Pharmacokinetics after an intravenous single dose of the opioid ketobemidone in children.

BACKGROUND: Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in children because these properties have not been reported previously. METHODS: Thirty children, newborn to 10 years, scheduled for elective surgery were included in the trial. Ketobemidone hydrochloride was administered as a single intravenous bolus dose and ketobemidone and norketobemidone concentrations were measured by LC-MS over 8 h. Pharmacokinetic parameters were determined using compartmental methods. RESULTS: Six children were excluded from pharmacokinetic analysis because of incomplete blood sampling. The values of ketobemidone clearance (l/h/kg) given as median (range) were 0.84 (0.29-3.0) in Group A (0-90 days), 0.89 (0.55-1.35) in Group B (1-2.5 years) and 0.74 (0.50-0.99) in Group C (7-10 years). The corresponding values for apparent volume of distribution (l/kg) were 4.4 (3.7-6.9) (Group A), 2.6 (2.0-5.6) (Group B) and 3.9 (2.7-5.0 (Group C), and for elimination half-life (h) 3.0 (1.4-8.9) (Group A), 2.0 (1.2-4.7) (Group B) and 3.7 (2.4-6.9) (Group C), respectively. In the two neonates the elimination half-life was almost 9 h. The metabolite norketobemidone did not reach levels above the limit of quantification (0.07 ng/ml) in any of the patients. CONCLUSION: The pharmacokinetic parameters of ketobemidone in children older than 1 month appear to be similar to those in adults. Because of the large interindividual variability of the pharmacokinetics in neonates, further studies especially in this age group are warranted.

The addition of tramadol to morphine via patient-controlled analgesia does not lead to better post-operative pain relief after total knee arthroplasty.

BACKGROUND: Tramadol is used as an analgesic in post-operative pain treatment. Intravenous tramadol is often combined with morphine to achieve better pain relief and less side-effects after orthopaedic surgery. However, the available evidence is insufficient to support this combination. For this reason, we conducted the present non-commercial, randomized, double-blind clinical trial. METHOD: Sixty-three patients with osteoarthritis of the knee, selected for primary total knee arthroplasty (TKA), were randomized to receive saline or tramadol 100 mg/ml intravenously every 6 h during the first post-operative day (total, 400 mg/24 h). All patients had access to morphine via a patient-controlled analgesia (PCA) pump. RESULTS: Neither during the 6 h after the first dose nor during the first post-operative day could we detect any statistically significant difference with regard to pain intensity, sedation and nausea between patients treated with tramadol and the placebo group. However, the withdrawal rate caused by insufficient pain relief was greater in the tramadol group (7/31) than in the saline group (2/32). This difference did not reach statistical significance. In the group of patients who remained in the study for 24 h ('per protocol'), those randomized to receive tramadol had a significantly (P < 0.05) lower morphine consumption (20 mg or 31%) than the placebo group. CONCLUSION: Our study does not support the combination of tramadol and morphine via PCA for post-operative pain relief after primary TKA. In addition, our study indicates that morphine via PCA as the sole means of post-operative analgesia does not provide sufficient pain relief after TKA. Thus, other means of post-operative analgesia should be used following TKA.

Gastroduodenal tolerance of 75 mg clopidogrel versus 325 mg aspirin in healthy volunteers. A gastroscopic study.

BACKGROUND: Clopidogrel is a new antiplatelet agent that offers increased protection over aspirin in preventing vascular ischaemic events in patients with symptomatic atherosclerosis. In a large, randomized, international study of clopidogrel and aspirin (n = 19,185 patients) clopidogrel was associated with a lower incidence of gastrointestinal adverse events, including gastrointestinal haemorrhage and hospitalizations because of gastrointestinal haemorrhage. The aim of the study was to determine whether macroscopic differences in the gastric mucosa between aspirin- and clopidogrel-treated subjects could be detected by gastroscopy after short-term treatment. METHODS: Thirty-six healthy volunteers were randomized in a double-blind, double-dummy, parallel design, to 75 mg/day of clopidogrel or 325 mg/day of aspirin for 8 days. Gastroscopy was performed at base line before administration of study drug and directly after treatment completion. Gastroduodenal effects were measured in accordance with a modified Lanza scale. RESULTS: At base line no difference between the groups was detected (median Lanza score, 0.0 in both groups). At the end of treatment the aspirin group showed a median score of 7.5, and the clopidogrel group showed an unchanged median score of 0.0 (P < 0.001). In the aspirin group 13 individuals reported 19 adverse events versus 8 individuals and 13 adverse events for clopidogrel, with approximately half of the adverse events being gastrointestinal in each group. No serious adverse events were reported. CONCLUSION: In contrast to aspirin, short-term treatment with clopidogrel does not induce macroscopic changes in the gastroduodenal mucosa. The study results show that in patients without gastroduodenal disease clopidogrel, but not aspirin, does not induce any gastroscopically evident erosions during short-term treatment.

Urine and plasma pharmacokinetics of codeine in healthy volunteers: implications for drugs-of-abuse testing.

Thirteen healthy volunteers participating in an open and randomized study received two single doses (25 and 50 mg) of codeine orally two weeks apart. Urine concentrations of opiates were studied for 96 h, and plasma concentrations of codeine and the metabolites codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were monitored for 24 h. Plasma was analyzed by high-performance liquid chromatography. Measurements of urine were made with the EMIT opiate-screening assay and with gas chromatography-mass spectrometry for total (conjugates liberated by acid hydrolysis) codeine, morphine, and norcodeine. In urine, the ratio between total recovered morphine and codeine as expressed in percent ranged from 2.3 to 23.3% with a mean value of 9.8%. This ratio increased with time, and, in all but three subjects, rose to greater than 1 after 22-36 h. In 58% of cases, this occurred within the detection time in the EMIT assay. The detection time in the EMIT screening assay was found to be 20-39 h after the 25-mg dose and 30-52 h after the 50-mg dose. Elimination rates calculated from urine data corrected for creatinine concentration showed that morphine was eliminated more slowly than codeine. In plasma, the highest concentrations and area-under-curve values were observed for C6G, followed by codeine and M3G. All compounds had peak plasma values 1-2 h after dosing. The elimination of M3G was slower than that of C6G. We concluded that the relative proportion of codeine and morphine varies both between individuals and as a function of time and that morphine may be present in concentrations above those of codeine even after moderate and single doses of codeine. This must be taken into consideration when interpreting the presence of opiates during drugs-of-abuse testing.

Subjective and objective symptoms in relation to plasma methadone concentration in methadone patients.

Two rating scales, which were originally developed for measurements of objective and subjective signs of opiate withdrawal, were used to evaluate potential estimates (correlates) of methadone effects in relation to plasma methadone concentrations. Patients participating in our regular methadone maintenance treatment project were studied during 24 h after the intake of the daily methadone dose. Methadone concentrations in plasma were compared to the subjective (estimated by the patients) and objective (estimated by the investigator) signs of the drug effects before, and 2.5, 5, 9 and 24 h after intake of methadone. Some new items possibly related to rising methadone concentrations were added to the subjective scale. Results indicated that, for subjective ratings, the majority of the items investigated corresponded well with the plasma methadone concentrations. The most significant associations were found for the following items: low psychomotor speed, alertness, running nose, yawning and anxiety. For objective ratings, only the items rhinorrhea, piloerection and signs of anxiety were significantly associated with the methadone concentrations. These rating scales may, together with plasma methadone determinations, be of considerable value when making dose adjustments for methadone maintenance patients. Further work is, however, needed to establish concentration-effect relationships.

Deficient performance of drugs of abuse testing in Sweden: an external control study.

Testing for drugs of abuse in urine is usually performed in two steps; after initial screening positive findings are confirmed with specific chromatographic techniques. The use of different methods with different cut-off levels, may lead to variable results in a test sample containing a drug. Sixty-eight Swedish laboratories were enrolled in an external quality study and received three control samples. The laboratories were instructed to perform only in-house tests for amphetamines, benzodiazepines, cannabinoids, cocaine and opiates. Nineteen out of the 68 laboratories reported fully correct results. Thirty reported one o more false positive drug findings. One laboratory performing confirmation with gas chromatography--mass spectrometry reported a false positive finding of amphetamines in the sample containing ephedrine. Since testing for drugs of abuse in urine is a delicate matter, with both medical and legal implications, such testing should be performed with a zero rate of false positive results. Routine use of specific methods for confirmation should be used since performance of these laboratories was better in this study. It is concluded that there is a need to continuously measure the level of quality of laboratories by a program for external quality control.

Evaluation of analytical procedures for urinary codeine and morphine measurements.

Different analytical procedures for quantitation of total morphine and codeine in urine were evaluated. Hydrolysis of urine with hydrochloric acid and four different enzymes was compared. In order to effect complete hydrolysis of glucuronide conjugates, hydrolysis with 6.5M HCl containing bisulphite and heating at 100 degrees C for 20 min was required. Results using this hydrolysis procedure agreed well with results from direct analysis of free and conjugated forms by liquid chromatography. Use of more dilute HCl but at a higher temperature was not sufficient. Some enzymatic procedures appeared to give effective hydrolysis with a higher variability, but these procedures were more time-consuming. There was a good quantitative agreement between FID gas chromatography and ion-trap gas chromatography/mass spectrometry. The validated analytical procedure was applied to authentic patient samples.

[Benzodiazepine findings in autopsy material. A study shows interacting factors in fatal cases]. / Bensodiazepinfynd i obduktionsmaterial. Studie påvisar samverkande faktorer vid dödsfall.

The paper consists in a report of a retrospective study (of data from 1987) on the prevalence of benzodiazepines in blood at the time of death. Of 2,007 autopsies, forensic chemical analyses were performed in 1,587 cases, in 159 of which benzodiazepines were found. Of these 159 deaths, 22 were considered to be due to natural causes, and in another 22 cases the cause of death was still unclear after examination; the remaining 115 deaths were due to accidents (N = 16), suicide (N = 60), drug addiction (N = 29) or alcoholism (N = 10). Multiple benzodiazepine intake was found in 37 cases, a subgroup including all 29 cases of death due to drug addiction. In a comparison of suicides and natural deaths, the concentrations both of flunitrazepam and nitrazepam were significantly higher among the suicides (P < 0.001 and P < 0.05, respectively). In four cases, the sole cause of death was benzodiazepine intake. It is concluded that some benzodiazepines, particularly flunitrazepam, may be more toxic than formerly supposed.

Detection of benzodiazepine intake in therapeutic doses by immunoanalysis of urine: two techniques evaluated and modified for improved performance.

We evaluated the EMIT (enzyme-multiplied immuno technique) and FPIA (fluorescence polarization immunoassay) urine screening systems for detection of benzodiazepine intake. Healthy male volunteers were given single oral therapeutic doses of alprazolam (2 mg), chlordiazepoxide (25 mg), flunitrazepam (1 mg), lorazepam (3.75 mg), nitrazepam (5 mg), and triazolam (0.25 mg), after which urine was collected for the next 32 h. The EMIT method failed to detect the intake of flunitrazepam, lorazepam, and nitrazepam. FPIA did not detect the intake of chlordiazepoxide, flunitrazepam, lorazepam, nitrazepam, and triazolam. Modification of the EMIT method to include enzymatic hydrolysis did not significantly alter the results obtained with this method. A modification of the FPIA method to include enzymatic hydrolysis and a lower cutoff value improved the results considerably, so that we reliably detected all studied substances but flunitrazepam. We conclude that (a) both EMIT and FPIA techniques, when used as intended by the manufacturers, are unreliable for the detection of intake of therapeutic doses of these benzodiazepines, and (b) the described modification of the FPIA should provide a much improved tool for detection of benzodiazepine intake.

[Diagnosis in acute narcotics poisoning]. / Diagnostik vid akut narkotikaintoxikation.

The article presents a brief summary of symptoms in acute narcotic drug intoxication. It emphasizes the need for correct diagnosis by using drugs of abuse testing, and when these tests may be applicable. With three case reports the authors show the need for correct diagnosis from both medical and legal aspects.

Importance of creatinine analyses of urine when screening for abused drugs.

We report here a simple method involving urine creatine measurements for testing authenticity and reducing false-negative results in urine testing for drugs of abuse. Urinary creatinine in consecutive patient samples (n = 176) ranged between 0.1 and 31.9 mmol/L (mean 9.8 +/- SD 6.2) and the osmolality in these urines ranged between 49 and 1183 mOsm/kg (mean 595 +/- SD 276). With other consecutive samples in which creatinine was (arbitrarily chosen) less than 4.3 mmol/L (n = 85), the correlation with osmolality was lower. In 10 randomly selected urine samples from different patients, all "clean" for all drugs of abuse in initial immunological drug testing with approved methodology (in which creatinine was less than 4.3 mmol/L and osmolality was less than 200 mOsm/kg), five patients turned out to be drug positive after a simple concentration by volume. In a formerly heavy smoker of cannabis, the excretion of cannabinoids and creatinine was monitored for 93 days. The substances showed very good correlation throughout this period (r = 0.93, P less than 0.001), whereas simple measurements of cannabinoid concentrations would have falsely indicated several relapses of cannabis abuse. Urine samples used in drug-abuse testing should be tested for creatinine; if creatinine is less than 4.0 mmol/L, negative results for drugs may not be valid.

Chiral analysis of methadone in plasma by high-performance liquid chromatography.

A method for the chiral high-performance liquid chromatographic analysis of methadone in plasma has been developed. The method employed organic solvent extraction, enantiomeric separation on a Chiral AGP column, and ultraviolet absorption detection at 212 nm. The intra-day variation in the quantification of methadone enantiomers was less than 9% at the 100 ng/ml level, and the values obtained correlated well with those from a gas chromatographic-mass spectrometric method. Results from patients indicate inter- and intra-individual differences in the ratio between l- and d-methadone in plasma during therapy with racemic methadone. In one patient, a higher level of d-methadone in plasma was caused by both faster elimination and lower bioavailability of l-methadone.

Intraindividual variation in 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute lymphoblastic leukaemia.

Intraindividual variation in 6-mercaptopurine (6-MP) kinetics has been little studied. It has now been examined in 18 children with acute lymphoblastic leukaemia (ALL). On 2 to 4 occasions in each patient drug concentrations in plasma and red cells were followed for 4 h after administration by means of HPLC. The mean individual coefficient of variation (C.V.) in AUC was 57.9% and it was not related to dose or concentration. The variation was the same in plasma and in red cells. It is concluded that regular monitoring of 6-mercaptopurine concentration would identify periods when a patient deviates strongly from the mean range. Both undertreatment and concentration-dependent toxicity could then be corrected.

Monitoring of plasma methadone: intercorrelation between immunoassay and gas chromatography-mass spectrometry.

Determination of plasma methadone is essential in connection with dose adjustments for patients participating in methadone maintenance programs. We successfully adapted the existing fluorescence polarization immunoassay (FPIA) kit intended for urinary methadone to plasma assays. A concentration interval of 50-900 ng/ml could be covered. The coefficient of variation was less than 7%, and the limit of detection below 50 ng/ml. The intercorrelation between the immunoassay and a specific gas chromatographic-mass spectrometric (GC-MS) method was studied in samples from 19 heroin addicts in methadone maintenance treatment. A total number of 97 plasma samples with a concentration range of 31-842 ng/ml were used. The slope and intercept of the regression line (CFPIA = 0.93 X CGC-MS + 15) was in good agreement with the theoretical relation (CFPIA = CGC-MS), with a coefficient of correlation of 0.978. The mean ratio, in quantitative result, between the techniques (CFPIA/CGC-MS) was 1.03 +/- 0.01 (SEM). We conclude that the immunoassay proposed in this study can be safely used in patients participating in methadone maintenance programs.

The course of biological parameters and 6-mercaptopurine pharmacokinetics during maintenance treatment of children with acute lymphoblastic leukaemia.

Twenty patients on maintenance therapy (MT) for acute lymphoblastic leukaemia (ALL) with oral 6-mercaptopurine (6-MP) and methotrexate (MTX) were studied. White cell and red cell indices and platelets counts were monitored every second week as were drug levels. Mean values for 6-MP and MTX doses, and blood component parameters were calculated for each 6-month period for the whole patient group. 6-MP plasma concentrations and liver-function tests were determined once every six months and mean values calculated. 6-MP and MTX mean doses did not change significantly during MT. The mean area under the concentration versus time curve (AUC) 0-4 hours varied slightly from the start to the end of the MT (257 and 296 ng/ml.h, respectively). The mean plasma peak concentration increased from 98 ng/ml to 195 ng/ml (p less than 0.01) during the same period. There were significant decreases between the initial white blood cell counts (WBC) and red blood cell counts (RBC) as compared to levels at the end of therapy (p less than 0.01 and 0.02, respectively). A linear correlation was found between 6-MP peak concentrations and both WBC (r = 0.96) and RBC (r = 0.87). At the end of MT liver function tests became normal in all except 6 patients. In conclusion, MT have moderate effects on bone marrow and liver and monitoring 6-MP plasma concentration might be of value for determination of the optimal WBC levels during MT.