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Fundamental & Clinical Pharmacology Feb 2021Morphine is a potent analgesic agent used to control acute or chronic pain. Chronic administration of morphine results in analgesic tolerance, hyperalgesia, and other... (Review)
Review
Morphine is a potent analgesic agent used to control acute or chronic pain. Chronic administration of morphine results in analgesic tolerance, hyperalgesia, and other side effects including dependence, addiction, respiratory depression, and constipation, which limit its clinical usage. Therefore, identifying the new analgesics with fewer side effects which could increase the effect of morphine and reduce its side effects is crucial. Melatonin, a multifunctional molecule produced in the body, is known to play an important role in pain regulation. The strong anti-inflammatory effect of melatonin is suggested to be involved in the attenuation of the pain associated with inflammation. Melatonin also increases the anti-nociceptive actions of opioids, such as morphine, and reverses their tolerance through regulating several cellular signaling pathways. In this review, published articles evaluating the effect of the co-consumption of melatonin and morphine in different conditions were investigated. Our results show that melatonin has pain-killing properties when administered alone or in combination with other anti-nociceptive drugs. Melatonin decreases morphine consumption in different pathologies. Furthermore, attenuation of morphine intake can be accompanied by reduction of morphine-associated side-effects, including physical dependence, morphine tolerance, and morphine-related hyperalgesia. Therefore, it is reasonable to believe that the combination of melatonin with morphine could reduce morphine-induced tolerance and hyperalgesia, which may result from anti-inflammatory and antioxidant properties of melatonin. Overall, we underscore that, to further ameliorate patients' life quality and control their pain in various pathological conditions, melatonin deserves to be used with morphine by anesthesiologists in clinical practice.
Topics: Analgesics; Arachidonate 5-Lipoxygenase; Calcium; Drug Tolerance; Humans; Hyperalgesia; Melatonin; Morphine
PubMed: 32415694
DOI: 10.1111/fcp.12566 -
Brain, Behavior, and Immunity Oct 2023Chronic morphine exposure causes the development of addictive behaviors, accompanied by an increase in neuroinflammation in the central nervous system. While previous...
Chronic morphine exposure causes the development of addictive behaviors, accompanied by an increase in neuroinflammation in the central nervous system. While previous researches have shown that astrocytes contribute to brain diseases, the role of astrocyte in morphine addiction through induced neuroinflammation remain unexplored. Here we show that morphine-induced inflammation requires the crosstalk among neuron, astrocyte, and microglia. Specifically, astrocytes respond to morphine-induced neuronal activation by increasing glycolytic metabolism. The dysregulation of glycolysis leads to an increased in the generation of mitochondrial reactive oxygen species and causes excessive mitochondrial fragmentation in astrocytes. These fragmented, dysfunctional mitochondria are consequently released into extracellular environment, leading to activation of microglia and release of inflammatory cytokines. We also found that blocking the nicotinamide adenine dinucleotide salvage pathway with FK866 could inhibit astrocytic glycolysis and restore the mitochondrial homeostasis and effectively attenuate neuroinflammatory responses. Importantly, FK866 reversed morphine-induced addictive behaviors in mice. In summary, our findings illustrate an essential role of astrocytic immunometabolism in morphine induced neural and behavioral plasticity, providing a novel insight into the interactions between neurons, astrocytes, and microglia in the brain affected by chronic morphine exposure.
Topics: Mice; Animals; Morphine Dependence; Astrocytes; Neuroinflammatory Diseases; Morphine; Microglia; Mitochondria
PubMed: 37543246
DOI: 10.1016/j.bbi.2023.07.030 -
International Journal of Cardiology Jan 2016Morphine has for a long time, been used in patients with acute pulmonary oedema due to its anticipated anxiolytic and vasodilatory properties, however a discussion about... (Review)
Review
Morphine has for a long time, been used in patients with acute pulmonary oedema due to its anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the keywords "pulmonary oedema" OR "lung oedema" OR "acute heart failure" AND "morphine" was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature, whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4.8 (95% CI: 4.52-5.18, p<0.001). Other, smaller studies have shown a significant association between morphine administration and mortality, which was lost after adjusting for confounding factors. Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect--and especially the risk--when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.
Topics: Acute Disease; Hospital Mortality; Humans; Morphine; Practice Guidelines as Topic; Pulmonary Edema; Treatment Outcome; Vasodilation
PubMed: 26476045
DOI: 10.1016/j.ijcard.2015.10.014 -
Acta Medica Portuguesa Mar 2016
Topics: Analgesics, Opioid; Humans; Morphine; Practice Guidelines as Topic
PubMed: 27285090
DOI: 10.20344/amp.7663 -
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 -
Aktuelle Urologie Jun 2022
Topics: Analgesics; Humans; Ketamine; Morphine; Renal Colic
PubMed: 35671965
DOI: 10.1055/a-1562-3877 -
Current Opinion in Supportive and... Jun 2017Pain management presents a major challenge in neonatal care. Newborn infants who require medical treatment can undergo frequent invasive procedures during a critical... (Review)
Review
PURPOSE OF REVIEW
Pain management presents a major challenge in neonatal care. Newborn infants who require medical treatment can undergo frequent invasive procedures during a critical period of neurodevelopment. However, adequate analgesic provision is infrequently and inconsistently provided for acute noxious procedures because of limited and conflicting evidence regarding analgesic efficacy and safety of most commonly used pharmacological agents. Here, we review recent advances in the measurement of infant pain and discuss clinical trials that assess the efficacy of pharmacological analgesia in infants.
RECENT FINDINGS
Recently developed measures of noxious-evoked brain activity are sensitive to analgesic modulation, providing an objective quantitative outcome measure that can be used in clinical trials of analgesics.
SUMMARY
Noxious stimulation evokes changes in activity across all levels of the infant nervous system, including reflex activity, altered brain activity and behaviour, and long-lasting changes in infant physiological stability. A multimodal approach is needed if we are to identify efficacious and well tolerated analgesic treatments. Well designed clinical trials are urgently required to improve analgesic provision in the infant population.
Topics: Acetaminophen; Administration, Cutaneous; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Brain; Humans; Infant, Newborn; Morphine; Pain; Pain Management; Pain Measurement; Randomized Controlled Trials as Topic
PubMed: 28375883
DOI: 10.1097/SPC.0000000000000270 -
International Journal of Molecular... Nov 2023Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for...
Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on the antinociceptive activity and itch-associated scratching behavior (LLS) in mice and elucidated the regulatory mechanisms. A hot-plate test was used to assess antinociception. LLS was automatically detected and recorded via a computer. IL-31RA mRNA expression was assessed using real-time polymerase chain reaction. Repeated pre-treatment with IL-31 resulted in significant antinociceptive activity. Repeated administration of morphine decreased the morphine-induced antinociceptive activity, LLS counts, and regular dose and inhibited IL-31-induced LLS. These results suggested that the repeated administration of morphine depleted inter-neuronal IL-31RA levels, preventing morphine-induced antinociception. Therefore, IL-31 may be helpful as an adjunct analgesic to morphine. To explore the benefits of IL-31, its influence on morphine-induced antinociceptive tolerance in mice was examined. An IL-31 and morphine combination increased the analgesic action, which increased the expression of DRG neuronal IL-31RA, elucidating the site of peripheral antinociception of morphine. This site may induce exocytosis of IL-31RA in the sensory nervous system. Collectively, the suppressive effect of IL-31 on morphine-induced antinociceptive tolerance may result from IL-31RA supplementation in sensory nerves.
Topics: Animals; Mice; Analgesics; Analgesics, Opioid; Dose-Response Relationship, Drug; Drug Tolerance; Interleukins; Morphine; Pruritus
PubMed: 38003738
DOI: 10.3390/ijms242216548 -
Molecular Therapy : the Journal of the... May 2023Repeated use of opioids such as morphine causes changes in the shape and signal transduction pathways of various brain cells, including astrocytes and neurons,...
Repeated use of opioids such as morphine causes changes in the shape and signal transduction pathways of various brain cells, including astrocytes and neurons, resulting in alterations in brain functioning and ultimately leading to opioid use disorder. We previously demonstrated that extracellular vesicle (EV)-induced primary ciliogenesis contributes to the development of morphine tolerance. Herein, we aimed to investigate the underlying mechanisms and potential EV-mediated therapeutic approach to inhibit morphine-mediated primary ciliogenesis. We demonstrated that miRNA cargo in morphine-stimulated-astrocyte-derived EVs (morphine-ADEVs) mediated morphine-induced primary ciliogenesis in astrocytes. CEP97 is a target of miR-106b and is a negative regulator of primary ciliogenesis. Intranasal delivery of ADEVs loaded with anti-miR-106b decreased the expression of miR-106b in astrocytes, inhibited primary ciliogenesis, and prevented the development of tolerance in morphine-administered mice. Furthermore, we confirmed primary ciliogenesis in the astrocytes of opioid abusers. miR-106b-5p in morphine-ADEVs induces primary ciliogenesis via targeting CEP97. Intranasal delivery of ADEVs loaded with anti-miR-106b ameliorates morphine-mediated primary ciliogenesis and prevents morphine tolerance. Our findings bring new insights into the mechanisms underlying primary cilium-mediated morphine tolerance and pave the way for developing ADEV-mediated small RNA delivery strategies for preventing substance use disorders.
Topics: Mice; Animals; Antagomirs; Morphine; MicroRNAs; Brain; Extracellular Vesicles
PubMed: 37012704
DOI: 10.1016/j.ymthe.2023.03.030 -
European Journal of Drug Metabolism and... Mar 2021Morphine is a standard analgesic drug for postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of morphine and its active metabolite... (Clinical Trial)
Clinical Trial
BACKGROUND AND OBJECTIVE
Morphine is a standard analgesic drug for postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide (M6G) in cardiac surgery patients during postoperative analgesia.
METHODS
Twenty-five adult patients undergoing cardiac surgery received postoperative pain therapy by patient-controlled analgesia with intravenous bolus doses of morphine. Plasma concentrations of morphine and M6G were determined from arterial samples. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling.
RESULTS
Data from twenty-one patients (aged 44-79 years) were analyzed. Pharmacokinetics were best described by a three-compartment model for morphine and a two-compartment model for M6G, linked by a transit compartment. Mean (±SD) population estimates for morphine were: clearance (CL) = 1.35±0.40 L/min, central volume of distribution (V) = 8.1±2.2 L, steady-state volume of distribution (V) = 207±83 L, terminal elimination half-life (T) = 177±50 min. Clearance of morphine was proportional to cardiac output. Mean (±SD) population estimates for M6G were: CL = 0.098±0.037 L/min, V = 5.5±0.8 L, V = 15.8±0.8 L, T = 227±74 min. The time to peak concentration of M6G after a bolus dose of morphine was 53±20 min. Clearance of M6G was proportional to estimated glomerular filtration rate.
CONCLUSIONS
The pharmacokinetics of morphine and M6G in pain therapy of cardiac surgery patients could be well described by standard compartmental models. Cardiac output was identified as a significant covariate for morphine clearance, whereas renal function was identified as the most significant covariate for clearance of M6G. These effects should be particularly considered if morphine is administered as a continuous infusion. The developed pharmacokinetic model also enables patient-controlled target-controlled infusion for pain therapy with morphine.
TRIAL REGISTRATION
Clinical Trials NCT02483221 (June 26, 2015).
Topics: Adult; Aged; Analgesia, Patient-Controlled; Analgesics, Opioid; Cardiac Output; Cardiac Surgical Procedures; Female; Half-Life; Humans; Male; Middle Aged; Models, Biological; Morphine; Morphine Derivatives; Pain, Postoperative; Tissue Distribution
PubMed: 33547559
DOI: 10.1007/s13318-020-00663-z