Dextrophropoxyphene effects on QTc-interval prolongation: Frequency and characteristics in relation to plasma levels.

OBJECTIVE: To evaluate frequency and risk factors for dextropropoxypheneinduced QT-interval prolongation in the clinical setting. DESIGN: Prospective, noninterventional, observational, longitudinal cohort approach. Electrocardiograms were blindly evaluated by independent professionals. SETTING: General ward of a public hospital of metropolitan Buenos Aires. PATIENTS, PARTICIPANTS: Ninety-two patients with indication of receiving dextropropoxyphene for analgesic purposes were included consecutively. All patients finished the study. INTERVENTIONS: All patients were monitored with electrocardiographic controls (previous to drug administration and during steady state) to diagnose and quantify changes in the duration of the QTc interval. MAIN OUTCOME MEASURE: Frequency of drug-induced QTc interval prolongation, QTc interval correlation with plasma drug, and metabolite levels. RESULTS: Ninety-two patients were studied (50 percent males). All patients received a (mean ± SD [range]) dextropropoxyphene dose of 125 ± 25[100-150] mg/d. Dextropropoxyphene and norpropoxyphene concentrations were 112 ± 38[45-199] and 65 ± 33[13-129] ng/mL, respectively. The intra-treatment QTc interval was >450 ms in only one patient (only with the Hodge correction). There were no cases of QTc > 500 ms, and there were no significant differences in the results considering different correction formulas (Bazzet, Fridericia, Framingham, Hodges). Dextropropoxyphene concentrations correlated with QTc (R > 0.45) interval and ΔQTc (R 0.52-0.87), whereas norpropoxyphene correlation was even greater for QTc (R > 0.40-0.64) and ΔQTc (R > 0.47-0.92). Depending on the QTc correction formula, eight patients presented ΔQTc > 30 ms and one patient with ΔQTc > 60 ms. No patient presented arrhythmia during the study. CONCLUSIONS: The authors did not observe a relationship between dextropropoxyphene and QTc interval prolongation at the therapeutic doses used in Argentina.

Simultaneous quantitation of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma using solid-phase extraction and gas chromatography/mass spectrometry: Method validation and application to cardiovascular safety of therapeutic doses.

RATIONALE: Several opioid analgesics have been related to the prolongation of cardiac repolarization, a condition which can be fatal. In order to establish a correct estimation of the risk/benefit balance of therapeutic doses of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene, it was necessary to develop an analytical method to determinate plasma concentrations of these opioids. METHODS: Here we describe a method which incorporates strong alkaline treatment to obtain norpropoxyphene amide followed by a one-elution step solid-phase extraction, and without further derivatization. Separation and quantification were achieved by gas chromatography/electron ionization mass spectrometry (GC/EI-MS) in selected-ion monitoring mode. Quantification was performed with 500 µL of plasma by the addition of deuterated analogues as internal standards. RESULTS: The proposed method has been validated in the linearity range of 25-1000 ng/mL for all the analytes, with correlation coefficients higher than 0.990. The lower limit of quantification was 25 ng/mL. The intra- and inter-day precision, calculated in terms of relative standard deviation, were 2.0-12.0% and 6.0-15.0%, respectively. The accuracy, in terms of relative error, was within a ± 10% interval. The absolute recovery and extraction efficiency ranged from 81.0 to 111.0% and 81.0 to 105.0%, respectively. CONCLUSIONS: A GC/MS method for the rapid and simultaneous determination of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma was developed, optimized and validated. This procedure was shown to be sensitive and specific using small specimen amounts, suitable for application in routine analysis for forensic purposes and therapeutic monitoring. To our knowledge, this is the first full validation of the simultaneous determination of these opioids and their metabolites in plasma samples.

The prevalence of marijuana in suspected impaired driving cases in Washington state.

In December 2012, the possession and private use of limited quantities of marijuana and marijuana products became legal in the state of Washington. At the same time, the state's driving under the influence statutes were amended to include a per se level of 5 ng/mL delta(9)-tetrahydrocannabinol (THC) in whole blood for drivers aged 21 years and older. The aim of this study was to assess the effect of marijuana legalization on the prevalence of marijuana in suspected impaired driving cases. The prevalence of both active THC and its metabolite carboxy-THC detected in such cases pre-legalization was compared with the prevalence post-legalization. In 2009-2012, the average yearly percentage of cases positive for THC and carboxy-THC was 19.1% (range: 18.2-20.2%) and 27.9% (range: 26.3-28.6%), respectively. In 2013, the percentages had significantly increased to 24.9 and 40.0%, respectively (P < 0.05). The median THC concentration over the 5-year period ranged from 5.2 to 6.3 ng/mL, with individual concentrations ranging up to 90 ng/mL. An average of 56% of cases were at or >5 ng/mL over the 5-year period. The prevalence of alcohol and the majority of other drugs in this same population of suspected impaired drivers submitted for testing did not change during this same 5-year period-marijuana was the only drug to show such an increase in frequency. Further, this observed increase remained after the data had been normalized to account for changes in laboratory testing procedures that occurred during this time period. Future studies need be conducted to ascertain whether the observed increase has had any effect on the incidence of crashes, serious injuries and/or traffic fatalities.

Comparison of fatal poisonings by prescription opioids.

There is a rising trend of fatal poisonings due to medicinal opioids in several countries. The present study evaluates the drug and alcohol findings as well as the cause and manner of death in opioid-related post-mortem cases in Finland from 2000 to 2008. During this period, fatal poisonings by prescription opioids (buprenorphine, codeine, dextropropoxyphene, fentanyl, methadone, oxycodone, tramadol) increased as a share of all drug poisonings from 9.5% to 32.4%, being 22.3% over the whole period. A detailed study including the most prevalent opioids was carried out for the age group of 14-44 years, which is the most susceptible age for drug abuse in Finland. Poisonings by the weak opioids, codeine and tramadol, were found to be associated with large, often suicidal overdoses resulting in high drug concentrations in blood. Methadone poisonings were associated with accidental overdoses with the drug concentration in blood remaining within a therapeutic range. The manner of death was accidental in 43%, 55% and 94% of cases in codeine, tramadol and methadone poisonings, respectively. The median concentration of codeine and the median codeine/morphine concentration ratio were higher in codeine poisonings (1.4 and 22.5 mg/l, respectively) than in other causes of death (0.09 and 5.9 mg/l, respectively). The median concentrations of tramadol and O-desmethyltramadol were higher in tramadol poisonings (5.3 and 0.8 mg/l, respectively) than in other causes of death (0.6 and 0.2 mg/l, respectively). In methadone poisonings, the median concentration of methadone (0.35 mg/l) was not different from that in other causes of death (0.30 mg/l). Sedative drugs and/or alcohol were very frequently found in fatal poisonings involving these prescription opioids.

Simultaneous analysis of some club drugs in whole blood using solid phase extraction and gas chromatography-mass spectrometry.

The use of psychoactive substances to improve social relations and increase body energy, in Rave Culture, has raised many legal and health public concerns, both for illicit trade and consumption. Therefore, forensic toxicology plays an important role in this area, mainly linked to the detection and quantitation of these substances, both in vivo and in post-mortem samples. In fact, at the moment, forensic sciences have been under public authorities' scrutiny and critical look, due to the increasing attention of the media and public opinion, always applying for the use of scientific knowledge to help solving forensic cases. However, forensic toxicology results are only reliable to solve legal cases if all the analytical methodologies used are appropriately validated. In this work, a methodology for the extraction and analysis of 7-aminoflunitrazepam, buprenorphine, flunitrazepam, ketamine, methadone, phencyclidine (PCP) and d-propoxyphene was developed for whole blood samples, with solid phase extraction (SPE), using OASIS(®) MCX SPE columns, and gas chromatography coupled to mass spectrometry. The procedure presented here proved to be reliable, specific, selective and sensitive, with good LODs and LOQs and good precision.The adoption of a SPE procedure with an automatic SPE extraction device, allowed an increased level of automation in sample treatment, being contemporarily less time-consuming, increasing productiveness, and allowing good recovery and appropriate selectivity being, also, simple and reproducible. The simultaneous detection and quantitation of all compounds by the same extraction and detection methodology is crucial and has a great potential for forensic toxicology and clinical analysis.

Propoxyphene (dextropropoxyphene): a critical review of a weak opioid analgesic that should remain in antiquity.

Propoxyphene (dextropropoxyphene) is a synthetic weak opioid introduced into the United States in 1957. It is most frequently prescribed in combination with acetaminophen and/or aspirin. After its ubiquitous introductory phase, it was soon discovered that this drug's iatrogenic events (cardiotoxicity, seizures, etc.) far outweighed any perceived therapeutic benefit. Propoxyphene analgesia was equated with that of merely acetaminophen or aspirin independently. The propoxyphenes euphorigenic component has created a problem in its prescribing. Use of this agent in the elderly should be avoided because of its complex pharmacokinetics and pharmacodynamics. The pharmacokinetics, pharmacodynamics, and pharmacology of this drug are discussed thoroughly in this article, including its arrhythmogenicity. Additional noncardiovascular pharmacotherapies that produce QTc prolongation or arrhythmogenicity are described. A list of the cytochrome P450 2D6 pharmacotherapies that will interact with propoxyphene is provided in the article. The use of this agent is highly discouraged. The rationale for this is discussed fully within this article. The toxicity of this drug is partially related to nor-propoxyphene a non-opioid cardiotoxic metabolite. The mere warnings of fatalities within the package insert should alert any cautious prescriber on the dangers of this agent and dampen its prescribing potential.

Profound metoprolol-induced bradycardia precipitated by acetaminophen-propoxyphene.

Pharmacokinetic studies demonstrate that propoxyphene is a potent inhibitor of cytochrome P450 (CYP) 2D6. Clinically significant sequelae have not been previously reported. We report a case of this inhibition manifested by life-threatening bradycardia in a patient receiving a CYP2D6 substrate, metoprolol. A 48-year-old man came to the emergency department complaining of dizziness 3 hours after ingesting metoprolol, at his usual dose, and 2 tablets of propoxyphene, newly begun postoperatively. Four hours after ingestion of both drugs, the patient was noted to have a ventricular rate of about 30 beats/min with underlying atrial fibrillation. The patient's ventricular response returned to normal within 11 hours of ingestion. We have demonstrated the clinical importance of the interaction between propoxyphene and metoprolol likely resulting from inhibition of hepatic clearance of metoprolol by propoxyphene. Underscoring the clinical relevance of CYP2D6 inhibition by an analgesic of questionable efficacy should proscribe its use.

Relation of postmortem blood alcohol and drug concentrations in fatal poisonings involving amitriptyline, propoxyphene and promazine.

Drugs and alcohol often occur together in fatal poisonings, complicating the process of determining the cause of death. Especially when found in concentrations generally regarded as toxic but not lethal, the question arises whether the combination of sublethal amounts was the likely cause of death. In this study, we examined poisoning deaths involving amitriptyline, propoxyphene and promazine, which are, after benzodiazepines, the most frequently occurring drugs in Finnish alcohol-related poisonings. From the forensic toxicology database, covering the years 1995-2002, we extracted 332 fatal poisonings, calculated median blood alcohol and drug concentrations, constructed concentration-concentration and concentration-response curves and evaluated the significance of the presence of therapeutic amounts of benzodiazepines. Median amitriptyline and propoxyphene concentrations were lower in alcohol-related cases than in clean drug poisonings. Correspondingly, the median blood alcohol concentrations in all drug-related poisonings were 1.5-2.2 mg/g lower than that found in clean alcohol poisonings. Alcohol concentration proved to be a more sensitive indicator of alcohol-drug interaction than drug concentration. This result suggests that when alcohol is present, relatively small overdoses of the studied drugs may result in fatal poisoning. In this context, fatal drug and alcohol concentrations and the issue of determining the most important agent in fatal drug-alcohol intoxications are discussed.

Simultaneous determination of paracetamol and dextropropoxyphene in human plasma by liquid chromatography/tandem mass spectrometry: application to clinical bioequivalence studies.

A liquid chromatography/mass spectrometry method for simultaneous determination of paracetamol and dextropropoxyphene in human plasma is described. Paracetamol and dextropropoxyphene, together with their internal standards (tolbutamide and pyrroliphene), were extracted from 0.5 mL of plasma using solid-phase extraction. The chromatography was performed using a Thermo Hypersil APS-2 Amino column (250 mm x 4.6 mm, 5 microm) with a mobile phase consisting of acetonitrile and 0.4% glacial acetic acid in water (20:80). The total run time was 6 min for each sample. The triple-quadrupole mass spectrometer was operated in both positive (for detection of dextropropoxyphene and its IS pyrroliphene) and negative (for detection of paracetamol and its IS tolbutamide) modes using a polarity-switching technique. Multiple reaction monitoring was used for quantification. The method was linear over the concentration range of 0.1-20 microg/mL for paracetamol and 0.5-80 ng/mL for dextropropoxyphene. The intra- and inter-day precision were less than 10%, and the accuracy ranged from 92.2-110.9%. The lower limits of quantification were 0.1 microg/mL for paracetamol and 0.5 ng/mL for dextropropoxyphene. The present method provides a robust, fast and sensitive analytical tool for both paracetamol and dextropropoxyphene, and has been successfully applied to a clinical bioequivalence study in 14 subjects.

A multicentre study of coproxamol poisoning suicides based on coroners' records in England.

AIMS: To examine in detail a series of coproxamol overdose deaths in order to provide information that will assist in the development of strategies to prevent such fatalities. METHOD: Inquest records in 24 coroners' jurisdictions in England on deaths between January 2000 and December 2001 which received a verdict of either suicide or undetermined cause (with a high or moderate probability of suicide) were examined. RESULTS: One hundred and twenty-three coproxamol poisoning suicides were identified. Alcohol was involved in 58.5% of the overdoses and these individuals generally had lower blood drug levels and consumed fewer tablets. Younger people were more likely to have consumed alcohol and to have lower levels of suicide intent. Nearly half the individuals had a history of self harm, and a third were under psychiatric care. The coproxamol had been prescribed for the individual in 81.5% of cases, although only in 55.0% of those aged 10-34 years. In other cases the source of the coproxamol was nearly always a family member or partner. Some deaths resulted from relatively small overdoses. CONCLUSIONS: Strategies to reduce self poisoning deaths due to coproxamol should take account of the high toxicity of coproxamol in overdose, especially when combined with alcohol, and the fact that risk of death extends beyond the person for whom the drug is prescribed.

The prevalence of analgesics containing dextropropoxyphene or codeine in individuals suspected of driving under the influence of drugs.

To investigate the prevalence of analgesics containing dextropropoxyphene (DXP) or codeine in individuals suspected of driving under the influence of drugs, we analysed all blood samples in which drugs were screened for in cases of suspected drunken driving in Sweden during the years 1992-1997. DXP was found in 130 (2.7%) and codeine in 388 (7.9%) of the 4896 drug-screened cases. The ratio between the number of DXP and of codeine cases and prescription of defined daily dose/1000 inhabitants during a 12-month period (DDD) was determined. The quotient for DXP was trebled from 1992 (0.99) to 1997 (2.89), while the codeine quotient decreased by 9% (from 6 to 5.5). The blood samples showed polydrug use in all but 28 cases of the 486 cases where DXP and/or codeine was found. In 71% of the 486 cases benzodiazepines were also present and in 38% of the cases amphetamine and/or cannabis were present. It was concluded that analgesics containing DXP or codeine are not drugs of primary interest in this specific population. Nevertheless, because of the high toxicity of DXP, especially when combined with alcohol or other drugs, the increase in the DXP prevalence gives reason for concern, since the studied population represents a group of individuals who use large doses of therapeutic or illegal drugs.

Correlation between prescription of various dextropropoxyphene preparations and their involvement in fatal poisonings.

In Sweden, the frequency of fatal poisoning by dextropropoxyphene (DXP) ingestion is constantly high. There are seven preparations containing DXP on the Swedish market; in three of them DXP is the sole analgesic ingredient, while four of them are combinations of analgesics. In an attempt to assess the death rate attributable to each DXP preparation on the basis of toxicological analyses, altogether 834 cases of dextropropoxyphene-related death over a 5-year period (1992-1996) in Sweden have been reviewed. The ratio between number of fatal poisonings and prescription of defined daily dose/1000 inhabitants during a 12-month period (DDD) was determined. The highest ratio, 27, was attributed to unmixed preparations. The ratio for DXP + paracetamol-related deaths was 6.3, and for DXP + phenazone, 6.4, while the lowest ratio, 2, was found among the DXP + chlorzoxazone cases. The unmixed preparations, representing 26% of all DXP prescriptions during the study years, were implicated in 62% of the DXP fatalities, a considerable over-representation. Unmixed preparations, with their higher content of DXP, may be more attractive for many consumers because of their narcotic (euphoric) effects rather than for any analgetic superiority. Another possibility is that unmixed preparations may erroneously have been regarded as safer than when combined with paracetamol, as reports of poisoning with compounds containing DXP + paracetamol have been most frequently reported, probably due to their predominance on the market.

The prevalence of dextropropoxyphene in autopsy blood samples.

The prevalence of dextroproxyphene (DXP) in the total medico-legal autopsy material in Sweden during 1992 to 1996 was examined. Simultaneous findings of paracetamol and alcohol in the blood were considered in the analyses. DXP in peripheral blood was found in 1782 (7.5%) of the 23,691 cases analysed during 1992-1996. The autopsy prevalence of DXP increased by 25% from 1992 to 1996. The mean blood DXP concentration was 1.62 micrograms/g (the blood level of DXP after a therapeutic dose is 0.05-0.75 microgram/g). The blood DXP level was < 0.75 microgram/g in 947 cases and > or = 0.75 microgram/g in 835 cases. The cases < 50 years of age had a significantly higher mean concentration (2.36 micrograms/g) than those > or = 50 years (1.04 micrograms/g). Paracetamol in the blood was found in 53% of the DXP cases (mean 75.0 micrograms/g; therapeutic level 2.5-25 micrograms/g) and alcohol in 43% (mean level 0.14%). According to the death certificates 54% (956) died from fatal poisoning. Among these, 74% (707) showed a blood DXP concentration > or = 0.75 microgram/g. Other Scandinavian countries, Denmark and Norway have reduced the rate of fatal DXP poisonings through government regulations for prescription. As the defined daily dose/1000 inhabitants during a 12-month period (DDD) of DXP preparations in Sweden (14.4 in 1996) is six times as high as in Denmark and nine times as high as in Norway, introduction of similar regulations in Sweden should be considered.

The manner of death among fatalities where dextropropoxyphene caused or contributed to death.

Dextropropoxyphene (DXP) is one of the most prescribed analgesic compounds in Sweden. To investigate the manner of death among fatalities where DXP caused or contributed to death all medico-legal autopsies performed in Sweden in 1992-1996 were analysed on the bases of toxicological analyses and death certificates. DXP in peripheral blood was found in 1782 (7.5%) of the total 23,691 blood samples. According to the death certificates 956 (54%) of the 1782 cases were classified as fatal DXP poisoning. Among these, the manner of death was classified as accidental in 49 cases (5%), suicidal in 542 cases (57%) and undetermined in 365 cases (38%). The reported manner of death differed between the six forensic medicine districts in Sweden. The accident rate differed significantly between the district with the highest rate (9%) and the districts with the lowest rate (1%). One district had a significantly higher incidence of suicide (73%) than four of the other districts, while another district had a significantly lower incidence of suicide (33%) than all the other districts. The accident classification rate among the physicians performing ten or more autopsies varied from 0% to 17%, the suicide classification rate from 25% to 83% and the rate of undetermined manner of death from 8% to 71%. A major conclusion drawn from this study is that accidental DXP fatalities may be underestimated. This may have serious consequences, as under-reporting of accidental DXP fatalities will increase the risk that knowledge of the high toxicity of DXP will not reach the population consuming this drug. Since valid death statistics concerning the manner of death at DXP fatalities are needed to provide the base for preventive actions, special attention should be paid to the classification process, in order to increase the uniformity of the assessments among the different physicians, and to avoid under-reporting of accidents.

Gas chromatographic-mass spectrometric quantitation of dextropropoxyphene and norpropoxyphene in hair and whole blood after automated on-line solid-phase extraction. Application in twelve fatalities.

After conversion of norpropoxyphene (NP) to its corresponding amide, dextropropoxyphene (DP) and NP are extracted from 1 ml of blood or 50 mg of powdered hair, on C18 cartridges and eluted using methanol containing 0.5% acetic acid. Automated extraction is conducted on-line with automated device, starting from buffered and centrifuged sample. After extraction, the dried residue is reconstituted with 40 microl of methanol, and then injected in a gas chromatograph at 250 degrees C. Quantitation is carried out by gas chromatography-mass spectrometry in the selected-ion monitoring mode, lidocaine being the internal standard. The method gave relative standard deviations lower than 6.2% in whole blood, and 6.0% in hair for the entire range of calibration from 0.5 to 10 microg/ml in blood and from 1 to 20 ng/mg in hair of both compounds. Limits of detection in blood and hair for DP are, respectively, 0.07 microg/ml and 0.05 ng/mg, whereas the respective limits of detection in whole blood and hair for NP are 0.09 microg/ml and 0.04 ng/mg. The present method was used for one year in our laboratory. Postmortem concentrations of DP in blood ranged from 1.6 to 44.0 microg/ml (mean=9.8microg/ml, n = 12) and are comparable to those found in the literature. Out of 30 hair samples from people who died from heroin overdose, 13 were positive both for DP and NP with concentrations ranging from 0.2 to 27.4 ng/mg (mean 8.7 ng/mg) for DP and 0.3 to 68.9 ng/mg (mean 24.1 ng/mg) for NP.

Extraction of selected drugs from serum using microwave irradiation.

Microwave irradiation is used as an alternative heating method for extraction over more conventional hot plate methods. We describe a fast, efficient method for the determination of selected drugs in human blood/serum using microwave extraction. The microwave extraction of organic substances requires special instrumentation and the results have been compared with the results from classical liquid/liquid extraction. The present microwave extractions were performed in an 'atmospheric pressure' system. Before irradiation with microwaves, an appropriate solvent mixture was added to the buffered specimen. Lidocaine, methadone, diazepam, nordiazepam, propoxyphene and norpropoxyphene were tested as model substances. The quantitation was performed by GC/NPD. The procedure has been applied successfully to a number of forensic cases. The use of microwaves decreases the time of extraction and the solvent consumption.

D-propoxyphene and norpropoxyphene kinetics after the oral administration of D-propoxyphene: a new approach to liver function?

In an attempt to design a liver function test which takes into account both portal-systemic shunting and hepatocellular dysfunction, we investigated a group of patients with cirrhosis with or without surgical porta-caval shunt for d-propoxyphene and its major metabolite, norpropoxyphene kinetics. A small dose of d-propoxyphene (0.7 mg/kg body weight) was given orally to seven normal subjects, 15 patients with cirrhosis and seven patients with cirrhosis and surgical portacaval shunt. D-propoxyphene and norpropoxyphene areas under the plasma concentration-time from 0 to 4-h (AUC) were determined by the trapezoidal method. As d-propoxyphene is a high extraction drug and since the production of norpropoxyphene should reflect the amount of d-propoxyphene available to the hepatocytes, we tested the hypothesis that norpropoxyphene/d-propoxyphene AUC ratios should reflect both the degree of portal-systemic shunting and the severity of hepatocyte dysfunction. Norpropoxyphene/d-propoxyphene AUC ratios were significantly lower in patients with cirrhosis (mean +/- S.D.: 0.92 +/- 0.59) than in controls (2.51 +/- 0.45) and also significantly lower in patients with cirrhosis and a surgical shunt (0.53 +/- 0.23) than in patients with cirrhosis but without surgical shunt (1.10 +/- 0.63). Moreover, there was an overall statistically significant correlation between norpropoxyphene/d-propoxyphene AUC ratios and branched to aromatic amino acids ratios (rs = 0.91) and fasting venous NH4 (rs = -0.63). On the other hand, there was only a weak correlation between norpropoxyphene/d-propoxyphene AUC ratios and the 14C-aminopyrine breath test (rs = 0.43). These data suggest that the norpropoxyphene/d-propoxyphene AUC ratio reflects both shunting and reduced hepatocellular function.(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous determination of dextromoramide, propoxyphene and norpropoxyphene in necropsic whole blood by liquid chromatography.

Dextromoramide, propoxyphene and its main metabolite, norpropoxyphene, were determined in blood after solid-liquid extraction by means of an HPLC method using photodiode-array detection. Two cases of fatal overdose resulting from abuse of the two drugs are presented. In case 1 the necropsic whole blood contained dextromoramide at toxic level (194 ng ml-1) and propoxyphene (614 ng ml-1) and norpropoxyphene (1100 ng ml-1) within the therapeutic range; the death could be due to the combined effect of the two analgesics and, perhaps, other associated drugs. In case 2, the necropsic whole blood concentrations of propoxyphene and norpropoxyphene were 4330 and 3800 ng ml-1, respectively, and could be considered as lethal.

Determination of dextropropoxyphene and norpropoxyphene in plasma by high-performance liquid chromatography.

A simple and sensitive procedure for the routine assay of the analgesic drug dextropropoxyphene and its main metabolite, norpropoxyphene, in plasma is described. After liquid-liquid extraction from alkalinized plasma and back-extraction into a small volume of an acidic aqueous phase, the aqueous phase was injected into a column packed with 3-microns octadecylsilica particles. Ultraviolet absorbance detection at 210 nm was used. Concentrations down to 2 nM could be determined for both compounds; at this level, the intra-assay coefficient of variation was 5%.