-
Blocking Palmitoylation of Apelin Receptor Alleviates Morphine Tolerance in Neuropathic Cancer Pain.International Journal of Biological... 2024Neuropathic cancer pain (NCP) is an important symptom in patients with cancer. However, significant analgesic tolerance and other side effects critically hamper the...
Neuropathic cancer pain (NCP) is an important symptom in patients with cancer. However, significant analgesic tolerance and other side effects critically hamper the administration of morphine. Protein palmitoylation mediated by the DHHC family may be involved in the glial activation and inflammatory responses underlying organ failure. In this study, we investigated the key role of protein palmitoylation in cancer pain and sought to target palmitoylation to suppress morphine tolerance. We found that long-term use of morphine led to the accumulation of the morphine metabolite, morphine-3-glucuronide, and activated ERK1/2 and microglia to release inflammatory factors through the apelin receptor APLNR. Palmitoyltransferase ZDHHC9 was upregulated in NCP, and APLNR was palmitylated to protect it from lysosomal degradation and to maintain its stability. We also designed competitive inhibitors of APLNR palmitoylation to inhibit the development of NCP, release of inflammatory factors, and attenuation of morphine tolerance. Therefore, targeting APLNR palmitoylation in combination with morphine is a potent method for cancer pain treatment. Our data provide a basis for the future clinical use of related drugs combined with morphine for the treatment of cancer-related pain.
Topics: Humans; Morphine; Apelin Receptors; Cancer Pain; Lipoylation; Neuralgia; Neoplasms
PubMed: 38164190
DOI: 10.7150/ijbs.86888 -
Panminerva Medica Jun 2022
Topics: Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Morphine
PubMed: 33325670
DOI: 10.23736/S0031-0808.20.04221-4 -
PloS One 2020To evaluate the efficacy, safety and cost-effectiveness of Oxycodone Hydrochloride Controlled-release Tablets (CR oxycodone) and Morphine Sulfate Sustained-release... (Comparative Study)
Comparative Study Meta-Analysis
OBJECTIVE
To evaluate the efficacy, safety and cost-effectiveness of Oxycodone Hydrochloride Controlled-release Tablets (CR oxycodone) and Morphine Sulfate Sustained-release Tablets (SR morphine) for moderate to severe cancer pain titration.
METHODS
Randomized controlled trials meeting the inclusion criteria were searched through Medline, Cochrane Library, Pubmed, EMbase, CNKI,VIP and WanFang database from the data of their establishment to June 2019. The efficacy and safety data were extracted from the included literature. The pain control rate was calculated to eatimate efficacy. Meta-analysis was conducted by Revman5.1.4. A decision tree model was built to simulate cancer pain titration process. The initial dose of CR oxycodone and SR morphine group were 20mg and 30mg respectively. Oral immediate-release morphine was administered to treat break-out pain. The incremental cost-effectiveness ratio was performed with TreeAge Pro 2019.
RESULTS
19 studies (1680 patients)were included in this study. Meta-analysis showed that the pain control rate of CR oxycodone and SR morphine were 86% and 82.98% respectively. The costs of CR oxycodone and SR morphine were $23.27 and $13.31. The incremental cost-effectiveness ratio per unit was approximate $329.76. At the willingness-to-pay threshold of $8836, CR oxycodone was cost-effective, while the corresponding probability of being cost-effective at the willingness-to-pay threshold of $300 was 31.6%. One-way sensitivity analysis confirmed robustness of results.
CONCLUSIONS
CR oxycodone could be a cost-effective option compared with SR morphine for moderate to severe cancer pain titration in China, according to the threshold defined by the WHO.
Topics: Cancer Pain; Cost-Benefit Analysis; Decision Trees; Delayed-Action Preparations; Economics, Pharmaceutical; Humans; Morphine; Oxycodone; Publication Bias; Risk; Treatment Outcome
PubMed: 32302346
DOI: 10.1371/journal.pone.0231763 -
British Journal of Pharmacology Oct 2018Chronic administration of medication can significantly affect metabolic enzymes leading to physiological adaptations. Morphine metabolism in the liver has been...
BACKGROUND AND PURPOSE
Chronic administration of medication can significantly affect metabolic enzymes leading to physiological adaptations. Morphine metabolism in the liver has been extensively studied following acute morphine treatment, but such metabolic processes in the CNS are poorly characterized. Long-term morphine treatment is limited by the development of tolerance, resulting in a decrease of its analgesic effect. Whether or not morphine analgesic tolerance affects in vivo brain morphine metabolism and blood-brain barrier (BBB) permeability remains a major question. Here, we have attempted to characterize the in vivo metabolism and BBB permeability of morphine after long-term treatment, at both central and peripheral levels.
EXPERIMENTAL APPROACH
Male C57BL/6 mice were injected with morphine or saline solution for eight consecutive days in order to induce morphine analgesic tolerance. On the ninth day, both groups received a final injection of morphine (85%) and d3-morphine (morphine bearing three H; 15%, w/w). Mice were then killed and blood, urine, brain and liver samples were collected. LC-MS/MS was used to quantify morphine, its metabolite morphine-3-glucuronide (M3G) and their respective d3-labelled forms.
KEY RESULTS
We found no significant differences in morphine CNS uptake and metabolism between control and tolerant mice. Interestingly, d3-morphine metabolism was decreased compared to morphine without any interference with our study.
CONCLUSIONS AND IMPLICATIONS
Our data suggests that tolerance to the analgesic effects of morphine is not linked to increased glucuronidation to M3G or to altered global BBB permeability of morphine.
Topics: Animals; Brain; Cells, Cultured; Drug Tolerance; Glucuronides; Isotope Labeling; Male; Mice; Mice, Inbred C57BL; Molecular Conformation; Morphine
PubMed: 30051501
DOI: 10.1111/bph.14454 -
Journal of Pain and Symptom Management Feb 1996The relationships between plasma morphine and metabolite (M3G and M6G) concentrations and analgesic efficacy were investigated in an open study of 39 cancer pain... (Clinical Trial)
Clinical Trial
The relationships between plasma morphine and metabolite (M3G and M6G) concentrations and analgesic efficacy were investigated in an open study of 39 cancer pain patients receiving chronic oral morphine therapy with either morphine sulfate solution or controlled-release morphine tablets. There were no differences in morphine, metabolite kinetics, or analgesic efficacy between equivalent doses of conventional or controlled-release formulations. The increase in morphine plasma concentration after a dose (1 hr for normal release, 2 hr for controlled release) was correlated significantly with the dose of morphine (r = 0.914, P < 0.001). There was a significant reduction in pain intensity (P < 0.05) and increase in pain relief (P < 0.001) after the dose of morphine administration, when compared with the predose score. One-half of the patients had mild and tolerable adverse effects. Patients were classified by mean pain relief between doses as having optimal, moderate, or poor pain control. No simple relationship was found between morphine plasma concentration and pain control. Morphine plus M6G concentrations in the "optimal control" group (751.2 +/- 194 nmol/L), however, were more than twice those found in the "moderate control" group (276.9 +/- 41.9 nmol/L) (P < 0.05), and no patient in the moderate control group had a morphine plus M6G concentration greater than 405 nmol/L. These results support the importance of M6G in morphine analgesia. For these hospitalized patients, there appeared to be a therapeutic range of morphine plus M6G plasma concentrations for optimal pain control with a lower limit of 400 nmol/L predose.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasms; Pain
PubMed: 8907140
DOI: 10.1016/0885-3924(95)00148-4 -
The American Journal of Hospice &... Oct 2022Opioids are known to induce delirium, but few studies have closely investigated differences in incidence of delirium among different opioids.
BACKGROUND
Opioids are known to induce delirium, but few studies have closely investigated differences in incidence of delirium among different opioids.
OBJECTIVES
To determine whether there is a clinically significant difference in the incidence of delirium between oral opioids in previously opioid-naive patients.
METHODS
Subjects were 259 opioid-naive in-patients with cancer who were started on morphine sulfate, oxycodone hydrochloride, or tapentadol hydrochloride extended-release tablets at our hospital between August 1, 2014, and September 30, 2018. The incidence of delirium during the first week of treatment was compared between the drugs.
RESULTS
The incidence of delirium was 4.8% (n = 83) for morphine sulfate, 6.9% (n = 131) for oxycodone hydrochloride, and 6.7% (n = 45) for tapentadol hydrochloride. The incidence did not significantly differ between oxycodone hydrochloride (OR = .69, 95% CI = .20-2.30, [Fisher's exact test] = .77) or tapentadol hydrochloride (OR = .71, 95% CI = .15-3.32, [Fisher's exact test] = .70) and morphine sulfate (reference group). Moreover, the incidence did not significantly differ between tapentadol hydrochloride (OR = 1.03, 95% CI = .27-3.00, [Fisher's exact test] = 1.00) and oxycodone hydrochloride (reference group).
CONCLUSION
The incidence of delirium in previously opioid-naive patients did not differ significantly among morphine sulfate, oxycodone hydrochloride, and tapentadol hydrochloride extended-release tablets, suggesting similar risk of delirium in opioid-naive patients among these oral opioids.
Topics: Analgesics, Opioid; Delirium; Humans; Incidence; Morphine; Oxycodone; Tapentadol
PubMed: 35045754
DOI: 10.1177/10499091211065171 -
AAPS PharmSciTech Sep 2010The objectives of this study were to develop morphine sulfate sustained-release tablet formulations and to evaluate the bioequivalence compared with a commercial brand.... (Comparative Study)
Comparative Study Randomized Controlled Trial
The objectives of this study were to develop morphine sulfate sustained-release tablet formulations and to evaluate the bioequivalence compared with a commercial brand. The physicochemical properties of the formulated and commercial tablets were determined and compared. The bioequivalence investigation was carried out in 15 healthy male volunteers who received a single dose in a randomized two-way crossover design. After dosing, serial blood samples were collected for a period of 24 h. Morphine concentration was assayed by high-performance liquid chromatography with electrochemical detector. The log-transformed C(max) and AUC(s) were statistically compared by analysis of variance, and the 90% confidence intervals (CIs) of the ratio of the log-transformed C(max) and AUC(s) between the most promising developed formulation and the commercial product were determined. It was found that the dissolution rate profile of a developed formulation was similar to the commercial brand. Their similarity and difference factors were well within limits. In the bioequivalence study, the AUC(last) and AUC(inf) between the test and the reference products were not statistically different (p = 0.227 and p = 0.468, respectively), with the 90% CIs of 83.4-102.6% and 87.7-139.4%, respectively. However, the C(max) of the two formulations was significantly different (p = 0.019). The 90% CI of the developed formulation was 72.0-93.0% compared to the commercial product. In vitro dissolution of locally prepared morphine sulfate sustained-release tablets was comparable to commercial brand. However, the results justified the conclusion of lack of bioequivalence of the developed product to the commercial one.
Topics: Adult; Cross-Over Studies; Delayed-Action Preparations; Drug Compounding; Humans; Male; Middle Aged; Morphine; Tablets; Therapeutic Equivalency; Young Adult
PubMed: 20845089
DOI: 10.1208/s12249-010-9518-5 -
Journal of the American Veterinary... May 2007To test the hypothesis that butorphanol or morphine induces antinociception with minimal respiratory depression in conscious red-eared slider turtles. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To test the hypothesis that butorphanol or morphine induces antinociception with minimal respiratory depression in conscious red-eared slider turtles.
DESIGN
Prospective crossover study.
ANIMALS
37 adult male and female red-eared slider turtles (Trachemys scripta).
PROCEDURES
Antinociception (n = 27 turtles) and respiratory (10 turtles) experiments were performed. Infrared heat stimuli were applied to the plantar surface of turtle limbs. Thermal withdrawal latencies were measured before and at intervals after SC administration of physiologic saline (0.9% NaCl) solution, butorphanol tartrate (2.8 or 28 mg/kg [1.27 or 12.7 mg/lb]), or morphine sulfate (1.5 or 6.5 mg/kg [0.68 or 2.95 mg/lb]). Ventilation was assessed in freely swimming turtles before and after SC administration of saline solution, butorphanol (28 mg/kg), or morphine (1.5 mg/kg).
RESULTS
For as long as 24 hours after injection of saline solution or either dose of butorphanol, thermal withdrawal latencies among turtles did not differ. Low- and high-dose morphine injections increased latencies significantly by 8 hours. Ventilation was not altered by saline solution administration, was temporarily depressed by 56% to 60% for 1 to 2 hours by butorphanol (28 mg/kg) administration, and was significantly depressed by a maximum of 83 +/- 9% at 3 hours after morphine (1.5 mg/kg) injection. Butorphanol and morphine depressed ventilation by decreasing breathing frequency.
CONCLUSIONS AND CLINICAL RELEVANCE
Although widely used in reptile species, butorphanol may not provide adequate antinociception for invasive procedures and caused short-term respiratory depression in red-eared slider turtles. In contrast, morphine apparently provided antinociception but caused long-lasting respiratory depression.
Topics: Analgesics, Opioid; Animals; Butorphanol; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Male; Morphine; Pain; Pain Measurement; Prospective Studies; Respiration; Time Factors; Turtles
PubMed: 17472564
DOI: 10.2460/javma.230.9.1356 -
European Journal of Heart Failure Oct 2022
Topics: Humans; Morphine; Pulmonary Edema; Heart Failure; Acute Disease
PubMed: 36161434
DOI: 10.1002/ejhf.2698 -
Harm Reduction Journal Apr 2023The injection of morphine from morphine sulfate capsules containing sustained-release microbeads (Skenan®) is a practice frequently described by French intravenous...
BACKGROUND
The injection of morphine from morphine sulfate capsules containing sustained-release microbeads (Skenan®) is a practice frequently described by French intravenous opioid users. They seek an injectable form of substitution for heroin. Depending on how the syringe is prepared, the morphine rates may vary. The dosage of the capsule, the temperature of the dissolving water and the type of filter used have been identified as the parameters most likely to influence the final quantity of morphine in solution before intravenous injection. The aim of our study was to determine the amounts of morphine actually injected, according to the different preparation modalities described by people who inject morphine and the harm reduction equipment made available to them.
METHODS
Different morphine syringes were prepared by varying the dosage of the capsule (100 or 200 mg), the temperature of the dissolving water before adding morphine, ambient (≈ 22 °C) or heat (≈ 80 °C) and four filtration devices: risk reduction Steribox® cotton, risk reduction filter "Sterifilt®", "Wheel" filter and cigarette filter. The quantification of the morphine in the syringe body was carried out by liquid phase chromatography coupled with a mass spectrometry detector.
RESULTS
The best extraction yields were obtained with heated water, independently of dosages (p < 0.01). Yields of 100 mg capsules varied according to the filter (p < 0.01) and the water temperature (p < 0.01), with maximum yields obtained for solutions dissolved in heated water, then filtered with the "Wheel" filter (83 mg). The yields of the 200 mg capsules varied according to the temperature of the water (p < 0.01), without difference according to the filter used (p > 0.01), and maximum yields obtained for solutions dissolved in heated water (95 mg).
CONCLUSIONS
No procedure for dissolving Skenan® led to the complete dissolution of the morphine it contains. Whatever the variations in preparation conditions, the extraction rates of the 200 mg morphine capsules were lower than those of 100 mg, without the risk reduction filters adversely impacting morphine extraction. Offering an injectable substitution to persons who inject morphine would make it possible to reduce the risks and damage, particularly overdoses, associated with variations in dosage due to preparation methods.
Topics: Humans; Morphine; Analgesics, Opioid; Capsules
PubMed: 37106464
DOI: 10.1186/s12954-023-00781-2