Sensitive determination of pethidine in body fluids by gas chromatography-tandem mass spectrometry.

We have presented a simple and sensitive method for determining pethidine, a narcotic analgesic drug in body fluids by gas chromatography-tandem mass spectrometry (GC-MS/MS). Pethidine and 4'-piperidinoacetophenone (internal standard) were extracted from body fluids with Bond Elut C(18) columns; the recoveries were above 85% for both compounds. The calibration curves for blood and urine showed good linearities in the range of 1.25-40 ng/ml. Its detection limits (signal-to-noise ratio=3) were estimated to be approximately 0.5 ng/ml of whole blood and urine.

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.

Central nervous system toxicity associated with meperidine use in hepatic disease.

Meperidine-associated central nervous system (CNS) excitatory toxicities are believed to be caused by accumulation of the active metabolite normeperidine. Normeperidine is eliminated by the kidneys and accumulates in patients with renal insufficiency, sickle cell disease, and cancer. In patients with cirrhosis, the metabolism of meperidine is decreased, leading to accumulation of the parent drug and possible CNS depressive effects similar to hepatic encephalopathy. Although the elimination of normeperidine is decreased as well in these patients, the ratio of normeperidine to meperidine is generally low, and the narcotic effects of meperidine usually predominate. This is the first reported case of CNS excitatory toxicities in a patient with alcoholic hepatitis and cirrhosis, and normal renal function. Administration of multiple doses of meperidine in patients with hepatic disease should be discouraged.

The effect of early labour, maternal analgesia and fetal acidosis on fetal plasma oxytocin concentrations.

OBJECTIVE: To determine the effect of early labour, maternal analgesia and fetal hypoxia on circulating fetal oxytocin concentrations. DESIGN: Prospective observational study. SETTING: Delivery suite in a District General Hospital. SUBJECTS: Fifty women at term who did not require oxytocin administration or more than one form of analgesia. Study groups: vaginal delivery with (1) no analgesia, (2) pethidine, or (3) epidural analgesia. Caesarean section under regional analgesia (4) prior to, and (5) after the onset of labour. INTERVENTIONS: Samples of blood were collected from the umbilical artery (UA) and umbilical vein (UV) immediately after fetal delivery prior to placental separation or oxytocic administration. MAIN OUTCOME MEASURES: Plasma oxytocin (OT) concentration, umbilical vein pH, cystine aminopeptidase activity. RESULTS: The geometric mean UA-OT was significantly greater than UV-OT in all groups and was not altered by pethidine; however, epidural administration increased the UA-UV difference. The UA-UV difference at caesarean section was not significantly altered by the onset of labour. There was no correlation between UV pH and UA-UV plasma oxytocin. Cystine aminopeptidase activity was not detectable in UA and UV plasma. CONCLUSIONS: Fetal OT production is increased by epidural but not by pethidine analgesia. It is not influenced by the onset of labour or fetal hypoxia.

Opioid agonists binding and responses in SH-SY5Y cells.

SH-SY5Y (human neuroblastoma) cultured cells, known to have mu-opioid receptors, have been used to assess and compare the ability of eight representative mu-selective compounds from diverse opioid families to recognize and activate these receptors. A wide range of receptor affinities spanning a factor of 10,000 was found between the highest affinity fentanyl analogs (Ki = 0.1nM) and the lowest affinity analog, meperidine (Ki = 1 microM). A similar range was found for inhibition of PGE1-stimulated cAMP accumulation with a rank order of activities that closely paralleled binding affinities. Maximum inhibition of cAMP accumulation by each compound was about 80%. Maximum stimulation of GTPase activity (approximately 50%) was also similar for all compounds except the lowest affinity meperidine. Both effects were naloxone reversible. These results provide further evidence that mu-receptors are coupled to inhibition of adenylate cyclase and that the SH-SY5Y cell line is a good system for assessment of mu-agonists functional responses.

Meperidina para controle do tremor transoperatorio durante cesariana sob anestesia peridural / Meperidina for control of shivering during cesarea section under epidural anesthesia

El temblor después de la anestesia peridural en obstetricia, no es sólo desagradable para la paciente como aumenta considerablemente el consumo de oxígenio y el débito cardíaco. Con el objetivo de verificar la eficacia de la meperidina en el control del temblor durante cesária bajo anestesia peridural, se realizó un estudio doble ciego donde 60 parturientas recibieron 30 mg de meperidina o solución salina. El temblor fue clasificado en una escala de a a 3 (grado ) = ausencia de temblor, grado 3 = temblor grave). El temblor y otros parámetros fueron evaluados al llegar la paciente a la sala de operación, después de realizada la peridural, despues de la incisión de piel, en el momento del nacimiento y a los 2, 5, 10,15, y 30 minutos después de la inyección venosa de meperidina. El uso de meperidina resultó en la disminución significativa de la incidencia (53 para 18% p < 0,01) y gravedad del temblor (43 para 0% p < 0,01) cuando comparado con solución salina (incidencia: 50 para 47%; gravedad: 47 para 40%). El efecto apareció en dos minutos y permaneció efectivo durante todo el estudio. No hubo diferencia significativa en relación a los signos vitales (PA, FC, FR). La incidencia de náusea y vómito fue la misma en ambos los grupos. El mecanismo de acción de meperidina en el control del temblor permanece obscuro

First pass uptake of fentanyl, meperidine, and morphine in the human lung.

The first pass uptake of fentanyl, meperidine, and morphine in human lung was studied in patients using a double indicator dilution technique. A bolus containing one of the drugs and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia for surgery. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of drug taken up by the lung during the first pass and the instantaneous extraction of drug at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. The total uptake (mean +/- SE) during the first pass through the human lung for fentanyl and meperidine was 75.2 +/- 3.2% and 64.7 +/- 7.8% of the injected dose, respectively. The pulmonary uptake of morphine was very small, with 96.5 +/- 7.1% of the injected dose recovered in arterial blood after the first pass through the lung. The arterial blood concentration of drug and dye versus time showed a slight delay of the fentanyl and meperidine peaks compared to ICG. It was also observed that greater than 90% of these drugs were extracted from the blood in the early part of the first pass, but the extraction decreased with time during the first pass through the lung. These findings indicate that some of the drug taken up by the lung can diffuse back out into the blood.2+off

A randomized prospective controlled study of the metabolism and hepatotoxicity of halothane in humans.

In a randomized prospective controlled study in humans, the metabolism and hepatic effects of a single administration of halothane were compared with enflurane and meperidine. Pre- and postoperative antipyrine pharmacokinetics, intraoperative indocyanine green clearance, liver histology, and postoperative liver function tests were determined in 24 patients undergoing abdominal surgery who were randomly allocated to receive either halothane (0.5%, group I), enflurane (0.8%, group II), or meperidine (group III) as a supplement to a common basal anesthetic regimen consisting of thiopental, nitrous oxide/oxygen/muscle relaxant. In addition, end-tidal concentrations of the volatile reductive metabolites of halothane, chlorodifluoroethylene (CDF), and chlorotrifluoroethane (CTF) were determined in group I patients and serum and urinary inorganic fluoride were determined in both group I and II patients. Indocyanine green clearance was measured before anesthesia (stage I), during basal anesthesia (stage II), in the presence of surgical stimuli (stage III), and after introduction of the selected anesthetic agent (stage IV). CDF and CTF were detectable within 20 min of the start of halothane anesthesia in every patient receiving halothane. Peak serum fluoride concentrations occurred at 2 and 24 hr in the enflurane and halothane groups, respectively, whereas urinary fluoride excretion was elevated postanesthesia in the enflurane group only. There was no difference between the pre- and postoperative disposition of antipyrine in group II or III, but after anesthesia, antipyrine clearance was significantly decreased (P less than 0.02) and plasma half-life increased (P less than 0.05) in group I patients (halothane). Concentrations of serum alanine aminotransferase (ALT) and bilirubin were significantly elevated (P less than 0.5) postoperatively in groups I and II but unchanged from preoperative values in group III patients. Three of the 24 liver biopsies taken at the end of stage IV showed several foci of acute liver cell necrosis; of these, two patients were from group I and one from group II. There were no significant differences in liver cell morphology (P greater than 0.5) in biopsies taken at the end of stage IV compared with biopsies at the end of stage III, from groups I and II. The results of this study show that reductive metabolism of halothane occurs routinely in patients undergoing halothane anesthesia under conditions of normoxia. This may be the cause of the changes in antipyrine clearance after halothane anesthesia.

Neurotoxicity of meperidine.

Meperidine neurotoxicity manifests as shakiness, tremors, myoclonus, and seizures. It is generally seen with repeated parenteral use. We report a case of meperidine neurotoxicity from oral use by an otherwise healthy woman. The pharmacology and clinical implications are discussed.

Epidural and intrathecal opiates in obstetrics.

The use of epidural and intrathecal opiates in obstetrics is reviewed. Opiate receptors in the substantia gelatinosa of the spinal cord appear to be the main site of drug action after both epidural and intrathecal modes of drug administration. However, an additional systemic effect for this selective spinal analgesia cannot be excluded, especially after epidural drug administration. Contrary to that of general surgery patients, the response of pregnant women at term to epidural opiates is unpredictable. The action of the opiates is of short duration. There are at least three anatomical reasons for this phenomenon: an extensive epidural venous blood flow during pregnancy, visceral fibers (uterine contraction pain) located deeper in the substantia gelatinosa than somatic fibers (skin and peritoneal pain), and A delta fibers (uterine pain) which bypass opiate receptors in the substantia gelatinosa. After intrathecal injection of opiates, there was a strong analgesic action during delivery, but an unacceptable amount of side effects prevents their routine use. In post-cesarean patients, epidurally administered opiates are quite effective analgesics, but they still have one serious unwanted effect: respiratory depression of delayed onset. Thus, in routine obstetric practice, epidural or intrathecal opiates play only a limited role.

Analgesic efficacy and pharmacokinetic evaluation of meperidine and hydroxyzine, alone and in combination.

As part of a study to evaluate the analgesic efficacy of meperidine and hydroxyzine, alone and in combination, a double-blind complete crossover study of meperidine (50 mg IM), hydroxyzine (100 mg IM), meperidine (50 mg IM) plus hydroxyzine (100 mg IM), and saline placebo was conducted. Thirty patients with chronic moderate to severe pain due to metastatic cancer were evaluated as to pain relief following administration of all four study medications. All of the treatment groups showed statistically significant analgesic activity as compared to placebo. Hydroxyzine provided sustained pain relief to six hours, whereas meperidine produced analgesia up to two hours. The combination produced additive analgesia only during the first 2 hr. The pharmacokinetics of meperidine and hydroxyzine were compared to observed analgesia. Significant correlation between serum drug levels of meperidine and hydroxyzine and pain relief resulted and the serum levels of meperidine and hydroxyzine necessary for analgesia were calculated to be 0.10-0.15 mg/ml and 60-70 ng/ml; respectively. The observed analgesia of the meperidine/hydroxyzine combination was correlated with the analgesia of the individual agents and the limited additive analgesia observed with the addition of meperidine to hydroxyzine does not justify the added toxicity of the narcotic.

Patient-controlled analgesic therapy, Part III: pharmacokinetics and analgesic plasma concentrations of ketobemidone.

The effects of anaesthesia and surgery on the pharmacokinetics of ketobemidone were studied in 12 patients. Plasma ketobemidone concentrations were assayed with a mass-fragmentographic method. The peroperative Vd(area) was 5.9 +/- 2.6L/kg and the terminal half-life was 3.9 +/- 1.7 h. In the postoperative period Vd(area) decreased to 3.7 +/- 0.4L/kg and the terminal half-life to 2.1 +/- 0.4 h. Plasma clearance (Clp) did not change significantly, peroperative Clp being 18 +/- 4.3 ml/min/kg and postoperative Clp being 22 +/- 7.5 ml/min/kg. The pharmacokinetics of ketobemidone were not influenced by the addition of a spasmolytic agent in the commercial combination ketobemidone preparation 'Ketogin'. Postoperative pain was relieved in 15 patients by patient-controlled intravenous administration of ketobemidone by means of a programmable drug injector. The mean ketobemidone consumption was 2.3 +/- 0.8 mg/h, which produced a mean plasma concentration of 28 +/- 11 mg/ml. Pseudosteady-state plasma concentrations of ketobemidone were established with a mean minimum effective concentration (MEC) of 25 +/- 11 ng/ml. Ketobemidone 'plain' and 'Ketogin' did not differ significantly in these respects. Analgesia was considered by all patients to be satisfactory.

Regional epidural analgesia: kinetics of pethidine.

Low intrathecal doses of opiates produce dose-dependent long-wasting elevation of the pain threshold in rats. The effect is postulated to be mediated by a direct action on the substantia gelatinosa of the spinal cord. Eight uncontrolled and two controlled studies in man showed a long duration of analgesia for most patients in the postoperative period. The duration of effect differs widely within and between studies. Using a double-blind design, we compared the relative efficacy of epidural and parenteral pethidine to control postoperative pain after total hip replacement. Preliminary pharmacokinetic data from six patients show that epidural doses of 20 or 60 mg pethidine give a similar pattern of absorption and elimination in plasma as 2 mg pethidine/kg body weight intramuscularly. The terminal elimination half-lives of pethidine in plasma are 5-7 h for all routes of administration. The possibility cannot be excluded that the analgesic effect of epidural pethidine is partly systemically mediated.

Pharmacokinetics of pethidine during anaesthesia and patient-controlled analgesic therapy.

The pharmacokinetics of pethidine has been studied in 12 patients subjected to major intraabdominal surgery. Pethidine and norpethine were analyzed in plasma samples collected during anesthesia and during patient-controlled administration of small intravenous doses of pethidine in the early postoperative period. A second study on the pharmacokinetics of pethidine was performed on the 3-5th postoperative day. The plasma clearance of pethidine was significantly lower in the preoperative study (8.9 +/- 1.8 ml x kg x min-1) compared with the postoperative study (12.0 +/- 3.1 ml x kg x min-1). Volume of distribution (Vd) was not significantly influenced, being 4.25 +/- 1.72 l x kg-1 peroperatively and 3.14 +/- 0.84 l x kg-1 postoperatively. Elimination half-life decreased from 5.91 +/- 3.57 h peroperatively to 3.25 +/- 1.40 h postoperatively. The kinetics of pethidine in the postoperative study agreed with pethidine kinetics reported for healthy volunteers. The fraction of unbound pethidine decreased from 0.26 +/- 0.1 peroperatively to 0.18 +/- 0.1 postoperatively. Norpethidine, a metabolite of pethidine, has been claimed to be responsible for several side effects like respiratory depression and convulsions during pethidine therapy. No side effect attributable to norpethidine was observed in the self-administration period. Norpethidine plasma concentrations did not exceed 500 ng/ml. The altered pethidine pharmacokinetics during anesthesia and the ensuing postoperative hours and the interindividual differences of the disposition of the drug strongly suggest that pethidine should be given by individualized regimens in surgical patients.

Single-dose kinetics and bioavailability of ketobemidone.

The single-dose kinetics and the oral and rectal bioavailability of ketobemidone have been studied in patients after surgery. Plasma concentrations were determined following intravenous administration of Ketogin 2 ml, containing ketobemidone chloride 10 mg and the spasmolytic substance N, N-dimethyl-3, 3-diphenyl-l-methylallylamine chloride 50 mg and following oral or rectal administration of Ketogin. Ketobemidone was analyzed by gas chromatography-mass spectrometry using a deuterated internal standard. Ketobemidone disappeared rapidly from plasma after i.v. or oral administration, yielding a mean plasma half-life between 2.25 and 2.45 h. After rectal administration the plasma half-life was somewhat prolonged (3.27 h), probably due to late absorption., The bioavailability of oral ketobemidone was 34% +/- 16% s.d. (n = 6), and when given rectally 44% +/- 9% s.d. (n = 5). In contrast to earlier investigations performed without plasma analysis, ketobemidone was found to have a rapid elimination when given intravenously, orally or rectally.

Multiple dose kinetics of ketobemidone in surgical patients.

Twelve patients scheduled for major abdominal surgery were selected for a study of the kinetics of ketobemidone during the day of surgery and in a follow-up study 3-5 days after surgery. In six patients ketobemidone was administered as ketobemidone plain and in the other six, it was given as Ketogin, a combination formula containing a spasmolytic substance in addition to ketobemidone. Plasma samples were collected for approximately 24 h following induction of anesthesia, during which time multiple doses of ketobemidone were administered. A single-dose study was performed 3-5 days after surgery using the same drug. No significant differences were found between the two formulations of ketobemidone. Plasma clearance did not change significantly between the two periods of study, being 18.0 +/- 4.4 ml . kg-1 . min-1 peroperatively and 21.7 +/- 7.6 ml . kg-1 . min-1 postoperatively. Peroperative Vd area was significantly larger than post-operative Vd area, 5.84 +/- 2.62 l . kg-1 and 3.63 +/- 0.38 l . kg-1, respectively. T1/2 terminal decreased from 3.84 +/- 1.6 h peroperatively to 2.06 +/- 0.44 h postoperatively.