Pharmacokinetics and pharmacodynamics of meperidine after intramuscular and subcutaneous administration in horses.

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 (T1/2 ), 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 T1/2 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.

Meperidine pharmacokinetics and effects on physiologic parameters and thermal threshold following intravenous administration of three doses to horses.

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.

Pharmacokinetics of meperidine (pethidine) in rabbit oral fluid: correlation with plasma concentrations after controlled administration.

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.

Meperidine-induced QTc-interval prolongation: prevalence, risk factors, and correlation to plasma drug and metabolite concentrations
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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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Chronopharmacodynamics and chronopharmacokinetics of pethidine in mice.

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.

Clearance of meperidine and its metabolite normeperidine in hemodialysis patients with chronic noncancer pain.

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.

Simultaneous determination of pethidine and norpethidine in mouse plasma by liquid chromatography-electrospray ionization source-mass spectrometry.

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.

Pharmacokinetics after a single intravenous dose of the opioid ketobemidone in neonates.

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.

Is maternal opioid use hazardous to breast-fed infants?

Over the last few decades, the rate of breastfeeding has increased steadily in the developed countries of the world. During this time, opioid use in the general population has steadily increased as well. Despite this, clinicians remain unclear whether opioid use is safe during breastfeeding. While the vast majority of medications used during breastfeeding occur without incident, case reports and studies have reported possible opioid toxicity in breast-fed infants. Multiple enzymes are involved in the metabolism of opioids. CYP2D6 catabolizes O-demethylation of codeine, tramadol, oxycodone, and hydrocodone to more potent metabolites. CYP3A4 inactivates methadone, meperidine, and buprenorphine. Glucoronide conjugation by the UGT enzyme family inactivates morphine and hydromorphone. Genetic polymorphisms and interfering medications affect the maternal metabolism, which in turn determines the exposure and risk to the breast-fed neonate. We review the production of breast milk, the transfer of xenobiotics from blood to milk, the characteristics that alter xenobiotic breast-milk concentrations, and we review the evidence of specific common opioids and infant toxicity. The short-term maternal use of prescription opioids is usually safe and infrequently presents a hazard to the newborn.

A comparison between remifentanil and meperidine for labor analgesia: a systematic review.

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.

Estimation of infant dose and exposure to pethidine and norpethidine via breast milk following patient-controlled epidural pethidine for analgesia post caesarean delivery.

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.

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

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

[Lethal intoxication while driving a car]. / Letale Intoxikation im fahrenden PKW.

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.

Evaluation of the P-glycoprotein (Abcb1) affinity status of a series of morphine analogs: comparative study with meperidine analogs to identify opioids with minimal P-glycoprotein interactions.

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.

Disposition and clinical outcome after intraperitoneal meperidine and ropivacaine administration during laparoscopic surgery.

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.

Should New Zealand continue signing up to the Pethidine Protocol?

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.

[Intranasal opioids for acute pain]. / Opioides por vía intranasal en el tratamiento del dolor agudo.

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.