Toxicology and pathology of deaths related to methadone: retrospective review.
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OBJECTIVES: To clarify the mechanisms and risk factors of methadone toxicity and to describe the findings of deaths related to methadone use Design Retrospective review of case notes in the records of the San Francisco Medical Examiner comparing the findings in cases where methadone was deemed the cause of death with findings in decedents where methadone was an incidental finding, and with 50 age-matched, disease and drug free, trauma victims. RESULTS: 38 cases out of the 3317 processed by our office during 1997-1998 were identified in which methadone had been detected. Cases were mostly male 28/38 (74%) and white, 28/38 (74%). In 17 of 38 cases death was deemed to have been caused by methadone toxicity. For the group the mean blood methadone concentration for all 38 patients, was 957 ng/ml SD = .681, SE = .14). The mean blood concentration of the main methadone metabolite (EDDP) was 253 ng/ml, SD = 529 ng/ml, SE = .089. The mean ratio of methadone in the blood to EDDP in the blood was 13.6:1 Values were not significantly different between cases in which methadone toxicity was the cause of death and in those in which it was an incidental finding. Cocaine, or the cocaine metabolite benzoylecgonine, was detected in the blood or urine of 16/38 cases (42%); morphine in one-third (13/38) and methamphetamine in only one. Pulmonary edema was evident in all cases, coronary artery disease in 9/38 (24%) and cirrhosis in 7/38 (18%) of the methadone users. Necrotizing fasciitis was the cause of death in 4 of the 38 methadone users (11%). Nationally, a sizeable percent of methadone deaths are from drugs diverted from treatment programs. CONCLUSIONS: The presence of methadone is often an incidental finding during postmortem examination which is unrelated to the cause of death. Postmortem measurements of methadone or its metabolite, or both, cannot be used in isolation to identify which deaths are associated with methadone toxicity. (+info)
EEG controlled rapid opioid withdrawal under general anaesthesia.
(18/1183)
We performed rapid opioid detoxification under propofol anaesthesia in 30 opioid addicts, using the opioid receptor antagonist naltrexone. Two strategies to obtain a sufficient depth of anaesthesia and to avoid anaesthetic overdose were evaluated. Patients were allocated randomly to one of two groups. In group 1, the effects of propofol were monitored by observing clinical signs, and in group 2, depth of anaesthesia was controlled using an EEG threshold method. Withdrawal symptoms and post-anaesthetic recovery time were assessed. All patients remained stable and no anaesthetic complications were noted. There were significant differences in the total dose of propofol given (group 1, mean 72 (SD 9) mg kg-1; group 2, 63 (8) mg kg-1; P < 0.01), duration of anaesthesia (318 (53) min vs 309 (42) min; P < 0.05), duration of recovery time (49 (13) min vs 40 (12) min; P < 0.01) and frequency of withdrawal symptoms between groups. In addition, the incidence of side effects was different between groups (62 vs 29 points on a withdrawal symptom scale; P < 0.01). To obtain a sufficient depth of anaesthesia but to avoid inappropriately large doses of anaesthetic, we consider that EEG monitoring is valuable during rapid opioid detoxification. (+info)
Morphine-related metabolites differentially activate adenylyl cyclase isozymes after acute and chronic administration.
(19/1183)
Morphine-3- and morphine-6-glucuronide are morphine's major metabolites. As morphine-6-glucuronide produces stronger analgesia than morphine, we investigated the effects of acute and chronic morphine glucuronides on adenylyl cyclase (AC) activity. Using COS-7 cells cotransfected with representatives of the nine cloned AC isozymes, we show that AC-I and V are inhibited by acute morphine and morphine-6-glucuronide, and undergo superactivation upon chronic exposure, while AC-II is stimulated by acute and inhibited by chronic treatment. Morphine-3-glucuronide had no effect. The weak opiate agonists codeine and dihydrocodeine are also addictive. These opiates, in contrast to their 3-O-demethylated metabolites morphine and dihydromorphine (formed by cytochrome P450 2D6), demonstrated neither acute inhibition nor chronic-induced superactivation. These results suggest that metabolites of morphine (morphine-6-glucuronide) and codeine/dihydrocodeine (morphine/dihydromorphine) may contribute to the development of opiate addiction. (+info)
Increased mesolimbic GABA concentration blocks heroin self-administration in the rat.
(20/1183)
Opiate reinforcement has been hypothesized to be mediated by an inhibition of mesolimbic gamma-aminobutyric acid (GABA) release that subsequently disinhibits ventral tegmental area (VTA) dopamine neurons. In support of this hypothesis, this study demonstrates that when administered directly into the lateral ventricle, the VTA, or the ventral pallidum, but not the nucleus accumbens, gamma-vinyl-GABA (GVG, an irreversible GABA-transaminase inhibitor, 20-50 microg) dose dependently blocked heroin (0.06 mg/kg) self-administration (SA), as assessed by an increase in heroin SA at low doses of GVG and an initial increase followed 1 to 2 h later by a blockade of heroin SA at higher GVG doses. This effect lasted 3 to 5 days. In drug-naive rats, intra-VTA GVG pretreatment also prevented or delayed acquisition of heroin SA for 2 days. This GVG effect was prevented or reversed by systemic or intra-VTA pretreatment with the GABA(B) antagonist 2-hydroxysaclofen, but not the GABA(A) antagonist bicuculline. Similarly, coadministration of heroin with aminooxy-acetic acid (1-4 mg/kg) or ethanolamine-O-sulfate (50-100 mg/kg), two reversible GABA transaminase inhibitors, dose dependently reduced heroin reinforcement. Coadministration of (+/-)-nipecotic acid (0.1-5 mg/kg) with heroin, or intra-VTA or -ventral pallidum pretreatment with (+/-)-nipecotic acid (10 microg) or NO-711 (2 microg), two GABA uptake inhibitors, significantly increased heroin SA behavior, an effect also blocked by systemic 2-hydroxysaclofen, but not bicuculline. Taken together, these experiments, for the first time, demonstrate that pharmacological elevation of mesolimbic GABA concentration blocks heroin reinforcement by activating GABA(B) receptors, supporting the GABAergic hypothesis of opiate reinforcement and the incorporation of GABA agents in opiate abuse treatment. (+info)
Unintentional opiate overdose deaths--King County, Washington, 1990-1999.
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Heroin and other opiates are central nervous system depressants; in an opiate overdose, respiration slows, potentially resulting in hypoxia, coma, or death. In 1998, 140 deaths from unintentional opiate overdoses occurred in King County (which includes Seattle). To characterize these deaths, public health staff analyzed medical examiner data during 1990-1999. This report summarizes the results of that analysis, which indicate that the annual number of opiate overdoses increased 134% (from 47 to 110) and the county population increased 11.3% (1998 estimated population: 1.7 million). (+info)
Price, cost and value of opiate detoxification treatments. Reanalysis of data from two randomised trials.
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BACKGROUND: Treatments in different settings have different costs. A dilemma arises if expensive treatments lead to better outcomes. AIMS: To investigate conflicts between the priorities of cost minimisation, clinical effectiveness, and cost-effectiveness in the detoxification of opiate addicts. METHOD: Cost and clinical effectiveness were examined using published outcome data. The main outcome measures were: achieving a drug-free state on completion of detoxification; the economic costs of treatment. RESULTS: In terms of simple cost, in-patient detoxification is much more expensive than out-patient treatment (ratio, 24:1). With adjustment for successful outcome, the costs are almost identical (ratio, 0.9:1). Comparison of specialist and general psychiatry in-patient settings showed that even when adjusted for clinical outcomes, the specialist setting is more costly (ratio, 1.9:1), although the outcomes are better. CONCLUSIONS: Naive adherence to cost and cost-containment considerations is dangerous. Discussion of treatment costs is misleading if not informed by, and adjusted for, evidence of effectiveness. This is especially important where marked differences in outcome between treatment options exist. (+info)
Monitoring opiate use in substance abuse treatment patients with sweat and urine drug testing.
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Although urine testing remains the standard for drug use monitoring, sweat testing for drugs of abuse is increasing, especially in criminal justice programs. One reason for this increase is sweat testing may widen the detection window compared to urine testing. Drug metabolites are rapidly excreted in urine limiting the window of detection of a single use to a few days. In contrast, sweat collection devices can be worn for longer periods of time. This study was designed to compare the efficacy of sweat testing versus urine testing for detecting drug use. Paired sweat patches that were applied and removed weekly on Tuesdays were compared to 3-5 consecutive urine specimens collected Mondays, Wednesdays, and Fridays (355 matched sweat and urine specimen sets) from 44 patients in a methadone-maintenance outpatient treatment program. All patches (N = 925) were extracted in 2.5 mL of solvent and analyzed by ELISA immunoassay for opiates (cutoff concentration 10 ng/mL). A subset (N = 389) of patches was analyzed by gas chromatography-mass spectrometry (GC-MS). Urine specimens (N = 1886) were subjected to qualitative analysis by EMIT (cutoff 300 ng/mL). Results were evaluated to (1) determine the identity and relative amounts of opiates in sweat; (2) assess replicability in duplicate patches; (3) compare ELISA and GC-MS results for opiates in sweat; and (4) compare the detection of opiate use by sweat and urine testing. Opiates were detected in 38.5% of the sweat patches with the ELISA screen. GC-MS analysis confirmed 83.4% of the screen-positive sweat patches for heroin, 6-acetylmorphine, morphine, and/or codeine (cutoff concentration 5 ng/mL) and 90.2% of the screen-negative patches. The sensitivity, specificity, and efficiency of ELISA opiate results as compared to GC-MS results in sweat were 96.7%, 72.2%, and 89.5%, respectively. Heroin and/or 6-acetylmorphine were detected in 78.1% of the GC-MS-positive sweat patches. Median concentrations of heroin, 6-acetylmorphine, morphine, and codeine in the positive sweat samples were 10.5, 13.6, 15.9, and 13.0 ng/mL, respectively. Agreement in paired sweat patch test results was 90.6% by ELISA analysis. For the purposes of this comparison of ELISA sweat patch to EMIT urine screening for opiates, the more commonly used urine test was considered to be the reference method. The sensitivity, specificity, and efficiency of sweat patch results to urine results for opiates were 68.6%, 86.1%, and 78.6%, respectively. There were 13.5% false-negative and 7.9% false-positive sweat results as compared to urine tests. Analysis of sweat patches provides an alternate method for objectively monitoring drug use and provides an advantage over urine drug testing by extending drug detection times to one week or longer. In addition, identification of heroin and/or 6-acetylmorphine in sweat patches confirmed the use of heroin in 78.1% of the positive cases and differentiated illicit heroin use from possible ingestion of codeine or opiate-containing foods. However, the percentage of false-negative results, at least in this treatment population, indicates that weekly sweat testing may be less sensitive than thrice weekly urine testing in detecting opiate use. (+info)
Identification of hydrocodone in human urine following controlled codeine administration.
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Allegations of illicit hydrocodone use have been made against individuals who were taking physician-prescribed oral codeine but denied hydrocodone use. Drug detection was based on positive urine opiate immunoassay results with subsequent confirmation of hydrocodone by gas chromatography-mass spectrometry (GC-MS). In these cases, low concentrations of hydrocodone (approximately 100 ng/mL) were detected in urine specimens containing high concentrations of codeine (> 5000 ng/mL). Although hydrocodone has been reported to be a minor metabolite of codeine in humans, there has been little study of this unusual metabolic pathway. We investigated the occurrence of hydrocodone excretion in urine specimens of subjects who were administered codeine. In a controlled study, two African-American and three Caucasian male subjects were orally administered 60 mg/70 kg/day and 120 mg/70 kg/day of codeine sulfate on separate days. Urine specimens were collected prior to and for approximately 30-40 h following drug administration. In a second case study, a postoperative patient self-administered 960 mg/day (240 mg four times per day) of physician-prescribed oral codeine phosphate, and urine specimens were collected on the third day of the dosing regimen. Samples from both studies were extracted on copolymeric solid-phase columns and analyzed by GC-MS. In the controlled study, codeine was detected in the first post-drug-administration specimen from all subjects. Peak concentrations appeared at 2-5 h and ranged from 1475 to 61,695 ng/mL. Codeine was detected at concentrations above the 10-ng/mL limit of quantitation for the assay throughout the 40-h collection period. Hydrocodone was initially detected at 6-11 h following codeine administration and peaked at 10-18 h (32-135 ng/mL). Detection times for hydrocodone following oral codeine administration ranged from 6 h to the end of the collection period. Confirmation of hydrocodone in a urine specimen was always accompanied by codeine detection. Codeine and hydrocodone were detected in all specimens collected from the postoperative patient, and concentrations ranged from 2099 to 4020 and 47 to 129 ng/mL, respectively. Analyses of the codeine formulations administered to subjects revealed no hydrocodone present at the limit of detection of the assay (10 ng/mL). These data confirm that hydrocodone can be produced as a minor metabolite of codeine in humans and may be excreted in urine at concentrations as high as 11% of parent drug concentration. Consequently, the detection of minor amounts of hydrocodone in urine containing high concentrations of codeine should not be interpreted as evidence of hydrocodone abuse. (+info)