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Objective: To describe the pharmacokinetics and pharmacodynamics of meperidine after IM and subcutaneous administration in horses., Study Design: prospective, randomized, blinded, crossover trial., Animals: Six adult horses weighing 494 ± 33 kg., Methods: Treatments included meperidine 1 mg/kg IM with saline 6 mL subcutaneously, meperidine 1 mg/kg subcutaneously with saline 6 mL IM, and saline 6 mL subcutaneously and 6 mL IM, with a 7-day washout between treatments. Plasma meperidine concentrations and pharmacodynamic values (thermal and mechanical thresholds, physiological variables, fecal production) were collected at various time points for 24 hours. Accelerometry data were obtained for 8 hours to measure locomotor activity. Data were analyzed with a mixed effects model, and α was set at .05., Results: Meperidine terminal half-life (T 1/2 ), maximal plasma concentrations, and time to maximal concentration were 186 ± 59 and 164 ± 56 minutes, 265.7 ± 47.2 and 243.1 ± 80.1 ng/mL at 17 ± 6, and 24 ± 13 minutes for IM at subcutaneous administration, respectively. No effect of treatment or time was observed on thermal or mechanical thresholds, heart rate, respiratory rate, locomotor activity, frequency of defecations, or fecal weight (P > .2 for all)., Conclusion: Maximum meperidine concentrations were achieved quickly with a short T 1/2 in both treatment groups. Neither IM nor subcutaneous meperidine influenced thermal or mechanical threshold or physiological variables., Clinical Significance: The short half-life and lack of detectable antinociceptive effect do not support IM or subcutaneous administration meperidine at 1 mg/kg for analgesia in horses., (© 2020 American College of Veterinary Surgeons.)

Background: Meperidine is a synthetic opioid that belongs to the phenylpiperidine class and is a weak mu receptor agonist. In horses there are a limited number of published studies describing the analgesic effects of systemically administered meperidine in horses. The objective of this study was to describe the pharmacokinetics, behavioral and physiologic effects and effect on thermal threshold of three doses of intravenously administered meperidine to horses. Eight University owned horses (four mares and four geldings, aged 3-8 years were studied using a randomized balanced 4-way cross-over design. Horses received a single intravenous dose of saline, 0.25, 0.5 and 1.0 mg/kg meperidine. Blood was collected before administration and at various time points until 96 hours post administration. Plasma and urine samples were analyzed for meperidine and normeperidine by liquid chromatography-mass spectrometry and plasma pharmacokinetics determined. Behavioral and physiologic data (continuous heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were collected at baseline through 6 hours post administration. The effect of meperidine administration on thermal nociception was determined and thermal excursion calculated., Results: Meperidine was rapidly converted to the metabolite normeperidine. The volume of distribution at steady state and systemic clearance (mean ± SD) ranged from 0.829 ± 0.138-1.58 ± 0.280 L/kg and 18.0 ± 1.4-22.8 ± 3.60 mL/min/kg, respectively for 0.5-1.0 mg/kg doses. Adverse effects included increased dose-dependent central nervous excitation, heart rate and cutaneous reactions. Significant effects on thermal nociception were short lived (up to 45 minutes at 0.5 mg/kg and 15 minutes at 1.0 mg/kg)., Conclusions: Results of the current study do not support routine clinical use of IV meperidine at a dose of 1 mg/kg to horses. Administration of 0.5 mg/kg may provide short-term analgesia, however, the associated inconsistent and/or short-term adverse effects suggest that its use as a sole agent at this dose, at best, must be cautiously considered.

Oral fluid assays for quantifying drugs are useful in forensic toxicology and drug monitoring. Compared with blood and urine specimens, oral fluid collection is simple, non-invasive, and more difficult to adulterate. Therefore, we investigated whether meperidine and its metabolites could be detected in oral fluid and whether there was a predictable relationship between oral fluid and plasma concentrations. Male New Zealand white rabbits (n = 10) were administered meperidine hydrochloride (20 mg/kg, intravenous). Then, plasma and oral fluid were collected at various time points up to 10 h after administration. We developed a simple and sensitive gas chromatography-mass spectrometry method for the determination of meperidine and normeperidine in oral fluid and plasma. We estimated the apparent pharmacokinetic parameters for meperidine in oral fluid and plasma and determined the ratio and correlation between oral fluid and plasma concentrations. The results demonstrate that this method has excellent specificity, linearity, precision, and recovery. Meperidine and normeperidine were detected in both body fluids; meperidine was the most abundant analyte in oral fluid. The oral fluid-to-plasma drug concentration ratios did not differ significantly over time (p > 0.05). In addition, oral fluid and plasma levels of meperidine and normeperidine were significantly correlated over time (r = 0.713 and 0.725, respectively; p < 0.05). These results provide context for interpreting meperidine and metabolite concentrations in oral fluid and support the utility of oral fluid as an alternative matrix in clinical and forensic testing.

A prolongation of the QTc-interval has been described for several opioids, including pethidine (meperidine)., Objective: To evaluate in the clinical setting the frequency and risk factors associated with the QT-interval prolongation induced by meperidine., Research Design and Methods: We recruited patients requiring meperidine administration and recorded their medical history and comorbidities predisposing to QT-interval prolongation. Ionograms and electrocardiograms (ECGs) were performed at baseline and during treatment; QT was corrected using the Bazzet, Fridericia, Framinghan, and Hogdes formulas. We measured meperidine and normeperidine by gas chromatography. Values are expressed as mean ± SD (range)., Results: 58 patients were studied (43.1% males). All patients received meperidine at a dose of 304 ± 133 (120 - 480) mg/day. Meperidine and normeperidine concentrations were 369 ± 60 (265 - 519) and 49 ± 17 (15 - 78) ng/mL, respectively. Intratreatment control found QTcB 370 ± 30 (305 - 433), QTcFri 353 ± 35 (281 - 429), QTcFra 360 ± 30 (299 - 429), QTcH 359 ± 27 (304 - 427), ΔQTcB +9 ± 42 (-90 to +136), ΔQTcFri +4 ± 45 (-86 to +137), ΔQTcFra +5 ± 40 (-77 to +129), and ΔQTcH +7 ± 40 (-76 to +129) ms. Meperidine concentration correlated with QTc-interval (R > 0.36) and ΔQTc (R > 0.69) but the correlation was even better for normeperidine concentration, QTc (R > 0.52) and ΔQTc (R > 0.81). Depending on the QTc correction formula used, 13 - 15 patients (22.41 - 25.86%) presented ΔQTc values > 30 ms, and 7 - 8 patients (12.07- 13.79%) showed ΔQTc values > 60 ms. Renal failure was associated with risk for ΔQTc > 30 ms of 3.74 (IC95% 1.73 - 8.10) and for ΔQTc > 60 ms of 4.27 (IC 95% 1.26 - 14.48). No patient developed arrhythmias during the study., Conclusions: Meperidine treatment causes ECG changes (QTc-interval prolongation) in high correlation with normeperidine plasma concentration. Renal failure increases the risk.
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Background: Many studies have demonstrated that the pharmacokinetics and pharmacodynamics of analgesic drugs vary according to the circadian time of drug administration. This study aims at determining whether the analgesic effect and pharmacokinetics of pethidine in male BALB/c mice are influenced by administration time., Methods: A hot-plate test was used to evaluate the analgesic effect after pethidine (20 mg/kg) or saline injection at different dosing times. Mouse blood samples were collected at different intervals after dosing at 9:00 am and 9:00 pm, and were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: A significant 24-h rhythm was observed in the latency to thermal response at 30 min after dosing, with the peak during the dark phase and the nadir during the light phase. Tolerance to analgesic effect was produced after chronic pethidine injection at 9:00 am or 9:00 pm, and the recovery from tolerance was faster during the dark phase. The peak concentration (Cmax) and area under the concentration-time curve (AUC) of pethidine and its metabolite norpethidine were significantly higher during the dark phase than during the light phase, but the total serum clearance (CL/F) exhibited the opposite trend. The rhythm of drug plasma concentration was positively correlated with the analgesic effect., Conclusion: These results suggest that the pharmacodynamics and pharmacokinetics of pethidine in mice vary significantly according to the dosing time, which implies that the time of administration should be considered in the rational clinical use of pethidine to maximise analgesia and minimise the adverse effects.

Context: Normeperidine accumulates in patients with impaired renal function and may cause central neurotoxicity. However, some uremic patients still undergo meperidine treatment for chronic pain., Objectives: To prevent normeperidine side effects and complications, we investigated the clearance rate and extraction ratio of meperidine and normeperidine in hemodialysis patients with chronic pain., Methods: Three hemodialysis patients, with diagnoses of chronic pancreatitis, chronic back pain, and intractable intra-abdominal pain, received long-term (more than six months) administration of meperidine for chronic noncancer pain. During regular hemodialysis, 72 blood samples in total were collected from the afferent port, efferent port, and ultradiafiltrate port at eight time points. The plasma concentrations of meperidine and normeperidine were determined by high-performance liquid chromatography., Results: The prehemodialysis plasma concentrations of meperidine and normeperidine were 2963 ± 315 and 2369 ± 1974 ng/mL, which declined to 591 ± 109 and 853 ± 765 ng/mL, with 80% and 65% reduction, respectively. The plasma clearance and extraction ratios of meperidine were 22.7 ± 9.8 mL/minute and 10.1 ± 5.6% and for normeperidine 26.0 ± 11.4 mL/minute and 10.8 ± 2.5%, respectively., Conclusion: Hemodialysis can efficiently remove meperidine and its active metabolite, normeperidine, in uremic patients receiving long-term meperidine therapy for chronic noncancer pain., (Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

This study aims to develop an analytical method for the simultaneous determination of pethidine and norpethidine in mouse plasma using the liquid chromatography-electrospray ionization source-tandem mass spectrometry (LC-ESI-MS-MS) method. After being alkalified, the plasma specimens were extracted by liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a C18 column (150 × 2.1 mm internal diameter, 5 μm) using a mobile phase consisting of acetonitrile/water (5 mM ammonium acetate in water, pH 6.2, 40:60, v/v) during a total run time of 4.0 min. The mass spectrometer was operated under the positive ionization mode. The multiple reaction monitoring with the transitions of m/z 248.1 → 174.2, 234.2 → 160.0 and 389.2 → 201.1 was used to quantify pethidine, norpethidine and cetirizine (internal standard), respectively. Linear calibration curves were obtained over concentration ranges of 8.24-8,440.00 ng/mL for pethidine, and 6.15-6,300.00 ng/mL for norpethidine. The intra- and interday precisions and accuracies were <15% (relative standard deviations, RSDs), and the accuracies were within the interval of 94-103% for both. The lower limits of quantification in mouse plasma were 8.24 ng/mL for pethidine and 6.15 ng/mL for norpethidine. Subsequently, the validated method was successfully applied to a pharmacokinetics study of pethidine and its metabolite, norpethidine, in mice.

Background: Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. In an earlier study, we have examined the pharmacokinetic properties in children in different age groups but have not focused on neonates. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in neonates., Methods: Fifteen full-term neonates (eight females) from 37 gestational weeks at birth and scheduled for elective surgery were included in the trial. Their median age was 3 days (range 1-18 days). Ketobemidone hydrochloride was administered as a single intravenous bolus dose, and ketobemidone concentrations were measured by liquid chromatography-mass spectrometry over 10 h. Pharmacokinetic parameters were calculated with standard compartmental methods., Results: The median (range) values for ketobemidone clearance, apparent volume of distribution, volume of central compartment, distribution half-life and elimination half-life were 0.46 (0.23-0.84) l/h/kg, 4.64 (3.50-7.31) l/kg, 1.71 (0.16-3.47) l/kg, 2.85 (1.04-10.78) min and 7.26 (3.5-11.3) h., Conclusion: Compared with our previous study in children older than 1 year of age, the elimination of ketobemidone appeared to be slower in full-term neonates. Despite a low pharmacokinetic variability of ketobemidone as observed in the present neonatal patient population, we recommend individualizing the dose of ketobemidone based on observations of analgesic efficacy., (© 2012 The Authors. Acta Anaesthesiologica Scandinavica © 2012 The Acta Anaesthesiologica Scandinavica Foundation.)

Background: Remifentanil is an ultrashort-acting opioid with favorable pharmacokinetic properties that make it suitable as a labor analgesic. Although it crosses the placenta freely, it is eliminated quickly in the neonate by rapid metabolism and redistribution. We aimed to determine whether remifentanil compared with meperidine is effective in reducing pain scores in laboring parturients. Other effects on the mother, the labor process, and the neonate were also examined., Methods: MEDLINE, CINAHL, Embase, Cochrane CENTRAL, and Maternity and Infant Care databases were searched without language restriction using multiple keywords for labor analgesia, remifentanil, and meperidine. Published abstracts from 5 key research meetings and references from retrieved articles were examined for additional studies. Randomized controlled trials in laboring parturients comparing remifentanil with meperidine were selected. Risk of bias was assessed using criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed for adequacy of sequence generation, allocation concealment, blinding, and completeness of follow-up. Data were extracted from each study using a standardized data collection form. The primary outcome was reduction in pain scores (visual analog scale [VAS], 0-100 mm). We also evaluated maternal side effects (sedation, oxygen desaturation, and bradypnea) and effects on the neonate (Apgar scores, umbilical cord pH, and Neurologic and Adaptive Capacity Scores)., Results: Seven studies (349 patients) were identified for inclusion; only 3 studies were suitable for quantitative synthesis in a meta-analysis (233 patients). We found that remifentanil reduces the mean VAS score at 1 hour by 25 mm more than meperidine (P < 0.001) (95% confidence interval = 19-31 mm). Limited conclusions can be made regarding the side-effect profile of remifentanil because of insufficient data., Conclusion: Compared with meperidine, remifentanil is superior in reducing mean VAS scores for labor pain after 1 hour.

Background: There is no information about the distribution of pethidine into breast milk and/or exposure of the breastfed infant during pethidine patient-controlled epidural analgesia after caesarean delivery., Methods: We conducted an observational study among 20 women. The mean (95% confidence interval) pethidine dose administered was 670 (346-818) mg over 41 (35-46) h. Maternal plasma and milk and neonatal plasma were collected near the time of pethidine cessation and 6h later. Absolute and relative infant doses via milk and infant exposure were calculated. Infant behaviour was assessed using the Neurologic and Adaptive Capacity Score., Results: At first and second sampling times, mean absolute infant doses for pethidine were 20 (14-27) μg/kg/day and 10 (7-13) μg/kg/day, while mean relative infant doses were 0.7 (0.1-1.4)% and 0.3 (0.1-0.5)% respectively. Similar values for norpethidine (expressed as pethidine equivalents) were 21 (16-26) μg/kg/day and 22 (12-32) μg/kg/day; and 0.7 (0.3-1)% and 0.6 (0.2-1)% respectively. Mean pethidine and norpethidine concentrations in neonatal plasma were 3 (0-6.1) μg/L and 0.6 (0.2-1) μg/L. Compared with a time-matched maternal sample, the infant's exposure was 1.4 (0.2-2.8)% for pethidine and 0.4 (0.2-0.6)% for norpethidine. The mean (95% confidence interval) neurologic and adaptive capacity score was 33.6 (32.2-34.9)., Conclusion: The combined absolute infant dose of pethidine and norpethidine received via milk was 1.8% of the neonatal therapeutic dose and the combined relative infant dose was below the 10% recommended safety level. Breastfed infants are at low risk of drug exposure when mothers self-administer epidural pethidine after caesarean delivery., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

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

This report concerns a passenger car crash, which at first looked like a case of multiple trauma resulting in the death of the pinned-in driver. Conspicuous was a cuff that had been applied to the left forearm. No significant injuries could be determined during the autopsy of the corpse. The forensic toxicology results showed lethal toxic concentrations of the painkiller pethidine, which suggests that the driver had applied a lethal dose of the medication immediately before the collision as part of a complex suicide.

One of the major shortcomings of many commonly used opioids is the fact that they are P-gp substrates, which represents a major obstacle towards effective pain management. P-gp can affect opioids' oral absorption, CNS accumulation, systemic clearance, antinociceptive activity, and tolerance development to their analgesic effects. Moreover, P-gp can be the locus of drug-drug interactions between opioids and other concomitantly administered drugs that are P-gp substrates/inhibitors. The objective of this study was to identify opioids that are non-P-gp substrates to overcome some of the mentioned shortcomings. We evaluated the P-gp affinity status (substrate, non-substrate, or inhibitor) of a series of morphine analogs (10 opioid agonist and 2 opioid antagonists) and compared them to previously reported meperidine analogs. The fold stimulation of the morphine analogs ranged from 1.01 to 1.54 while for the meperidine analogs the fold stimulation ranged from 1.10 to 3.66. From each series (morphine and meperidine analogs) we selected potential candidate opioids that are non-P-gp substrates and conducted in vivo assessments of their antinociceptive effects using P-gp knockout and P-gp competent mice. 6-Desoxymorphine, meperidine and N-phenylbutyl normeperidine did not significantly (p>0.05) stimulate the basal P-gp ATPase activity, where, the fold stimulations of the basal P-gp ATPase activity were 1.01+/-0.11, 1.51+/-0.29 and 1.10+/-0.23, respectively. Evaluation of the influence of P-gp ablation on their antinociceptive effects indicated that P-gp did not significantly (p>0.05) affect their antinociceptive effects. Among the evaluated opioids in vivo, 6-desoxymorphine showed high potency and induced no apparent toxicity upon low- and high-dose administration. 6-Desoxymorphine is therefore an ideal lead compound to create a library of opioids that have negligible P-gp affinity for better management of pain.

Background: Limited evidence supports the efficacy of intraperitoneal (IP) meperidine or local anesthetic for postoperative analgesia. Our study aims were to investigate analgesic efficacy and to quantify the plasma concentrations of meperidine and ropivacaine after IP administration. The null hypothesis was that there was no significant difference among groups for dynamic pain in the first 24 h after major abdominal laparoscopic surgery., Methods: This double-blind, five parallel group, placebo-controlled, two-center trial randomized 250 women having laparoscopic surgery to receive IP meperidine 50 or 100 mg (groups M50 and M100), ropivacaine 150 mg (group R150), meperidine 50 mg and ropivacaine 150 mg (group M50R150), all with intramuscular saline, or IP saline, with intramuscular meperidine 50 mg (group C). The primary outcome was pain during recovery. A pharmacokinetic profile of the drugs was obtained., Results: There were no significant differences among groups for mean (sd) dynamic pain scores in the postoperative care unit (2.2 [2.8], 2.5 [3.3], 1.6 [2.5], 2.6 [3.2], 2.7 [3.2] for groups C, M50, M100, R150, and M50R150, P = 0.50) or thereafter. There were no significant differences among groups for pain scores at rest, IV morphine use, recovery characteristics and patient satisfaction. After IP administration of meperidine 50 mg the plasma concentration (median average 55-60 microg/L) was approximately half that of an equivalent intramuscular dose (median average 113 mug/L)., Conclusions: Compared with systemic opioid, IP meperidine and ropivacaine, alone or in combination, did not produce better pain relief or opioid dose-sparing after laparoscopic surgery.

Intranasal drug administration is an easy, well-tolerated, noninvasive transmucosal route that avoids first-pass metabolism in the liver. The nasal mucosa provides an extensive, highly vascularized surface of pseudostratified ciliated epithelium. It secretes mucus that is subjected to mucociliary movement that can affect the time of contact between the drug and the surface. Absorption is influenced by anatomical and physiological factors as well as by properties of the drug and the delivery system. We review the literature on intranasal administration of fentanyl, meperidine, diamorphine, and butorphanol to treat acute pain. The adverse systemic effects are similar to those described for intravenous administration, the most common being drowsiness, nausea, and vomiting. Local effects reported are a burning sensation with meperidine and a bad taste.

Pethidine is no longer considered a first-line analgesic. The evidence for this view is critically presented. Clinicians around the World recommend its removal from health-systems or restriction of its use. New Zealand needs to follow these trends.

Opioid drugs such as morphine and meperidine are widely used in clinical pain management, although they can cause some adverse effects. A number of studies indicate that N-methyl-D-aspartate (NMDA) receptors may play a role in the mechanism of morphine analgesia, tolerance and dependence. Being an antitussive with NMDA antagonist properties, dextromethorphan (DM) may have some therapeutic benefits when coadministered with morphine. In the present study, we investigated the effects of DM on the antinociceptive effects of different opioids. We also investigated the possible pharmacokinetic mechanisms involved. The antinociceptive effects of the mu-opioid receptor agonists morphine (5 mg kg(-1), s.c.), meperidine (25 mg kg(-1), s.c.) and codeine (25 mg kg(-1), s.c.), and the kappa-opioid agonists nalbuphine (8 mg kg(-1), s.c.) and U-50,488H (20 mg kg(-1), s.c.) were studied using the tail-flick test in male Sprague-Dawley rats. Coadministration of DM (20 mg kg(-1), i.p.) with these opioids was also performed and investigated. The pharmacokinetic effects of DM on morphine and codeine were examined, and the free concentration of morphine or codeine in serum was determined by HPLC.It was found that DM potentiated the antinociceptive effects of some mu-opioid agonists but not codeine or kappa-opioid agonists in rats. DM potentiated morphine's antinociceptive effect, and acutely increased the serum concentration of morphine. In contrast, DM attenuated the antinociceptive effect of codeine and decreased the serum concentration of its active metabolite (morphine). The pharmacokinetic interactions between DM and opioids may partially explain the differential effects of DM on the antinociception caused by opioids.

Dora V., a 88-year-old pensioner suffering from a hiatus hernia, died at the home of an orthopaedist and his wife, an anaesthetist, immediately after she had received a dose of 300 mg pethidine via intravenous infusion in a timeframe of about 90 min. One day before her death a befriended notary of the couple visited Dora V. and obtained a blank signature. After her death, a will was forged using this signature, rendering the couple sole heirs of Dora V.'s estate with a value of several million euros. Post-mortem toxicology was performed in three different institutes of legal medicine. The concentrations of pethidine in peripheral venous blood were between 6.1 and 6.5mg/l and 9.5 and 17.2mg/kg in brain. Pharmacokinetic calculation confirms the given dose. There was no doubt that the cause of death was acute pethidine intoxication. The accused couple claimed that this dose of pethidine was indicated to relief pain, and as the pathologists said in their expert opinions that the hiatus hernia could explain her death, the court had to acquit the accused. This very special case demonstrates that preconceived murder of a sick person with suitable analgesics cannot be proven--at least not with the methods available to forensic toxicology and pathology. This has to be taken into consideration if euthanasia will be legalised under special circumstances.

The efflux transporter P-glycoprotein (P-gp) is an important component of the blood-brain barrier (BBB) that limits accumulation of many compounds in brain. Some opioids have been shown to interact with P-gp in vitro and in vivo. Genetic or chemical disruption of P-gp has been shown to enhance the antinociceptive and/or toxic effects of some opioids, although the extent of this phenomenon has yet to be understood. The purpose of this study was to assess quantitatively the influence of mdr1a P-gp on initial brain uptake of chemically diverse opioids in mice. The brain uptake of opioids selective for the mu (fentanyl, loperamide, meperidine, methadone, and morphine), delta (deltorphin II, DPDPE, naltrindole, SNC 121) and kappa (bremazocine and U-69593) receptor subtypes was determined in P-gp-competent (wild-type) and P-gp-deficient [mdr1a(-/-)] mice with an in situ brain perfusion model. BBB permeability of the opioids varied by several orders of magnitude in both mouse strains. The difference in brain uptake between P-gp-competent and P-gp-deficient mice ranged from no detectable effect (meperidine) to >/=8-fold increase in uptake (DPDPE, loperamide, and SNC 121). In addition, loperamide efflux at the BBB was inhibited by quinidine. These results demonstrate that P-gp modulation of opioid brain uptake varies substantially within this class of compounds, regardless of receptor subtype. P-gp-mediated efflux of opioids at the BBB may influence the onset, magnitude, and duration of analgesic response. The variable influence of P-gp on opioid brain distribution may be an important issue in the context of pharmacologic pain control and drug interactions.

Physiologically based pharmacokinetic (PBPK) models can be used to predict drug disposition in humans from animal data and the influence of disease or other changes in physiology on the pharmacokinetics of a drug. The potential usefulness of a PBPK model must however be balanced against the considerable effort needed for its development. Proposed methods to simplify PBPK modeling include predicting the necessary tissue:blood partition coefficients (kp) from physicochemical data on the drug instead of determining them in vivo, formal lumping of model compartments, and replacing the various kp values of the organs and tissues by only two values, for "fat" and "lean" tissues, respectively. The aim of this study was to investigate the effects of simplifying complex PBPK models on their ability to predict drug disposition in humans. Arterial plasma concentration curves of fentanyl and pethidine were simulated by means of a number of successively reduced models. Median absolute prediction errors were used to evaluate the performance of each model, in relation to arterial plasma concentration data from clinical studies, and the Wilcoxon matched pairs test was used for comparison of predictions. An originally diffusion-limited model for fentanyl was simplified to perfusion-limitation, and this model was either lumped, reducing 11 organ/tissue compartments to six, or changed to a model based on only two kp values, those of fat (used for fat and lungs) and muscle (used for all other tissues). None of these simplifications appreciably changed the predictions of arterial drug concentrations in the 10 patients. Perfusion-limited models for pethidine were set up using either experimentally determined [Gabrielsson et al. 1986] or theoretically calculated [Davis and Mapleson 1993] kp values, and predictions using the former were found to be significantly better. Lumping of the models did not appreciably change the predictions; however, going from a full set of kp values to only two ("fat" and "lean") had an adverse effect. Using a kp for lungs determined either in rats or indirectly in humans [Persson et al. 1988], i.e., a total of three kp values, improved these predictions. In conclusion, this study strongly suggested that complex PBPK models for lipophilic basic drugs may be considerably reduced with marginal loss of power to predict standard plasma pharmacokinetics in humans. Determination of only two or three kp values instead of a "full" set can mean an important reduction of experimental work to define a basic model. Organs of particular pharmacological or toxicological interest should of course be investigated separately as needed. This study also suggests and applies a simple method for statistical evaluation of the predictions of PBPK models.

Objective: To evaluate the efficacy and safety of propofol and meperidine plus midazolam for sedation during esophagogastroduodenoscopy (EGD) in children., Methods: Data were collected prospectively and retrospectively from neurologically intact children (0.2-17.7 years of age) who underwent ambulatory diagnostic EGD during a 4-year period. Data were included from 155 consecutive patients receiving propofol with or without premedication with midazolam (PM group). One hundred five consecutive patients who received sedation with a midazolam plus meperidine combination served as a comparison (MM group). Outcome variables were: time required for induction of sedation, length of procedure, time for recovery, need for additional supportive measures, and need for physical restraint., Results: The onset of sedation was faster and the length of procedure and recovery were significantly shorter in the PM group as compared with the MM group (P < 0.01). Patients in the MM group required restraint more often than in the PM group. A higher dose of meperidine and midazolam was used in the prospective study. This led to deeper sedation but increased need for additional support., Conclusions: Propofol is safe and effective for facilitating EGD in children.

The present study was designed to test the hypothesis that a synergistic interaction could be recorded after epidural administration of ketamine-an N-methyl-D-aspartate (NMDA) antagonist and pethidine--an opioid agonist. Twelve adult mongrel dogs of either sex were randomly divided in three groups A, B and C of four animals each. Ketamine (5%) at 2.5 mg/kg and pethidine (3%) 2 mg/kg were injected at lumbosacral epidural space in animals of groups A and B, respectively. In animals of group C ketamine (2.5 mg/kg) and pethidine (2 mg/kg) were injected. Heart rate increased significantly up to 15 min in group A, whereas in groups B and C, the increase was non-significant for a period of 10 and 45 min, respectively. Respiration increased gradually up to 45-60 min in group A and for 15-20 min in group B. However, in animals of group C respiration fell below the baseline during the first 10-15 min and then returned near the baseline. Rectal temperature decreased only marginally in all the groups. Ketamine alone produced complete analgesia at tail and perineal region for a period of 5-10 min and then moderate analgesia for the next 20-30 min. Analgesia at the flank was moderate to complete between 5 and 15 min. In group B complete analgesia was only moderate at the tail and perineal region up to 30 min. In animals of group C, complete analgesia was observed only at perineal region for a very short period (5 min). Analgesia was not associated with sedation in any of the groups but animals of groups A and C showed signs of motor incoordination. Results of the study suggest rather antagonistic than synergistic interaction between epidurally administered ketamine and pethidine. Further studies are needed to confirm the antagonistic interaction between the two drugs.

Aims: To study the pharmacokinetics of orally and intravenously administered ketobemidone in critically ill patients., Methods: Seventeen patients were studied during their stay in the intensive care unit at Huddinge University Hospital. Nine patients received a single intravenous dose of ketobemidone (0.04 mg kg-1) and eight patients received a single oral dose of 5 mg. Plasma concentrations of ketobemidone were measured using liquid chromatography-mass spectrometry. The pharmacokinetic analysis was performed using WinNonlin trade mark software., Results: There was a wide variation in the different pharmacokinetic parameters among patients. Mean clearance in patients treated intravenously was 74.5 (95% CI 43.2, 128.3) and mean Vd was 2.4 l kg-1 (95% CI 2.0, 2.8). t1/2,z also varied widely with a mean value of 4.41 h (95% CI 2.7, 7.0). The corresponding values for MRT were 5.4 and 3.3, 8.8. Mean oral clearance (CL/F) was 102 l h-1 (95% CI 82.7, 125.8), mean Vz/F was 11.2 l kg-1 (95% CI 9.7, 13.1) and mean t1/2,z was 6.0 (95% CI 4.9, 7.3) in orally treated patients. Cmax showed a mean of 38 nmol l-1 (95% CI of 31, 47). A significant correlation was observed between the glomerular filtration rate (GFR) and the half-life of ketobemidone (r = -0.72, P < 0.05). t1/2,z was generally longer and the variation larger in critically ill patients compared with healthy individuals. However, there was no correlation between the elimination of ketobemidone in critically ill patients and plasma C-reactive protein, white blood count or plasma albumin concentrations., Conclusions: The disposition of ketobemidone is highly variable in critically ill patients. In order to ensure sufficient analgesia and avoid toxicity, therapeutic monitoring should be employed when using ketobemidone in this group of patients.

The glucuronide conjugates of ketobemidone, norketobemidone and hydroxymethoxyketobemidone were identified in human urine post-intravenous administration of Ketogan Novum. The human urine was extracted on a mixed-mode solid-phase micro-column before analysis with liquid chromatography/electrospray ionization time-of-flight mass spectrometry (LC/ESI-TOF-MS) and tandem MS (MS/MS). Accurate mass and collision-induced dissociation product ion spectra were used for identification of the glucuronide conjugates. Two different TOF mass spectrometers were used and the accurate mass measurements were performed on three separate days with each instrument. The accuracy of the mass measurements was better than 2.1 ppm for two out of three conjugates and the inter-day relative standard deviation was within +/-0.00049%. The MS/MS fragmentation patterns of the conjugates were in accordance with those of the synthetic aglycones and included peaks originating from the [M + H](+) ion of the respective aglycone., (Copyright 2002 John Wiley & Sons, Ltd.)

The pharmacokinetics of orally administered ketobemidone were investigated in three groups of healthy volunteers with respect to cytochrome P450 (CYP) 2D6 and CYP2C19 phenotypes: extensive metabolisers (EMs) of debrisoquine and mephenytoin (EMdeb/EMmeph), poor metabolisers (PMs) of debrisoquine (PMdeb/EMmeph) and poor metabolisers of mephenytoin (PMmeph/EMdeb). Peak plasma concentration, oral clearance, area under the plasma concentration-time curve, half-life, volume of distribution and mean residence time were not significantly different among the three groups. There was no correlation between oral clearance of ketobemidone and debrisoquine or mephenytoin metabolic ratios. Further, the urinary excretion of ketobemidone and norketobemidone was not affected by the phenotype for either CYP2D6 or CYP2C19. However, a substantial variation in plasma concentration was observed within all three groups. The results indicate that the metabolism of ketobemidone is not dependent on CYP2D6 or CYP2C19. PMs of debrisoquine or mephenytoin, as well as patients who are concomitantly treated with inhibitors of CYP2D6 or CYP2C19, are not expected to be at higher risk of adverse effects. However, due to the interindividual variability in plasma levels of ketobemidone, independent of phenotype, individual dosing based on the clinical response and therapeutic drug monitoring is recommended.

Meperidine was initially synthesized as an anticholinergic agent but was soon discovered to have analgesic properties. Although meperidine's anticholinergic effects were demonstrated in vivo, the anticholinergic effects on the biliary and renal tracts have not been demonstrated in vivo. Studies have clearly demonstrated that meperidine is no more efficacious in treating biliary or renal tract spasm than comparative mu opioids. The initial studies demonstrating the analgesic efficacy of meperidine were mostly case reports and not double-blind, randomized, controlled trials in specific populations. Subsequent comparative studies failed to demonstrate any advantages of meperidine over comparable doses of other analgesics. Meperidine was portrayed in practice and teaching as having unique clinical advantages. The analgesic effects of meperidine are not pronounced, and, in addition, meperidine use is complicated by unique side effects including serotonergic crisis and normeperidine toxicity. Meperidine's poor efficacy, toxicity, and multiple drug interactions have resulted in a movement to replace meperidine with more efficacious and less toxic opioid analgesics.

A simple and fast gas chromatographic method for the determination of pethidine hydrochloride in rabbit plasma is described and validated. This method is an improvement on the GC method which uses a glass column, and was described previously by Koska et al. [Anaesth. Analg. 60 (1981) 8]. The samples were analysed by a GC 5890 HP system using Rtx-5, fused-silica capillary column linked to a nitrogen-phosphorus ionization detector. Lidocaine hydrochloride was used as the internal standard. Calibration curves were linear within the range 5-200 ng/ml. The limit of quantification was about 5 ng using a 1-ml biological sample and no interference was observed in the blank plasma. The mean recovery of the drug from plasma samples was 95.71+/-2.82%. This procedure turned out to be sensitive and convenient enough for the use in pharmacokinetic studies of pethidine.

Pharmacokinetics of morphine, buprenorphine and pethidine were determined in 10 cats. Six cats received morphine (0.2 mg/kg) intravenously and four intramuscularly. Five received buprenorphine (0.01 mg/kg) intravenously and six intramuscularly. Six received pethidine (5 mg/kg) intramuscularly. Jugular venous blood samples were collected at time points to 24 h, and plasma morphine concentrations were measured by high performance liquid chromatograpy (HPLC), buprenorphine by radioimmunoassay (RIA) and pethidine by gas chromatography. Our data for morphine show elimination half-life (t1/2el) 76.3 min intravenous (i.v.) and 93.6 min intramuscular (i.m.); mean residence time (MRT) 105.0 and 120.5 min; clearance (Clp) 24.1 and 13.9 mL/kg/min; and volume of distribution (V(dss)) 2.6 and 1.7 L/kg, respectively. Comparable data for buprenorphine are t1/2el 416.8 and 380.2 min; MRT 417.6 and 409.8 min; Clp 16.7 and 23.7 mL/kg/min; and V(dss) 7.1 and 8.9 L/kg. For i.m. pethidine, t1/2el 216.4 min; MRT 307.5 min; Clp 20.8 mL/kg/min and V(dss) 5.2 L/kg. For i.m. dosing, the tmax for morphine, buprenorphine and pethidine were 15, 3 and 10 min, respectively. The pharmacokinetics of the three opioids in cats are broadly comparable with those of the dog, although there is a suggestion that the cat may clear morphine more slowly.

Evaluation of analgesic agents is multifactorial. The authors know of no direct comparisons among the choices in analgesic agents that suggest one therapy over another in global outcomes such as mortality or morbidity. Therefore, until further outcome differentiation between agents is proved, understanding the primary difference of delivery routes, mechanisms of action, pharmacokinetics, and adverse effects serves as the best guide for selecting the appropriate agent for each patient.

Results from this survey need to be viewed within the context of the small number of responses (20%), which may not fully represent the knowledge base of all house officers. Recommendations established by the Agency for Health Care Policy and Research (AHCPR) define standards of care for acute and chronic pain management and address many of the problems seen nationally with meperidine and its metabolite, normeperidine. Data from this survey have assisted us in providing educational programs which are in line with these guidelines for house officers.

Unlabelled: Obstetric analgesia in the form of pethidine (meperidine) to mothers during delivery has adverse effects on some aspects of the behaviour of their newborn infants. The non-nutritive sucking (NNS) pattern of nine healthy full-term infants exposed to pethidine in utero was compared to that of a control group of infants. The pattern was analysed and quantified using an automatic computer-based method. The results are discussed in the context of endogenous and exogenous opiates and their effect on brain-stem rhythm generators., Conclusions: The typical NNS pattern with alternating sucking activity (bursts) and pauses is preserved in the exposed infants. There is a significantly lower sucking frequency (md 1.74 vs 1.90 Hz, p = 0.030*) and a tendency to a less stable rhythm in pethidine-exposed infants.

In a frequently performed pharmacokinetics study, different subjects are given different doses of a drug. After each dose is given, drug concentrations are observed according to the same sampling design. The goal of the experiment is to obtain a representation for the pharmacokinetics of the drug, and to determine if drug concentrations observed at different times after a dose are linear in respect to dose. The goal of this paper is to obtain a representation for concentration as a function of time and dose, which (a) makes no assumptions on the underlying pharmacokinetics of the drug; (b) takes into account the repeated measure structure of the data; and (c) detects nonlinearities in respect to dose. To address (a) we use a multivariate adaptive regression splines representation (MARS), which we recast into a linear mixed-effects model, addressing (b). To detect nonlinearity we describe a general algorithm that obtains nested (mixed-effect) MARS representations. In the pharmacokinetics application, the algorithm obtains representations containing time, and time and dose, respectively, with the property that the bases functions of the first representation are a subset of the second. Standard statistical model selection criteria are used to select representations linear or nonlinear in respect to dose. The method can be applied to a variety of pharmacokinetics (and pharmacodynamic) preclinical and phase I-III trials. Examples of applications of the methodology to real and simulated data are reported.

Study Objective: To determine the effects of ritonavir on the pharmacokinetics of meperidine and normeperidine., Design: Open-label, crossover, pharmacokinetic study., Setting: United States government research hospital., Subjects: Eight healthy volunteers who tested negative for the human immunodeficiency virus., Intervention: Subjects received oral meperidine 50 mg and had serial blood samples collected for 48 hours. They then received ritonavir 500 mg twice/day for 10 days, followed by administration of a second 50-mg meperidine dose and collection of serial samples., Measurements and Main Results: Plasma samples were assayed for meperidine, normeperidine, and ritonavir. Meperidine's area under the curve (AUC) decreased in all subjects by a mean of 67+/-4% in the presence of ritonavir (p<0.005). Mean +/- SD maximum concentration was decreased from 126+/-47 to 51+/-21 ng/ml. Normeperidine's mean AUC was increased 47%, suggesting induction of hepatic metabolism., Conclusion: Meperidine's AUC is significantly reduced, not increased, by concomitant ritonavir. Based on these findings, the risk of narcotic-related adverse effects from this combination appears to be minimal. However, increased concentrations of normeperidine suggest a potential for toxicity with increased dosages or long-term therapy.

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.

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.

In a double-blind, randomized, crossover study of 25 patients after abdominal aortic surgery, we compared patient-controlled analgesia (PCA) with epidural versus intravenous pethidine. All patients received continuous epidural infusions of 0.125% bupivacaine adjusted to maintain appropriate sensory levels. The 48 hour study period commenced 36 to 48 hours after surgery and covered postoperative days 2 and 3. There was a crossover in PCA mode (epidural or intravenous) after 24 hours. Plasma pethidine concentration at the end of each 24 hour period and the total 24 hour pethidine dose did not change significantly between postoperative days 2 and 3. Pethidine plasma concentration was lower after 24 hours epidural than after intravenous PCA [125 (SD 108) ng/ml versus 171 (SD 107) ng/ml, P = 0.03], although pethidine dose did not differ significantly [mean 147 (SD 124) mg/24 h]. Visual analog pain scores (VAS) did not differ significantly between postoperative days 2 and 3, or at rest between epidural and i.v. groups. However, VAS with coughing and with abdominal palpation were lower in the epidural PCA group (P = 0.05, 0.008). With a background epidural infusion of 0.125% bupivacaine, PCA with epidural pethidine provided better pain control than PCA intravenous pethidine and this was achieved at lower plasma pethidine concentrations.

We investigated the effect of diluent volume on analgesia and systemic absorption from epidural meperidine after cesarean section in a randomized, double-blind study. At the first request for postoperative analgesia, 36 parturients were given epidural meperidine 25 mg diluted with saline to either 2 mL (12.5 mg/mL), 5 mL (5 mg/mL), or 10 mL (2.5 mg/mL). Visual analog pain scores measured in the first 30 min were greater in the 2-mL group compared with both the 5-mL group (P = 0.028) and the 10-mL group (P = 0.031). Onset of analgesia (time for visual analog pain scores to decrease by 50%) was also slower in the 2-mL group (17.5 min) compared with the 5-mL group (9 min; P = 0.015) and the 10-mL group (12 min; P = 0.003); there were no differences between the 5-mL group and the 10-mL group. Duration of analgesia and plasma concentrations of meperidine were similar among groups. No adverse side effects were recorded. Previous work has suggested that injection of epidural opioids in large volumes increases the potential risk of respiratory depression from cephalad spread of the drug. Therefore, we conclude that analgesia is optimum when epidural meperidine is administered diluted to 5 mL.

Background: Different opioids have different delays (hysteresis) between their concentrations in blood and their cerebral effects. Possible mechanisms include differences in their rate of penetration into the brain and differences in their distribution volume in the brain. There have been few in vivo studies of the cerebral kinetics of opioids to differentiate these mechanisms., Methods: The cerebral kinetics of meperidine and alfentanil were examined using conscious sheep that were fitted with long-term monitoring equipment to measure relative changes in cerebral blood flow and opioid concentration gradients across the brain through frequent sampling of arterial and sagittal sinus blood. The data were compared using hybrid physiologic modeling with membrane-limited (consistent with mechanism 1) and flow-limited (consistent with mechanism 2) models of cerebral kinetics., Results: Alfentanil had a variable effect on relative cerebral blood flow, whereas meperidine induced a transient increase. The arteriovenous concentration gradients were small after alfentanil but large after meperidine. The flow-limited model gave acceptable descriptions of observed sagittal sinus concentrations for alfentanil and meperidine, whereas the membrane-limited model collapsed to a flow-limited model. The half-lives of equilibrium between blood and brain were 6.3 and 0.8 min for meperidine and alfentanil, respectively:, Conclusions: The rate of penetration of both opioids into the brain was rapid and not rate-limiting. Large differences in the cerebral distribution volume of meperidine and alfentanil accounted for the respective delays in their peak brain concentration relative to blood.

We compared patient-controlled epidural analgesia (PCEA) with patient-controlled intravenous analgesia (PCIA) using pethidine or fentanyl in a randomized, double-blind crossover study of 80 patients after caesarean section. Patients received pethidine by PCEA or PCIA, or fentanyl by PCEA or PCIA, with a crossover of the route of administration at 12h. For pethidine, pain scores were lower with PCEA vs PCIA from 4 to 16h (P < 0.05). Pethidine consumption was lower with PCEA vs PCIA from 12 to 24h (P = 0.0005). Patients preferred PCEA to PCIA (P = 0.015). For fentanyl, pain scores were lower with PCEA vs PCIA at 12h (P = 0.045). Fentanyl consumption was lower with PCEA vs PCIA from 0 to 12h (P = 0.0007). Patients had similar preference for PCEA and PCIA. Pain scores and side-effects were similar between drugs. Plasma pethidine was similar between groups. Plasma fentanyl was higher with PCIA vs PCEA at 12h (P = 0.002). PCEA has advantages over PCIA and pethidine may be the preferred drug.

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.

Increased numbers of erythrocytes have been shown ex vivo to increase meperidine uptake, and one of the major physiologic changes that occurs at high altitude is an increase in hematocrit and erythrocytes. A study was therefore conducted to evaluate the effects of high altitude on the pharmacokinetics of meperidine. Intramuscular doses (0.75 mg/kg) of meperidine were given to three groups of healthy volunteers (age range, 18-20 years): participants living at sea level (group L), those same participants the day after arrival at high altitude (4,360 m; group HA), and participants who had lived at high altitude for > or = 10 months (group HC). Blood samples were collected for 12 hours after drug administration. Meperidine was measured in whole blood, plasma, and plasma water. Elimination rate constant (lambda z) and clearance uncorrected for bioavailability (Cl/F) were significantly lower at high altitudes than at sea level in plasma (HA and HC) and in whole blood (HA only). Mean residence time (MRT) was significantly higher at high altitudes than at sea level in plasma (HA and HC) and in whole blood (HA only). Hematocrit was significantly increased at both time points at high altitude in comparison to values at sea level, and was also higher after a long-term stay at high altitude than after arrival at high altitude. Erythrocyte binding increased significantly from 41.3% at sea level to 43.8% at arrival at high altitude to 50.9% after a long-term stay at high altitude. The extent of protein binding tended to decrease with high altitude, but this decrease was not significant. Free concentrations of meperidine in plasma water measured 1, 2, and 4 hours after administration were significantly increased after 2 and 4 hours.