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Pain Physician 2011Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA, King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic,... (Review)
Review
BACKGROUND
Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA, King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic, moderate-to-severe pain, contain pellets of extended-release morphine sulfate with a sequestered naltrexone core (MS-sNT). Taken as directed, morphine provides analgesia while naltrexone remains sequestered; if tampered with by crushing, naltrexone is released to mitigate morphine-induced euphoric effects. While it is necessary to establish that formulations intended to reduce attractiveness for abuse are successful in doing so, it is also necessary to demonstrate that product therapeutic integrity is maintained for patients.
OBJECTIVES
Data were reviewed from 3 studies to determine: 1) the quantity of naltrexone released when MS-sNT pellets are crushed (MS-sNTC) for at least 2 minutes with mortar and pestle); 2) the extent to which the naltrexone released upon crushing mitigated morphine-induced subjective effects; and 3) whether sequestered naltrexone precipitates opioid withdrawal when MS-sNT is taken as directed.
METHODS
The naltrexone bioavailability study compared naltrexone release from MS-sNTC with that from whole intact MS-sNT capsules (MS-sNTW) and an equal naltrexone solution (NS) dose. Equivalent bioavailability was established if 90% confidence intervals (CIs) for geometric mean ratios (maximum plasma naltrexone concentration [Cmax] and area under the concentration-time curve extrapolated to infinity [AUC∞]) fell between 80% and 125%. The oral pharmacodynamic study assessed drug liking and euphoria and pharmacokinetic properties of MS-sNTC and MS-sNTW compared with morphine sulfate solution (MSS) and placebo. The 12-month, open-label (OL) safety study evaluated safety of MS-sNT administered orally as directed in patients with chronic, moderate-to-severe pain. Safety assessments included withdrawal symptoms based on the Clinical Opiate Withdrawal Scale (COWS).
RESULTS
Naltrexone from MS-sNTC met criteria for equivalent bioavailability to NS. Although morphine relative bioavailability was similar for MS-sNTC and MSS, mean peak (Emax) visual analog scale (VAS) scores for drug liking and Cole/Addiction Research Center Inventory Stimulation-Euphoria were significantly reduced for MS-sNTC vs MSS (p < 0.001). In these 2 studies, a total of 6 participants had one measurement of plasma naltrexone after MS-sNTW that was above the lower limit of quantification. In the OL safety study, 72/93 participants (77%) had no quantifiable naltrexone concentrations. There was neither evidence of naltrexone accumulation for any participant nor any significant correlation with MS-sNT dose, age, or sex. Of 4 participants with the highest naltrexone concentrations, none had COWS scores consistent with moderate opioid withdrawal symptoms. Only 5 participants had COWS scores consistent with moderate opioid withdrawal; all 5 had not taken MS-sNT as directed.
LIMITATIONS
Study populations may not be fully representative of patients receiving opioid therapy for the management of chronic, moderate-to-severe pain and of opioid abusers.
CONCLUSIONS
When MS-sNT capsules are crushed, all of the sequestered naltrexone (relative to oral NS) is released and immediately available to mitigate morphine-induced effects. When MS-sNT was crushed, the naltrexone released abated drug liking and euphoria relative to that from an equal dose of immediate-release morphine from MSS administration in a majority of participants. Naltrexone concentrations were low over a period of 12 months without evidence of accumulation, and there were no observable opioid withdrawal symptoms when MS-sNT was taken as directed.
Topics: Area Under Curve; Biological Availability; Capsules; Drug Combinations; Humans; Morphine; Naltrexone; ROC Curve
PubMed: 21785483
DOI: No ID Found -
Acta Medica Portuguesa Mar 2016
Topics: Analgesics, Opioid; Humans; Morphine; Practice Guidelines as Topic
PubMed: 27285090
DOI: 10.20344/amp.7663 -
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 -
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 -
The Journal of Physiology May 19741. To find the site where morphine acts when producing hyperglycaemia on injection into the cerebral ventricles in unanaesthetized cats, morphine sulphate was infused or...
1. To find the site where morphine acts when producing hyperglycaemia on injection into the cerebral ventricles in unanaesthetized cats, morphine sulphate was infused or injected through an implanted Collison cannula into different parts of the liquor space in an amount of 0.75 mg except on microinfusion into the posterior hypothalamus, when the amounts were 80 or 160 mug. The glucose was determined in blood samples collected from the inferior vena cava.2. Microinfusions of morphine into the posterior hypothalamus did not produce hyperglycaemia.3. Infusion of morphine into the liquor space at the entrance of the aqueduct or of the fourth ventricle produced hyperglycaemia. Any structures in the walls of the third ventricle as well as the peri-aqueductal grey are thus excluded as the site of action.4. Infusion of morphine into the subarachnoid space just above the corpora quadrigemina or below the ventral surface of the brain stem produced hyperglycaemia. With these routes the morphine does not enter any part of the ventricular cavities and the action would appear to be on structures at the ventral surface of the brain stem.5. Injection of morphine into the cisterna magna produces hyperglycaemia when the doses are larger than those already effective on injection into the cerebral ventricles. This also suggests an action on structures at the ventral surface of the brain stem, as this surface is reached more readily from the ventricles than from the cisterna.6. It is concluded that on injection into the cerebral ventricles, the morphine has to pass into the subarachnoid space, through the foramina of Luschka, in order to produce hyperglycaemia. It then reaches the ventral surface of the brain stem and probably acts there on structures in the upper part of the medulla oblongata.7. Infusion of morphine into the corpora quadrigemina near the caudal end of the superior corpora can produce profound hypoglycaemia.8. Anaesthesia depresses the morphine hyperglycaemia, but when the dose injected into the cerebral ventricles is increased four times or more, hyperglycaemia is also produced in pentobarbitone sodium anaesthesia.
Topics: Anesthesia; Animals; Blood Glucose; Brain Stem; Catheterization; Cats; Cerebral Ventricles; Consciousness; Dose-Response Relationship, Drug; Female; Hyperglycemia; Hypothalamus; Injections; Male; Morphine; Pentobarbital; Subarachnoid Space; Tectum Mesencephali
PubMed: 4853259
DOI: 10.1113/jphysiol.1974.sp010539 -
Anais Da Academia Brasileira de Ciencias 2022Exercise and addiction influence brain functions. The preventive effects of fixed and progressive forced exercises on both brain functions and body weight were...
Exercise and addiction influence brain functions. The preventive effects of fixed and progressive forced exercises on both brain functions and body weight were investigated in morphine-addicted rats. Thirty-five rats were allocated to control, morphine, fixed exercise-morphine, and progressive exercise-morphine groups. Forced exercise was applied 1h/day for 21 days with morphine sulfate administered at doses of 10, 20, 30, 40, and 50 mg/kg for 5 consecutive days. The 50 mg/kg dose was repeated over the five subsequent days. Brain performance was evaluated using the passive avoidance test and EEG recordings. The passive avoidance test revealed no significant changes in brain functions (namely, latency, total dark stay time, and number of times entering the dark compartment). Compared to the control, the morphine group exhibited significantly lower alpha and beta waves but significantly higher delta and theta ones. Compared to the morphine group, the progressive and fixed exercise-morphine groups exhibited significant changes in their passive avoidance performance and only in the alpha wave of their EEG recordings. Progressive exercise improved learning, memory, and memory consolidation but reduced locomotor activity whereas fixed exercise affected EEG recordings in the addicted subjects. Clearly, different (fixed or progressive) exercise models produced different changes in brain functions.
Topics: Animals; Avoidance Learning; Brain; Exercise Therapy; Humans; Morphine; Rats; Rats, Wistar
PubMed: 35830068
DOI: 10.1590/0001-3765202220200596 -
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 Veterinary Research Jun 2012To compare the cardiorespiratory, gastrointestinal, analgesic, and behavioral effects between IV and IM administration of morphine in conscious horses with no signs of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To compare the cardiorespiratory, gastrointestinal, analgesic, and behavioral effects between IV and IM administration of morphine in conscious horses with no signs of pain.
ANIMALS
6 healthy adult horses.
PROCEDURES
Horses received saline (0.9% NaCl) solution (IM or IV) or morphine sulfate (0.05 and 0.1 mg/kg, IM or IV) in a randomized, masked crossover study design. The following variables were measured before and for 360 minutes after drug administration: heart and respiratory rates; systolic, diastolic, and mean arterial blood pressures; rectal temperature; arterial pH and blood gas variables; intestinal motility; and response to thermal and electrical noxious stimuli. Adverse effects and horse behavior were also recorded. Plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were measured via liquid chromatography-mass spectrometry.
RESULTS
No significant differences in any variable were evident after saline solution administration. Intravenous and IM administration of morphine resulted in minimal and short-term cardiorespiratory, intestinal motility, and behavioral changes. A decrease in gastrointestinal motility was detected 1 to 2 hours after IM administration of morphine at doses of 0.05 and 0.1 mg/kg and after IV administration of morphine at a dose of 0.1 mg/kg. Morphine administration yielded no change in any horse's response to noxious stimuli. Both morphine-3-glucuronide and morphine-6-glucuronide were detected in plasma after IV and IM administration of morphine.
CONCLUSIONS AND CLINICAL RELEVANCE
Clinically relevant doses of morphine sulfate yielded minimal and short-term behavioral and intestinal motility effects in healthy horses with no signs of pain. Neither dose of morphine affected their response to a noxious stimulus.
Topics: Analysis of Variance; Animals; Body Temperature; Cross-Over Studies; Gastrointestinal Motility; Heart Rate; Horses; Injections, Intramuscular; Injections, Intravenous; Morphine; Morphine Derivatives; Motor Activity; Pain Threshold; Respiratory Rate
PubMed: 22620693
DOI: 10.2460/ajvr.73.6.799 -
BMJ (Clinical Research Ed.) Feb 1993
Topics: Humans; Morphine; Nociceptors; Pain
PubMed: 8448453
DOI: 10.1136/bmj.306.6876.473 -
American Journal of Veterinary Research Sep 2017OBJECTIVE To evaluate the antinociceptive efficacy of IM morphine sulfate or butorphanol tartrate administration in tegus (Salvator merianae). ANIMALS 6 healthy juvenile... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE To evaluate the antinociceptive efficacy of IM morphine sulfate or butorphanol tartrate administration in tegus (Salvator merianae). ANIMALS 6 healthy juvenile (12- to 24-month-old) tegus (mean ± SD body weight, 1,484 ± 473 g). PROCEDURES In a crossover study design, tegus were randomly assigned to treatment order, with a minimum washout period of 15 days between treatments. Each of 5 treatments was administered IM in a forelimb: saline (0.9% NaCl) solution (0.5 mL), morphine sulfate (5 or 10 mg/kg), or butorphanol tartrate (5 or 10 mg/kg). A withdrawal latency test was used to evaluate antinociception, with a noxious thermal stimulus applied to the plantar surface of the hind limb before (0 hours; baseline) and 0.5, 1, 2, 3, 4, 6, 12, and 24 hours after each treatment. Observers were unaware of treatment received. RESULTS With saline solution, mean hind limb withdrawal latencies (interval to limb withdrawal from the thermal stimulus) remained constant, except at 12 hours. Tegus had higher than baseline mean withdrawal latencies between 0.5 and 1 hour and at 12 hours with morphine at 5 mg/kg and between 1 and 12 hours with morphine at 10 mg/kg. With butorphanol at 5 and 10 mg/kg, tegus maintained withdrawal responses similar to baseline at all assessment points. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that morphine, but not butorphanol, provided antinociception at 5 and 10 mg/kg in tegus as measured by thermal noxious stimulus testing. These data supported the hypothesis that μ-opioid (but not κ-opioid) receptor agonists provide antinociception in reptiles.
Topics: Analgesics; Analgesics, Opioid; Animals; Butorphanol; Cross-Over Studies; Lizards; Male; Morphine
PubMed: 28836839
DOI: 10.2460/ajvr.78.9.1019