-
Acta Anaesthesiologica Scandinavica Jan 1997Morphine is a potent opioid analgesic widely used for the treatment of acute pain and for long-term treatment of severe pain. Morphine is a member of the... (Review)
Review
Morphine is a potent opioid analgesic widely used for the treatment of acute pain and for long-term treatment of severe pain. Morphine is a member of the morphinan-framed alkaloids, which are present in the poppy plant. The drug is soluble in water, but its solubility in lipids is poor. In man, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major metabolites of morphine. The metabolism of morphine occurs not only in the liver, but may also take place in the brain and the kidneys. The glucuronides are mainly eliminated via bile and urine. Glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier. Although morphine glucuronidation has been demonstrated in human brain tissue, the capacity is very low compared to that of the liver, indicating that the M3G and M6G concentrations observed in the cerebrospinal fluid (CSF) after systemic administration reflect hepatic metabolism of morphine and that the morphine glucuronides, despite their high polarity, can penetrate into the brain. Like morphine, M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors while M3G does not appear to compete for opioid receptor binding. The analgesic properties of M6G were recognised in the early 1970s and more recent work suggests that M6G might significantly contribute to the opioid analgesia after administration of morphine. The analgesic potency of M6G after intracerebroventricular (ICV) or intrathecal (IT) administration in rats is from 45-800 timer greater than that of morphine, depending on the animal species and the experimental antinociceptive test used. Furthermore, the development of a sensitive high-performance liquid chromatography (HPLC) assay for the quantitative determination of morphine, M6G and M3G has revealed that M6G and M3G were present in abundance after chronic oral morphine administration and that the area under the plasma concentration-time curve exceeded that of morphine. M3G has been found to antagonise morphine and M6G induced analgesia and ventilatory depression in the rat, which has led to the hypothesis that M3G may influence the development of morphine tolerance. M3G exhibits no analgesic effect after ICV or IT administration. Some studies do, however, indicate that M3G may cause non-opioid mediated hyperalgesia/allodynia and convulsions after IT administration in rats. These observations led to the hypothesis that M3G might be responsible for side-effects, hyperalgesia/allodynia and myoclonus seen after high-dose morphine treatment.
Topics: Analgesics, Opioid; Animals; Humans; Morphine; Morphine Derivatives; Receptors, Opioid
PubMed: 9061094
DOI: 10.1111/j.1399-6576.1997.tb04625.x -
Neuroscience Mar 2013Morphine derived from Papaver somniferum is commonly used as an analgesic compound for pain relief. It is now accepted that endogenous morphine, structurally identical... (Review)
Review
Morphine derived from Papaver somniferum is commonly used as an analgesic compound for pain relief. It is now accepted that endogenous morphine, structurally identical to vegetal morphine-alkaloid, is synthesized by mammalian cells from dopamine. Morphine binds mu opioid receptor and induces antinociceptive effects. However, the exact role of these compounds is a matter of debate although different links with infection, sepsis, inflammation, as well as major neurological pathologies (Parkinson's disease, schizophrenia) have been proposed. The present review describes endogenous morphine and morphine derivative discovery, synthesis, localization and potential implications in physiological and pathological processes.
Topics: Animals; Astrocytes; Dopamine; History, 20th Century; Mammals; Morphine; Morphine Derivatives; Neurons; Opioid Peptides
PubMed: 23266549
DOI: 10.1016/j.neuroscience.2012.12.013 -
American Journal of Hospital Pharmacy Aug 1994
Comparative Study Review
Topics: Animals; Half-Life; Humans; Morphine; Morphine Derivatives; Rats; Renal Insufficiency
PubMed: 7977426
DOI: No ID Found -
Anesthesia and Analgesia Jun 2006In searching for an analgesic with fewer side effects than morphine, examination of morphine's active metabolite, morphine-6-glucuronide (M6G), suggests that M6G is... (Review)
Review
In searching for an analgesic with fewer side effects than morphine, examination of morphine's active metabolite, morphine-6-glucuronide (M6G), suggests that M6G is possibly such a drug. In contrast to morphine, M6G is not metabolized but excreted via the kidneys and exhibits enterohepatic cycling, as it is a substrate for multidrug resistance transporter proteins in the liver and intestines. M6G exhibits a delay in its analgesic effect (blood-effect site equilibration half-life 4-8 h), which is partly related to slow passage through the blood-brain barrier and distribution within the brain compartment. In humans, M6G's potency is just half of that of morphine. In clinical studies, M6G is well tolerated and produces adequate and long lasting postoperative analgesia. At analgesic doses, M6G causes similar reduction of the ventilatory response to CO2 as an equianalgesic dose of morphine but significantly less depression of the hypoxic ventilatory response. Preliminary data indicate that M6G is associated less than morphine with nausea and vomiting, causing 50% and 75% less nausea in postoperative and experimental settings, respectively. Although the data from the literature are very promising, we believe that more studies are necessary before we may conclude that M6G is superior to morphine for postoperative analgesia.
Topics: Analgesics, Opioid; Humans; Morphine; Morphine Derivatives; Pain, Postoperative
PubMed: 16717327
DOI: 10.1213/01.ane.0000217197.96784.c3 -
Postgraduate Medical Journal 1991The well established use of oral morphine in the treatment of chronic cancer pain has developed empirically and a knowledge of its pharmacokinetics is not necessary in... (Review)
Review
The well established use of oral morphine in the treatment of chronic cancer pain has developed empirically and a knowledge of its pharmacokinetics is not necessary in order to use the drug effectively. However recent information about the pharmacokinetics of morphine may help resolve the controversy about oral to parenteral relative potency ratios, and may also in the future shed some light on the problem of patients whose pain does not respond to morphine.
Topics: Administration, Oral; Drug Administration Schedule; Humans; Morphine; Morphine Derivatives; Neoplasms; Pain
PubMed: 1758818
DOI: No ID Found -
Expert Opinion on Pharmacotherapy Aug 2008In contemporary medicine, morphine remains the drug of choice in the treatment of severe postoperative pain. Nevertheless, morphine has several side effects, which can... (Comparative Study)
Comparative Study Review
BACKGROUND
In contemporary medicine, morphine remains the drug of choice in the treatment of severe postoperative pain. Nevertheless, morphine has several side effects, which can seriously compromise its analgesic effectiveness and the patient safety/compliance. The search for opioid analgesics with a better side-effect profile than morphine has led to a morphine metabolites, morphine-6-glucuronide (M6G).
OBJECTIVE
The objectives of the current paper are to give an overview of the analgesic properties of M6G, assess the dose range at which it produces equianalgesia to morphine and explore its side-effect profile.
METHODS
A review of published clinical studies (Phase II - III) on M6G in the treatment of experimental and clinical pain is given.
RESULTS/CONCLUSIONS
M6G > 0.2 mg/kg is an effective analgesic with a slower onset but longer duration of action (> 12 h) compared with morphine. Side effects, most importantly postoperative nausea and vomiting, occur less frequent after M6G treatment. M6G is an attractive alternative to morphine in the treatment of severe postoperative pain.
Topics: Analgesics, Opioid; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Morphine; Morphine Derivatives; Pain, Postoperative; Patient Compliance; Postoperative Nausea and Vomiting
PubMed: 18627332
DOI: 10.1517/14656566.9.11.1955 -
European Journal of Pharmaceutical... Jul 2015Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to... (Review)
Review
Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.
Topics: Acute Pain; Analgesics, Opioid; Animals; Biological Availability; Biotransformation; Half-Life; Humans; Models, Biological; Morphine; Morphine Derivatives; Precision Medicine; Renal Insufficiency; Tissue Distribution
PubMed: 25861720
DOI: 10.1016/j.ejps.2015.03.020 -
Drug Development Research Sep 2021Morphine-6-O-sulfate (M6S), a polar, zwitterionic sulfate ester of morphine, is a powerful and safe analgesic in several rat models of pain. A sensitive liquid...
Morphine-6-O-sulfate (M6S), a polar, zwitterionic sulfate ester of morphine, is a powerful and safe analgesic in several rat models of pain. A sensitive liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated for the simultaneous determination of M6S and morphine (MOR) in rat plasma and brain after M6S administration. Morphine-d was used as internal standard. Multiple reaction monitoring was used for detection and quantitation of M6S, MOR, and morphine-d in the turbo ion spray positive mode. The chromatographic separation was carried out on an Alltech Altima C18 column. The analytical method was validated for linearity, precision, accuracy, specificity, and stability over a concentration range of 3-8000 ng/ml in rat plasma and 10-10,000 ng/ml in brain samples for both M6S and MOR. The validated method was applied to determine the PK profile of M6S in plasma after i.v., i.p., and oral dosing in male Sprague-Dawley rats. Rats were administered M6S by i.p. administration (5.6 and 10.0 mg/kg) or orally (10 and 30 mg/kg) and bioavailability compared to an i.v. injection (1 mg/kg) of M6S. The in vivo results indicate that M6S is not a prodrug of morphine, since M6S is not biotransformed into MOR in plasma after either i.p. or oral administration, and MOR was not detected in brain. The bioavailability of M6S was >93% and about 5% after i.p. and oral dosing, respectively. The low oral bioavailability of M6S may be due to poor permeation of the intestinal epithelial membrane. After i.p.-administration, M6S appears to reach brain tissues in low, but significant, concentrations.
Topics: Animals; Brain; Male; Morphine; Morphine Derivatives; Rats; Rats, Sprague-Dawley
PubMed: 33427316
DOI: 10.1002/ddr.21785 -
Medical Science Monitor : International... Jun 2006Since the 80s, intrigued by presence of morphine precursors in some mammalian cells, different laboratories were able to characterize morphine and morphine precursors in... (Review)
Review
Since the 80s, intrigued by presence of morphine precursors in some mammalian cells, different laboratories were able to characterize morphine and morphine precursors in animal tissues. Endogenous morphine studies continued during 90s and this alkaloid was successfully characterized from more organs and fluids of vertebrates, including brain, adrenal gland, heart, cerebrospinal fluid and urine. Then, in the last three years a high rate of publications dealing with this topic emerged, leading to a better understanding of the endogenous morphine system. In this regard, this article comment all the new data recently collected on this rising subject and replace the morphine and its derivative, morphine-6-glucuronide, in the mammalian physiology.
Topics: Animals; Cattle; Chromaffin Cells; Endocrine System; Humans; Morphine; Morphine Derivatives; Neurosecretory Systems
PubMed: 16733499
DOI: No ID Found -
Life Sciences Jul 2014Morphine is extensively metabolized to neurotoxic morphine-3-glucuronide (M3G) and opioid agonist morphine-6-glucuronide (M6G). Due to these different roles,...
AIMS
Morphine is extensively metabolized to neurotoxic morphine-3-glucuronide (M3G) and opioid agonist morphine-6-glucuronide (M6G). Due to these different roles, interindividual variability and co-administration of drugs that interfere with metabolism may affect analgesia. The aim of the study was to investigate the repercussions of administration of an inducer (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and an inhibitor (ranitidine) of glucuronidation in morphine metabolism and consequent analgesia, using the Guinea pig as a suitable model.
MAIN METHODS
Thirty male Dunkin-Hartley guinea pigs were divided in six groups: control, morphine, ranitidine, ranitidine+morphine, TCDD and TCDD+morphine. After previous exposure to TCDD and ranitidine, morphine effect was assessed by an increasing temperature hotplate (35-52.5°C), during 60min after morphine administration. Then, blood was collected and plasma morphine and metabolites were quantified.
KEY FINDINGS
Animals treated with TCDD presented faster analgesic effect and 75% reached the cut-off temperature of 52.5°C, comparing with only 25% in morphine group. Animals treated with ranitidine presented a significantly lower analgesic effect, compared with morphine group (p<0.05). Moreover, significant differences between groups were found in M3G levels and M3G/morphine ratio (p<0.001 and p<0.0001), with TCDD animals presenting the highest values for M3G, M6G, M3G/morphine and M6G/morphine, and the lowest value for morphine. The opposite was observed in the animals treated with ranitidine.
SIGNIFICANCE
Our results indicate that modulation of morphine metabolism may result in variations in metabolite concentrations, leading to different analgesic responses to morphine, in an animal model that may be used to improve morphine effect in clinical practice.
Topics: Analgesics, Opioid; Animals; Guinea Pigs; Male; Morphine; Morphine Derivatives; Pain; Pain Measurement; Polychlorinated Dibenzodioxins; Ranitidine
PubMed: 24968302
DOI: 10.1016/j.lfs.2014.06.010