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BMC Palliative Care Oct 2015The feasibility and clinical implication of drug monitoring of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) need further investigation. This... (Observational Study)
Observational Study
BACKGROUND
The feasibility and clinical implication of drug monitoring of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) need further investigation. This study aimed to determine what predicts serum concentrations of morphine in cancer patients receiving continuously intravenous morphine, the relationships between serum concentration of morphine/its metabolites and urinary concentrations, and the relation between morphine concentrations and with clinical outcomes.
METHODS
We collected serum and urine samples from 24 patients with advanced cancer undergoing continuously intravenous morphine therapy. Serum samples were obtained at day one. Spot urine samples were collected once daily on three consecutive days. Pain and adverse drug events were assessed using the Korean version of MD Anderson Symptom Inventory.
RESULTS
A total of 96 samples (72 urine and 24 serum samples) were collected. Median dose of morphine was 82.0 mg/24 h. In a multivariate analysis, total daily morphine dose was the most significant predictors of both serum and urine concentration of morphine. Morphine, M6G, and M3G in serum and urine were statistical significantly correlated (correlation coefficient = 0.81, 0.44, 0.56; p values < 0.01, 0.03, 0.01, respectively).
CONCLUSION
Spot urine concentrations of morphine and its metabolites were highly correlated to those of serum. Total dose of daily morphine was related to both serum and urine concentration of morphine and its metabolites.
Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Republic of Korea
PubMed: 26507979
DOI: 10.1186/s12904-015-0052-9 -
Cannabis and Cannabinoid Research Oct 2021An escalating number of fatalities resulting from accidental opioid overdoses typically attributed to respiratory depression continue to define the opioid epidemic....
An escalating number of fatalities resulting from accidental opioid overdoses typically attributed to respiratory depression continue to define the opioid epidemic. Opioid respiratory depression results from a decrease in reflexive inspiration within the preBötzinger complex in the brainstem. Cannabinoid receptor agonism is reported to enhance opioid analgesia, yet whether cannabinoids enhance or inhibit opioid-induced respiratory depression is unknown. Studies herein sought to define the roles of cannabinoid-1 receptor (CB1R) and cannabinoid-2 receptor (CB2R) on respiratory depression using selective agonists alone and in combination with morphine in male mice. Using whole body plethysmography, the nonselective CB1R and CB2R agonist (Δ-tetrahydrocannabinol) and the CB1R synthetic cannabinoid, AM356, induced respiratory depression, whereas the well-published selective CB2 agonist, JWH 133, and the novel CB2 agonist (AM2301) did not. Moreover, a selective CB2R agonist (AM2301) significantly attenuated morphine sulfate-induced respiratory depression. Notably, findings suggest that attenuation of opioid-induced respiratory depression relies on CB2R activation, supporting selective CB2R agonism as an opioid adjunct therapy.
Topics: Analgesics, Opioid; Animals; Cannabinoid Receptor Agonists; Cannabinoids; Male; Mice; Morphine; Respiratory Insufficiency
PubMed: 33998869
DOI: 10.1089/can.2020.0076 -
Acta Neurobiologiae Experimentalis 2022Chronic opioid abuse can impair the hippocampal region of the brain. This study evaluates the neuroprotective effect of Achillea millefolium (Ach) on chronic...
Chronic opioid abuse can impair the hippocampal region of the brain. This study evaluates the neuroprotective effect of Achillea millefolium (Ach) on chronic morphine‑induced learning and memory impairment, oxidative stress, and neuronal apoptosis in the CA1 region of the rat hippocampus. Thirty‑two male Wistar rat rats were classified into four treatment groups (n=8). Morphine sulfate was administered chronically. The treatment groups were given Ach aqueous extract (100, 250, and 500 mg/kg), orally, each day. After 28 days, the Morris water maze test was performed on all subjects. Caspase‑3, Bax, and Bcl‑2 proteins expression in the CA1 region of hippocampal tissue was analyzed using the western blot method. Also, malondialdehyde concentration, glutathione peroxidase activity, and superoxide dismutase activity were evaluated. The results indicated that Ach extract can improve spatial learning and memory defects in morphine‑treated rats. Ach administration also ameliorated apoptosis and oxidative stress indicator levels in hippocampal CA1 of morphine‑treated animals. Based on the present study, Ach improved spatial learning and memory defects, and reduced oxidative stress and apoptosis in the hippocampus CA1 region, in chronic morphine‑treated animals.
Topics: Achillea; Animals; Apoptosis; Hippocampus; Humans; Male; Maze Learning; Morphine; Neurons; Neuroprotective Agents; Oxidative Stress; Plant Extracts; Rats; Rats, Wistar; Spatial Learning
PubMed: 35833817
DOI: 10.55782/ane-2022-016 -
Journal of the American Veterinary... Jul 2008To test the hypothesis that administration of butorphanol or morphine induces antinociception in bearded dragons and corn snakes.
OBJECTIVE
To test the hypothesis that administration of butorphanol or morphine induces antinociception in bearded dragons and corn snakes.
DESIGN
Prospective crossover study.
ANIMALS
12 juvenile and adult bearded dragons and 13 corn snakes.
PROCEDURES
Infrared heat stimuli were applied to the plantar surface of bearded dragon hind limbs or the ventral surface of corn snake tails. Thermal withdrawal latencies (TWDLs) were measured before (baseline) and after SC administration of physiologic saline (0.9% NaCl) solution (equivalent volume to opioid volumes), butorphanol tartrate (2 or 20 mg/kg [0.91 or 9.1 mg/lb]), or morphine sulfate (1, 5, 10, 20, or 40 mg/kg [0.45, 2.27, 4.5, 9.1, or 18.2 mg/lb]).
RESULTS
For bearded dragons, butorphanol (2 or 20 mg/kg) did not alter hind limb TWDLs at 2 to 24 hours after administration. However, at 8 hours after administration, morphine (10 and 20 mg/kg) significantly increased hind limb TWDLs from baseline values (mean +/- SEM maximum increase, 2.7+/-0.4 seconds and 2.8+/-0.9 seconds, respectively). For corn snakes, butorphanol (20 mg/kg) significantly increased tail TWDLs at 8 hours after administration (maximum increase from baseline value, 3.0+/-0.8 seconds); the low dose had no effect. Morphine injections did not increase tail TWDLs at 2 to 24 hours after administration.
CONCLUSIONS AND CLINICAL RELEVANCE
Compared with doses used in most mammalian species, high doses of morphine (but not butorphanol) induced analgesia in bearded dragons, whereas high doses of butorphanol (but not morphine) induced analgesia in corn snakes.
Topics: Analgesics, Opioid; Animals; Butorphanol; Cross-Over Studies; Dose-Response Relationship, Drug; Lizards; Morphine; Pain; Pain Measurement; Respiration; Snakes; Species Specificity; Time Factors
PubMed: 18627230
DOI: 10.2460/javma.233.2.267 -
JAMA Network Open Jan 2024Pain is a common out-of-hospital symptom among patients, and opioids are often prescribed. Research suggests that overprescribing for acute traumatic pain is still... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Pain is a common out-of-hospital symptom among patients, and opioids are often prescribed. Research suggests that overprescribing for acute traumatic pain is still prevalent, even when limits restricting opioid prescriptions have been implemented. Ketamine hydrochloride is an alternative to opioids in adults with out-of-hospital traumatic pain.
OBJECTIVE
To assess the noninferiority of intravenous ketamine compared with intravenous morphine sulfate to provide pain relief in adults with out-of-hospital traumatic pain.
DESIGN, SETTING, AND PARTICIPANTS
The Intravenous Subdissociative-Dose Ketamine Versus Morphine for Prehospital Analgesia (KETAMORPH) study was a multicenter, single-blind, noninferiority randomized clinical trial comparing ketamine hydrochloride (20 mg, followed by 10 mg every 5 minutes) with morphine sulfate (2 or 3 mg every 5 minutes) in adult patients with out-of-hospital trauma and a verbal pain score equal to or greater than 5. Enrollment occurred from November 23, 2017, to November 26, 2022, in 11 French out-of-hospital emergency medical units.
INTERVENTIONS
Patients were randomly assigned to ketamine (n = 128) or morphine (n = 123).
MAIN OUTCOMES AND MEASURES
The primary outcome was the between-group difference in mean change in verbal rating scale pain scores measured from the time before administration of the study drug to 30 minutes later. A noninferiority margin of 1.3 was chosen.
RESULTS
A total of 251 patients were randomized (median age, 51 [IQR, 34-69] years; 111 women [44.9%] and 140 men [55.1%] among the 247 with data available) and were included in the intention-to-treat population. The mean pain score change was -3.7 (95% CI, -4.2 to -3.2) in the ketamine group compared with -3.8 (95% CI, -4.2 to -3.4) in the morphine group. The difference in mean pain score change was 0.1 (95% CI, -0.7 to 0.9) points. There were no clinically meaningful differences for vital signs between the 2 groups. The intravenous morphine group had 19 of 113 (16.8% [95% CI, 10.4%-25.0%]) adverse effects reported (most commonly nausea [12 of 113 (10.6%)]) compared with 49 of 120 (40.8% [95% CI, 32.0%-49.6%]) in the ketamine group (most commonly emergence phenomenon [24 of 120 (20.0%)]). No adverse events required intervention.
CONCLUSIONS AND RELEVANCE
In the KETAMORPH study of patients with out-of-hospital traumatic pain, the use of intravenous ketamine compared with morphine showed noninferiority for pain reduction. In the ongoing opioid crisis, ketamine administered alone is an alternative to opioids in adults with out-of-hospital traumatic pain.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03236805.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Acute Pain; Analgesia; Analgesics, Opioid; Hospitals; Ketamine; Morphine; Single-Blind Method
PubMed: 38285446
DOI: 10.1001/jamanetworkopen.2023.52844 -
Life Sciences Sep 2017Slow-release morphine sulfate pellets and osmotic pumps are common routes of chronic morphine delivery in mouse models, but direct comparisons of these drug delivery... (Comparative Study)
Comparative Study
AIMS
Slow-release morphine sulfate pellets and osmotic pumps are common routes of chronic morphine delivery in mouse models, but direct comparisons of these drug delivery systems are lacking. In this study, we assessed the efficacy of slow-release pellets versus osmotic pumps in delivering morphine to adult mice.
MAIN METHODS
Male C57BL/6NCr mice (8weeksold) were implanted subcutaneously with slow-release pellets (25mg morphine sulfate) or osmotic pumps (64mg/mL, 1.0μL/h). Plasma morphine concentrations were quantified via LC-MS/MS, analgesic efficacy was determined by tail flick assay, and dependence was assessed with naloxone-precipitated withdrawal behaviors (jumping) and physiological effects (excretion, weight loss).
KEY FINDINGS
Morphine pellets delivered significantly higher plasma drug concentrations compared to osmotic pumps, which were limited by the solubility of the morphine sulfate and pump volume/flow rate. Within 96h post-implantation, plasma morphine concentrations were indistinguishable in pellet vs. pump-treated samples. While osmotic pump did not have an antinociceptive effect in the tail flick assay, pumps and pellets induced comparable dependence symptoms (naloxone-precipitated jumping behavior) from 24-72h post-implantation.
SIGNIFICANCE
In this study, we compared slow-release morphine pellets to osmotic minipumps for morphine delivery in mice. We found that osmotic pumps and subcutaneous morphine sulfate pellets yielded significantly different pharmacokinetics over a 7-day period, and as a result significantly different antinociceptive efficacy. Nonetheless, both delivery methods induced dependence as measured by naloxone-precipitated withdrawal.
Topics: Analgesics, Opioid; Animals; Chromatography, Liquid; Delayed-Action Preparations; Drug Delivery Systems; Drug Implants; Male; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Narcotic Antagonists; Osmosis; Substance Withdrawal Syndrome; Tandem Mass Spectrometry; Time Factors
PubMed: 28723417
DOI: 10.1016/j.lfs.2017.07.016 -
Environmental Health Perspectives Oct 1978The manner in which general anesthesia affects circulatory control was studied by examining the effects of commonly employed anesthetics on left ventricular function and... (Review)
Review
The manner in which general anesthesia affects circulatory control was studied by examining the effects of commonly employed anesthetics on left ventricular function and distribution of cardiac output, and the extent to which responses to physiological and pharmacological stimuli are modified by general anesthesia. While commonly employed anesthetics affect almost every aspect of the circulatory system, the importance of general anesthesia on the circulation tends to be underestimated by considering only its direct effects. More important is the modification of the organism's integrative response to any perturbation. Major differences often directionally opposite, in responses of conscious and anesthetized animals were found for reflex control of the circulation, effects of hemorrhage and alterations in preload and after load. In addition, commonly employed pharmacologic agents, e.g., cardiac glycosdies, catecholamines, and morphine sulfate exerted differing actions in the conscious and anesthetized states. Thus, while it is generally held that the overall responses to complex physiological functions such as exercise or eating can be best described in the intact, conscious organism, the importance of conducting any experiment involving integrative control of the circulation in the conscious organism should also be recognized.
Topics: Anesthesia, General; Animals; Blood Pressure; Coronary Vessels; Digitalis Glycosides; Halothane; Heart Rate; Hemodynamics; Hemorrhage; Morphine; Myocardial Contraction; Pentobarbital; Reflex; Regional Blood Flow; Sympathomimetics; Time Factors; Vascular Resistance
PubMed: 363416
DOI: 10.1289/ehp.7826193 -
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 -
British Journal of Pharmacology Jan 2015The effect of opioids on tumour growth and metastasis has been debated for many years, with recent emphasis on the possibility that they might influence the rate of... (Comparative Study)
Comparative Study Review
UNLABELLED
The effect of opioids on tumour growth and metastasis has been debated for many years, with recent emphasis on the possibility that they might influence the rate of disease-free survival after tumour resection when used in the perioperative pain management of cancer surgery patients. The literature presents conflicting and inconclusive in vitro and in vivo data about the potential effect of opioids, especially morphine, on tumour growth and metastasis. To inform clinical practice, appropriate animal models are needed to test whether opioids alter the course of tumour growth and metastasis. Here, we review the literature on animal-based studies testing the effect of morphine on cancer so far, and analyse differences between the models used that may explain the discrepancies in published results. Such analysis should elucidate the role of opioids in cancer and help define ideal pre-clinical models to provide definitive answers.
LINKED ARTICLES
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: Animals; Disease Models, Animal; Drug Administration Routes; Humans; Morphine; Neoplasm Metastasis; Neoplasms; Pain; Perioperative Period; Receptors, Opioid
PubMed: 24467261
DOI: 10.1111/bph.12589 -
British Journal of Anaesthesia May 1990The analgesic efficacy and CSF pharmacokinetics of intrathecal morphine sulphate and morphine-6-glucuronide (M6G) were compared in a single-blind crossover study. Lumbar... (Clinical Trial)
Clinical Trial Comparative Study
The analgesic efficacy and CSF pharmacokinetics of intrathecal morphine sulphate and morphine-6-glucuronide (M6G) were compared in a single-blind crossover study. Lumbar intrathecal catheters were sited in three patients with chronic cancer pain, and morphine sulphate 500 micrograms or M6G 500 micrograms given via the catheter on separate days. CSF was sampled for 24 h following drug administration and analysed for morphine and M6G by high pressure liquid chromatography. The mean (SD) requirement for patient controlled analgesia with pethidine was 393.3 (227.4) mg/24 h during the morphine limb of the trial and 226.7 (113.6) mg/24 h during the M6G limb. M6G was not detected in CSF following administration of morphine. Fitting of CSF concentrations to triexponential curves revealed mean (SD) alpha, beta and gamma half-lives of 13.2 (7.4), 54.9 (31.5) and 222.5 (100) min for morphine and 11.2 (2.4), 67.3 (49.9) and 619.3 (629.7) min for M6G.
Topics: Aged; Chronic Disease; Humans; Injections, Spinal; Male; Middle Aged; Morphine; Morphine Derivatives; Pain; Single-Blind Method
PubMed: 2354092
DOI: 10.1093/bja/64.5.547