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Purpose: Meperidine has local anesthetic properties and, therefore, when given epidurally it has the potential to cause hemodynamic changes. Our objective was to study the hemodynamic effects of an analgesic dose of epidural meperidine (50 mg) in 34 ASA 1-2 term parturients scheduled for elective Cesarean section under epidural anesthesia., Methods: A lumbar epidural catheter was inserted and patients lay in the supine left wedge position. Intravenous fluid preload was withheld, and hemodynamic measurements comprising of mean arterial pressure, cardiac output and heart rate were made using automatic oscillotonometry (Dinamap 1486SX) and transthoracic electrical bioimpedance (Bomed NCCOM3). Following baseline measurements, the hemodynamic effects of sequential epidural injection of first, 10 ml saline, and 20 min thereafter, 50 mg meperidine diluted to 10 ml with saline, were recorded. Sensory blockade was assessed following each injection using loss of temperature discrimination to ice. Paired Student t tests were used to compare changes in hemodynamic variables., Results: Epidural meperidine produced a small increase from the saline values in the mean (SD) cardiac output of 5.81 +/-1.44 to 6.04+/-1.54 L x min(-1) (P<0.05), and mean arterial pressure of 77.1+/-8.8 to 79.3+/-9.9 mm Hg (P<0.05). Sensory changes, the upper level of which ranged from L1 to T1, were detected in 94% of patients given epidural meperidine. Epidural saline injection had no such hemodynamic effects, but produced a detectable sensory level in two patients., Conclusion: Epidural meperidine, 50 mg, caused minimal hemodynamic changes in term parturients.

Background: Among opioids, meperidine (pethidine) also shows local anesthetic activity when applied locally to peripheral nerve fibers and has been used for this effect in the clinical setting for regional anesthesia. This study investigated the blocking effects of meperidine on different ion channels in peripheral nerves., Methods: Experiments were conducted using the outside-out configuration of the patch-clamp method applied to enzymatically prepared peripheral nerve fibers of Xenopus laevis. Half-maximal inhibiting concentrations were determined for Na+ channels and different K+ channels by nonlinear least-squares fitting of concentration-inhibition curves, assuming a one-to-one reaction., Results: Externally applied meperidine reversibly blocked all investigated channels in a concentration-dependent manner, i.e., voltage-activated Na+ channel (half-maximal inhibiting concentration, 164 microM), delayed rectifier K+ channels (half-maximal inhibiting concentration, 194 microM), the calcium-activated K+ channel (half-maximal inhibiting concentration, 161 microM), and the voltage-independent flicker K+ channel (half-maximal inhibiting concentration, 139 microM). Maximal block in high concentrations of meperidine reached 83% for delayed rectifier K+ channels and 100% for all other channels. Meperidine blocks the Na+ channel in the same concentration range as the local anesthetic agent lidocaine (half-maximal inhibiting concentration, 172 microM) but did not compete for the same binding site as evaluated by competition experiments. Low concentrations of meperidine (1 nM to 1 microM) showed no effects on Na+ channels. The blockade of Na+ and delayed rectifier K+ channels could not be antagonized by the addition of naloxone., Conclusions: It is concluded that meperidine has a nonselective inhibitory action on Na+ and K+ channels of amphibian peripheral nerve. For tonic Na+ channel block, neither an opioid receptor nor the the local anesthetic agent binding site is the target site for meperidine block.

In this study, the effect of ceramide on GH-releasing hormone (GHRH)-stimulated cAMP accumulation and GH release in rat anterior pituitary cells was investigated. C2-, C6-, and C8-ceramide were found to enhance GHRH-stimulated cAMP accumulation. In contrast, their effects on GHRH-stimulated GH release were inhibitory. Treatment with a glucosylceramide synthase inhibitor produced a similar enhancing effect on cAMP accumulation and an inhibitory effect on GH release. To identify the pathway through which ceramide mediated its effect, it was found that ceramide inhibited GH release stimulated by KCl, BayK 8644, and a GH-releasing peptide, but not that stimulated by ionomycin or an activator of protein kinase C. Direct measurement of intracellular Ca2+ revealed that C2-ceramide inhibited GHRH- and KCl-mediated increases in intracellular Ca2+, suggesting that ceramide probably inhibits GH release through inhibition of the L-type Ca2+ channels. As for its mechanism on cAMP accumulation, the enhancing effect of ceramide on GHRH-stimulated cAMP accumulation was abolished in the presence of a phosphodiesterase inhibitor, isobutylmethylxanthine, suggesting that ceramide enhances the cAMP response through inhibition of its metabolism. Taken together, our results suggest that ceramide plays an important role in the regulation of GHRH-stimulated responses in somatotrophs. By reducing GH secretion while enhancing cAMP accumulation, ceramide may promote the synthesis and storage of GH in rat anterior pituitary cells.

Background and Objectives: The perioperative use of continuous psoas compartment block (CPCB) was compared with traditional pain management for patients with fracture of the femur. The anatomy of CPCB was also tested in cadavers., Methods: Forty consecutive patients (range, 67-96 years old) were prospectively randomized either to group A (given local anesthetics using a CPCB) or group B (given perioperative analgesia with meperidine). In another part of the study, CPCB was performed in 15 fresh cadavers, and dissection of the lumbar region was performed after dye injection., Results: Continuous psoas compartment block was performed successfully in all patients in group A and was used in the pre- (16-48 hours) and postoperative (72 hours) periods. Visual analog scale score in group A was lower than in group B in 5/7 preoperative and 9/9 postoperative 8 hourly assessments. Differences reached statistical significance (P < .05) in 3 and 5 of the assessments, respectively. Patient satisfaction was higher in group A in the pre- (P < .05) and postoperative periods (P<.03). The block failed to achieve surgical anesthesia in 85% (17/20) of the patients, and additional anesthesia was needed. The anatomic study failed to support the existence of a defined "psoas compartment" previously described, and supported the clinical findings. Injected dye was found in the region of the origin of the sciatic nerve (essential for the production of anesthesia for hip surgery) in only 26% (4/15) of cadavers., Conclusions: The CPCB seems to be an appropriate technique for efficient and safe perioperative pain control. However, in our dissections, the psoas compartment was not well defined in all patients, thus, using this route for anesthesia may result in only partial success.

Background: The opioid meperidine induces spinal anesthesia and blocks nerve action potentials, suggesting it is a local anesthetic. However, whether it produces effective clinical local anesthesia in peripheral nerves remains unclear. Classification as a local anesthetic requires clinical local anesthesia but also blockade of voltage-dependent Na+ channels with characteristic features (tonic and phasic blockade and a negative shift in the voltage-dependence of steady-state inactivation) involving an intrapore receptor. The authors tested for these molecular pharmacologic features to explore whether meperidine is a local anesthetic., Methods: The authors studied rat skeletal muscle mu1 (RSkM1) voltage-dependent Na+ channels or a mutant form heterologously coexpressed with rat brain Na+ channel accessory beta1, subunit in Xenopus oocytes. Polymerase chain reaction was used for mutagenesis, and mutations were confirmed by sequencing. Na+ currents were measured using a two-microelectrode voltage clamp. Meperidine and the commonly used local anesthetic lidocaine were applied to oocytes in saline solution at room temperature., Results: Meperidine and lidocaine produced tonic current inhibition with comparable concentration dependence. Meperidine caused phasic current inhibition in which the concentration-response relationship was shifted to fivefold greater concentration relative to lidocaine. Meperidine and lidocaine negatively shifted the voltage dependence of steady-state inactivation. Mutation of a putative local anesthetic receptor reduced phasic inhibition by meperidine and lidocaine and tonic inhibition by lidocaine, but not meperidine tonic inhibition., Conclusions: Meperidine blocks Na+ channels with molecular pharmacologic features of a local anesthetic. The findings support classification of meperidine as a local anesthetic but with less overall potency than lidocaine.

The myocardial kinetics of meperidine and the relationship between these kinetics and the effect of meperidine on myocardial contractility (maximum positive rate of change of left ventricular pressure) were examined by analysis of previously published data collected in sheep after the i.v. injection of 100 mg of meperidine over 1 s. There was significant hysteresis between reductions in myocardial contractility and the arterial concentrations of meperidine, but not the coronary sinus blood (effluent from the heart) or calculated myocardial concentrations. The peak reduction in contractility occurred after the peak arterial concentration, at the time of the peak myocardial concentration, but before the peak coronary sinus concentration, suggesting that the site of drug action in the heart was not in equilibrium with either arterial blood or effluent blood from the heart. The most appropriate form of a dynamic model (a linear model with a threshold) was determined, without the need to assume a kinetic model, by directly fitting the observed reductions in myocardial contractility to the calculated myocardial concentrations. To determine the optimal kinetic and combined kinetic-dynamic models, a variety of one-, two-, and three-compartment models of the myocardium were fitted to the coronary sinus concentrations by using hybrid modeling. These included "tank in series" models that accounted well for drug dispersion and "peripheral compartment" models that accounted well for deep distribution. The most appropriate model was a "compilation" model, which incorporated features of both these extremes and was a better fit to the observed data than either a traditional single flow-limited compartment or a traditional membrane-limited model.

The subjective, psychomotor, and physiological effects of three opioid mu-receptor agonists were studied in healthy volunteers using a cumulative-dosing procedure. Sixteen volunteers with no history of drug abuse received i.v. injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperidine (MEP) in a randomized double-blind crossover design. Subjects received 1 injection/h for the first 4 h, and a 3-h recovery period followed. SAL was injected first during each session, then SAL or increasing doses of each drug were administered every hour for the next 3 h. The absolute doses per injection were MOR: 2.5, 5, and 10 mg/70 kg; HM: 0.33, 0.65, and 1.3 mg/70 kg; and MEP: 17.5, 35, and 70 mg/70 kg. These injections resulted in cumulative doses of MOR: 2.5, 7.5, and 17.5; HM: 0.33, 0.98, and 2.28; and MEP: 17.5, 52.5, and 122.5 mg/70 kg. Subjects completed mood forms and psychomotor tests, and physiological measures were recorded at various times after each injection and during recovery. MEP tended to produce the most intense effects immediately after drug injection, which dissipated rapidly. MOR produced the mildest effects but was associated with unpleasant side effects during recovery and after the session. HM's effects were stronger than MOR's, and the recovery from HM was slower than with MEP. None of the opioids produced consistent effects that are typically associated with abuse liability. Orderly dose-response functions suggested that our cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects within the same study.

Study Objective: To evaluate the effect of epidural and pethidine analgesia on the frequency of uterine contractions during the first stage of labor., Design: Retrospective study., Setting: Delivery ward of a public hospital., Patients: Forty consecutive parturients., Measurements and Main Results: The mean number of contractions in the 30 min before administration of pethidine analgesia was 8.2+/-1.7 as compared to 8.7+/-1.3 after administration of the analgesia. The mean number of contractions in the 30 min before administration of epidural analgesia was 8.0+/-1.4 as compared to 8.8+/-1.9 after administration of the analgesia. The differences between the two groups and between the number of contractions before and after the administration of both types of analgesia were not statistically significant., Conclusion: Properly and timely administered epidural analgesia during the first stage of labor has no effect on frequency of uterine activity.

Unlabelled: The intrathecal injection of 0.7-1 mg/kg meperidine provides spinal anesthesia of only short duration. In this study, we investigated the effects of three different doses of meperidine for spinal anesthesia on the duration and level of sensory block and the incidence of side effects. Forty-five African men were randomly allocated to receive one of three doses of intrathecal meperidine: Group A = 1.2 mg/kg, Group B = 1.5 mg/kg, and Group C = 1.8 mg/kg. The duration of sensory block was significantly longer after 1.5 mg/kg compared with 1.2 mg/kg meperidine (112 +/- 19 vs 79 +/- 27 min; P = 0.001). Increasing the dose to 1.8 mg/kg did not further increase the duration of block. The level and the onset of the block were not affected by the dose. Common side effects were fatigue (27%), pruritus (20%), and nausea (7%). Seven patients had respiratory depression and seven had a decrease of systolic arterial blood pressure (SAP) >30% from baseline. There was no difference in the incidence of any side effect among groups. Respiratory depression and decreases in SAP were observed 5-50 min after meperidine injection. Twenty-two patients had no pain after the sensory block had terminated. We conclude that increasing the dose of meperidine from 1.2 to 1.5 mg/kg increased the duration, but not the level, of sensory block without an increase in side effects., Implications: Intrathecal meperidine 1 mg/kg provides surgical anesthesia for only 40-90 min. We investigated the effects of three larger doses of meperidine in 45 African men. The 1.5 and 1.8 mg/kg doses provide a longer duration of anesthesia compared with 1.2 mg/kg. Nausea, pruritus, and respiratory depression were common in all dose groups. We conclude that increasing the dose of meperidine from 1.2 to 1.5 mg/kg increased the duration, but not the level, of sensory block without an increase in side effects.

Unlabelled: Intravenous regional anesthesia (IVRA) with meperidine in doses > or = 100 mg provides effective postoperative analgesia. However, this technique is associated with excessive opioid-related side effects, which limit its clinical usefulness. The minimal dose of meperidine that is effective for IVRA has yet to be established. We added 0, 10, 20, 30, 40, or 50 mg of meperidine to 0.5% lidocaine IVRA for either carpal tunnel or tenolysis surgery. Pain and sedation scores and the incidence of side effects were assessed in the postanesthesia care unit. The duration of analgesia, defined as the time to first request for pain medications, and use of acetaminophen/codeine (T3) tablets were measured. The duration of analgesia increased, in a dose-dependent manner, in the groups that received 0, 10, 20, and 30 mg of meperidine. There was no significant difference in the duration of analgesia for patients receiving > or = 30 mg of meperidine. T3 use was similar in the groups that received 0, 10, and 20 mg of meperidine and in the groups that received 30, 40, and 50 mg. T3 use was significantly lower in the larger dose groups. The incidence of sedation and of all other side effects was significantly higher in the groups that received 30-50 mg of meperidine compared with those that received smaller doses. We conclude that doses of meperidine large enough to produce the most effective postoperative analgesia with IVRA lidocaine causes a significant incidence of side effects, thus limiting its clinical usefulness., Implications: Meperidine may be a useful addition to 0.5% lidocaine for i.v. regional anesthesia. We showed that 30 mg is the optimal dose of meperidine with respect to postoperative analgesia. However, this dose caused a significant incidence of sedation, dizziness, and postoperative nausea and vomiting.

Background/aims: Children 5 years old and younger often require sedation for esophageal motility studies (EMS). At our institution, an intramuscular cocktail of meperidine, promethazine and chlorpromazine (MPC) has been used as the standard sedative for young children undergoing EMS. Administering the intramuscular sedative may, however, be more traumatic to the child than the procedure. Moreover, its effect on esophageal motility is not known and prolonged sedation is common. The aim of this study was to determine the effects of MPC and two orally-administered sedatives on esophageal sphincter function, using the cat model, with a goal to identify a potentially suitable orally-administered sedative for use in young children requiring sedation for EMS., Methods: We measured upper (UESP) and lower (LESP) esophageal sphincter pressures in 25 cats initially without sedation, and then following sedation with midazolam, chloral hydrate and MPC. The results were compared., Results: All three sedatives significantly decreased LESP compared to the control (p<0.05). Midazolam decreased LESP the most; however, the difference from the other sedatives did not reach statistical significance. All three sedatives decreased UESP, compared to control, but the differences were not statistically significant. Of the two oral sedatives, chloral hydrate had the least effect on the esophageal sphincters although its effect was not statistically different from that of midazolam., Conclusions: Ethically appropriate studies are needed to determine which oral sedative would be most beneficial for use in sedating children undergoing esophageal motility studies. Until studies can be done, the choice between chloral hydrate and midazolam should be based on the experience and comfort of the attending physician with regard to the potential side effects of the medications.

Diclofenac (a non-steroidal anti-inflammatory drug) and pethidine (a synthetic opiate) are the two analgesics most commonly used to relieve the pain of ureteric colic. Fast frame renography is a non-invasive means of imaging ureteric peristalsis and renal drainage. The aim of this study was to determine the effects of each of these drugs on the drainage pattern of the upper tracts. Twelve normal male volunteers were studied. All underwent a standard fast frame renogram using 75 MBq of technetium-99m-mercaptoacetyltriglycine, and were then administered either 100 mg pethidine or 75 mg diclofenac by intramuscular injection. Fast frame renography was then repeated. Peristalsis was determined from the condensed image of each ureter and the renogram curves were analysed to obtain standard parameters and deconvolution analysis. Diclofenac caused a profound disruption to both ureteric peristalsis and the renogram curve. This effect was not seen after the administration of pethidine. Deconvolution analysis suggests the effects of diclofenac are mediated via a direct effect on drainage rather than by any alteration of blood flow to the kidney. This study suggests that pethidine is the analgesic of choice prior to renography and that inferences about alterations of drainage in the presence of diclofenac should be interpreted with care.

An attempt is made to induce the pethidine suppressed gonadal activities by the administration of exogenous gonadotropins (hCG, PMSG, hCG + PMSG). Administration of 5 IU gonadotropins either separately or in combination to the rats treated with pethidine for 30 days resulted in the significant increase in the weight of testis, diameter of testis and seminiferous tubules. Gonadotropin(s) treatment stimulated the spermatogenic activity which was inhibited by pethidine. Therefore the number of spermatogonia, spermatocytes, spermatids in the seminiferous tubules and spermatozoa in cauda epididymis is increased significantly. Decreased testicular cholesterol, increased protein content and weight of accessory sex organs indicate the rejuvenation of steroidogenesis. Combination of both the gonadotropins is more effective in bringing all these activities.

Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.

Retrospective analysis of eclamptic patients was done during two time periods. In time period A (Jan. 1987-Dec. 1988), 79 patients of eclampsia were treated with lytic cocktail and in time period B (April 1992-April 1994), 104 eclamptic patients were treated with magnesium sulfate. The severity of disease, details of labour, delivery, incidence of persistent convulsions and the maternal and perinatal outcomes were compared. Incidence of persistent convulsions was significantly lower with magnesium sulphate (4.8%) compared to lytic cocktail (26.6%). No difference was observed in duration of labour and mode of delivery. Perinatal mortality was significantly lower in magnesium sulphate treated group. Maternal mortality was similar in both the groups (lytic cocktail-3.8%, Magnesium sulphate-2.9%).

We studied a group of spontaneously breathing patients anaesthetised for routine orthopaedic surgery using a circle system and isoflurane in a Komesaroff vaporiser within the circle. We observed and recorded: (1) the change in inspired isoflurane concentration caused by changing the fresh gas flow, (2) the increased respiration produced by surgical stimulus and the resulting increase in isoflurane concentration, (3) the respiratory depression produced by opioids and the consequent decrease in isoflurane concentration. We consider this regulation of anaesthetic uptake by the patient to be beneficial.

Pethidine is an effective epidural opioid for the treatment of acute pain. Its use has been well described in Australian and New Zealand practice, particularly in the field of obstetric anaesthesia. Reported methods of delivery have included bolus injection, continuous infusion and patient-controlled epidural analgesia. Areas of application have included treatment of postoperative pain, labour pain and intraoperative pain. Because of its intermediate lipid solubility, pethidine may have advantages over many other epidural opioids. However, potential for accumulation of norpethidine limits its use to relatively short durations of treatment.

Pethidine is the only member of the opioid family that has clinically important local anaesthetic activity in the dose range normally used for analgesia. Pethidine is unique as the only opioid in current use that is effective as the sole agent for spinal anaesthesia. In lower doses, intrathecal pethidine is also an effective analgesic for treating pain in labour. This paper reviews the pharmacology of intrathecal pethidine and clinical experience reported to date. Articles reviewed include those identified by a Medline search using keywords "intrathecal" or "spinal anaesthesia/ anesthesia" and "pethidine" or "meperidine". Reference lists from identified papers were scrutinized to identify further relevant articles.

Background: Thermoregulatory shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core temperature deviation), and maximum intensity. Meperidine (a combined mu- and kappa-agonist) treats shivering better than equianalgesic doses of pure mu-opioid agonists. Meperidine's special antishivering action is mediated, at least in part, by a disproportionate decrease in the shivering threshold. That is, meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold, whereas alfentanil (a pure mu-agonist) decreases the vasoconstriction and shivering thresholds comparably. However, reductions in the gain or maximum shivering intensity might also contribute to the clinical efficacy of meperidine. Accordingly, we tested the hypothesis that meperidine reduces the gain and maximum intensity of shivering much more than alfentanil does., Methods: Ten volunteers were each studied on three separate days: (1) control (no drug); (2) a target total plasma meperidine concentration of 1.2 microg/ml; and (3) a target plasma alfentanil concentration of 0.2 microg/ml. Skin temperatures were maintained near 31 degrees C, and core temperatures were decreased by central-venous infusion of cold lactated Ringer's solution until maximum shivering intensity was observed. Shivering was evaluated using oxygen consumption and electromyography. A sustained increase in oxygen consumption identified the shivering threshold. The gain of shivering was calculated as the slope of the oxygen consumption versus core temperature regression, and as the slope of electromyographic intensity versus core temperature regression., Results: Meperidine and alfentanil administration significantly decreased the shivering thresholds. However, neither meperidine nor alfentanil reduced the gain of shivering, as determined by either oxygen consumption or electromyography. Opioid administration also failed to significantly decrease the maximum intensity of shivering., Conclusions: The authors could not confirm the hypothesis that meperidine reduces the gain or maximum intensity of shivering more than alfentanil does. These results suggest that meperidine's special antishivering effect is primarily mediated by a disproportionate reduction in the shivering threshold.

Interaction between sphingomyelin metabolism and cyclic nucleotide synthesis in rat pinealocytes was investigated by determining the effect of ceramide on adrenergic-stimulated cAMP and cGMP accumulation. Although C2-, C6-, and C8-ceramide had no effect on basal, isoproterenol-, or norepinephrine-stimulated cAMP and cGMP accumulation, they inhibited the potentiation caused by depolarising concentrations of K+ or BayK 8644. Similar inhibition was observed when ceramide metabolism was inhibited by a glucosylceramide synthase inhibitor. In contrast, the potentiation of cAMP and cGMP accumulation caused by other intracellular Ca(2+)-elevating agents such as ionomycin or thapsigargin or by an activator of protein kinase C was not affected by ceramide. Taken together, our results suggest that ceramide selectively inhibits cyclic nucleotide synthesis when the nucleotide synthesis is potentiated by an increase in intracellular Ca2+ through L-type Ca2+ channels and that the sphingomyelin cycle probably plays an important role in the regulation of these channels.

The opioid, ketobemidone, has previously been shown to be a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. In Denmark, ketobemidone is available in a formulation which contains ketobemidone and a spasmolytic compound, (RS)-3-dimethylamino-1,1-diphenylbut-1-ene, hydrochloride (A29), in a one to five ratio. Using in vitro receptor binding techniques and an in vitro electrophysiological preparation consisting of rat cerebral cortex, we have characterized the interaction between A29 and the different glutamate receptor subtypes. A29 selectively inhibited binding of the non-competitive NMDA receptor antagonist 3H-MK-801 with a Ki value 16 +/- 4.5 microM, but was inactive in assays measuring affinities for other glutamate receptors. In agreement with the binding studies, A29 was found to selectively inhibit responses to NMDA in the rat cortical wedge preparation, whereas responses to kainate and AMPA were unaffected. Analysis of dose response curves showed A29 to be a NMDA receptor antagonist with an IC50 value of 100 microM versus responses to 10 microM NMDA. The inhibitory effects of ketobemidone and A29 on responses to 10 microM NMDA were additive. These data show that the combination of A29 and ketobemidone exert more potent antagonism at the NMDA receptor than does ketobemidone alone.

Mu opiate agonists morphine, fentanyl and meperidine are administered short-term to pediatric patients, from the neonatal period through adolescence. However, there has been no assessment of the effect of age on the analgesic efficacy or the concentration-response relationship for these opioids in human pediatric patients. Few studies in animals have correlated opioid anti-nociception and tissue levels of these opioids commonly administered to pediatric patients. The present study was conducted to examined the role of age on opioid anti-nociceptive potency and efficacy and brain and plasma opioid levels to provide predictive information on the effect of opioids in developing humans. Administration of trace amounts of tritiated drug with anti-nociceptive doses of unlabeled drug was used for the assessment of anti-nociception in the tail-flick test and for the measurement of brain and plasma drug equivalent levels in postnatal rats (PND 3-21). Morphine and fentanyl were completely efficacious in all postnatal ages examined, although age-related differences in drug potency, as well as, differences in brain and plasma levels were observed. There was a good correlation between morphine (r = 0.96) and fentanyl (r = 0.89) ED(50) values and their respective brain and plasma EC(50) equivalent levels. Meperidine had limited efficacy in young rats (PND 3-9) but was completely efficacious in older rats (PND 14-17). However, PND 21 rats experienced tonic-clonic seizures which limited its efficacy to 70% anti-nociception. Our data suggest that pharmacokinetics, the development of the blood-brain barrier and ontogeny of opioid receptor function may play important roles in the sensitivity of postnatal rats to mu receptor agonists.

Background: Postanesthetic shivering develops in as many as one half of patients recovering from isoflurane anesthesia. Cholinergic stimulation of the hypothalamic-pituitary-adrenal axis and adrenal medulla by physostigmine enhances secretion of arginine vasopressin, epinephrine, and norepinephrine. Because the hypothalamus is the dominant thermoregulatory controller in mammals, and these neurotransmitters may be involved in body temperature control, physostigmine administration may influence the incidence of shivering. Accordingly, the authors tested the hypothesis that physostigmine administration inhibits postanesthetic shivering. Its efficacy was compared with that of saline (negative control) and meperidine and clonidine (positive controls)., Methods: Sixty patients having surgery of the ear or nose were tested. General anesthesia was induced with 2 mg/kg propofol, 0.1 mg/kg vecuronium, and 1.5 microg/kg fentanyl and maintained with isoflurane (1.5 +/- 0.4%) in 70% nitrous oxide. At the end of surgery, the patients were randomly assigned to receive an intravenous bolus of 0.04 mg/kg physostigmine, isotonic saline, 0.5 mg/kg meperidine, or 1.5 microg/kg clonidine. Heart rate, mean arterial blood pressure, oxygen saturation, visual analog pain score, temperature, and postanesthetic shivering were measured during recovery., Results: Postanesthetic shivering occurred in 6 of 15 (40%) patients given saline. In contrast, postanesthetic shivering was significantly reduced in physostigmine-treated patients (1 of 15, or 7%) and was absent in patients given clonidine or meperidine., Conclusions: Physostigmine inhibited shivering as well as did two established treatments, meperidine and clonidine. These data suggest that cholinergic systems contribute to the genesis and control of postanesthetic shivering.

Background: The infusion of amphotericin-B (AmB) often produces clinically distressing rigors and chills, which promptly abate with intravenous injection of meperidine, although its mechanism of action is unknown., Objective: To examine the effects of meperidine on the transcription or secretion of Interleukin 1 beta (IL-1 beta) in human mononuclear leukocytes (MNL) exposed in vitro to the lipopolysaccharide (LPS) contained in Escherichia coli endotoxin or to AmB., Methods: Blood was drawn from eight healthy adult volunteers. The blood was centrifuged, and the layer containing MNL was separated; incubated with various combinations of medium, meperidine, and AmB; then tested for IL-1 content to determine the effect of meperidine on MNL secretion of IL-1 beta. To determine the effect on MNL transcription of IL-1 beta, the RNA was extracted from cells and the IL-1 beta was measured using one of two different methods., Results: Incubation of human MNL in the presence of LPS or AmB significantly increased transcription of IL-1 beta mRNA and secretion of IL-1 beta. Addition of meperidine to these cultures significantly reduced LPS-induced, but not AmB-induced, secretion of IL-1 beta in vitro. Meperidine did not alter IL-1 beta mRNA levels in MNL exposed to LPS or AmB., Conclusions: These data suggest that meperidine decreases rigors and chills in part by decreasing MNL secretion of IL-1 beta through a posttranscriptional mechanism.

Objective: To examine the effectiveness of the acoustic stimulation test in the interpretation of suspicious cardiotocograms obtained after meperidine administration to the mother during the first stage of labor., Subjects and Methods: We studied 45 unselected parturients who received 50 mg meperidine i.m. when cervical dilatation was 5 cm. In all cases a decreased beat-to-beat variability of the fetal heart rate and fetal movements was noted after the injection of meperidine. A vibratory acoustic stimulation was performed in 25 patients (group A) while the remaining 20 (group B) had no stimulation., Results: After the meperidine injection, the acoustic-induced reactivity returned immediately in group A, while the spontaneous reactivity returned 30 minutes later. The mean number of fetal movements in all parturients was 8.71 +/- 2.18 before meperidine administration. Sixty minutes after the meperidine injection the mean number was 8.52 +/- 2.48 in group A and 1.65 +/- 1.81 in group B (p < 0.0001)., Conclusion: The acoustic stimulation test is an effective method of interpreting suspicions CTG's obtained after meperidine administration to the mother during the first stage of labour.

Background: There is a current interest in local anaesthetic drugs/formulations exhibiting long durations of sensory block and minor motor-blocking effects., Objectives: To compare the duration of sensory and motor blockade in peripheral nerve blocks induced by the new agents ropivacaine and levobupivacaine, with that of racemic bupivacaine and pethidine., Methods: Groups of 8 male Sprague-Dawley rats were subjected to infraorbital (IONB) or sciatic nerve block (SNB) employing 0.2 ml of differently concentrated solutions of bupivacaine, levobupivacaine, ropivacaine or pethidine. The sensory blocking effect in IONB is expressed as (i) the time to elicitation of an abdominal jerk by electrical stimulation at arbitrarily chosen (threshold) intensities (IONB degree 3, 5, 8 and 10), and as (ii) the area under the curve (AUC, threshold intensities vs time). The duration of motor block in SNB is given as the time from injection to regained ability to walk and grip normally with the toes. Comparisons of the dose-effect relationships for the investigated agents were made by analysis of covariance., Results: In IONB the log (dose)-log (effect) lines for bupivacaine, levobupivacaine and ropivacaine did not deviate from parallelism. The duration of sensory block induced by equimolar doses of these agents was similar, although bupivacaine exerted more pronounced effects than levobupivacaine (AUC by 25%, P=0.001; IONB degree 3 by 14%, P=0.03). In SNB only the log (dose)-log (duration) lines for bupivacaine vs levobupivacaine were found not to deviate from parallelism, both agents exerting similar durations of action. The motor-blocking effects of ropivacaine showed an inverse dose-duration relationship (P=0.019)., Conclusions: Equimolar doses of the investigated local anaesthetics exerted similar durations of sensory blockade in a peripheral nerve block model in the rat.

During severe hypothermia, shivering is absent. To simulate severe hypothermia, shivering in eight mildly hypothermic subjects was inhibited with meperidine (1.5 mg/kg). Subjects were cooled twice (meperidine and control trials) in 8 degrees C water to a core temperature of 35.9 +/- 0.5 (SD) degrees C, dried, and then placed in sleeping bags. Meperidine caused a 3.2-fold increase in core temperature afterdrop (1.1 +/- 0.6 vs. 0.4 +/- 0.2 degree C), a 4.3-fold increase in afterdrop duration (89.4 +/- 31.4 vs. 20.9 +/- 5.7 min), and a 37% decrease in rewarming rate (1.2 +/- 0.5 vs. 1.9 +/- 0.9 degrees C/h). Meperidine inhibited overt shivering. Oxygen consumption, minute ventilation, and heart rate decreased after meperidine injection but subsequently returned toward preinjection values after 45 min postimmersion. This was likely due to the increased thermoregulatory drive with the greater afterdrop and the short half-life of meperidine. These results demonstrate the effectiveness of shivering heat production in attenuating the postcooling afterdrop of core temperature and potentiating core rewarming. The meperidine protocol may be valuable for comparing the efficacy of various hypothermia rewarming methods in the absence of shivering.

Opioids may depress respiration and contribute to airway obstruction after adenotonsillectomy for obstructive sleep disorder. We compared the respiratory and analgesic effects of nalbuphine, which has a ceiling effect for respiratory depression, and pethidine in 90 children (aged 2-12 years) with a history of obstructive sleep disorder undergoing adenotonsillectomy. Children were scored for their obstructive sleep disorder history and were randomly allocated to receive intravenously at induction of anaesthesia either nalbuphine 0.1 mg.kg-1 (group N) or pethidine 1 mg.kg-1 (group P). End-tidal carbon dioxide was measured in the recovery period using a nasopharyngeal catheter and oxygen saturation whilst breathing air; pain and sedation scores were recorded for 6 h postoperatively. Both groups were similar with respect to the demographic data and respiratory measurements: mean (SD) oxygen saturation on air in the recovery area (96.2% (1.2) vs. 96.5% (1.1) in group N and P, respectively) and mean (SD) end-tidal carbon dioxide (46.4 (5.5) mmHg vs. 47.7 (4) mmHg in group N and P, respectively). High obstructive sleep disorder score, history of apnoea, hyperactivity and loud snoring were found to be the best predictors of early postoperative oxygen desaturation in both groups.

beta-Funaltrexamine (beta-FNA), an irreversible antagonist at the mu-opioid receptor, was administered intracisternally to rats discriminating between subcutaneous injections of saline and 3.0 mg/kg of morphine in order to reduce the size of the receptor reserve. beta-FNA alone (10 micrograms) occasioned substantial morphine-appropriate responding for at least 6 h but mainly saline-appropriate responding 24 h after administration, the pretreatment interval for most experiments. beta-FNA (3.0-30 micrograms) dose-dependently shifted to the right stimulus-generalization curves for morphine and fentanyl; 10 micrograms also shifted to the right the curves for meperidine and buprenorphine. In all cases, antagonism was fully surmounted by higher doses of the agonist, even after inactivation of more than 75% of mu-opioid receptors. This antagonist effect of beta-FNA is smaller than that reported previously in tests of analgesia, suggesting that the receptor reserve for the discriminative effects of morphine-like drugs is larger than the receptor reserve for their analgesic effects. beta-FNA produced larger rightward displacements of the morphine and buprenorphine curves than of the fentanyl curve and inactivated a larger fraction of the receptors acted upon by those drugs compared to fentanyl. Results with meperidine were intermediate. This suggests that the receptor population mediating morphine-like discriminative effects of fentanyl is not identical to the receptor population mediating these effects of morphine and buprenorphine.

Level pressing by squirrel monkeys was maintained under a fixed-ratio 30 schedule of food presentation. The response rate-decreasing effects of meperidine and morphine were examined alone and in combination with several doses of the irreversible, mu-selective opioid antagonist beta-funaltrexamine and the reversible, opioid antagonist naltrexone. beta-Funaltrexamine alone decreased response rates to greater than 50% of control at all doses in two of the four monkeys and at the highest dose in one monkey. In the monkeys in which beta-funaltrexamine decreased rates, beta-funaltrexamine either did not shift the meperidine or the morphine dose-effect curve or it shifted these curves to the left. In the monkeys in which beta-funaltrexamine alone did not decrease rates, it shifted the meperidine and the morphine dose-effect curves to the right. Naltrexone also shifted both the meperidine and morphine dose-effect curves rightward, although not in a dose-dependent manner. These data suggest that the rate-decreasing effects of meperidine and morphine in squirrel monkeys are altered by beta-funaltrexamine and naltrexone in a similar manner, providing additional evidence that the rate-decreasing effects of both meperidine and morphine are mediated by mu-opioid receptors.

Background: Meperidine administration is a more effective treatment for shivering than equianalgesic doses of other opioids. However, it remains unknown whether meperidine also profoundly impairs other thermoregulatory responses, such as sweating or vasoconstriction. Proportional inhibition of vasoconstriction and shivering suggests that the drug acts much like alfentanil and anesthetics but possesses greater thermoregulatory than analgesic potency. In contrast, disproportionate inhibition would imply a special antishivering mechanism. Accordingly, the authors tested the hypothesis that meperidine administration produces a far greater concentration-dependent reduction in the shivering than vasoconstriction threshold., Methods: Nine volunteers were each studied on three days: 1) control (no opioid); 2) a target total plasma meperidine concentration of 0.6 microgram/ml (40 mg/h); and 3) a target concentration of 1.8 micrograms/ml (120 mg/h). Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core-temperature thresholds (at a designated skin temperature of 34 degrees C) were computed using established linear cutaneous contributions to control sweating (10%) and vasoconstriction and shivering (20%). The dose-dependent effects of unbound meperidine on thermoregulatory response thresholds was then determined using linear regression. Results are presented as means +/- SDs., Results: The unbound meperidine fraction was approximately 35%. Meperidine administration slightly increased the sweating threshold (0.5 +/- 0.8 degree C.microgram-1.ml; r2 = 0.51 +/- 0.37) and markedly decreased the vasoconstriction threshold (-3.3 +/- 1.5 degrees C.microgram-1.ml; r2 = 0.92 +/- 0.08). However, meperidine reduced the shivering threshold nearly twice as much as the vasoconstriction threshold (-6.1 +/- 3.0 degrees C.microgram-1.ml; r2 = 0.97 +/- 0.05; P = 0.001)., Conclusions: The special antishivering efficacy of meperidine results at least in part from an uncharacteristically large reduction in the shivering threshold rather than from exaggerated generalized thermoregulatory inhibition. This pattern of thermoregulatory impairment differs from that produced by alfentanil, clonidine, propofol, and the volatile anesthetics, all which reduce the vasoconstriction and shivering thresholds comparably.

Despite relatively widespread use of various forms of patient controlled analgesia (PCA), there remain conflicting results in the literature as to the efficacy of PCA. This study was conducted to assess the efficacy and postoperative outcomes of intravenous PCA compared to intramuscular (IM) injections in 73 patients who received major abdominal surgery. These patients were randomly selected and randomly assigned preoperatively to receiving IM or PCA modes of analgesia postoperatively. The following factors were compared: amount of pain; amount of analgesia use; degree of patient satisfaction with pain control both while on parenteral analgesia and after switching to oral; length of time to first ambulation; and length of stay in hospital. Results of the study did not demonstrate a statistically significant difference in any of these, using a P-value of 0.01. The PCA patients took an average of 4.5 hours longer than the IM patients to ambulate postoperatively and the IM patients received at least three times as much antiemetic (P = 0.001). Locus of control was not found to be a major factor in satisfaction or pain levels. Subsequent meta-analyses have also failed to yield significant differences between IM and PCA groups except in patient satisfaction. It is recommended that expansion of PCA programmes with abdominal surgery patients be considered only in cases where there is fiscal advantage or where patient satisfaction can be a driving force.

In summary, both mu-receptor and combined mu/kappa-receptor opioids impair thermoregulatory control. Alfentanil, a pure mu-receptor agonist slightly increased the thresholds for sweating and markedly decreased the thresholds for vasoconstriction and shivering. However, the vasoconstriction-to-shivering range remained normal during alfentanil administration as it does during general anesthesia. Meperidine, a combined mu- and kappa-receptor agonist, also slightly increased the threshold for sweating and reduced the thresholds for vasoconstriction. However, meperidine reduced the shivering threshold twice as much as the vasoconstriction threshold, thus significantly increasing the vasoconstriction-to-shivering range. Furthermore, shivering during meperidine administration, once triggered, was of low intensity suggesting that the drug also decreased the gain of shivering. The special antishivering action of meperidine appears to result, at least in part, from its kappa-receptor activity.

Narcotic sedation is commonly accomplished with nitrous oxide (N2O) coadministration. Concerns regarding respiratory morbidity and mortality with drug combinations have been reported in the literature, particularly in patients not receiving supplemental oxygen (O2). The purpose of this investigation was to determine the effect of meperidine alone and in combination with N2O on respiration in laboratory rats by evaluating cardiovascular and arterial blood gas data. Fifty-four Sprague-Dawley rats were assigned to one of six groups (nine per group). Groups were allocated based upon the dosage of meperidine administered (0, 4.0, or 8.0 mg/kg intraperitoneally [i.p.]) and exposure to N2O (50% with oxygen) or O2 (100%). Following meperidine administration, animals were placed into a sealed chamber through which flowed either N2O or O2. Arterial blood was obtained, at baseline and at 15-min intervals, from a femoral artery catheter and pH, O2, CO2 (mm Hg), and oxygen saturation (%) were determined. Plasma samples were analyzed using a System 1306 pH/blood gas analyzer. Group comparisons demonstrated that: (a) N2O coadministration, in animals pretreated with meperidine, did not result in increased arterial CO2 levels, and (b) as expected, arterial O2 levels in all groups increased significantly from preexposure baseline values (P < 0.05). This investigation demonstrated that the coadministration of N2O to meperidine-sedated animals did not enhance respiratory depression.

We have previously shown that multidrug-resistant cancer cells display elevated levels of glucosylceramide (Lavie, Y., Cao, H., Bursten, S. L., Giuliano, A. E., and Cabot, M. C. (1996) J. Biol. Chem. 271, 19530-19536). In this study we used the multidrug-resistant human breast cancer cell line MCF-7-Adriamycin-resistant (AdrR), which exhibits marked accumulation of glucosylceramide compared with the parental MCF-7 wild type (drug-sensitive) cell line, to define the relationship between glycolipids and multidrug resistance (MDR). Herein it is shown that clinically relevant concentrations of tamoxifen, verapamil, and cyclosporin A, all circumventors of MDR, markedly decrease glucosylceramide levels in MCF-7-AdrR cells (IC50 values, 1. 0, 0.8, and 2.3 microM, respectively). In intact cells, tamoxifen inhibited glycosphingolipid synthesis at the step of ceramide glycosylation. In cell-free assays for glucosylceramide synthase, tamoxifen (1:10 molar ratio with ceramide) inhibited glucosylceramide formation by nearly 50%. In cell cultures, inhibition of glucosylceramide synthesis by tamoxifen is correlated with its ability to sensitize MCF-7-AdrR cells to Adriamycin toxicity. Moreover, treatment of cells with 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, an inhibitor of glucosylceramide synthesis, likewise sensitized MCF-7-AdrR cells to Adriamycin. It is concluded that high cellular levels of glucosylceramide are correlated with MDR, and that glycolipids are a target for the action of MDR-reversing agents such as tamoxifen. The data entertain the notion that drug resistance phenomena are aligned with cell capacity to metabolize ceramide.

Objective: To examine and compare the pharmacokinetics and pharmacodynamics of meperidine when administered intramuscularly at gluteal and deltoid sites in elderly postoperative patients., Design: Prospective, randomized investigation., Setting: Tertiary care university teaching hospital., Patients: Fourteen patients 60 years of age or older who were undergoing general surgery., Intervention: A single dose of meperidine 0.75 mg/kg given intramuscularly at either a deltoid or gluteal site., Main Outcome Measures: Pharmacokinetic (based on concentration-time curves) and pharmacodynamic (i.e., pain scales, need for additional pain medication) comparisons were made, based on site of meperidine injection., Results: No statistically significant differences were found in the maximum plasma concentration, volume of distribution, or clearance of meperidine by site of injection. Substantial interpatient variability in pharmacokinetic parameters was noted for both sites (range of maximum concentrations: 191-500 ng/mL gluteal, 166-374 ng/mL deltoid). Although pain scores were similar for the two groups, four of the patients in the group given gluteal injection required additional breakthrough pain management within 4 hours of meperidine injection compared with one patient in the group given deltoid injection., Conclusions: There is no obvious relationship between meperidine pharmacokinetic and pharmacodynamic parameters, regardless of intramuscular injection site. Breakthrough pain is common when patients are given intramuscular injections postoperatively, particularly when the gluteal route is used. When meperidine is used for analgesia in elderly postoperative patients, consideration should be given to more rapid and predictable routes (e.g., intravenous injection) of meperidine administration.

There are clinical observations that neurogenic pain can respond well to the opioid ketobemidone, in contrast to pethidine and morphine. This has led us to the hypothesis that the analgesic effect of ketobemidone in neurogenic pain may be due to both opioid as well as additional non-opioid effects. The present study was therefore made to evaluate the effects of ketobemidone. The study consists of two parts. (1) Single unit recordings were made from dorsal horn neurones in the halothane-anaesthetised rat. Neurones were activated by transcutaneous electrical stimulation of their receptive fields at C-fibre strength and their responses quantified. The wind-up of the neurones, due to N-methyl-D-aspartate (NMDA) receptor activation, leading to marked increases in C-fibre responses and an associated post-discharge was also measured. Ketobemidone, applied to the spinal cord, equivalent to an intrathecal injection, dose-dependently and selectively reduced C-fibre evoked responses. Ketobemidone was also found to block wind-up more effectively than morphine at equieffective doses, but unlike morphine in a non-naloxone-reversible manner. (2) In a binding study ketobemidone was shown to inhibit [3H]MK-801 binding with a Ki value of 26 microM. Therefore, ketobemidone appears to possess both mu opioid agonist as well as NMDA blocking effects.

The local anesthetic effects of opioids have been demonstrated in both clinical and laboratory studies. Clinically, both meperidine and sufentanil can produce segmental sensory anesthesia. However, previous studies of the effects of opioids on nerve conduction have all made use of peripheral nerve preparations and yielded conflicting results. In the present study we describe the local anesthetic effects of phenylpiperidine opioids on individual dorsal root axons, the probable target for intrathecal local anesthetics. Dorsal roots were removed from anesthetized adult male rats and maintained in vitro. Standard single fiber recording techniques were used to isolate activity in the individual axons. Drug exposure was accomplished by perfusing the isolated dorsal root with an artificial cerebrospinal fluid containing the study drug at a clinically relevant concentration. Steady-state drug effects were measured after 15-30 min of exposure and compared to control measurements in the same preparation. Meperidine (705 microM) blocked conduction in 61.5% of 39 myelinated and unmyelinated axons, and significantly reduced conduction velocity in the remaining unblocked axons. These effects were not naloxone reversible. Fentanyl (0.6 microM and 3 microM) and sufentanil (1.04 microM) failed to affect the nerve conduction in any dorsal root axon. The discrepancy between laboratory and clinical observations is discussed. We suggest that the site of conduction block may occur at the proximal end of the dorsal root as it passes through the dorsal root entry zone, an anatomically unique segment of the primary sensory pathway with decreased conduction safety for action potential propagation.

The human epidermoid carcinoma cell line A431 becomes highly sensitive to Shiga toxin upon treatment with butyric acid. This strong sensitization (> 1000-fold) is accompanied by an increase in the fraction of cell-associated toxin transported to the Golgi apparatus and to the endoplasmic reticulum (ER). Furthermore, our previous work showed that the length of the fatty acyl chain of Gb3, the Shiga toxin receptor, also was changed (longer fatty acids). We have not investigated the importance of this change by testing whether glycolipid synthesis is required for the changed intracellular sorting and the toxin sensitivity. We demonstrate here that inhibition of glycosphingolipid synthesis by inhibition of N-acyltransferase with fumonisin B1, by inhibition of glucosylceramide synthetase by PDMP or PPMP, or by inhibition of serine palmitoyl transferase by beta-fluoroalanine, inhibited the butyric acid-induced change in sensitivity and the increase in the fraction of cell-associated Shiga toxin transported to the Golgi apparatus and the ER. The block in butyric acid-induced sensitization caused by beta-fluoroalanine could be abolished by simultaneous addition of sphinganine or sphingosine. Thus, the data suggest that the fatty acyl chain length of glycosphingolipids is important for intracellular sorting and translocation of Shiga toxin to the cytosol.

Background: Opioids are traditionally avoided during sphincter of Oddi manometry because of indirect evidence suggesting that these agents cause sphincter of Oddi spasm. This study was undertaken to determine the direct effects of meperidine on the biliary and pancreatic sphincter., Methods: Forty-seven patients were prospectively evaluated by sphincter of Oddi manometry in the conventional retrograde fashion. Manometry was initially performed with intravenous diazepam sedation alone. The manometry was repeated 3 to 5 minutes after meperidine was administered., Results: The basal sphincter pressure of the biliary sphincter, pancreatic sphincter, and the combined sphincter group were not significantly altered by meperidine. Concordance (normal versus abnormal) between the basal sphincter pressure before and after meperidine was seen in 44 of 47 patients (94%). Meperidine produced a significant increase in the pancreatic, biliary, and combined sphincter phasic frequency and a significant decrease in the phasic duration. The pancreatic and combined sphincter phasic pressures were significantly reduced following meperidine administration. Seventeen manometry tracings (36%) were believed to be qualitatively better after meperidine, while only four (8.5%; p < .001) were qualitatively better with diazepam alone., Conclusion: Meperidine can be used for additional analgesia during sphincter of Oddi manometry if the basal sphincter pressure is the parameter used to determine therapy.

This study was designed to assess the effects of isoflurane (ISO) on the electrophysiological properties of the accessory pathway, atrium, ventricle, and AV node in children with the Wolff-Parkinson-White (WPW) syndrome. The results of programmed electrical stimulation were analyzed in 51 patients (4 months to 17 years of age) with WPW. The study population was divided into two groups. Twenty-seven patients received local anesthesia and intramuscular injection of meperidine, promethazine, and chlorpromazine (MPC group). Twenty-four patients received general anesthesia with ISO inhalation (ISO group). We compared the antegrade effective refractory period of the accessory pathway (antegrade APERP), ventricular effective refractory period (VERP), atrial effective refractory period (AERP), AH interval, and cycle length of circus movement tachycardia (CMT-CL) in 12 pairs of age and sex matched patients selected from the MPC and ISO groups. Of the 12 pairs of age and sex matched patients, antegrade APERP in patients who received ISO (299 +/- 17 ms, mean +/- SEM) was significantly longer as compared with matched patients in the MPC group (262 +/- 5 ms, P < 0.025). The VERP and AERP in patients from the ISO group were significantly prolonged compared with the MPC patients (239 +/- 7 vs 210 +/- 8 ms, P < 0.025, and 228 +/- 11 vs 180 +/- 6 ms, P < 0.01, respectively). There was no significant difference in the AH interval or CMT-CL between the two subgroups. Thus, ISO prolongs the antegrade APERPs as well as the effective refractory periods of atrial and ventricular muscle in children with WPW, while the AH interval and CMT-CL appear to be unaffected. Care must be taken in interpreting measurements of the antegrade APERP made in patients under general anesthesia for RF ablation of accessory pathways.

In a prospective, double-blind, randomized study, ketorolac 60 mg, meperidine 50 mg plus promethazine 25 mg, and normal saline given by intramuscular injection were compared as treatment for acute headache crises. Thirty patients (6 men and 24 women) presenting to an urban emergency department with any type of benign headache were randomized into three groups and filled out the McGill Short-Form Pain Questionnaire with a Pain Rating Index and a Visual Analogue Pain scale. They received one of the study medications and repeated the testing after 1 hour. The objective was to test the efficacy of ketorolac in this population. Separate analyses of the McGill Short-Form (Total, Sensory, Affective, and Pain Rating Index scales) and the Visual Analogue Pain scale responses showed that the three treatments produced a significant reduction in pain (P < .0001), but that pain reduction did not differ among the treatments. This profound reduction observed after administration of a placebo prevented accurate evaluation of the effects of ketorolac. The placebo response must be considered in the design of future trials using intramuscular medications in the acute intervention of headache crises. In addition, the use of a standard analgesic is necessary to demonstrate both assay sensitivity and magnitude of response to placebo.

Meperidine is widely used for pain control in the hospital setting. It is also known for its propensity to cause mental status changes in renally and hepatically impaired patients. A case is reported of a 37-year-old man with chronic renal failure maintained on peritoneal dialysis in whom delirium developed when he was treated with meperidine not only on one occasion but also on two subsequent admissions. The pharmacology of meperidine is reviewed and the implications of using the medication in patients with renal impairment are discussed.

Several derivatives of thienylcyclidine (1-[1-(2-thienyl)cyclohexyl]piperidine, CAS 1867-65-8, TCP) were synthesized and characterized. The compounds were evaluated for analgesic agonism in mice using tail-flick test as a model for antinociceptive activity. The most potent compounds are 7 and 11, which are about twice as active as the standard pethidine. The influence of naloxone on the antinociceptive activity of these compounds is also reported. The present pharmacological data are discussed and compared with those previously reported for structurally related phencyclidine analgesics.

Meperidine has atypical opioid receptor agonist effects and shares some structural features with the phenyltropane (WIN) analogs of cocaine. In combination with 0.1 mg/kg naltrexone, meperidine produced cocaine-like discriminative stimulus effects in monkeys, whereas morphine was inactive. Both cocaine and meperidine inhibited [3H]dopamine uptake in chopped rat caudate putamen with comparable potencies; meperidine differed from cocaine in that its effects could be characterized as having predominantly a single high-affinity component. Morphine was not active in inhibiting [3H]dopamine uptake, indicating that the effect of meperidine was not via a classic mu-opioid receptor agonist action. Further, meperidine but not morphine displaced [3H]WIN 35,428 (2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane) binding. These data suggest that the actions of meperidine that are atypical of opioids are due to activity at the dopamine transporter. In addition, meperidine appears to interact predominantly with the high-affinity component of the dopamine transporter, and this high-affinity component may be the site of importance for the production of cocaine's behavioral effects.

60 parturients were given the following drugs on purpose to achieve painless postoperative period--group 1--moradol--M, group 2--tramal--T, group 3--lydol--L, and group 4--promedol--P. Preparations M and T compared with L and P proved to be with better analgetic effect with no suppression on the contractile activity of the uterus, no blockade of hypothalamus-hypophysis-adrenal system and no influence on the respiration, pulse, blood pressure, acid-base balance and interchange of gases.

Background: Objectives were to study the effects of variations in the pH and the buffer capacity of solutions of lignocaine or pethidine on their analgesic efficacy in peripheral nerve block., Methods: Infraorbital nerve blocks (IONB) were induced in rats during light pentobarbitone anaesthesia employing 0.2 ml of test solutions containing 10 mg center dot ml-1 of lignocaine or pethidine dissolved in normal saline, 50 mmol and 150 mmol tris-hydroxymethylaminomethane (THAM) hydrochloride (THAM center dot HCl) of pH 4.8 and 4.5, respectively, or 100 mmol THAM + THAM center dot HCl of pH 7.4. The pH of solutions in saline was varied from 3.0 to 9.3 by adding HCl or NaHCO3. The analgesic efficacy is expressed as the interval from injection to elicitation of a minimal response to electric stimulation at various intensities (threshold intensities) within the blocked area (IONB 3 to 10), and in terms of the area under the curve (AUC, threshold intensities vs. time)., Results: When dissolved in saline, pH 7.4, pethidine exerted more pronounced effects than lignocaine [AUC by 3.5 times (P<0.001), IONB 3 to 10 by 2.7 (P<0.05) to 3.6 (P<0.001) times]. Variations of the pH of solutions did not affect their analgesic efficacy. Lignocaine exerted more pronounced local analgesic effects when mixed with 150 mmol THAM center dot HCl than when mixed with saline (pH 7.4), but manifested even more pronounced effects when dissolved in THAM + THAM center dot HCl [AUC by 3.7 times (P<0.001), IONB 3 to 10 by 2.7 (P<0.01) to 3.8 (P<0.001) times]. When dissolved in THAM + THAM center dot HCl, the analgesic efficacy of pethidine increased by 2.0 to 2.8 times (P<0.001), as compared to a solution in saline at the same pH., Conclusions: It is concluded that variations in the pH of solutions of lignocaine or pethidine in saline does not affect the analgesic efficacy of the drugs, presumably due to the low buffer capacity of the medium, whereas when dissolved in THAM + THAM center dot HCl, their effect is enhanced.

Although the effects of local anaesthetics (LA) on motor and sensory transmission in the spinal cord have been described, the effects of opioids are controversial. Our aim was to evaluate the action of clinically relevant doses of subarachnoid (SA) meperidine (MP) and fentanyl (FN), on somatosensory (SSEP) and cortical motor evoked responses (CMER) in awake subjects. Thirty ASA I-II patients scheduled for infra umbilical surgery received SA (N = 10/group): 1 mg/kg lidocaine (LD), 1 mg/kg MP or 25 mu g FN. SSEP elicited by stimulation of the posterior tibial nerve at the ankle, and cortical motor evoked response at rest (r-CMER) and during facilitation (f-CMER) were obtained prior and 30 min after treatment. Conduction at the proximal segment of the motor nerve (F-wave) was evaluated by stimulation of the posterior tibial nerve at the popliteal fossa. Motor/sensory block and side effects were clinically assessed. LD completely abolished SSEP and CMER. At the same dose, MP abolished SSEP in 40% of the patients, while r-CMER and f-CMER were absent in 70% and 30%, respectively; in addition, the F-wave was absent in 50% of the patients. Fentanyl induced small changes in the latencies of SSEP and F-wave; however, a 28% decrease in the amplitude of the f-CMER (P<0.05) was observed. Pruritus was present in 60% of patients in the FN group (P<0.006). Our results show that while LD and MP block sensory and motor conduction at the spinal roots, FN seems to decrease the excitability of the spinal interneurons in the corticospinal tract.