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Meperidine is a synthetic opioid analgesic frequently prescribed in the emergency department. Meperidine is most often administered intramuscularly or intravenously, due to its poor oral bioavailability, and is metabolized extensively by the liver. Analgesic effects usually last 3-4 hours with parenteral administration, and some adverse effects such as nausea may be reduced when meperidine is combined with antiemetic or antihistaminic medications. Although meperidine is often a preferred analgesic by both patients and physicians in the treatment of disorders such as migraine headaches, its analgesic efficacy has rarely proven superior to alternative parenteral pain medications in controlled trials. In addition, meperidine can precipitate monoamine oxidase inhibitor reactions, and during metabolism it is demethylated to normeperidine, a compound with significant central nervous system (CNS) toxicity. Meperidine should be considered a second line agent in the treatment of pain when opioid analgesics are required.

Background and Objectives: The purpose of the study was to investigate the role of adrenaline (ADR), noradrenaline (NDR), and cortisol in the pathogenesis of the analgesic potency, duration, and epilepsy-like toxic effect of meperidine. Materials and Methods: The experimental animals were separated into 11 groups of six rats. In the meperidine (MPD) and metyrosine + meperidine (MMPD) groups, paw pain thresholds were measured before and after the treatment between the first and sixth hours (one hour apart). In addition, ADR and NDR analyses were performed before and after the treatment, between the first and fourth hours (one hour apart). For the epilepsy experiment, caffeine, caffeine + meperidine, and caffeine + meperidine + metyrapone groups were created, and the treatment was applied for 1 day or 7 days. Groups were created in which caffeine was used at both 150 mg/kg and 300 mg/kg. Epileptic seizures were observed in epilepsy groups, latent periods were determined, and serum cortisol levels were measured. Results: In the MPD group, pain thresholds increased only at the first and second hours compared to pre-treatment, while ADR increased at the third hour, leading to a decrease in pain thresholds. In the MMPD group, the increase in paw pain thresholds at 1 and 6 h was accompanied by a decrease in ADR and NDR. In the caffeine (150 mg/kg) + meperidine group, 1-day treatment did not cause epileptic seizures, while seizures were observed and cortisol levels increased in the group in which treatment continued for 7 days. When cortisol levels were compared between the group in which caffeine (300 mg/kg) + meperidine + metyrapone was used for 7 days and the animals receiving caffeine (300 mg/kg) + metyrapone for 7 days, it was found that cortisol levels decreased and the latent period decreased. Conclusions: The current study showed that if serum ADR and cortisol levels are kept at normal levels, a longer-lasting and stronger analgesic effect can be achieved with meperidine, and epileptic seizures can be prevented. [ABSTRACT FROM AUTHOR]

Gastrointestinal endoscopy in patients with advanced liver disease poses various challenges, a major one being procedural sedation and its associated considerations. While sedation during endoscopy can improve patient comfort, decrease anxiety, and facilitate procedural completion, in patients with advanced liver disease, it is also associated with substantial and unique risks due to alterations in drug metabolism and other factors. As such, the choice of sedative agent(s) and related logistics may require careful inter-disciplinary planning and individualized considerations. Furthermore, a large proportion of agents require dose reductions and particular monitoring of the vital signs, level of consciousness, and other indices. In the present review, we provide a contemporary overview of procedural sedation considerations, commonly used intravenous sedatives, and second-line as well as novel sedatives for gastrointestinal endoscopy in patients with advanced liver disease. [ABSTRACT FROM AUTHOR]

In this article, we compared the content validity of two instruments used in measuring pediatric pain knowledge and attitudes. This was considered necessary due to the universal differences in culture, semantics and healthcare resources in different parts of the globe. Thirteen (13) pediatric experts in Ghana assessed the content validity of two instruments: the 42-item Pediatric Nurses' Knowledge and Attitudes Survey Regarding Pain (PNKAS) and the 41-item Pediatric Healthcare Providers' Knowledge and Attitudes Survey Regarding Pain (PHPKASRP). The relevance and clarity of each item on these instruments were rated on a four-point likert scaled options from 1 (not relevant/ not clear) to 4 (very relevant/ very clear). The item-level content validity index (I-CVI) was calculated by dividing the number of experts who rated an item with 3 or 4 by the total number of experts. The average scale-level content validity index (S-CVI/Ave) was also estimated by summing up the I-CVIs of all items and dividing them by the total number of items. The I-CVIs on the PNKAS ranged from 0.62 to 1.00 for the relevance component and 0.69 to 1.00 for the clarity component. The I-CVIs on the PHPKASRP ranged from 0.62 to 1.00 for both the relevance and clarity components. The S-CVI/Ave were 0.87 and 0.89 for the relevance and clarity aspects on the PNKAS respectively. The S-CVI/Ave for the PHPKASRP instrument were 0.86 and 0.89 for the relevance and clarity aspects correspondingly. At the end of the validation process, 5 items were revised on both instruments whilst 37 and 36 items were maintained on the PNKAS and PHPKASRP instruments respectively. The PNKAS and PHPKASRP have an acceptable level of content validity in the Ghanaian context and recommended for educational and research purposes. Other forms of validity and reliability of these instruments should also be examined in future studies. [ABSTRACT FROM AUTHOR]

1. Meperidine is an opioid analgesic that undergoes N-demethylation to form the neurotoxic metabolite normeperidine. Previous studies indicate that meperidine N-demethylation is catalyzed by cytochrome P450 2B6 (CYP2B6), CYP3A4, and CYP2C19. 2. The purpose of this study was to examine the relative P450 contributions to meperidine N-demethylation and to evaluate the effect of CYP2C19 polymorphism on normeperidine generation. Experiments were performed using recombinant P450 enzymes, selective chemical inhibitors, enzyme kinetic assays, and correlation analysis with individual CYP2C19-genotyped human liver microsomes. 3. The catalytic efficiency (kcat/Km) for meperidine N-demethylation was similar between recombinant CYP2B6 and CYP2C19, but markedly lower by CYP3A4. 4. In CYP2C19-genotyped human liver microsomes, normeperidine formation was significantly correlated with CYP2C19 activity (S-mephenytoin 4´-hydroxylation). 5. CYP2C19 inhibitor (+)-N-3-benzylnirvanol and CYP3A inhibitor ketoconazole significantly reduced microsomal normeperidine generation by an individual donor with high CYP2C19 activity, whereas donors with lower CYP2C19 activity were sensitive to inhibition by ketoconazole but not benzylnirvanol. 6. These findings demonstrate that the relative CYP3A4, CYP2B6, and CYP2C19 involvement in meperidine N-demethylation depends on the enzyme activities in individual human liver microsomal samples. CYP2C19 is likely an important contributor to normeperidine generation in individuals with high CYP2C19 activity, but additional factors influence inter-individual metabolite accumulation. [ABSTRACT FROM AUTHOR]

Pain management in the pediatric population is complex for many reasons. Mild pain is usually managed quite well with oral acetaminophen or ibuprofen. Situations involving more severe pain often require the use of an opioid, which may be administered by many different routes, depending on clinical necessity. Acute and chronic disease states, as well as the constantly changing maturational process, produce unique challenges at every level of pediatrics in dosing and management of all medications, especially with regard to high-risk opioids. Although there has been significant progress in the understanding of opioid pharmacokinetics and pharmacodynamics in neonates, infants, children, and adolescents, somewhat limited data exist from which necessary information, concerning the safe and effective use of these agents, may be drawn. The evidence here provided is intended to be helpful in directing the practitioner to patient-specific reasons for preferring one opioid over another. As our knowledge of opioids and their effects has grown, it has become clear that older medications like codeine and meperidine (pethidine) have very limited use in pediatrics. This review provides pharmacokinetic and pharmacodynamic evidence on the currently available opioids: morphine, fentanyl (and derivatives), codeine, meperidine, oxycodone, hydrocodone, hydromorphone, methadone, buprenorphine, butorphanol, nalbuphine, pentazocin, ketobemidone, tramadol, piritramide, naloxone and naltrexone. Morphine, being the most studied opioid analgesic, is the standard against which all others are compared. Pharmacokinetic parameters of morphine that have been found in neonates, i.e., higher volume of distribution, immature metabolic processes that develop at various rates, elimination that is variable based on age and weight, as well as treated and untreated disease processes, are an example of all opioids in the population discussed in this review. Outside the premature and neonatal population, the use of opioids in infants, children, and adolescents quickly begins to resemble the established values found in adults. As such, the concerns (risks) of these medications become comparable to those seen in adults. [ABSTRACT FROM AUTHOR]

Introduction: Optimal pain management is crucial to the postoperative recovery process. We aimed to evaluate the efficacy and safety of intravenous oxycodone with intravenous fentanyl, morphine, sufentanil, pethidine, and hydromorphone for acute postoperative pain. Methods: A systematic literature search of PubMed, Cochrane Library, and EMBASE databases was performed for randomized controlled trials published from 2008 through 2017 (inclusive) that evaluated the acute postoperative analgesic efficacy of intravenous oxycodone against fentanyl, morphine, sufentanil, pethidine, and hydromorphone in adult patients (age ≥ 18 years). Outcomes examined included analgesic consumption, pain intensity levels, side effects, and patient satisfaction. Results: Eleven studies were included in the review; six compared oxycodone with fentanyl, two compared oxycodone with morphine, and three compared oxycodone with sufentanil. There were no eligible studies comparing oxycodone with pethidine or hydromorphone. Overall, analgesic consumption was lower with oxycodone than with fentanyl or sufentanil. Oxycodone exhibited better analgesic efficacy than fentanyl and sufentanil, and comparable analgesic efficacy to morphine. In terms of safety, there was a tendency towards more side effects with oxycodone than with fentanyl, but the incidence of side effects with oxycodone was comparable to morphine and sufentanil. Where patient satisfaction was evaluated, higher satisfaction levels were observed with oxycodone than with sufentanil and comparable satisfaction was noted when comparing oxycodone with fentanyl. Patient satisfaction was not evaluated in the studies comparing oxycodone with morphine. Conclusions: Our findings suggest that intravenous oxycodone provides better analgesic efficacy than fentanyl and sufentanil, and comparable efficacy to morphine with less adverse events such as sedation. No studies comparing intravenous oxycodone with pethidine or hydromorphone were identified in this review. Better alignment of study methodologies for future research in this area is recommended to provide the best evidence base for a meta-analysis. Funding: Mundipharma Singapore Holding Pte Ltd, Singapore. [ABSTRACT FROM AUTHOR]

Drugs may cause serotonin toxicity by a number of different mechanisms including inhibition of serotonin uptake and metabolism, increased serotonin synthesis and release, activation of serotonin receptors, and inhibition of cytochrome P450 oxidases. Some drug interactions involving opioids can increase intrasynaptic levels of serotonin, and opioid analgesic drugs are now recognized as being involved in some cases of serotonin toxicity especially if administered in conjunction with other serotonergic medications including monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants. In March 2016, the FDA issued a Drug Safety Communication concerning the association of the entire class of opioid pain medicines with serotonin toxicity. Reports of the involvement of individual opioids particularly tramadol, tapentadol, meperidine, methadone, oxycodone, fentanyl, and dextromethorphan are reviewed. While relevance to human serotonin toxicity of animal models, including many studies on rat brain synaptosomes, is questionable, important insights have recently been forthcoming from research utilizing 5-HT receptors, serotonin transporter (SERT), and knockout mice. In studies with human SERT-transfected human HEK293 cells, the synthetic opioids tramadol, meperidine, methadone, tapentadol, and dextromethorphan inhibited SERT, but fentanyl and a number of phenanthrenes including morphine and hydromorphone did not. Receptor ligand-binding assays revealed interaction of fentanyl with 5-HT1A receptors and interaction of meperidine, methadone, and fentanyl with 5-HT2A receptors. Although the opioids most often associated with serotonin toxicity in humans inhibit human SERT in vitro, fentanyl and oxycodone are not inhibitory even though their clinical involvement has been reported. This suggests some SERT-independent effects on the serotonin system in vivo. Heightened clinician awareness of the possibility of serotonin toxicity among patients taking opioids and serotonergic antidepressants is called for. [ABSTRACT FROM AUTHOR]

Opioid analgesics are commonly prescribed for acute and chronic pain, but are subject to abuse. Consequently, toxicology testing programs are frequently implemented for both forensic and clinical applications. Understanding opioid metabolism and disposition is essential for assessing risk of toxicity and, in some cases, providing additional information regarding risk of therapeutic failure. Opioids significantly metabolized by the cytochrome P450 (CYP450) enzyme system may be subject to drug-drug interactions, including codeine, hydrocodone, oxycodone, fentanyl, meperidine, methadone, buprenorphine, and tramadol. CYP2D6 metabolism is polymorphic, and pharmacogenetic testing has been investigated for codeine, tramadol, oxycodone, and hydrocodone. CYP2B6 pharmacogenetic testing of methadone may reduce the risk of cardiac toxicity associated with the S-enantiomer. Opioids metabolized primarily by uridine 5’-diphospho-glucuronsyltransferase (UGT) enzymes include morphine, hydromorphone, dihydrocodeine, oxymorphone, levorphanol, and tapentadol. Parent and metabolite disposition is described for blood, oral fluid, and urine. Parent drug is most commonly detected in blood and oral fluid, whereas metabolites typically predominate in urine. Oral fluid/blood ratios exceed 1 for most opioids, making this an excellent alternative matrix for testing of this drug class. Metabolites of codeine, hydrocodone, and oxycodone are commercially available, and knowledge of metabolism is necessary for correct interpretation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Meperidine (Demerol®) is a mu- and kappa-opiate receptor agonist used for moderate to severe pain. Overdose can result in respiratory depression, hypotension and coma, while accumulation of its toxic metabolite, normeperidine, can cause delirium and seizures. Little data exist examining the inter- and intrasubject variability of the normeperidine-to-meperidine metabolic ratio (MR) in urine. This retrospective data analysis examined meperidine and normeperidine urine concentrations collected from chronic pain patients. In 98 subjects with multiple visits, the geometric mean urinary MR = 6.1 (coefficient of variation, %CV = 68%). From single specimens obtained from 799 subjects, the geometric mean urinary MR = 6.2 (%CV = 212%). The urinary MR increased in young subjects compared with elderly (P = 0.004) and middle-aged subjects (P = 0.01). A 27% difference was found between the male and female urinary MR (male geometric mean MR = 5.1, female geometric mean MR = 7.0, P = 0.02). Intersubject variability in meperidine metabolism was 3-fold greater than intrasubject variability. A significant difference in the urinary MR was found between males and females. The substantial variability in meperidine metabolism and the serious side effects of its metabolite normeperidine require greater vigilance in patient medication monitoring. [ABSTRACT FROM PUBLISHER]

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ABSTRACT BACKGROUND. Little is known about physician attitudes, goals, or satisfaction regarding acute postoperative and cancer pain management. OBJECTIVES. To provide quantitative data regarding the status of acute postoperative and cancer pain management by Michigan physicians. To measure physician confidence, preference, and satisfaction as well as identify their pain care goals for acute postoperative and cancer pain management. To evaluate variability in acute postoperative and cancer pain decision making based upon physician demographic characteristics, knowledge, and attitudes. RESEARCH DESIGN. A cross-sectional survey, which included two cancer and three acute postoperative pain vignettes. SUBJECTS. A randomly-selected sample of three hundred sixty-eight licensed Michigan physicians who provide clinical care for acute postoperative and cancer pain patients. RESULTS. The majority of respondents (>50%) reported providing acute postoperative pain care frequently, while a minority (<20%) reported doing so for cancer pain. The majority of the physicians (>75%) reported goals of at least adequate pain relief without distress for both acute postoperative and cancer pain. Physicians more frequently chose the optimal pain management response for men following prostatectomy (56.2%) than for women following myomectomy (42%). They also chose the optimal response for metastatic prostate cancer more frequently (16.3%) than for metastatic breast cancer pain management (10.7%). CONCLUSION. These data highlight physician variability in acute postoperative and cancer pain management decision making. Further study of the physician variable is necessary to improve the management of acute postoperative and cancer pain. [ABSTRACT FROM AUTHOR]

Background. The role of physician variability in pain management is unknown. Objective. To assess the role of physician variability in the management of pain and provide quantitative data regarding the status of pain management in Michigan. Design. A multi-item mail survey was used to determine the physician's perceived knowledge of pain management modalities, goals, satisfaction, and confidence with pain treatment. Participants. The focus of this report was a group of 368 licensed Michigan physicians who provide clinical care. Results. Overall, 30% of the study group reported no formal education in pain management, although younger physicians reported more education (correlation coefficient = -0.252, P < .001). The physicians reported greater confidence in their knowledge of meperidine than other Schedule II opioids (P < .001 ). In regards to the opinion that prescribing strong opioids would attract a medical review, the physician responses ranged from 1 (strongly disagree) to 5 (strongly agree). The median score for this scale was 4, accounting for 46% of the responses. The study group expressed less satisfaction with their treatment of chronic pain as well as lower goals for relief (mean: 3.8; 95% confidence interval: 3.7–3.9). Conclusions. Lower expectations for relief and less satisfaction in its management may contribute to the undertreatment of chronic pain. Perceptions of regulatory scrutiny may contribute to suboptimal pain management. These preliminary data highlight physician variability in pain decision making while providing insights into educational needs. [ABSTRACT FROM AUTHOR]

See Commentary, page 271. [ABSTRACT FROM AUTHOR]

The pharmacokinetics, metabolism, alleged adverse effects and evidence on adverse effects of meperidine are compared to those of other commonly used opioids. Comparative effects of meperidine and other opioids on respiratory depression, spasmogenicity, new borns when drugs are used in labor and delivery and neurological status are discussed. Anecdotal reports of fewer side effects of meperidine as compared to morphine and other opioids may be due to cmparison of non-equivalent doses in some cases. Some evidence that indicates differences between meperidine and other opioids does not indicate clinically important differences. Alternative medications to meperidine are suggested for cases when such alternatives may be desired. [ABSTRACT FROM PUBLISHER]

Studies of most drugs of abuse utilize in vivo animal experimentation so that the responses measured reflect the pharmacokinetics of the administered drug as well as its pharmacodynamics. These drugs are generally lipid soluble chemicals and their elimination is dependent on metabolism, so an understanding of this process is critical to the interpretation of responses. This review summarizes the interaction between drugs of abuse and cytochromes P450, the oxidative enzymes that catalyze the first step of the metabolic process. Although they process their substrates by a common chemical mechanism, these enzymes differ markedly in their regulation, i.e. induction and inhibition, their substrate selectivities, the metabolites they generate and their relative concentration in different species. The activity of an enzyme catalyzing a specific metabolic reaction can be altered by prior xenobiotic exposure, by its genetics and by a co-administered drug, so that the pharmacokinetics of the drug under study can vary with the history of the individual subject. These issues are obviously important in human studies so, when possible, the relevant human enzymes involved in the processes described have been identified. [ABSTRACT FROM AUTHOR]

A letter to the editor about meperidine overdose and toxicity is presented.