morphine-3-glucuronide and Pain--Postoperative

Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children.. The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method.. A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites.. This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.

Topics: Administration, Oral; Analgesics, Opioid; Child; Child, Preschool; Codeine; Cytochrome P-450 CYP2D6; Female; Humans; Male; Models, Biological; Morphine; Morphine Derivatives; Pain, Postoperative; Polymorphism, Genetic; Tertiary Care Centers

Although intravenous morphine titration (IMT) is widely used to control moderate to severe postoperative pain, the relationships between plasma concentrations of morphine and its metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), and IMT outcomes in the postanesthesia care unit (PACU) have not been yet investigated. IMT was administrated as a bolus of 2 or 3 mg every 5 min. Titration was interrupted in case of pain relief (visual analog score ≤30), adverse events, sedation, or failure of morphine titration. Blood samples were collected at the end of morphine titration to determine plasma concentration of morphine and its two metabolites. Data from 214 patients were analyzed; 143 (67%) of the patients achieved complete pain relief, 39 (18%) experienced adverse events, and 32 (15%) failure of morphine titration. At the end of titration, there were no significant differences in morphine, M6G, M3G concentrations between sedated and nonsedated patients (32 vs. 42 ng/mL (P = 0.07), 38 vs. 45 ng/mL (P = 0.51), 300 vs. 342 ng/mL (P = 0.29), respectively), or patients with or without adverse events (40 vs. 41 ng/mL (P = 0.95), 37 vs. 46 ng/mL (P = 0.51), 287 vs. 340 ng/mL (P = 0.72), respectively). Our study demonstrated a lack of relationship between plasma concentrations or ratios of morphine, M3G, and M6G, with IMT outcomes in PACU. This result suggests that the kinetics of morphine and its metabolites have limited value for explaining clinical effects of morphine in this clinical setting.

Topics: Age Factors; Aged; Female; Humans; Injections, Intravenous; Male; Middle Aged; Morphine; Morphine Derivatives; Obesity; Pain Measurement; Pain, Postoperative; Postoperative Care; Sex Characteristics; Treatment Failure; Treatment Outcome

To compare the time course of morphine and metabolite concentrations in serum and cerebrospinal fluid (CSF) after intravenous and intramuscular administration after surgery.. This was a randomized double-blind, double-dummy study in patients who had undergone hip replacement surgery. Morphine (M, 10 mg) was administered intravenously (IV) or intramuscularly (IM). Arterial blood and CSF samples (from a spinal catheter) were drawn simultaneously at 10, 30, 60, and 120 min after administration. Morphine and metabolites [morphine-3-glucuronide (M-3-G), morphine-6-glucuronide (M-6-G), and normorphine (NM)] were determined by a validated liquid chromatography-tandem mass spectrometry method.. Thirty-eight patients were included: 13 men and 25 women, 20 in the IV, 18 in the IM group. Serum concentrations of M after 10 min were consistently higher after IM than IV, concentrations of M-3-G and M-6-G after IM surpassed those of IV after 45 min. NM was not found. None of the metabolites was found in CSF. CSF morphine concentrations and CSF/serum concentration ratios were consistently higher after IV compared to IM. The mean AUC(CSF)/AUC(serum) (0-120 min) concentration ratios were 0.18 and 0.09 after IV and IM, respectively.. The uptake of morphine to the CSF was consistently higher after IV administration than after IM already after 10 min. The higher CSF concentration may be caused by an initially higher morphine blood/CSF gradient following IV morphine injection. The pharmacokinetic findings are compatible with a more rapid and extensive initial effect of IV morphine compared with IM.

Topics: Aged; Analgesics, Opioid; Area Under Curve; Arthroplasty, Replacement, Hip; Bupivacaine; Double-Blind Method; Female; Humans; Injections, Intramuscular; Injections, Intravenous; Male; Midazolam; Middle Aged; Morphine; Morphine Derivatives; Pain Measurement; Pain, Postoperative; Postoperative Care

Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of size from those related to age during infancy.. Postoperative children 0-3 yr old were given an intravenous loading dose of morphine hydrochloride (100 micro g kg(-1) in 2 min) followed by either an intravenous morphine infusion of 10 micro g h(-1) kg(-1) (n=92) or 3-hourly intravenous morphine boluses of 30 micro g kg(-1) (n=92). Additional morphine (5 micro g kg(-1)) every 10 min was given if the visual analogue (VAS, 0-10) pain score was >/=4. Arterial blood (1.4 ml) was sampled within 5 min of the loading dose and at 6, 12 and 24 h for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The disposition of morphine and formation clearances of morphine base to its glucuronide metabolites and their elimination clearances were estimated using non-linear mixed effects models.. The analysis used 1856 concentration observations from 184 subjects. Population parameter estimates and their variability (%) for a one-compartment, first-order elimination model were as follows: volume of distribution 136 (59.3) litres, formation clearance to M3G 64.3 (58.8) litres h(-1), formation clearance to M6G 3.63 (82.2) litres h(-1), morphine clearance by other routes 3.12 litres h(-1) per 70 kg, elimination clearance of M3G 17.4 (43.0) litres h(-1), elimination clearance of M6G 5.8 (73.8) litres h(-1). All parameters are standardized to a 70 kg person using allometric 3/4 power models and reflect fully mature adult values. The volume of distribution increased exponentially with a maturation half-life of 26 days from 83 litres per 70 kg at birth; formation clearance to M3G and M6G increased with a maturation half-life of 88.3 days from 10.8 and 0.61 litres h(-1) per 70 kg respectively at birth. Metabolite formation decreased with increased serum bilirubin concentration. Metabolite clearance increased with age (maturation half-life 129 days), and appeared to be similar to that described for glomerular filtration rate maturation in infants.. M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of adult values by 6 months. A mean steady-state serum concentration of 10 ng ml(-1) can be achieved in children after non-cardiac surgery in an intensive care unit with a morphine hydrochloride infusion of 5 micro g h(-1) kg(-1) at birth (term neonates), 8.5 micro g h(-1) kg(-1) at 1 month, 13.5 micro g h(-1) kg(-1) at 3 months and 18 micro g h(-1) kg(-1) at 1 year and 16 micro g h(-1) kg(-1) for 1- to 3-yr-old children.

Topics: Aging; Analgesics, Opioid; Body Weight; Child, Preschool; Drug Administration Schedule; Female; Half-Life; Humans; Infant; Infant, Newborn; Male; Models, Biological; Morphine; Morphine Derivatives; Pain, Postoperative; Single-Blind Method

We compared analgesic effects and pharmacokinetics of intraarticular versus intravenous administration of morphine after arthroscopic anterior cruciate ligament surgery. In a double-blind placebo-controlled study, 40 patients were randomly allocated to one of four treatment groups. Group I received 1 mg morphine intraarticularly and saline intravenously; group II received 5 mg morphine intraarticularly and saline intravenously; group III received 5 mg saline intraarticularly and morphine intravenously and group IV, the control group, received saline both intraarticularly and intravenously. The pain scores were significantly lower in groups I and II at 24 hours postoperatively than in group IV, and in group II during the rest of the postoperative period, as compared to groups III and IV. After intraarticular injection of 1 mg and 5 mg morphine, respectively, low concentrations of morphine-6-glucuronide (M6G) were found in the circulation, while morphine-3-glucuronide (M3G) appeared late after the injection in concentrations that considerably exceeded those of morphine in groups I and II. The analgesic effect of intraarticular morphine together with the low levels of morphine and morphine-6-glucuronide in plasma further strengthens the view that opioids have a peripheral mechanism of action.

Topics: Adolescent; Adult; Analgesics, Opioid; Anterior Cruciate Ligament; Arthroscopy; Double-Blind Method; Female; Humans; Injections, Intra-Articular; Injections, Intravenous; Male; Morphine; Morphine Derivatives; Pain Measurement; Pain, Postoperative; Prospective Studies

Differences in the patterns of urinary morphine metabolites were determined in 15 patients after the prolonged administration of morphine via various routes (oral, subcutaneous, intravenous). The possible correlation between metabolite pattern and the route of prolonged morphine administration was investigated. It was established that the concentration ratios of the active metabolite, morphine-6-glucuronide to morphine and its inactive metabolite, morphine-3-glucuronide are significantly (p less than 0.05) higher after prolonged oral morphine treatment than after the systemic administration (subcutaneous or intravenous infusion) of morphine. It may therefore be concluded that patients receiving morphine orally produced significantly greater amounts of its pharmacologically more active metabolite than patients subjected to chronic systemic morphine treatment.

Topics: Administration, Oral; Biotransformation; Humans; Infusions, Intravenous; Morphine; Morphine Derivatives; Pain, Postoperative; Retrospective Studies; Time Factors

Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB) is required for optimizing their use in this growing population.. The aim of this case-controlled pharmacokinetic (PK) study was to compare morphine and its glucuronidated metabolites (morphine-3-glucuronide and morphine-6-glucuronide) plasma PKs between patients with RYGB and their controls.. University hospital, Lariboisière Hospital, Paris.. Thirty milligrams of morphine as a sustained-release formulation was orally administered in 12 women who had undergone RYGB for at least 2 years (RYGB group) and in their nonsurgical controls matched for sex, body mass index (±2 points), and age (±5 yr). Morphine, morphine-3-glucuronide, and morphine-6-glucuronide plasma concentrations over a 12-hour period were determined by a validated method using liquid chromatography mass spectrometry in tandem. Drowsiness, respiratory rate, and oxygen saturation were monitored during the PK visit.. Morphine oral area under the curve (for time 0-12 hr; 115.8 ± 108.0 nmol.hr/L and 86.9 ± 38.8 nmol.hr/L for RYGB group and control group, respectively, P = .71), morphine at maximal concentration, metabolites oral area under the curve (for time 0-12 hr). No dose adjustment seems to be needed for sustained release morphine when prescribed to RYGB patients.

Topics: Administration, Oral; Adolescent; Adult; Aged; Analgesics, Opioid; Body Mass Index; Case-Control Studies; Chromatography, Liquid; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Gastric Bypass; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Obesity, Morbid; Pain, Postoperative; Young Adult

In spite of numerous investigations and decades of research, there is still a void in the complete understanding of the therapeutic action of morphine due to the complex nature of its pharmacokinetic/metabolic disposition coupled with elusive pharmacodynamics. This commentary attempts to collate current information on this very important topic and provide perspective to further tease out the relationship between morphine and its metabolites to its purported clinical effect. Similar to numerous acute therapies that need a close vigil for therapy optimization, postoperative pain management with morphine is a challenge due to its extreme intrasubject variability, a fragile therapeutic index, and complex pharmacology interlinked with formation and transport of active metabolite(s). Although numerous investigations of pharmacokinetics and pharmacodynamic effects of morphine and its active glucuronide metabolites have been carried out and excellent data published, still there remains a void in complete understanding of desired therapeutic levels for a meaningful therapeutic outcome without the avoidance of morphine-related side effect profile. The 2009 report of Hammoud et al. (Pain. 2009;144:139-146) confirms the challenges of which one need to be aware during postoperative pain management with morphine in spite of well-controlled intravenous titration using an institutional protocol. These authors have attempted to correlate the plasma concentrations of morphine and its key metabolites, morphine-3-glucuronide (3MG) and morphine-6-glucuronide (6MG), with clinical outcomes such as sedation and adverse effects. This report assumes high significance, since such an investigation to titrate postoperative patients to a fixed desired clinical efficacy outcome has hitherto been not performed in patients who underwent postoperative pain managemnt. Moreover, the intravenous titration option used in the study provided a clean collection of pharmacokinetic surrogate data of morphine along with its metabolites without the issue of absorption and/or oral bioavailability setback if morphine was given by oral route. However, the various pharmacokinetic surrogates used in this study was found insufficient to distinguish the clinical effects. Given the complicated pharmacokinetic and pharmacodynamic profiles of morphine and its metabolites (6MG and 3MG), this commentary provides some thoughts to seek answers for this interesting dilemma.

Topics: Analgesics, Opioid; Humans; Morphine; Morphine Derivatives; Pain; Pain, Postoperative

There is great variability in the need for morphine in the postoperative period. We performed a pharmacokinetic-pharmacodynamic study considering the potential effect of the two main metabolites of morphine.. Fifty patients with moderate to severe pain received morphine as an IV titration, followed by IM administration postoperatively. The plasma concentration of morphine, morphine-6-glucuronide (M-6-G), morphine-3-glucuronide (M-3-G), and pain intensity were measured at frequent intervals. Pharmacokinetic and pharmacodynamic fitting was performed with the software NONMEM.. The pharmacokinetics were largely predictable. M-6-G and M-3-G clearances were markedly decreased in patients with renal failure. The pharmacodynamics was less predictable, with an important interindividual variability. M-6-G was 7.8 times more potent than morphine, but the average time to peak concentration in the effect compartment after a bolus injection of morphine was 4.25 h for M-6-G, when compared to 0.33 h for morphine. M-3-G showed mild inhibition of the analgesic properties of morphine and of M-6-G. The time to M-3-G peak concentration in the effect compartment after a bolus injection of morphine was 10 h.. M-6-G is a potent opioid agonist and M-3-G a mild opioid antagonist. Both are poorly excreted in patients with renal failure. However, the metabolism of morphine was rapid when compared to the transfer of metabolites through the blood-brain barrier, which appears to be the limiting process. Because poor analgesia due to M-3-G's effect may occur in some patients after 1 or 2 days, a switch to other molecules should be considered.

Topics: Adult; Aged; Female; Humans; Male; Metabolic Networks and Pathways; Middle Aged; Morphine; Morphine Derivatives; Pain, Postoperative; Postoperative Period

Intra-articular morphine (5 mg in 25 ml) was administered to patients for post-operative analgesia following arthroscopic knee surgery. At various time intervals, 30 min to 4 h post morphine, venous blood samples were taken in order to determine plasma levels of morphine and its primary metabolites, morphine-3-glucuronide and morphine-6-glucuronide. Measurable amounts of morphine and morphine-3-glucuronide were found in the plasma of 7/10 patients whereas morphine-6-glucuronide was detected in only 2/10 patients. The plasma levels of morphine were lower than that regarded sufficient for post-operative analgesia in all but two patients, indicating a possibility of peripheral analgesia. In addition, synovial biopsy samples were assayed for the presence of opioid binding sites. Tissue samples from 11 different patients were analysed and 6/11 exhibited specific binding of [3H]naloxone, indicating the presence of opioid binding sites/receptors. The receptor type (i.e. mu-, delta- or k-) is at present unknown. Taken together, these data provide evidence that locally administered opiates can act on specific opioid receptors in the synovium to mediate analgesia.

Topics: Adult; Analgesia; Arthroscopy; Female; Humans; Knee; Male; Morphine; Morphine Derivatives; Pain, Postoperative; Radioligand Assay; Receptors, Opioid; Synovitis

We report a case of long lasting respiratory depression after intravenous administration of morphine to a 7 year old girl with haemolytic uraemic syndrome. The plasma concentrations of the active metabolite M6G were more than 10 times those normally seen and the half-lives of M6G and morphine were prolonged.

Topics: Child; Depression, Chemical; Female; Hemolytic-Uremic Syndrome; Humans; Morphine Derivatives; Pain, Postoperative; Respiration Disorders