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PloS One 2019Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of... (Clinical Trial)
Clinical Trial
OBJECTIVE
Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population.
STUDY DESIGN
Term and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants.
RESULTS
244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C- 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 μg/L) during hypothermia.
CONCLUSIONS
Clearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect.
TRIAL REGISTRATION
www.trialregister.nl NTR2529.
Topics: Asphyxia Neonatorum; Brain Diseases; Female; Humans; Hypothermia, Induced; Infant, Newborn; Male; Morphine; Prospective Studies
PubMed: 30763356
DOI: 10.1371/journal.pone.0211910 -
Respiratory Medicine Apr 2021Chronic breathlessness is a frequent symptom in advanced Chronic Obstructive Pulmonary Disease (COPD) and has major impact on quality of life, daily activities and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Chronic breathlessness is a frequent symptom in advanced Chronic Obstructive Pulmonary Disease (COPD) and has major impact on quality of life, daily activities and healthcare utilization. Morphine is used as palliative treatment of chronic breathlessness. The aim is to analyze cost-effectiveness of regular, low-dose morphine in patients with advanced COPD from a healthcare and societal perspective.
METHODS
In a randomized controlled trial, participants with advanced COPD were assigned to 10 mg regular, oral sustained-release morphine or placebo twice daily for four weeks. Quality of life (COPD Assessment Test; CAT), quality-adjusted life years (QALY's; EQ-5D-5L), healthcare costs, productivity, and patient and family costs were collected. Incremental cost-effectivity ratio's (ICERs) using healthcare costs and CAT scores, and incremental cost-utility ratio's (ICURs) using societal costs and QALY's were calculated.
RESULTS
Data of 106 of 124 participants were analyzed, of which 50 were in the morphine group (mean [SD] age 65.4 [8.0] years; 58 [55%] male). Both ICER and ICUR indicated dominance for morphine treatment. Sensitivity analyses substantiated these results. From a healthcare perspective, the probability that morphine is cost-effective at a willingness to pay €8000 for an minimal clinically important difference of 2 points increase in CAT score is 63%. From a societal perspective, the probability that morphine is cost-effective at a willingness to pay €20,000 per QALY is 78%.
CONCLUSION
Morphine for four weeks is cost-effective regarding the healthcare and the societal perspective. To estimate the long-term costs and effects of morphine treatment, a study of longer follow-up should be performed.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT02429050).
Topics: Aged; Chronic Disease; Cost-Benefit Analysis; Delayed-Action Preparations; Dyspnea; Female; Health Care Costs; Humans; Male; Middle Aged; Morphine; Pulmonary Disease, Chronic Obstructive
PubMed: 33611087
DOI: 10.1016/j.rmed.2021.106330 -
Anaesthesia May 2020
Topics: Anesthesia, Conduction; Bupivacaine; Humans; Male; Morphine; Prostatectomy; Robotics
PubMed: 31944262
DOI: 10.1111/anae.14980 -
Journal of Biosciences 2023Morphine is a potent analgesic opiate used to treat chronic pain, mostly in cancer patients. In addition, it is widely used as a drug of abuse. Due to the continuous...
Morphine is a potent analgesic opiate used to treat chronic pain, mostly in cancer patients. In addition, it is widely used as a drug of abuse. Due to the continuous rise of morphine-associated addiction, there is an urgent need to develop pre-clinical animal models to understand the behavioural pattern of drug dependence and its withdrawal. Recently, the experimental use of zebrafish has attained significance in behavioural neuroscience studies. The literature on zebrafish is conflicting with regard to morphine withdrawal symptoms. Unfortunately, no single model provides comprehensive details to evaluate zebrafish behaviour on opiate exposure. Further, the current models have various limitations, such as short duration, complexity of phenotypes, intricate quantification, and difficulty in studying withdrawal symptoms. Consequently, a firm standardization of the protocol to understand the influence of opiates on physiological and psychological behaviours is required. In this study, we have tried to overcome the shortcomings associated with the existing models and to optimize the protocols involving an array of parameters. We observed that the administration of morphine caused a significant increase in zebrafish behavioural patterns of spiral movements, circular movements, erratic movements, upper transitions, water surface transitions, wall licking, wall licking with upper transitions, wall licking with lower transitions, absolute angle changes, and time spent in the upper compartment. A decline in the freezing bouts and time spent in the lower compartment were noticed. In essence, this study offers a zebrafish model to comprehensively examine changes in behaviour of animals on opiate dependence and its withdrawal. The present study also reported that in zebrafish, the influence of chronic exposure of morphine modulates key gene targets involved in behaviour, neuroinflammation, and autophagy, which directly or indirectly are associated with morphine addiction in a chronic morphine model.
Topics: Animals; Morphine; Zebrafish; Autophagy; Models, Animal; Opiate Alkaloids
PubMed: 37671534
DOI: No ID Found -
Physiology & Behavior Apr 2018Preclinical studies report that the effective dose for morphine is approximately 2-fold higher in females than males. Following systemic administration, morphine is...
Preclinical studies report that the effective dose for morphine is approximately 2-fold higher in females than males. Following systemic administration, morphine is metabolized via Phase II glucuronidation in the liver and brain into two active metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), each possessing distinct pharmacological profiles. M6G binds to μ opioid receptors and acts as a potent analgesic. In contrast, M3G binds to toll-like receptor 4 (TLR4), initiating a neuroinflammatory response that directly opposes the analgesic effects of morphine and M6G. M3G serum concentrations are 2-fold higher in females than males, however, sex-specific effects of morphine metabolites on analgesia and glial activation in vivo remain unknown. The present studies test the hypothesis that increased M3G, and subsequent TLR4-mediated activation of glia, is a primary mechanism driving the attenuated response to morphine in females. We demonstrate that intra-PAG M6G results in a greater analgesic response in females than morphine alone. M6G analgesia was reversed with co-administration of (-)-naloxone, but not (+)-naloxone, suggesting that this effect is μ opioid receptor mediated. In contrast, intra-PAG administration of M3G significantly attenuated the analgesic effects of systemic morphine in males only, increasing the 50% effective dose of morphine two-fold (5.0 vs 10.3mg/kg) and eliminating the previously observed sex difference. An increase in IL-1β, IL-6 and TNF was observed in females following intra-PAG morphine or M6G. In males, only IL-1β levels increased following morphine. Changes in cytokine levels following M3G were limited to TNF in females. Together, these data implicate sex differences in morphine metabolism, specifically M3G, as a contributing factor in the attenuated response to morphine observed in females.
Topics: Analgesics, Opioid; Animals; Cytokines; Dose-Response Relationship, Drug; Female; Male; Morphine; Morphine Derivatives; Naloxone; Narcotic Antagonists; Nociception; Pain Threshold; Periaqueductal Gray; RNA, Messenger; Rats; Rats, Sprague-Dawley; Sex Characteristics; Time Factors; Toll-Like Receptor 4
PubMed: 29199028
DOI: 10.1016/j.physbeh.2017.11.030 -
Clinical Cardiology Sep 2021While morphine has long been widely used in treating acute heart failure (AHF) due to its vasodilatory properties and anticipated anxiolysis, it remains unclear whether... (Meta-Analysis)
Meta-Analysis Review
While morphine has long been widely used in treating acute heart failure (AHF) due to its vasodilatory properties and anticipated anxiolysis, it remains unclear whether the application of morphine to those patients is reasonable. We aim to conduct a systematic review and meta-analysis to assess the safety of morphine in patients with AHF. We searched PubMed, Cochrane Library, and Embase electronic databases from inception through March 2020. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the outcomes. Seven studies with 172, 226 patients were included. The results showed that morphine usage was not associated with increased in-hospital mortality (OR: 1.94; 95% CI 0.93 to 4.03; p = 0.08). However, the use of morphine significantly increased the risk of invasive ventilation (OR: 2.72; 95% CI 1.09 to 6.80; p = 0.03). Furthermore, the subgroup analysis indicated that the application of morphine was not associated with increased 7-day all-cause mortality in patients with AHF (OR: 1.69; 95% CI 0.80 to 3.22; p = 0.11) but significantly increased the risk of 30-day all-cause mortality (OR: 1.59; 95% CI 1.16 to 2.17; p = 0.004). Based on current evidence, our results suggested that although morphine therapy did not significantly increase the risk of short-term death (in the hospital or within 7 days) in patients with AHF, the risk of long-term death and invasive ventilation were significantly increased. This result needs to be further confirmed by an ongoing randomized control trial.
Topics: Heart Failure; Hospital Mortality; Humans; Morphine
PubMed: 34236089
DOI: 10.1002/clc.23691 -
Neurotherapeutics : the Journal of the... Oct 2021Opioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological...
Opioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them, N-palmitoylethanolamide (PEA), an endogenous lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of morphine tolerance. A selective augmentation in endogenous PEA levels can be achieved by inhibiting N-acylethanolamine acid amidase (NAAA), one of its primary hydrolyzing enzymes. This study aimed to test the hypothesis that NAAA inhibition, with the novel brain permeable NAAA inhibitor AM11095, modulates morphine's antinociceptive effects and attenuates the development of morphine tolerance in rats. We tested this hypothesis by measuring the pain threshold to noxious mechanical stimuli and, as a neural correlate, we conducted in vivo electrophysiological recordings from pain-sensitive locus coeruleus (LC) noradrenergic neurons in anesthetized rats. AM11095 dose-dependently (3-30 mg/kg) enhanced the antinociceptive effects of morphine and delayed the development of tolerance to chronic morphine in behaving rats. Consistently, AM11095 enhanced morphine-induced attenuation of the response of LC neurons to foot-shocks and prevented the attenuation of morphine effects following chronic treatment. Behavioral and electrophysiological effects of AM11095 on chronic morphine were paralleled by a decrease in glial activation in the spinal cord, an index of opioid-induced neuroinflammation. NAAA inhibition might represent a potential novel therapeutic approach to increase the analgesic effects of opioids and delay the development of tolerance.
Topics: Amidohydrolases; Analgesia; Analgesics, Opioid; Animals; Ethanolamines; Morphine; Pain; Pain Management; Rats
PubMed: 34553321
DOI: 10.1007/s13311-021-01116-4 -
Molecular Pain 2023Kappa-opioid receptor (KOR) agonists are known for having opposite and/or different effects compared with Mu-opioid receptor (MOR) agonists. This study is aimed at...
BACKGROUND
Kappa-opioid receptor (KOR) agonists are known for having opposite and/or different effects compared with Mu-opioid receptor (MOR) agonists. This study is aimed at clarifying the analgesic effect and tolerance of nalbuphine combined with morphine, and quantifying the mRNA and protein expression of spinal MOR and KOR in a mouse bone cancer pain (BCP) model treated with nalbuphine and morphine.
METHOD
BCP model was prepared in C3H/HeNCrlVr Mice by implanting the sarcoma cells into the intramedullary space of the femur. The paw withdrawal thermal latency (PWL) measured by thermal radiometer was used to assess thermal hyperalgesia. PWL testing was performed after implantation and drug administration according to the protocol. Hematoxylin-eosin staining in the spinal cord and x-ray in the femoral intramedullary canal was detected. Real-time PCR and western blot analysis played a role in detecting spinal MOR and KOR expression changes.
RESULTS
In tumor-implanted mice, the spinal MOR and KOR protein and mRNA expression was down-regulated when compared to that in sham-implanted mice ( < 0.05). Morphine therapy can lead to a decrease in spinal μ receptor expression. Similarly, the nalbuphine therapy can lead to a decrease in the expression of κ receptor protein and mRNA at the spinal cord level ( < 0.05). Morphine, nalbuphine, or nalbuphine co-administration with morphine all can extend the paw withdrawal thermal latency (PWL) to radiant thermal stimulation in tumor-implanted mice ( < 0.05). Compared with the morphine treatment group, nalbuphine co-administration with morphine delayed the reduction of PWL value again ( < 0.05).
DISCUSSION
BCP itself may induce down-regulation of the spinal MOR and KOR expression. A low dose of nalbuphine co-administration with morphine led to the delayed emergence of morphine tolerance. The part of the mechanism may be due to the regulation of spinal opioid receptors expression.
Topics: Animals; Mice; Mice, Inbred C3H; Cancer Pain; Nalbuphine; Morphine; Bone Neoplasms; Pain; Receptors, Opioid; Disease Models, Animal
PubMed: 37226458
DOI: 10.1177/17448069231178741 -
European Journal of Pharmaceutical... Apr 2022The inclusion complex formation of morphine and its 18 opioid derivatives with β-cyclodextrin has been studied using nuclear magnetic resonance spectroscopy. Initially,...
The inclusion complex formation of morphine and its 18 opioid derivatives with β-cyclodextrin has been studied using nuclear magnetic resonance spectroscopy. Initially, the protonation equilibria and the acid-base properties of dibasic opioid compounds have been fully characterized. Apparent protonation constants and the relative concentration of the microspecies in cyclodextrin excess were also determined. The 1:1 complex stoichiometry was confirmed by the continuous variation method of Job using UV-VIS spectroscopy. The stability constants of the different protonation forms were determined by H NMR titrations. The highest stability was observed in highly alkaline solutions where the amino group is in its unprotonated, neutral state. The structures of the complexes were investigated by two-dimensional ROESY experiments. Based on the stability constants and ROESY experiments, morphine derivatives with longer side chain on the nitrogen atom such as nalbuphine and naltrexone show stronger complexation. The protonation state of the phenolate group, positioned outside the CD cavity, has only a slight influence on the complex stability.
Topics: Analgesics, Opioid; Cyclodextrins; Magnetic Resonance Spectroscopy; Molecular Structure; Morphine; beta-Cyclodextrins
PubMed: 34999212
DOI: 10.1016/j.ejps.2022.106120 -
Biomedical Chromatography : BMC Apr 2022In this study, different injection solutions containing opioid and nonopioid compounds used for patient-controlled analgesia in hospice and palliative care were...
Stability evaluation of morphine, hydromorphone, metamizole and esketamine containing analgesic mixtures applied for patient-controlled analgesia in hospice and palliative care.
In this study, different injection solutions containing opioid and nonopioid compounds used for patient-controlled analgesia in hospice and palliative care were evaluated in terms of analyte stability. Investigated injection solutions contained different combinations of morphine, hydromorphone, metamizole and esketamine. For the practical implementation, samples from infusion pumps were daily drawn over a period of 7 days at 22 and 37°C. Quantitative measurements were performed on a high-performance liquid chromatography system with ultraviolet detection applying a validated analytical method. All compounds apart from morphine showed no evident changes in concentration. However, a significant loss of morphine was observed for injection mixtures containing both morphine and metamizole at 37°C. After 7 days, only 72% of the initially measured morphine concentration was measured in the binary and 77% in the ternary mixture. Furthermore, an additional compound was detected that could represent the morphine-metamizole-adduct, "metamorphine". Based on these results, a significantly reduced morphine concentration must be expected after only 3 days if an injection solution mixture containing both morphine and metamizole is administered to a patient at 37°C. Since the analgesic effects of morphine-metamizole adducts have not yet been thoroughly investigated, further clinical studies are necessary before accurate conclusions can be drawn in this regard.
Topics: Analgesia, Patient-Controlled; Analgesics, Opioid; Dipyrone; Hospices; Humans; Hydromorphone; Ketamine; Morphine; Palliative Care
PubMed: 35043434
DOI: 10.1002/bmc.5340