mg/L, 52 mg/L, 26 mg/kg, 88 mg/kg, 82 mg/L, and 976 mg/L, respectively. Total morphine concentrations in heart blood, vitreous fluid, brain, liver, and stomach contents were 421 mg/L, 238 mg/L, 65 mg/kg, 256 mg/kg, and 325 mg/L, respectively. Records indicate that the infusion pump may have continued to deliver the drug for 15-45 min following death. Despite compelling toxicological data, the cause of death was determined to be complication of adenocarcinoma of the pancreas, and the manner was natural. This report highlights issues surrounding postmortem toxicological interpretation within the context of chronic pain management.

<b>Comparison of activity scores measured by the wrist actigraph, morphine concentrations in blood and visual analogue scale scores before and after </b><b>the subcutaneous administration of a rescue </b><b>morphine for patients with cancer pain </b>

<b>Comparison of activity scores measured by the wrist actigraph, morphine concentrations in blood and visual analogue scale scores before and after </b><b>the subcutaneous administration of a rescue </b><b>morphine for patients with cancer pain </b>

Fatal intoxication as a consequence of intranasal administration (snorting) or pulmonary inhalation (smoking) of heroin

In recent years we have noticed an increasing proportion of mortalities resulting from an overdose of heroin that involve routes of administration other than injection. Of 239 cases of fatal heroin intoxication examined at our department during the period 1997–2000, 18 deaths were associated with non-parental administration. Seven of these fatalities were experienced heroin users who had begun to use more sporadically, seven were recreational “party-users”, while the remaining four persons had relapsed into heroin use following long periods of abstinence. The median blood morphine concentration of these non-injectors was 0.095 μg/g (range: 0.02–0.67 μg/g), significantly lower than that of the injectors. Concurrent use of alcohol, other illicit drugs and/or pharmaceutical preparations was observed in 17 of the 18 cases. However, there were no statistically significant differences between the victims of heroin intoxication by injection or by other routes with respect to the proportion who had simultaneously consumed alcohol or benzodiazepines. Pathological alterations like lung fibrosis, liver cirrhosis, endocarditis, etc. were not found to play a significant role in any of the 18 mortalities. We conclude that snorting or smoking heroin probably involves a reduced risk of obtaining high blood concentrations of morphine but still constitutes a considerable risk of lethal outcome due to high variability in blood concentrations. Furthermore, decreased tolerance resulting from periods of reduced or sporadic use appears to be an important risk factor in connection with heroin overdosing by snorting or smoking, which indicate that some heroin addicts may inaccurately assume that these routes of administration are safe when resuming their use of heroin after a period of abstinence.

Blood morphine levels in naltrexone-exposed compared to non-naltrexone-exposed fatal heroin overdoses.

The aim of this study was to investigate the association between prior exposure to naltrexone and increased risk of fatal heroin overdose using a review of toxicology reports for heroin-related fatalities between July 1997 to August 1999 for two groups: those treated with oral naltrexone and those who were not treated. Additional information for the oral naltrexone group was obtained from clinic files. Naltrexone-treated deaths were identified from the patient database at the Australian Medical Procedures Research Foundation (AMPRF), Perth, Western Australia (WA) through the Western Australian Department of Health, Data Linkage Project. Non-treated cases were identified from the database at the Forensic Science Laboratory, State Chemistry Centre (WA). We identified and investigated blood morphine concentrations following 21 fatal heroin overdoses with prior exposure to naltrexone and in 71 non-naltrexone-exposed cases over the same time period. The proportion of deaths where heroin use was a major contributing factor was little different in the non-naltrexone compared to the naltrexone-exposed group. Furthermore, in 'acute opiate toxicity' deaths, blood morphine levels were lower in non-naltrexone-exposed compared with naltrexone-exposed cases. Although there was a higher number of deaths designated as rapid (i.e. occurring within 20 minutes) in the naltrexone-exposed (89%) compared with the non-exposed group (72%) this was not statistically significant. Other drug use in relation to heroin-related fatalities is discussed. Findings do not support the hypothesis that prior exposure to naltrexone increases sensitivity to heroin toxicity.

Codeine and Morphine Blood Concentrations Increase During Blood Loss

During extensive blood loss, a plasma volume refill will take place by transfer of extravascular fluid into the circulation. Drugs present in this fluid may follow and cause a rise or a drop in blood drug concentration, depending on their levels and accessibility in the restoration fluid. This study explored the possible changes of codeine, and its metabolite morphine, in whole blood during a standardized exsanguination in the rat. Three doses containing 5 mg codeine were given orally. In eight rats, blood loss was accomplished by slowly withdrawing 0.8 mL blood at 10 min intervals during 70 min. In control rats, blood was withdrawn only at 0 and 70 min. At 70 min, the final/initial codeine and morphine concentration ratios were 0.70 +/- 0.38 and 0.88 +/- 0.47, respectively, in controls, but increased to 1.28 +/- 0.44 (p = 0.014) and 1.41 +/- 0.34 (p = 0.021), respectively, in exsanguinated rats. It is concluded that blood loss can affect blood drug concentrations.

Use of morphine and 6-monoacetylmorphine in blood for the evaluation of possible risk factors for sudden death in 192 heroin users.

To detect risk factors for sudden death from heroin injection. Evaluation of data from forensic investigations of all fatal cases of suspected heroin death in a metropolitan area. Only cases with detectable morphine and 6-monoacetylmorphine (6-MAM) in blood were included in order to select heroin intoxication cases. Stockholm, Sweden. Autopsy investigation and toxicological analysis of blood and urine; and police reports. In two-thirds of the 192 cases, death occurred in public places, and mostly without any time delay. Blood concentrations of morphine ranged from 50 to 1200 ng/g, and of 6-MAM from 1 to 80 ng/g. Codeine was detected in 96% of the subjects. In the majority of cases the forensic investigation indicated polydrug use, the most common additional findings being alcohol and benzodiazepines. However, in one-quarter of the cases other drug combinations were found. Previous abstinence from heroin and use of alcohol were identified as risk factors. For 6-MAM there was also a correlation with the presence of THC and benzodiazepines. Despite a high frequency of heart abnormalities (e.g. myocarditis and focal myocardial fibrosis), these conditions did not correlate with morphine or 6-MAM blood concentrations. We confirm that alcohol intake and loss of tolerance are risk factors for death from heroin use, whereas no connection to heart pathology was observed. Further, prospective, studies should focus on other possible risk factors.

Codeine and clinical impairment in samples in which morphine is not detected

Codeine metabolises partly to morphine by the liver enzyme CYP2D6, which is subject to genetic polymorphism. It has been suggested that analgesic effects of codeine are due to the morphine metabolite. Codeine effects other than analgesia have been less investigated in this regard, but it has been suggested that sedation, for example, might be independent of morphine formation. The aim of our study was to investigate the influence of codeine alone, without concomitant presence of morphine, on a clinical test for drunkenness (CTD) performed in relation to suspected drugged driving. Cases with detected codeine but not morphine, nor any other drug above the limit of detection, were selected from the database of suspected drugged drivers at National Institute for Forensic Toxicology, Oslo, Norway. Codeine blood concentration in these samples was compared with the conclusions from the corresponding individual CTD. Of the 43 cases fulfilling the selection criteria, 23 were judged as "not impaired", and 20 as "impaired". Mean blood codeine concentration in the "not impaired" group was 143 ng/ml (95% CI 48-238, median 63 ng/ml). Mean concentration in the "impaired" group was 213 ng/ml (95% CI 146-279, median 159 ng/ml). There was a statistically significant concentration difference between the two groups. Codeine blood concentrations were further grouped as "moderate", "medium high" and "high". When adjusted for age, gender and chronic use, the odds ratios for being judged as impaired were 6 (95% CI 1-32, P=0.04) and 19 (95% CI 2-182, P=0.01) for the "medium high" group and the "high" group, respectively, relative to the "moderate" group. Codeine appeared to have some dose-dependent effect on the central nervous system that may lead to impairment as judged from a CTD, independent of measurable blood morphine concentrations. This supports the view that some codeine effects do not seem to be mediated by morphine.

Fatal versus non-fatal heroin “overdose”: blood morphine concentrations with fatal outcome in comparison to those of intoxicated drivers

The study was performed to distinguish fatal from non-fatal blood concentrations of morphine. For this purpose, blood levels of free morphine and total morphine (free morphine plus morphine conjugates) in 207 cases of heroin-related deaths were compared to those in 27 drivers surviving opiate intoxication. The majority of both survivors and non-survivors were found to show a concomitant use of depressants including alcohol or stimulants. Blood morphine levels in both groups varied widely, with a large area of overlap between survivors (free morphine: 0–128 ng/ml, total morphine: 10–2110 ng/ml) and non-survivors (free morphine: 0–2800 ng/ml, total morphine: 33–5000 ng/ml). Five (18.5%) survivors and 87 (42.0%) non-survivors exhibit intoxication only by morphine. In these cases, too, both groups overlapped (survivors-free morphine: 28–93 ng/ml, total morphine: 230–1451 ng/ml; non-survivors-free morphine: 0–2800 ng/ml, total morphine: 119–4660 ng/ml). Although the blood levels of free or total morphine do not allow a reliable prediction of survival versus non-survival, the ratio of free/total morphine may be a criterion to distinguish lethal versus survived intoxication. The mean of the ratio of free to total morphine for all lethal cases ( N=207) was 0.293, for those that survived ( N=27) 0.135, in cases of intoxication only by morphine 0.250 ( N=87) and 0.080 ( N=5), respectively. Applying a cut-off of 0.12 for free/total morphine and performing ROC analyses, fatal outcome can be predicted in 80% of the cases correctly, whereas 16% of the survivors were classified as dead. Nevertheless, in this study, all cases with a blood concentration of 200 ng/ml and more of free morphine displayed a fatal outcome.

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

To compare heroin and other opiate use of heroin overdose fatalities, current street heroin users and drug-free therapeutic community clients. 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). Sydney, Australia. 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). 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.

Assessment of the acuteness of heroin deaths from the analysis of multiple blood specimens.

Data was compiled from 126 morphine-involved cases investigated by the Office of the Chief Medical Examiner, State of Maryland, USA. An investigation was conducted into whether comparison of morphine concentrations from a central and peripheral site could be used to determine whether a morphine death was acute or delayed. Fifty cases were identified as 'acute' because the urine free morphine concentration by radioimmunoassay (RIA) was less than 25 ng/mL; 76 cases were classified as 'random' because they had a urine morphine concentration greater than 25 ng/mL by RIA. The average heart blood to peripheral blood morphine concentration ratio in the acute deaths was 1.40. The average heart blood to peripheral blood morphine concentration ratio in the random deaths was 1.18. Because there was considerable overlap between the two groups of data, the authors conclude that it was not possible to predict 'acute' opiate intoxication deaths versus 'delayed' deaths when the only information available is heart and peripheral blood free morphine concentrations.

Driving and intrathecal morphine administration

Since Belgian law recently set a limit to morphine concentration detectable in blood and urine while driving a vehicle, questions arose about the implications for the medical use of opiates. We determined morphine concentrations in whole blood and urine by gas chromatography–mass spectrometry in 15 patients on continuous intrathecal morphine administration. Effects on blood and urine concentration after water intake and the correlation with the intrathecal morphine daily dose were also evaluated. Our results confirm that, in all patients examined, the legally determined maximum blood morphine concentration of 20ng/ml was never exceeded. Even patients on high intrathecal morphine dose schedules did never reach the maximum legal blood concentration. However, morphine concentration in urine reached levels which exceeded by far the legally determined maximum concentration of 300ng/ml. Although legal actions against driving under the influence of morphine can only be taken after a positive urine and a subsequent positive blood sample, drivers on intrathecal opiates must be aware of the possibility of a positive roadside drug test.

Concentration Ratios of Morphine to Codeine in Blood of Impaired Drivers as Evidence of Heroin Use and not Medication with Codeine

Both the illicit drug heroin and the prescription drug codeine are metabolized to morphine, which tends to complicate interpretation of opiate-positive samples. We report here the concentrations of morphine and codeine, the morphine/codeine ratios, and 6-acetylmorphine (6-AM) in blood specimens from individuals arrested for driving under the influence of drugs (DUID) in Sweden. The results were compared with positive findings of 6-AM in urine as evidence of heroin intake. In 339 DUID suspects, both blood and urine specimens were available for toxicologic analysis. In another 882 cases, only blood was available. All specimens were initially analyzed by immunoassay, and the positive results were verified by isotope-dilution gas chromatography-mass spectrometry. In routine casework, the limits of quantification (LOQs) for unconjugated opiates were 5 ng/g for blood and 20 microg/L for urine. The median concentration of morphine in blood was 30 ng/g with 2.5 and 97.5 percentiles of 5 and 230 ng/g, respectively (n = 979). This compares with a median codeine concentration of 20 ng/g and 2.5 and 97.5 percentiles of 5 and 592 ng/g, respectively (n = 784). The specific metabolite of heroin, 6-AM, was identified in only 16 of 675 blood specimens (2.3%). This compares with positive findings of 6-AM in 212 of 339 urine samples (62%) from the same population of DUID suspects. When 6-AM was identified in urine, the morphine/codeine ratio in blood was always greater than unity (median, 6.0; range, 1-66). In 18 instances, 6-AM was present in urine, although morphine and codeine were below the LOQ in blood. The morphine/codeine ratio in blood was greater than unity in 85% of DUID cases when urine was not available (n = 506), and the median morphine and codeine concentrations were 70 ng/g and 10 ng/g, respectively. When morphine/codeine ratios in blood were less than unity (n = 76), the median morphine and codeine concentrations were 10 ng/g and 180 ng/g, respectively. Only 2.3% of opiate-positive DUID suspects were verified as heroin users on the basis of positive findings of 6-AM in blood. A much higher proportion (62%) were verified heroin users from 6-AM identified in urine. When urine was not available for analysis, finding a morphine/codeine concentration ratio in blood above unity suggests heroin use and not medication with codeine. This biomarker indicated that 85% of opiate-positive DUID blood samples were from heroin users.

Alternate strategies for postmortem drug testing.

Alternate strategies for postmortem drug testing.

Heroin-related deaths in New South Wales, Australia, 1992–1996

The coronial files of all heroin-related fatalities that occurred in New South Wales (NSW) over the period 1992–1996 were inspected. There were 953 heroin-related fatalities in NSW over the study period. There was a substantial, statistically significant increase in heroin-related fatalities over the study period, from 152 deaths in 1992 to 226 during 1996. The mean age of cases was 31.0 years, 85% were male, and 85% were classified as dependent on heroin at the time of death. There was a significant increase in the age of cases over the study period and the proportion of cases that were employed. Fatalities predominantly occurred in home settings (61%). No intervention occurred in 79% of cases. Fifty deaths (5%) occurred in the month following release from prison, 16 of which occurred the first 24 hours after release. Morphine concentrations rose from 0.24 mg/l in 1992 to 0.38 mg/l in 1996. Seventy six percent of cases involved heroin in combination with other drugs: alcohol (46%), benzodiazepines (27%), antidepressants (7%) and cocaine (7%). In only 24% of cases was morphine the sole drug detected. Males were significantly more likely to have alcohol detected at autopsy (49 vs. 24%), while females were more likely to have benzodiazepines detected (41 vs. 17%). The median blood morphine concentration among cases in which alcohol was detected was significantly lower than other cases (0.27 vs. 0.39 mg/l). It is concluded that heroin-related deaths continued to rise throughout the study period, and that deaths were predominantly among older, untreated males. Despite the rise in blood morphine concentrations, polydrug use remained the predominant toxicological pattern.

Fetal response to maternally administered morphine

Objective: We sought to determine the effects of maternally administered morphine on fetal response. Study Design: Singleton pregnancies requiring fetal blood sampling were enrolled. Only study patients were given morphine intramuscularly. Maternal vital signs, fetal heart rate, biophysical profile score, and umbilical artery Doppler indices (systolic/diastolic ratio, resistance index, and pulsatility index) were completed before and after fetal blood sampling. Maternal and cord blood morphine concentrations were measured. Results: Ten study and 6 control patients were enrolled. A significantly lower biophysical profile score was observed in study patients (P =.001) as a result of absent fetal breathing movements and nonreactive nonstress tests. Gross and fine fetal movements were unaffected. A significant correlation was measured between the biophase morphine concentration and each of the Doppler indices. Conclusion: Morphine administered to the mother causes a significant decrease in the biophysical profile score. Correlation between the biophase morphine concentration and the Doppler indices was calculated. These results suggest that morphine acts as a vasoconstrictor of the placental vasculature but do not support the use of intramuscular morphine to suppress fetal movement. (Am J Obstet Gynecol 2000;183:424-30.)

Fatal heroin overdoses resulting from non-injecting routes of administration, NSW, Australia, 1992-1996.

To document cases of fatal heroin overdose in New South Wales by non-injecting routes of administration, and to compare the characteristics and toxicology of these cases with injecting fatalities. Examination of coronial files. New South Wales, Australia. All fatal heroin overdose cases in NSW between 1992 and 1996. There were 10 cases of death resulting from non-injecting routes of heroin administration between 1992 and 1996, representing 1% of cases. In three cases the route of administration was by inhalation, in five cases by nasal administration and in two cases by swallowing. The mean age of cases was 29.6 years, and nine of the cases were male. The median blood morphine concentration of non-injectors was 0.31 mg/l (range 0.06-0.99 mg/l). Drugs other than morphine were also detected in seven cases. Heroin overdose deaths are not restricted to the injection of heroin. While injection may constitute a greater overdose risk-factor, there is no safe, overdose-free way to use heroin.

Heroin-related deaths in regional New South Wales, 1992-96

The coronial files of all 188 heroin-related fatalities that occurred in regional New South Wales between 1992 and 1996 were inspected. There was a significant increase in fatalities, rising from 23 deaths in 1992 to 53 during 1996. The regions in which the most deaths occurred were Wollongong/ Illawarra (43 deaths), Newcastle/Hunter (35) and the far north coast (25). The mean age of cases was 31.5 years and 83% were male, and there were no significant trends in demographic characteristics of cases over the study period. The median blood morphine concentration of cases was 0.39mg/l (range 0.05-4.5mg/l). Alcohol was detected in 50% of cases and benzodiazepines in 29%. There were large regional variations in toxicology results, with median blood morphine concentrations ranging from 0.25mg/l among south coast cases to 0.56mg/l in mid-western New South Wales. Compared to Sydney metropolitan cases, regional cases had a higher median blood morphine concentration, were less likely to have cocaine detected, were ...

Demonstration of morphine in ganglion cells of the hippocampus from victims of heroin overdose by means of anti-morphine antiserum

To investigate the topography of morphine distribution in the human brain, a method has been developed to detect morphine immunohistochemically. In this study hippocampus tissue from victims of heroin overdose (blood morphine concentrations 220 ng/g-1500 ng/g; 6-MAM positive urine sample), known for its high concentration of mu-opiate receptors was used. The immunohistochemical staining was performed with an anti-morphine antiserum originally developed for radio-immunoassays. In comparison with control specimens from cases of sudden death without morphine exposition or a history of heroin abuse, the brains from victims of heroin overdose showed selectively stained ganglion cells, axons and dendrites, suggesting a massive concentration of morphine in the neuronal structures.

The role of alcohol abuse in the etiology of heroin-related deaths. Evidence for pharmacokinetic interactions between heroin and alcohol.

In order to evaluate pharmacokinetic interactions between heroin and alcohol and their role in the etiology of heroin-related deaths (HRD), the alcohol concentration in blood (BAC), the free (FM) and total morphine (TM) concentrations in blood (determined by DPC Coat-A-Count radioimmunoassay before and after enzymatic hydrolysis), and the TM concentration in urine and bile (DPC Coat-A-Count after enzymatic hydrolysis) in a population of 39 lethal cases included in the records of the Department of Legal Medicine and Public Health at the University of Pavia from the period January 1997-April 1998 were examined. The cause of death in each case was attributed to either heroin or associated heroin-ethanol intoxication. Cases were arbitrarily divided into two groups according to BAC (low-ethanol group, LE, BAC < or = 1000 mg/L and high-ethanol group, HE, BAC > 1000 mg/L). The differences in the FM and TM concentrations in blood, bile, and urine and in the FM/TM ratios between the two . groups were statistically evaluated (Mann-Whitney U test). A similar statistical evaluation was carried out on data from a previously published study concerning the disposition of heroin and its metabolites (6-acetylmorphine and morphine) in blood and urine in 23 lethal cases attributed to either heroin or heroin and alcohol intoxication. The values of the following variables in the LE and HE groups were compared: FM, TM, and 6-acetylmorphine concentrations in blood (6-AM); the FM/ (FM + 6-AM) ratio; the FM/TM ratio; and the urinary concentrations of heroin, 6-acetylmorphine, and free morphine. Statistical analyses of data indicated that high BACs are associated with reduced hydrolysis of 6-AM to morphine (FM/[FM + 6-AM], p = 0.0022) and that a good inverse correlation exists between BAC and hydrolysis of 6-AM to morphine (r2 = 0.67). High BACs were also found to be associated with an increased FM/TM ratio and with reduced excretion of free and total morphine. These results suggest the hypothesis that pharmacokinetic interactions between heroin and alcohol do occur in individuals exposed to high doses of these substances.