morphine-6-glucuronide and Respiratory-Insufficiency

Morphine-6-glucuronide (M6G) appears to show equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. The purpose of this review is to examine the evidence behind this statement and to identify the possible reasons that may contribute to the profile of M6G. The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1) Morphine has a slightly higher affinity for the micro-opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the micro-opioid receptor, (3) M6G has a lower affinity for the kappa-opioid receptor than morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from morphine. However, none of these are adequate alone to explain the clinical differences between M6G and morphine. The ADME differences are perhaps most likely to explain some of the differences but seem unlikely to be the whole story. Further work is required to examine further the profile of M6G, notably whether M6G penetrates differentially to areas of the brain involved in pain and those involved in nausea, vomiting, and respiratory control or whether micro-opioid receptors in these brain areas differ in either their regulation or pharmacology.

Topics: Animals; Humans; Morphine Derivatives; Nausea; Pain; Receptors, Opioid; Respiratory Insufficiency; Vomiting

Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist-antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers.. Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 microg naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 microg naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal Pco2. A mechanism-based pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data.. Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (koff M6G = 0.0327 +/- 0.00455 min versus morphine 0.138 +/- 0.0148 min; values are typical +/-SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration.. Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration.

Topics: Adolescent; Adult; Female; Humans; Male; Models, Biological; Morphine; Morphine Derivatives; Naloxone; Respiratory Insufficiency; Single-Blind Method; Young Adult

To investigate age-related differences in morphine requirements and metabolism in full-term neonates.. Randomized double-blind study in the pediatric surgical intensive care unit.. Sixty-eight neonates (52 aged under 7 days, 16 aged 7 day or older) following major surgery.. After surgery patients were randomly assigned to continuous morphine (10 micro g/kg per hour) or intermittent morphine (30 micro g/kg per 3 hours). Additional morphine was administered on guidance of pain scores.. Pain was measured by the Comfort behavioral scale and visual analogue scale. Morphine and morphine-6-glucuronide (M6G) plasma concentrations were determined before and 0, 6, 12, and 24 h after surgery. The younger neonates differed significantly from the older neonates in morphine requirement (median 10 vs. 10.8 micro g/kg per hour), morphine plasma concentration [23.0 vs. 15.3 ng/ml), and M6G/morphine ratio (0.6 vs. 1.5). Pain scores did not differ between age groups or morphine treatment groups. Neonates who were mechanically ventilated longer than 24 h had significantly higher morphine plasma concentrations than the spontaneously breathing neonates 12 and 24 h after surgery (29.1 vs. 13.1 ng/ml and 26.9 vs. 12.0 ng/ml, respectively). Morphine plasma concentrations were not correlated with analgesia or respiratory depression. Five neonates (intermittent morphine) showed respiratory insufficiency; however, the difference between the groups was not significant.. Neonates aged 7 days or younger require significantly less morphine postoperatively than older neonates. The two morphine regimens (continuous, intermittent) were equally effective and safe. Mechanical ventilation decreases morphine metabolism and clearance.

Topics: Age Factors; Analgesics, Opioid; Birth Weight; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Female; Humans; Infant, Newborn; Infusions, Intravenous; Male; Metabolic Clearance Rate; Morphine; Morphine Derivatives; Pain Measurement; Pain, Postoperative; Respiration, Artificial; Respiratory Insufficiency; Safety; Time Factors; Treatment Outcome

To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure.. Prospective pharmacokinetic-pharmacogenomic observational study.. Thirteen PICUs across the United States.. Pediatric subjects (n = 66) mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions.. Serial blood sampling for drug quantification and a single blood collection for genomic evaluation.. Concentrations of morphine, the two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were quantified by high-performance liquid chromatography tandem mass spectrometry/mass spectroscopy. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed-effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. A two-compartment model with linear elimination and two individual compartments for metabolites best describe morphine disposition in this population. Our analysis demonstrates that body weight and postmenstrual age are relevant predictors of pharmacokinetic parameters of morphine and its metabolites. Furthermore, our research shows that a duration of mechanical ventilation greater than or equal to 10 days reduces metabolite formation and elimination upwards of 30%. However, due to the small sample size and relative heterogeneity of the population, no heritable factors associated with uridine diphosphate glucuronyl transferase 2B7 metabolism of morphine were identified.. The results provide a better understanding of the disposition of morphine and its metabolites in critically ill children with acute respiratory failure requiring mechanical ventilation due to nonheritable factors. It also provides the groundwork for developing additional studies to investigate the role of heritable factors.

Topics: Acute Disease; Adolescent; Age Factors; Analgesics, Opioid; Body Weight; Child; Child, Preschool; Critical Illness; Female; Genotype; Glucuronosyltransferase; Humans; Infant; Male; Morphine; Morphine Derivatives; Pharmacogenomic Testing; Prospective Studies; Respiration, Artificial; Respiratory Insufficiency; Time Factors

For patients experiencing inadequate analgesia and intolerable opioid-related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles.. Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine-6-glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D-penicillamine(2,5) ]-enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail-flick test, the castor oil-induced diarrhoea test and whole body plethysmography respectively.. These opioid agonists produced dose-dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell-shaped dose-response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression.. For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of 'opioid rotation'.. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Topics: Analgesics, Opioid; Animals; Benzeneacetamides; Buprenorphine; Castor Oil; Constipation; Diarrhea; Enkephalin, D-Penicillamine (2,5)-; Fentanyl; Hot Temperature; Male; Morphine; Morphine Derivatives; Oxycodone; Pain; Pyrrolidines; Rats, Sprague-Dawley; Respiratory Insufficiency

Opioids are known to induce respiratory depression. We aimed to characterize in rats the effects of four opioids on arterial blood gases and plethysmography after intraperitoneal administration at 80% of their LD(50) in order to identify opioid molecule-specific patterns and classify response severity. Opioid-receptor (OR) antagonists, including intravenous 10 mg kg(-1)-naloxonazine at 5 min [mu-OR antagonist], subcutaneous 30 mg kg(-1)-naloxonazine at 24 h [mu1-OR antagonist], subcutaneous 3 mg kg(-1)-naltrindole at 45 min [delta-OR antagonist], and subcutaneous 5 mg kg(-1)-Nor-binaltorphimine at 6 h [kappa-OR antagonist] were pre-administered to test the role of each OR. Methadone, morphine, and fentanyl significantly decreased PaO(2) (P<0.001) and increased PaCO(2) (P<0.05), while buprenorphine only decreased PaO(2) (P<0.05). While all opioids significantly increased inspiratory time (T(I), P<0.001), methadone and fentanyl also increased expiratory time (T(E), P<0.05). Intravenous 10 mg kg(-1)-naloxonazine at 5 min completely reversed opioid-related effects on PaO(2) (P<0.05), PaCO(2) (P<0.001), T(I) (P<0.05), and T(E) (P<0.01) except in buprenorphine. Subcutaneous 30 mg kg(-1)-naloxonazine at 24 h completely reversed effects on PaCO(2) (P<0.01) and T(E) (P<0.001), partially reversed effects on T(I) (P<0.001), and did not reverse effects on PaO(2). Naltrindole reversed methadone-induced T(E) increases (P<0.01) but worsened fentanyl's effect on PaCO(2) (P<0.05) and T(I) (P<0.05). Nor-binaltorphimine reversed morphine- and buprenorphine-induced T(I) increases (P<0.001) but worsened methadone's effect on PaO(2) (P<0.05) and morphine (P<0.001) and buprenorphine's (P<0.01) effects on pH. In conclusion, opioid-related respiratory patterns are not uniform. Opioid-induced hypoxemia as well as increases in T(I) and T(E) are caused by mu-OR, while delta and kappa-OR roles appear limited, depending on the specific opioid. Regarding severity of opioid-induced respiratory effects at 80% of their LD(50), all drugs increased T(I). Methadone and fentanyl induced hypoxemia, hypercapnia, and T(E) increases, morphine caused both hypoxemia and hypercapnia while buprenorphine caused only hypoxemia.

Topics: Animals; Blood Gas Analysis; Buprenorphine; Catheterization; Fentanyl; Lactic Acid; Male; Methadone; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Narcotics; Plethysmography, Whole Body; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Respiratory Insufficiency; Respiratory Mechanics

Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic properties. The influence of M6G on respiratory and antinociceptive responses was investigated in mice lacking the micro -opioid receptor (MOR) and compared with morphine.. Experiments were performed in mice lacking exon 2 of the MOR (n=18) and their wild type (WT) littermates (n=20). The influence of M6G and morphine on respiration was measured using whole body plethysmography during three elevations of inspired carbon dioxide. Antinociception was assessed using tail flick and hotplate tests.. In WT but not null mutant mice, a dose-dependent depression of the slope of the ventilatory carbon dioxide response was observed after M6G and morphine. Similarly, both opioids were devoid of antinociceptive effects in null mutant mice, but showed potent dose-dependent analgesia in WT animals. Potency differences between M6G and morphine in WT mice were of the same order of magnitude for analgesia and respiration.. The data indicate that the desired (antinociceptive) and undesired (respiratory depression) effects of M6G and morphine are linked to the same gene product; that is the MOR. Other opioid- and non-opioid-receptor systems may play a minor role in the actions of M6Gs and morphine. The clinical implications of our findings are that any agent acting at the MOR will invariably cause (potent) analgesia in combination with (variable) respiratory depression.

Topics: Analgesics, Opioid; Animals; Carbon Dioxide; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Knockout; Morphine; Morphine Derivatives; Pain Threshold; Plethysmography, Whole Body; Reaction Time; Receptors, Opioid, mu; Respiratory Insufficiency; Sensation

The major side effect of morphine and its active metabolite, morphine-6-glucuronide (M6G), is respiratory depression, which is mediated by mu opioid receptors in the medulla and pons. Although the effect of morphine on coupling between mu opioid receptors and G proteins has been studied, the effect of M6G on this coupling has not. Therefore, stimulation of guanylyl-5'-O-([gamma(35)S]-thio)-triphosphate ([(35)S]-GTPgammaS) binding by these two narcotic analgesic drugs was compared to the mu-specific synthetic opioid peptide [D-Ala(2), N-MePhe(4), Gly-ol(5)]enkephalin in Chinese hamster ovarian cells stably transfected with the murine mu opioid receptor and in brainstem membranes prepared from 3-, 7-, and 14-day-old guinea pigs. All three agonists stimulated [(35)S]-GTPgammaS binding in transfected cells and neural tissue, and the stimulation was antagonized by naloxone. In brainstem membranes, but not transfected cells, M6G was less efficacious but more potent than morphine, which may be due to differences between murine and guinea pig mu opioid receptors or in the G proteins in these two tissues. Efficacy of the agonists did not change during development, but overall potency decreased between 3 and 14 days after birth. In vivo potency differences for respiratory depression between morphine and M6G are qualitatively similar to in vitro potency differences of these drugs to stimulate [(35)S]-GTPgammaS binding in neonatal guinea pig brainstem membranes. Tolerance to opioid effects on [(35)S]-GTPgammaS binding developed in transfected cells incubated with morphine with the maximum decrease in potency occurring 18 h later than the maximum decline in efficacy.

Topics: Analgesics, Opioid; Animals; Animals, Newborn; Binding Sites; Brain Stem; Cell Membrane; CHO Cells; Cricetinae; Drug Tolerance; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Morphine; Morphine Derivatives; Naloxone; Narcotic Antagonists; Radioligand Assay; Receptors, Opioid, mu; Respiratory Insufficiency; Respiratory Physiological Phenomena; Subcellular Fractions; Sulfur Radioisotopes

A 46-year-old woman suffering from a reactive depression was admitted to the emergency room in coma and with severe respiratory failure. She later developed cardiovascular instability and general convulsions. Two days following admission the patient had no respiratory effort but was able to communicate in writing that she had ingested a large amount of controlled-release morphine tablets. Following treatment with naloxone she was successfully weaned from the respirator the next day.. Sampling for determination of plasma and urine concentrations of morphine and its metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was started 60 h after the presumed time of intake and continued up to 8 days after admission.. The initial plasma concentrations of morphine, M3G and M6G were 2160, 13100 and 2330 nM, respectively, compatible with a lethal dose in an opioid-naive patient. The urinary recovery of morphine, M3G and M6G corresponded to 6.8 mmol, equivalent to an oral intake of at least 2500 mg.. The plasma concentrations of morphine and morphine metabolites documented in this case, indicative of considerable absorption of drug, demonstrate that prolonged observation is necessary following intoxications with controlled-release morphine tablets. This case also highlights the importance of continuous follow-up of oral morphine therapy, so that unused drug is not left unaccounted for in the patient's home.

Topics: Absorption; Analgesics, Opioid; Coma; Delayed-Action Preparations; Depression; Female; Follow-Up Studies; Humans; Middle Aged; Morphine; Morphine Derivatives; Respiratory Insufficiency; Seizures; Suicide, Attempted; Tablets

Patients with impaired renal function may experience severe and prolonged respiratory depression when treated with morphine. This has been attributed to accumulation of the drug during renal failure. Three patients are described who had classical signs of intoxication with morphine in the absence of measurable quantities of morphine in the plasma. The observed clinical effect is attributed to accumulation of the pharmacologically active metabolite morphine-6-glucuronide, which is usually renally excreted. It is concluded that morphine does not accumulate in patients with renal failure but that accumulation of metabolites does occur. The previously reported observations of morphine accumulation during renal failure probably result from the use of radioimmunoassays that cannot distinguish between morphine and morphine-6-glucuronide. Thus the apparent morphine concentration measured with these assays in fact reflects the total quantity of morphine and morphine-6-glucuronide present.

Topics: Acute Kidney Injury; Adult; Aged; Female; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Morphine; Morphine Derivatives; Respiratory Insufficiency