A comparison of 50, 100 and 200 mg of intra-articular pethidine during knee joint surgery, a controlled study with evidence for local demethylation to norpethidine.

Pethidine (meperidine) is a compound with both local anaesthetic and opioid agonist properties. We have in a recent study demonstrated that pethidine could be an interesting alternative to prilocaine in arthroscopy with local anaesthetic technique. Therefore, we investigated, in a controlled randomized double-blind study, the effect of three doses of pethidine compared with a standard local anaesthetic, in patients subjected to arthroscopic knee joint surgery. Ten patients in each group received 50 mg (P50), 100 mg (P100), 200 mg (P200) of pethidine or prilocaine (5 mg/ml) + adrenaline (4 mg/ml) (PC), injected intra-articularly (i.a.) before surgery. We measured pain intensity and discomfort during arthroscopy and pain intensity at rest and at movement, nausea and tiredness for 3 days post-operatively at regular intervals using the VAS-technique. We also measured the concentration of pethidine and its demethylated metabolite, norpethidine, in plasma by collecting blood samples at 20, 40, 60, 80, 140 and 200 min following injection, and in synovial fluid which was collected through the arthroscope at the start and the end of the surgery. It was found that significantly more patients in the P50 group (n = 6) needed general anaesthesia due to intense pain than those in the P100 group (n = 1), P200 group (n = 0) or the PC group (n = 1). The PC group required significantly more analgesics and had a significantly higher calculated total sum of pain scores at movement post-operatively, than the other three groups. The P200 group more often reported tiredness post-operatively than the other three groups. We conclude that 100 or 200 mg pethidine i.a. produces satisfactory anaesthesia for surgery. There was a rapid transfer of pethidine from synovial fluid to plasma, resulting in plasma levels earlier reported to produce centrally mediated effects, such as analgesia and tiredness. We found much higher concentrations of norpethidine in the synovial fluid than in plasma, suggesting a local demethylation in the knee joint tissues. This site of drug oxidation has not earlier been demonstrated neither in vitro nor in vivo. The results suggest that pethidine given i.a. in the dose range of 50 to 200 mg results in analgesia due to both peripheral and central mechanisms. The significant systemic uptake of pethidine can cause unwanted side-effects.

No increase in carbamazepine-10,11-epoxide during addition of lamotrigine treatment in children.

It has been suggested that lamotrigine (LTG) may enhance the toxicity of carbamazepine (CBZ) by increasing the concentration of the active metabolite carbamazepine-10,11-epoxide (CBZ-E) in adult patients. The authors investigated this hypothesis in an add-on study in 11 children and 3 adolescents, aged 6-22 years, who had been treated for more than 1 year with CBZ in monotherapy or with CBZ in combination with one or two other antiepileptic drugs. The LTG dosage was increased step by step until clinical response or side effects were observed. The plasma concentrations of LTG, CBZ, and CBZ-E were monitored during steady state conditions before and after the addition of LTG. It was found that LTG had no effect on mean CBZ concentrations and that it decreased rather than increased the mean plasma concentration of CBZ-E from 6.4 +/- 2.6 to 4.9 +/- 2.4 mumol/l (mean +/- SD, n = 14, P = 0.019). Observed side effects were diplopia in two children, agitation in two, and increased number of seizures in one. None of these five patients had unusually high CBZ-E levels when the side effect developed. It is concluded that addition of lamotrigine in children treated with carbamazepine children does not result in a pharmacokinetic interaction with a toxic accumulation of carbamazepine-10,11-epoxide.

Effects of routinely given pethidine during labour on infants' developing breastfeeding behaviour. Effects of dose-delivery time interval and various concentrations of pethidine/norpethidine in cord plasma.

A standard dose of 100 mg of pethidine was given im to 13 healthy primiparae during labour. The aim of the study was to investigate whether developing breastfeeding behaviour in the newborn infant was associated with the dose-delivery time interval (DDI) or with the plasma concentration of pethidine and norpethidine in mixed cord blood at birth. The DDI was found to be unevenly distributed with no pethidine exposures in the time interval 5.4-8 h. The material was therefore divided into a "short DDI" group (1.1-5.3 h) and a "long DDI" group (8.1-9.9 h). The infants in the "short DDI" group had a depressed sucking behaviour in 15-45 min of observation and a delayed initiation of lip and mouth movements when compared with the infants in the "long DDI" group. Six of the thirteen infants did not suck their mothers' breasts during the observation period. These infants had higher median plasma concentrations of pethidine at birth than the seven infants who did start sucking. No differences wer found between the plasma levels of norpethidine and the behaviour. It was concluded that 100 mg of pethidine im as an analgesic given under routine conditions may have unfavourable effects on infants' developing breastfeeding behaviour if the DDI is short.

Rectal administration of morphine in children. Pharmacokinetic evaluation after a single-dose.

BACKGROUND: There is limited knowledge about the pharmacokinetics of morphine and its metabolites after rectal administration in children. In this study the pharmacokinetics of two different rectal formulations of morphine were examined and compared with intravenous morphine. METHODS: Children undergoing elective surgery received rectal morphine 0.2 mg/kg before start of surgery. Ten children (mean age 14 months) received morphine rectally in a hydrogel formulation and another 10 children (mean age 16 months) received morphine rectally in a parenteral formulation. For comparison, 6 children (mean age 21 months) were given the same dose intravenously. The plasma concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were measured by HPLC over 6 h after drug administration. RESULTS: The mean rectal bioavailability of morphine was 35% (range 18-59) after hydrogel administration and 27% (range 6-93) after the solution. Mean values of Cmax were 76 nmol/l (25-129) and 56 nmol/1 (15-140), respectively. The results showed that morphine gel had a significantly higher bioavailability (P < 0.02) than the solution. The ratios of plasma (M3G + M6G) to morphine were higher after rectal administration (mean 7.5-8.7) than after i.v. injection (mean 5.3), indicating the presence of first-pass metabolism using the rectal route. CONCLUSIONS: The rectal morphine hydrogel has pharmacokinetic properties which makes it a useful formulation for premedication and pain alleviation in paediatric patients.

Flunarizine of limited value in children with intractable epilepsy.

Fourteen ambulatory children and adolescents with intractable epilepsy were studied in an open phase II study to investigate the pharmacokinetics and pharmacodynamics of flunarizine as an add-on treatment. Flunarizine was given in increasing doses starting with 0.1-0.3 mg/kg/day until effect was observed or a steady-state plasma concentration of 50-60 ng/ml was reached. Treatment was continued for 3 months at steady state. Pharmacokinetics were determined during the immediate posttreatment period. Positive antiepileptic effect (> or = 50% reduction in seizure frequency) was observed in 4 of 14 patients (29%; 95% CI: 52-5). Independently of antiepileptic effect, 10 of 14 parents (71.4%; 95% CI: 95-48) observed positive cognitive effects. In all patients treatment was withdrawn due to either lack of effect or weight gain. Flunarizine was rapidly absorbed; mean time of peak concentration (Tmax) was 2.7 hours (range: 1-8). The mean terminal half-life was 23.2 days (range: 7-48), the total plasma clearance of flunarizine per fraction of the dose absorbed (CLp/F) was 0.28 ml/min/kg (range: 0.07-042), and the volume of distribution of flunarizine per fraction of the dose absorbed (Vd/F) was 187 L/kg (range: 99-348). We conclude that flunarizine (0.1-0.3 mg/kg/day) seems to be of limited antiepileptic value in children with intractable epilepsy. The pharmacokinetic profile of flunarizine complicates its clinical use.

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.

Plasma acetylsalicylic acid and salicylic acid levels during aspirin provocation in aspirin-sensitive subjects.

The ability of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit the cyclo-oxygenase which catalyzes formation of prostaglandins appears to be central to the mechanisms involved in aspirin sensitivity. We have investigated whether the plasma levels of acetylsalicylic acid (ASA) and its main metabolite salicylic acid (SA) at the time of intolerance reactions correspond with the concentrations required for enzyme inhibition in vitro. Twelve aspirin-sensitive and 15 aspirin-tolerant subjects were followed during provocation with aspirin. ASA and SA concentrations in plasma were determined by HPLC. After oral provocation (up to 460 mg cumulative dose), the levels of ASA and SA in plasma were equivalent in aspirin-sensitive and aspirin-tolerant subjects. For the aspirin-sensitive subjects, at the time of adverse reaction, the concentration range was 2.9-33.3 microM for ASA and 18.1-245 microM for SA. Oral provocation with sodium salicylate yielding 10-fold higher SA levels did not elicit intolerance reactions. Statistically significantly lower levels of ASA and SA (P < or = 0.01) evoked airway obstruction, as compared with merely extrapulmonary symptoms. Bronchial absorption of aspirin was found after inhalation of lysine-aspirin and was comparable in asthmatic and nonasthmatic subjects. In three aspirin-sensitive subjects who developed airway obstruction, the plasma levels for ASA and SA were 0.9-2.6 microM and 0.0-6.7 microM, respectively. In conclusion, the plasma levels of ASA reached at the time of a positive reaction are of the magnitude known to inhibit cyclo-oxygenases. Neither differences in bioavailability of ASA nor the formation of SA seems to contribute to the aspirin-elicited reactions.

Analgesic effect and plasma concentrations of codeine and morphine after two dose levels of codeine following oral surgery.

A double blind randomised cross over investigation was carried out in 25 male patients undergoing two oral surgical extractions, one for each lower wisdom tooth. The two extractions were performed about 6 weeks apart and were carried out under local anaesthesia. One hour after each extraction the patients randomly received 90 or 45 mg codeine. During the following 5 h the patients rated the intensity of their pain on a visual analogue scale. Blood was simultaneously sampled and assayed for codeine and its metabolite morphine. Mean pain intensity difference was just significantly higher after 90 mg codeine compared to 45 mg. The mean plasma concentrations of codeine and morphine were significantly higher after the 90 mg dose. However, for the two dose levels of codeine there was no obvious relationship between the difference in analgesic effect and the difference in the plasma concentration of codeine or morphine. The plasma concentrations of morphine were 2-3% of those of codeine and the levels were relatively low. Local formation of morphine from codeine within the human brain should therefore be investigated. Four patients were unable to demethylate codeine to a detectable plasma concentration of morphine after 90 mg codeine. In those patients the analgesic effect during the first hours was better after 90 mg codeine than after 45 mg. This suggests some analgesic effect of codeine itself.

Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

1. Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2. The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163 and 123 nmol l-1 in the younger and 309, 251 and 169 nmol l-1 in the older patients. The corresponding concentrations of morphine were 8.3, 7.4 and 4.5 nmol l-1 and 6.8, 5.5 and 2.8 nmol l-1 respectively. One patient in each age group had no detectable amounts of morphine. 3. In the four children, the rectal dose was repeated 6-hourly for four doses. The plasma concentrations of codeine and morphine following the fifth dose were similar to those after the first dose. The mean AUC(0,5 h) of morphine was 1.6% that of codeine. 4. In the infants the mean plasma half-lives of codeine and morphine were 2.6 and 2.5 h. The two infants with the lowest body weights had the longest half-lives. 5. The mean morphine/codeine concentration ratio was 4.3% in the infants and 1.6% in the children, suggesting impaired glucuronidation of morphine in the former group. The hourly concentration ratios were almost identical following the first and fifth dose in the children. 6. We conclude that at the age of 6 months infants are capable of O-demethylating codeine to morphine.

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.

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.

Immunological screening of benzodiazepines in urine: improved detection of oxazepam intake.

Immunological screening analysis of benzodiazepines in urine using the EMIT (enzyme multipled immuno-technique) and FPIA (fluorescence polarization immunoassay) techniques does not reliably detect the intake of therapeutic doses of oxazepam. In 23 patient urine samples, in which the presence of oxazepam could be verified chromatographically, only about 50% were detected as positive in the immunoassay systems. However, when the screening procedure was modified to include a simple step of hydrolysis of urine using the enzyme beta-glucuronidase to liberate conjugated oxazepam, improved detection of oxazepam intake was achieved. With EMIT 95% and with FPIA 100% of the samples were detected as positive. Since oxazepam arises in vivo also as a metabolite of other common benzodiazepines, the modification will most likely contribute to the generally improved detection of benzodiazepines.

Monitoring of phenytoin in epileptic children: value of the single morning sample.

The intra-individual variation in plasma concentration of phenytoin was studied in ten clinically well controlled children on monotherapy. The drug concentration was determined in routine pre-dose samples taken on three to five different mornings. On two of these occasions, plasma phenytoin was also determined at 0.5, 1, 2, 3, 5 and 7 h after the dose. The difference between the highest and lowest morning concentrations in a patient varied between 7.5 and 40 mumol/l (mean 20.1 mumol/l). Half of all morning concentration values were lower than 40 mumol/l. This often-recommended lower limit for good seizure control should therefore be reconsidered. The two concentration versus time curves in each patient during 7 h after administration differed considerably in shape, and the first curve could not be used for prediction of the second curve. The ratio between unbound and total drug was very stable and amounted to 9.4, SD 0.94% (n = 168). It is concluded that the conventional single morning sample is satisfactory for routine monitoring in well-controlled children on monotherapy with phenytoin. In problem patients, and during combination therapy, however, more extensive investigation will be necessary, including repeated morning samples as well as determination of dose-interval curves and protein binding.

Pain in the newborn--pharmacodynamic aspects.

Pain is subjective and can be quantitated in others only through cognitive cooperation between the sufferer and the observer. The newborn infant can neither describe pain nor remember it later in life. Thus, strictly speaking, we will never know if a pain experience can occur in the newborn period. However, many observations suggest that a nociceptive function exists at birth: (1) the neuronal pathways and transmitter systems required for pain conduction in adults seem to be present already during fetal life: (2) noxious stimulation of the newborn leads to behavioural responses and stress-related biochemical changes, and (3) the use of anaesthetic and analgesic drugs may improve the clinical outcome following surgery. The main features of the pharmacokinetics in the newborn period of both peripherally and centrally acting analgesics are now relatively well known and at least the short-term side effects are predictable and generally avoidable. Even if long-term adverse drug effects due to impaired imprinting have been suggested it appears that nociceptive stimuli in the newborn should be considered being disadvantageous to the patient. If they cannot be avoided, they should be treated.

The role of therapeutic drug monitoring in children.

Routine use of therapeutic drug monitoring in children is helpful in individualizing the dosage during long term treatment (e.g. theophylline and antiepileptic drugs) and in checking against toxic accumulation of drug in neonates (e.g. digoxin, theophylline/caffeine and aminoglycoside antibiotics). In individual patients, measurements of drug concentrations in plasma may be the only way to elucidate clinically unexpected drug effects or to handle interaction phenomena. Knowledge of the pharmacokinetic and pharmacodynamic changes during development is a prerequisite for a correct interpretation of the concentration values. Unfortunately, the quantitative relation between kinetics and clinical effect is still relatively poorly known for many drugs in the paediatric age groups. Apart from the pharmacokinetic informative value, therapeutic drug monitoring also has some merit as an aid to the physician in explaining to the patient and the parents why the drug should be taken as instructed. This may improve compliance.

Liquid-chromatographic quantification compared with gas-chromatographic-mass-spectrometric determination of verapamil and norverapamil in plasma.

A high-performance liquid chromatographic (HPLC) method for determining verapamil and norverapamil in plasma is presented and compared with gas chromatography/mass spectrometry (GC-MS). The plasma samples were extracted at alkaline pH with hexane containing 2-butanol (20 mL/L) and then back-extracted into phosphate buffer (0.1 mol/L, pH 3.0). For chromatography we used a reversed-phase column (Supelcosil LC-18 DB) with a mobile phase of the phosphate buffer and acetonitrile (70/30 by vol). Fluorescence detection was used (excitation at 203 nm, emission at 320 nm). Overall analytical recovery was 85%. Standard curves were linear from 1 to 1000 micrograms/L. The detection limit was 1 microgram/L. The assays are accurate and precise. We found no interferences by those substances tested. Results by HPLC and GC-MS agreed well (r = 0.99) for both verapamil and norverapamil determinations.

CSF and plasma pharmacokinetics of pethidine and norpethidine in man after epidural and intrathecal administration of pethidine.

The disposition of pethidine and its main metabolite, norpethidine, in cerebrospinal fluid (CSF) and plasma was studied in 11 thoracic surgery patients after lumbar epidural (100 mg; n = 6) or lumbar intrathecal (25 mg; n = 5) administration of pethidine. Pethidine appeared more slowly in plasma after intrathecal than after epidural administration (tmax 2.3 h and 14 min, respectively), but systemic bioavailability was similar. The CSF concentrations of pethidine were higher than those in plasma after both routes of administration. The maximal CSF/plasma concentration ratio was 6000 to 45,000 after intrathecal administration but was only 26 to 97 after the epidural route. Pethidine was rapidly distributed in CSF; nine to ten h after the intrathecal and epidural injections the CSF/plasma concentration ratios were 12 to 89 and 2 to 33, respectively. The calculated bioavailability in CSF of epidural pethidine was 10.3%. The terminal elimination half-life of pethidine was 6.0 h (CSF) and 5.4 h (plasma) after intrathecal administration and 8.6 h (CSF) and 8.8 h (plasma) after epidural injection. The volume of distribution of unchanged pethidine in the subarachnoid space was 13 ml.kg-1 and clearance from the CSF was 15 microliters.kg-1.min-1. In all patients receiving intrathecal pethidine and in some patients after epidural pethidine, CSF norpethidine concentrations were higher than those in plasma; the maximum CSF norpethidine was 102 to 1211 ng.ml-1 and 14 to 210 ng.ml-1 and the maximum CSF/plasma norpethidine concentration ratios were 21 to 652 and 0.6 to 14 times after intrathecal and epidural administration, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-adrenoceptor function in white blood cells from newborn infants: no relation to plasma catecholamine levels.

The maturity of beta-adrenoceptors in newborn infants was studied in relation to the catecholamine surge during labor. Umbilical blood was collected at birth from 12 infants delivered vaginally and 13 infants delivered by elective cesarean section. Granulocytes and lymphocytes were isolated. Receptor numbers and binding affinity were determined in the granulocytes by incubation with 125I-iodohydroxybenzylpindolol. Receptor responsiveness was tested by assessing isoproterenol-induced cyclic AMP accumulation in lymphocytes. Significantly higher plasma noradrenaline, adrenaline, and dopamine concentrations were found in infants born vaginally (108; 8.9; 0.9 nmol/liter, liter, respectively, median values) as compared with those delivered by cesarean section (11.0; 2.4; 0.2 nmol/liter). No significant differences in beta-adrenoceptor binding sites (receptor number: 39.2 +/- 2.6 versus 44.7 +/- 5.9 fmol/mg protein and binding affinity: 66.6 +/- 7.8 versus 65.0 +/- 6.2 pM) or responsiveness (maximal isoprenaline induced cAMP formation 52.4 +/- 10.3 versus 40.6 +/- 8.9 pmol/10(6) cells) were found between the two groups of infants. Lymphocyte beta-adrenoceptor sensitivity was similar to that found in adults. The beta-adrenoceptors on whole blood cells seem to be mature at birth and have the same responsiveness as in adults. The higher catecholamine surge during vaginal delivery as compared to elective cesarean section does not seem to affect beta-adrenoceptor function. Our results do not support the idea that reduced beta-adrenoceptor function is the cause of the previously observed inappropriately small cardiovascular and metabolic responses to the exceptionally high plasma catecholamine concentrations at birth.

Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration.

Plasma concentrations of codeine and its demethylated metabolite, morphine, were determined after single and repeated oral administration of codeine. Twelve healthy volunteers received two doses of codeine 60 mg, 2.8 h apart. In order to achieve steady-state conditions codeine 60 mg was then taken every 8 h for a further five doses. The plasma concentrations of codeine and morphine after the first, second and seventh doses were analyzed by GC-MS. The maximum plasma concentrations of codeine and morphine were reached about 1 h after administration and this time interval did not change on repeated administration. The peak plasma codeine was higher after the second dose of codeine than after the first and the concentration resembled that at steady-state. For morphine, the plasma concentration did not increase significantly after the second dose. Both after a single dose and during steady-state the plasma concentration of morphine was only 2-3% of that of codeine. It seems unlikely that morphine plays a significant role in the analgesic efficacy of single or repeated doses of codeine.