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Bioanalysis Aug 2020Morphine (MO) as an opioid analgesic is used for the treatment of moderate-to-severe pains, particularly cancer-related pains. Pharmacologic studies on MO are... (Review)
Review
Morphine (MO) as an opioid analgesic is used for the treatment of moderate-to-severe pains, particularly cancer-related pains. Pharmacologic studies on MO are complicated due to drugs binding to the protein or metabolization to active metabolites, and even inter-individual variability. This necessitates the selection of a reliable analytical method for monitoring MO and the concentrations of its metabolites in the biological samples for the pharmacokinetic or pharmacodynamic investigations. Therefore, this study was conducted to review all the analytical research carried out on MO and its metabolites in the biological samples during 2007-2019 as an update to the study by Bosch . (2007).
Topics: Humans; Morphine; Pain
PubMed: 32757855
DOI: 10.4155/bio-2020-0070 -
Journal of Equine Veterinary Science Jul 2021The study aim is to compare the effects of epidural administration of two different doses of romifidine combined with morphine in horses. A prospective crossover blinded...
The study aim is to compare the effects of epidural administration of two different doses of romifidine combined with morphine in horses. A prospective crossover blinded experimental design was used. Five adult healthy horses two males and three females with a mean body weight of 380 ± 45 Kg (335-425 kg), were studied. Treatments consisted of romifidine 30 μg/kg (R30) or 60 μg/kg (R60) combined with morphine 0.1 mg/kg with a washout interval of 72 hours, administered through an epidural catheter placed at the first intercoccygeal space. Heart rate (HR) and respiratory rate (f), pH, blood gases, arterial blood pressures (mmHg), and threshold for electrical noxious stimulation was evaluated for 120 minutes and after 240 minutes of epidural injection. Data were collected before injections and every 15 minutes for 120 minutes, and at 240 minutes of epidural administration. Significant sedation occurred in both treatments with no statistically significant difference between them. There were significant changes in f and HR from baseline but no difference between treatments. Arterial blood pressures were significantly lower in R60 treatment from 75 up to 120 minutes post epidural injection. Analgesia was considered moderate for both treatments lasting longer with romifidine at 60 μg/kg. Epidurally administered romifidine and morphine combination in horses produces dose-dependent sedation, arterial hypotension, and antinociceptive effects.
Topics: Analgesics; Animals; Female; Horses; Imidazoles; Male; Morphine; Prospective Studies
PubMed: 34119202
DOI: 10.1016/j.jevs.2021.103459 -
Clinical Drug Investigation Dec 2022An orodispersible tablet (ODT) formulation of morphine sulfate has been developed to provide a novel alternative for patients with severe pain requiring opioids. This... (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacokinetics of Morphine Sulfate Orodispersible Tablets and Bioequivalence with Immediate-Release Oral Morphine Sulfate Formulations in Healthy Adult Subjects Under Fasting Conditions: Single-Dose Comparative Bioavailability Studies.
BACKGROUND AND OBJECTIVE
An orodispersible tablet (ODT) formulation of morphine sulfate has been developed to provide a novel alternative for patients with severe pain requiring opioids. This formulation has been developed in a range of doses (1-30 mg), enabling relief from severe pain to be achieved and maintained with the lowest possible morphine dose for each patient. The ODT formulation is particularly suitable for patients with swallowing difficulties.
OBJECTIVE
The aim of this study was to compare the pharmacokinetics and bioequivalence of the ODTs with reference formulations of morphine sulfate.
METHODS
Three randomized, single-dose, laboratory-blinded, phase I, crossover studies were conducted in adult healthy volunteers under fasting conditions. The pharmacokinetics of a 30 mg morphine sulfate ODT were compared with those of equivalent doses of currently marketed oral immediate-release formulations: tablets (Sevredol), capsules (Actiskenan), and a solution (Oramorph). The bioequivalence of 30 mg and 10 mg doses of the ODTs and tablets was then assessed in two further studies. Subjects were asked to complete a product appreciation questionnaire for two morphine formulations (ODT and solution).
RESULTS
A total of 104 subjects were included across the three studies. The pharmacokinetics of the ODTs were assessed in 100 subjects and were found to be similar to those of the reference formulations. The time to maximum plasma concentration (T) for the ODTs was 0.8 h, within the range observed for the reference formulations (0.75-1.25 h). Maximum plasma concentrations (C) for the ODTs were 7.7 ± 2.7 ng/mL for the 10 mg dose and 26.1 ± 10.0 ng/mL for the 30 mg dose. These values were similar to those obtained for the 10 mg and 30 mg tablets (8.0 ± 2.9 ng/mL and 28.5 ± 11.9 ng/mL, respectively), and for the 30 mg capsule (29.9 ± 13.0 ng/mL). A higher C was observed for the solution (37.9 ± 16.5 ng/mL). Plasma exposure to morphine (area under the plasma drug concentration-time curve [AUC]) after ODT administration was similar to that observed for the reference formulations: 39.8 ± 14.8 ng·h/mL and 115.5 ± 34.6 ng·h/mL for the 10 mg and 30 mg ODTs, versus 40.7 ± 13.5 ng·h/mL and 117.4 ± 31.5 ng·h/mL for the 10 mg and 30 mg tablets, and 121.8 ± 32.0 ng·h/mL and 121.0 ± 35.7 ng·h/mL for the 30 mg solution and capsule, respectively. Bioequivalence of the 30 mg and 10 mg ODTs and tablets, assessed in 83 patients across two studies, was demonstrated for both the C and AUC from time zero to time t (AUC). No serious or unexpected drug-related events were reported. A product appreciation questionnaire concluded that both ODTs and oral solution products were considered pleasant by most of the subjects.
CONCLUSION
The ODTs were safe, well tolerated, and showed similar pharmacokinetics to those of the reference formulations. The development of a range of doses of morphine sulfate ODTs may provide a new alternative for the oral administration of immediate-release morphine for pain management in pediatric, geriatric and adult populations with swallowing problems.
Topics: Adult; Aged; Child; Humans; Administration, Oral; Area Under Curve; Biological Availability; Cross-Over Studies; Fasting; Morphine; Pain; Sulfates; Tablets; Therapeutic Equivalency
PubMed: 36331670
DOI: 10.1007/s40261-022-01214-x -
Acta Neurobiologiae Experimentalis 2021Morphine and tramadol are the opioid analgesic drugs acting via activation of μ‑opioid receptors. It is important to understand which mechanism (synergistic or...
Morphine and tramadol are the opioid analgesic drugs acting via activation of μ‑opioid receptors. It is important to understand which mechanism (synergistic or additive anti‑nociceptive activity) induced potent anti‑nociceptive effect by co‑administration of morphine and tramadol. Identification of new strategies that can potentiate analgesic effects of opioids will be good therapeutic approaches for pain relief. To this aim, male mice were cannulated in the left ventricle by a stereotaxic instrument. A tail‑flick test was used to record the pain threshold. The results revealed that intracerebroventricularly injection of morphine induced an anti‑nociceptive effect in non‑sensitized and morphine‑sensitized mice. We found that infusion of tramadol produced an anti‑nociceptive response in non‑sensitized mice, whereas tramadol in doses of 0.5 and 1 μg/mouse induced analgesia in morphine‑sensitized mice. Co‑injection of a non‑effective dose of tramadol or morphine (0.25 μg/mouse) with different doses of morphine or tramadol (0.25, 0.5, and 1 μg/mouse) respectively potentiated the analgesic effect of the previous drug. An isobolographic analysis of data was performed, indicating a synergistic interaction between morphine and tramadol in non‑sensitized and morphine‑sensitized mice. Our data indicated that both morphine and tramadol elicit more anti‑nociceptive response in morphine sensitized mice; there is a synergistic effect between morphine and tramadol upon induction of analgesic effect in non‑sensitized and morphine‑sensitized mice.
Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Male; Mice; Morphine; Pain; Pain Measurement; Tramadol
PubMed: 35014984
DOI: No ID Found -
Current Opinion in Supportive and... Sep 2014Inhaled nebulized and intranasal opioid administration is available with a proven short onset of action for the relief of pain. As breathlessness episodes are short,... (Review)
Review
PURPOSE OF REVIEW
Inhaled nebulized and intranasal opioid administration is available with a proven short onset of action for the relief of pain. As breathlessness episodes are short, these routes of administration seem to be attractive for breathlessness management. This review describes the recent studies evaluating the effectiveness of inhaled nebulized and intranasal application of opioids for patients suffering from refractory breathlessness.
RECENT FINDINGS
Since 2012, one systematic review and three primary studies have been identified. The systematic review summarized five studies including seventy patients testing nebulized fentanyl and two studies including five patients evaluating intranasal application. Two randomized controlled trials tested inhaled fentanyl or morphine and one retrospective chart review described the application of intranasal fentanyl in newborn babies. Inhaled fentanyl did not improve the intensity or unpleasantness of perceived dyspnea, but the rate of increase in dyspnea intensity and unpleasantness ratings between isotime and peak exercise was less after treatment with fentanyl. Inhaled morphine improved breathlessness in chronic obstructive pulmonary disease patients.
SUMMARY
There is currently not enough evidence to support the use of inhaled application of opioids for the relief of breathlessness. There are no controlled trials assessing the efficacy and effectiveness of intranasal opioid application, but a pilot trial is underway to provide preliminary data.
Topics: Administration, Inhalation; Administration, Intranasal; Analgesics, Opioid; Dyspnea; Fentanyl; Humans; Morphine
PubMed: 25004175
DOI: 10.1097/SPC.0000000000000071 -
American Heart Journal Jun 2016With potent analgesic properties, perceived hemodynamic benefits and limited alternatives, morphine is the analgesic mainstay for patients with nitrate resistant chest... (Review)
Review
With potent analgesic properties, perceived hemodynamic benefits and limited alternatives, morphine is the analgesic mainstay for patients with nitrate resistant chest pain due to acute Myocardial Infarction (MI). However, observational data suggest that morphine administration during MI may have negative consequences. While vomiting, hypotension and respiratory depression are established side effects, recent reports have demonstrated attenuated and delayed oral anti-platelet agent absorption, as well as suboptimal reperfusion after MI, all of which may translate into adverse cardiovascular outcomes. These data have resulted in reduced support for morphine in recent European and U.S. clinical practice guidelines for MI; despite the absence of any prospective randomized outcomes trials addressing this question. As such, randomized trials are now necessary to confirm whether or not morphine, which is administered in up to 30% of MI cases, causes adverse clinical outcomes in these patients. However, given that placebo-controlled randomized trial designs evaluating morphine in MI are limited by an ethical requirement for appropriate analgesia, alternative investigational approaches may be necessary. In this article we review the updated evidence for morphine in MI and outline novel strategies that may facilitate future investigation of this clinical dilemma.
Topics: Acute Coronary Syndrome; Analgesics, Opioid; Humans; Morphine; Practice Guidelines as Topic; Treatment Outcome
PubMed: 27264228
DOI: 10.1016/j.ahj.2016.04.004 -
Molecular Psychiatry Apr 2021Opioids, such as morphine, are clinic analgesics which induce euphoria. Morphine exposure modifies the excitability and functional interactions between neurons, while...
Opioids, such as morphine, are clinic analgesics which induce euphoria. Morphine exposure modifies the excitability and functional interactions between neurons, while the underlying cellular and molecular mechanisms, especially how morphine assembles heterogeneous interneurons (INs) in prelimbic cortex (PrL) to mediate disinhibition and reward, are not clear. Using approaches of optogenetics, electrophysiology, and cell type-specific RNA-seq, we show that morphine attenuates the inhibitory synaptic transmission from parvalbumin (PV)-INs onto pyramidal neurons in PrL via μ-opioid receptor (MOR) in PV-INs. Meanwhile, morphine enhances the inhibitory inputs from somatostatin (SST)-INs onto PV-INs, and thus disinhibits pyramidal neurons via δ-opioid receptor (DOR)-dependent Rac1 upregulation in SST-INs. We show that MOR in PV-INs is required for morphine-induced behavioral sensitization, while DOR as well as Rac1 activity in SST-INs is required for morphine-induced conditioned place preference and hyper-locomotion. These results reveal that SST- and PV-INs, functioning in PrL as a disinhibitory architecture, are coordinated by morphine via different opioid receptors to disinhibit pyramidal neurons and enhance reward.
Topics: Interneurons; Morphine; Parvalbumins; Pyramidal Cells; Reward
PubMed: 31413370
DOI: 10.1038/s41380-019-0480-7 -
Journal of Trace Elements in Medicine... Jul 2020Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical... (Review)
Review
Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical dopaminergic pathways play an important role in modulation of cognitive processes and decision making and, therefore, changes in dopamine metabolism are considered the central basis for the development of dependence. Disturbances caused by excesses or deficiency of certain elements have a significant impact on the functioning of the central nervous system (CNS) both in physiological conditions and in pathology and can affect the cerebral reward system and therefore, may modulate processes associated with the development of addiction. In this paper we review the mechanisms of interactions between morphine and zinc, manganese, chromium, cadmium, lead, fluoride, their impact on neural pathways associated with addiction, and on antinociception and morphine tolerance and dependence.
Topics: Animals; Humans; Morphine; Morphine Dependence; Neural Pathways; Transition Elements
PubMed: 32179426
DOI: 10.1016/j.jtemb.2020.126495 -
American Journal of Respiratory and... Dec 2021
Topics: Analgesics, Opioid; Fentanyl; Humans; Infusions, Intravenous; Intensive Care Units; Morphine
PubMed: 34644514
DOI: 10.1164/rccm.202109-2112ED -
Journal of Clinical Pharmacology Jan 2022While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we... (Randomized Controlled Trial)
Randomized Controlled Trial
While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration-effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT-Behavior (COMFORT-B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up-titration). In responders to morphine up-titration, the COMFORT-B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT-B score is expected. In general, lower baseline COMFORT-B scores (2.1 points on average) in younger children (postnatal age <10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT-B score is maximized at a morphine concentration between 5 and 30 ng/mL for children aged <10 days, and between 5 and 40 ng/mL for children >10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.
Topics: Analgesics, Opioid; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Infant, Newborn; Male; Morphine; Pain, Postoperative
PubMed: 34383975
DOI: 10.1002/jcph.1952