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The AAPS Journal May 2006The metabolites of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), have been extensively studied for their contribution to clinical effects... (Review)
Review
The metabolites of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), have been extensively studied for their contribution to clinical effects following administration of morphine. Those contributions to both the desired effect (ie, analgesia) and the undesired effects (eg, nausea, respiratory depression) are the subject of clinical controversy. Much attention and effort have been directed at investigating the properties of M6G because of interest in this substance as a possible substitute for morphine. It exhibits increased potency and the possibility of a better side effect profile compared with morphine, although the reported relative benefits vary widely. M3G is not analgesic, but its role in producing side effects, including the development of clinical tolerance, has been proposed. This review is focused on M6G and the factors that contribute to its clinical utility. The formation and distribution of M6G are presented, as are the analgesic effect and the onset of this effect. The impact of genetics, age, and gender on M6G and its effects is also reviewed.
Topics: Aging; Analgesia; Animals; Biotransformation; Female; Glucuronides; Humans; Male; Morphine; Morphine Derivatives
PubMed: 16796385
DOI: 10.1007/BF02854905 -
Ugeskrift For Laeger Jun 1995During the last ten years hyperalgesia (H), allodynia (A) and myoclonia (M) has been reported at an increased frequency in human beings treated with morphine. The side... (Review)
Review
During the last ten years hyperalgesia (H), allodynia (A) and myoclonia (M) has been reported at an increased frequency in human beings treated with morphine. The side effects are most common in cancer patients treated with high dose morphine, and has been reported for all routes of administration. The mechanisms are unknown, but human cases and experimental works have resulted in the following theories: 1) Morphine and morphine metabolites change the postsynaptic pain-transmission in dorsal horn neurones via non opioid-receptors (glycine and/or N-methyl-D-aspartate). 2) Morphine and morphine metabolites activate other opioid receptor populations. 3) Supplemental drugs in cancer management. 4) An abnormal metabolism of morphine or morphine metabolites. 5) A combination of one or more of the above-mentioned theories. The first mentioned theory is the most likely. The treatment of morphine induced H, A, and M seems to be to discontinue morphine administration and to initiate therapy with other opioids (fentanyl, sufentanyl, methadone or ketobemidone).
Topics: Humans; Hyperalgesia; Morphine; Morphine Derivatives; Myoclonus; Neoplasms; Palliative Care; Peripheral Nervous System Diseases
PubMed: 7543228
DOI: No ID Found -
Palliative Medicine Mar 1999Morphine metabolites are involved in various ways in determining the complex effects of morphine, both favourable and adverse, and may complicate the clinical use of... (Review)
Review
Morphine metabolites are involved in various ways in determining the complex effects of morphine, both favourable and adverse, and may complicate the clinical use of morphine in the treatment of cancer pain. The production and effects of the principal morphine metabolites, morphine-3-glucuronide and morphine-6-glucuronide, in both normal and pathological states have been reviewed in the current literature. Therapeutic implications are also reviewed on the basis of experimental and clinical reports. The presence of these metabolites should be recognized in the chronic treatment of cancer pain with morphine, especially in the presence of renal impairment, and should be considered to have an important influence on opioid responsiveness, defined as a balance between the achievement of an optimal analgesia and the occurrence of adverse effects.
Topics: Analgesics, Opioid; Humans; Morphine; Morphine Derivatives; Neoplasms; Pain
PubMed: 10474692
DOI: 10.1191/026921699678158579 -
European Journal of Pharmacology May 2020Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the...
Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord. This study shows that chronic intrathecal M3G sensitises animals to mechanical stimulation and elevates substance P levels in the nociceptive laminae of the spinal cord. Chronic M3G also induces antinociceptive cross-tolerance to morphine. Thus, chronic M3G exposure might contribute to morphine-induced tolerance and opioid-induced hyperalgesia.
Topics: Animals; Central Nervous System Stimulants; Disease Models, Animal; Drug Administration Schedule; Drug Tolerance; Humans; Hyperalgesia; Injections, Spinal; Male; Morphine; Morphine Derivatives; Nociception; Pain Measurement; Rats; Spinal Cord; Substance P
PubMed: 32112778
DOI: 10.1016/j.ejphar.2020.173021 -
Huan Jing Ke Xue= Huanjing Kexue May 2024It is a new approach to identify legal or illegal use of morphine through information on municipal wastewater. However, the sources of morphine in wastewater are...
It is a new approach to identify legal or illegal use of morphine through information on municipal wastewater. However, the sources of morphine in wastewater are complex, and distinguishing the contribution of different sources has become a key issue. A total of 262 influent samples from 61 representative wastewater treatment plants in a typical city were collected from October 2022 to March 2023. The concentrations of morphine, codeine, thebaine, papaverine, noscapine, and monoacetylmorphine were analyzed in wastewater and poppy straws. Combined with the proportion of alkaloids in poppy straws, the source analysis of alkaloids in wastewater was analyzed using the ratio method and positive matrix factorization model (PMF). Only five alkaloids were detected in wastewater, and monoacetylmorphine, a metabolite of heroin, was not detected. The concentrations of morphine and codeine were significantly higher than those of noscapine, papaverine, and thebaine. By constructing the ratios of codeine/(morphine + codeine) and noscapine/(noscapine + codeine), the source of poppy straw could be qualitatively distinguished. The PMF results showed that three sources of morphine for medical use, poppy straw, and codeine contributed 44.9%, 43.7%, and 9.4%, respectively. The different sources varied in these months due to the COVID-19 and influenza A outbreaks, in which the use of drugs containing poppy straws and codeine was the main source, whereas the use of morphine analgesics remained relatively stable. Inventory analysis further demonstrated the reliability of the source contributions from the PMF model, and morphine was not abused in this city.
Topics: Morphine; Wastewater; Papaverine; Thebaine; Noscapine; Reproducibility of Results; Codeine; Morphine Derivatives; Alkaloids; Papaver
PubMed: 38629538
DOI: 10.13227/j.hjkx.202306005 -
British Journal of Clinical Pharmacology Nov 19891. The metabolism of morphine was studied in 12 children and nine premature neonates on a continuous infusion of morphine (10-360 micrograms kg-1 h-1). 2. The mean...
1. The metabolism of morphine was studied in 12 children and nine premature neonates on a continuous infusion of morphine (10-360 micrograms kg-1 h-1). 2. The mean plasma clearance of morphine was significantly higher in children than neonates (25.7 and 4.7 ml min-1 kg-1, respectively) (P less than 0.01). 3. All the neonates and children had detectable concentrations of morphine-3-glucuronide (M3G) in plasma. All the children and five neonates had detectable concentrations of morphine-6-glucuronide (M6G) in plasma or urine. 4. The M3G/morphine ratios in plasma and urine, and M6G/morphine ratios in urine were significantly higher in children than neonates (P less than 0.01), suggesting that morphine glucuronidation capacity is enhanced after the neonatal period. 5. There was no difference in the M3G/M6G ratio in children and neonates, indicating a parallel development of both glucuronidation pathways.
Topics: Adolescent; Child; Child, Preschool; Humans; Infant, Newborn; Infusions, Intravenous; Morphine; Morphine Derivatives
PubMed: 2590614
DOI: 10.1111/j.1365-2125.1989.tb03548.x -
The Journal of Pediatrics May 1992To examine the manner in which morphine is metabolized in acutely ill premature infants, we measured the levels of morphine, morphine-3- and -6-glucuronides, and codeine...
To examine the manner in which morphine is metabolized in acutely ill premature infants, we measured the levels of morphine, morphine-3- and -6-glucuronides, and codeine in timed urine specimens and paired plasma specimens at 4 hours and 24 hours after a single dose of morphine in 16 preterm infants (less than 32 weeks of gestational age). A large amount of unmetabolized morphine was found in the urine in 13 (81.2%) of the 16 infants at 4 hours; in 12 of them, morphine was excreted even at 24 hours. Urinary morphine levels varied greatly; the coefficient of variation was 130% at 4 hours and 118% at 24 hours. Codeine was not found in any of the infants. In 10 (62.5%) of the 16 infants, at least one metabolite was found in either plasma or urine. Plasma and urinary levels of morphine conjugates also varied greatly among these 10 infants (coefficient of variation: 109% to 317%). All six infants (37.5%) who had no metabolites excreted large amounts of unmetabolized morphine in the urine for up to 24 hours. Birth weight, gestational age, postnatal age, systemic blood pressure, and other clinical or physiologic variables did not differ significantly between the 10 infants who had morphine conjugates and the six who did not. We conclude that (1) nearly two thirds of acutely ill preterm infants born at less than 32 weeks of gestational age conjugate morphine; (2) irrespective of their ability to produce morphine conjugates, preterm infants excrete large amounts of morphine unmetabolized, as late as 24 hours after a single dose; (3) morphine handling patterns are highly variable among premature infants, and no obvious factors account for the variability; and (4) such variability in morphine handling in general, and the production of the highly potent morphine-6-glucuronide in particular, could explain the variance in morphine pharmacokinetic measures and in the clinical responses to morphine during the newborn period.
Topics: Chromatography, High Pressure Liquid; Codeine; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Morphine; Morphine Derivatives; Respiration, Artificial
PubMed: 1578319
DOI: 10.1016/s0022-3476(05)80251-3 -
Journal of Opioid Management 2012Interindividual variability in analgesic response and adverse effects of opioids because of narrow therapeutic indices are major clinical problems. Morphine is an opioid... (Clinical Trial)
Clinical Trial
OBJECTIVE
Interindividual variability in analgesic response and adverse effects of opioids because of narrow therapeutic indices are major clinical problems. Morphine is an opioid commonly used in children to manage perioperative pain. Al-though size and age often are considered primary covariates for morphine pharmacokinetic models, the impact of other factors important in personalizing care such as race and genetic variations on morphine disposition is not well documented.
DESIGN
Genotype blinded clinical observational pharmacokinetic study. One hundred forty-six African American and Caucasian children scheduled for elective outpatient adenotonsillectomy were enrolled in our prospective genotype blinded observational study with standard perioperative clinical care.
SETTING
Tertiary care pediatric institution.
INTERVENTIONS
Morphine bolus for intraoperative analgesia in children and pharmacokinetic analyses in different races.
MAIN OUTCOME MEASURES
Pharmacokinetics and pharmacogenetics of intravenous morphine in a homogeneous pediatric outpatient surgical pain population were evaluated.
RESULTS
The authors observed that African American children have higher morphine clearance than Caucasian children. The increased clearance is directed toward the formation of morphine-3-glucuronide formation, rather than the formation of morphine-6-glucuronide. Common uridine diphosphate glucuronosyl transferase (UGT) 2B7 genetic variations (2161C>T and 802C>T) were not associated with observed racial differences in morphine's clearance although the wild type of the UGT2B7 isozyme is more prevalent in the African Americans.
CONCLUSIONS
Race of the child is an important factor in perioperative intravenous morphine's clearance and its potential role in personalizing analgesia with morphine needs further investigation.
Topics: Adolescent; Black or African American; Analgesics, Opioid; Child; Female; Genotype; Glucuronosyltransferase; Humans; Individuality; Male; Morphine; Morphine Derivatives; Pain Measurement; Pain, Postoperative; Pharmacogenetics; Prospective Studies; White People
PubMed: 22941849
DOI: 10.5055/jom.2012.0119 -
Methods of Biochemical Analysis 1977
Review
Topics: Analgesics, Opioid; Chemical Phenomena; Chemistry; Chromatography, Gas; Computers; Mass Spectrometry; Morphine; Morphine Derivatives
PubMed: 22023
DOI: 10.1002/9780470110447.ch1 -
Pain Jun 2023
Plasma morphine and morphine-6-glucuronide during chronic morphine therapy for cancer pain: plasma profiles, steady-state concentrations and the consequences of renal failure: erratum.
Topics: Humans; Morphine; Cancer Pain; Morphine Derivatives; Renal Insufficiency; Neoplasms
PubMed: 37171205
DOI: 10.1097/j.pain.0000000000002918