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Pharmacology & Therapeutics Jan 2023Morphine prescribed for analgesia has caused drug-related deaths at an estimated incidence of 0.3% to 4%. Morphine has pharmacological properties that make it... (Review)
Review
Morphine prescribed for analgesia has caused drug-related deaths at an estimated incidence of 0.3% to 4%. Morphine has pharmacological properties that make it particularly difficult to assess the causality of morphine administration with a patient's death, such as its slow transfer between plasma and central nervous sites of action and the existence of the active metabolite morphine-6-glucuronide with opioid agonistic effects, Furthermore, there is no well-defined toxic dose or plasma/blood concentration for morphine. Dosing is often adjusted for adequate pain relief. Here, we summarize reported deaths associated with morphine therapy, including associated morphine exposure and modulating patient factors such as pharmacogenetics, concomitant medications, or comorbidities. In addition, we systematically analyzed published numerical information on the stability of concentrations of morphine and its relevant metabolites in biological samples collected postmortem. A medicolegal case is presented in which the causality of morphine administration with death was in dispute and pharmacokinetic modeling was applied to infer the administered dose. The results of this analytical review suggest that (i) inference from postmortem blood concentrations to the morphine dose administered has low validity and (ii) causality between a patient's death and the morphine dose administered remains a highly context-dependent and collaborative assessment among experts from different medical specialties.
Topics: Humans; Morphine; Analgesics, Opioid; Data Science; Morphine Derivatives; Pain
PubMed: 36423714
DOI: 10.1016/j.pharmthera.2022.108312 -
European Journal of Pharmacology May 2020Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the...
Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord. This study shows that chronic intrathecal M3G sensitises animals to mechanical stimulation and elevates substance P levels in the nociceptive laminae of the spinal cord. Chronic M3G also induces antinociceptive cross-tolerance to morphine. Thus, chronic M3G exposure might contribute to morphine-induced tolerance and opioid-induced hyperalgesia.
Topics: Animals; Central Nervous System Stimulants; Disease Models, Animal; Drug Administration Schedule; Drug Tolerance; Humans; Hyperalgesia; Injections, Spinal; Male; Morphine; Morphine Derivatives; Nociception; Pain Measurement; Rats; Spinal Cord; Substance P
PubMed: 32112778
DOI: 10.1016/j.ejphar.2020.173021 -
The American Journal of Nursing Mar 2021This series on palliative care is developed in collaboration with the Hospice and Palliative Nurses Association (HPNA; https://advancingexpertcare.org). The HPNA aims to...
This series on palliative care is developed in collaboration with the Hospice and Palliative Nurses Association (HPNA; https://advancingexpertcare.org). The HPNA aims to guide nurses in preventing and relieving suffering and in giving the best possible care to patients and families, regardless of the stage of disease or the need for other therapies. The HPNA offers education, certification, advocacy, leadership, and research.
Topics: Administration, Oral; Analgesics, Opioid; Dose-Response Relationship, Drug; Hospice and Palliative Care Nursing; Humans; Infusions, Parenteral; Morphine; Nurse's Role; Oxycodone; Pain Measurement; Palliative Care
PubMed: 33625014
DOI: 10.1097/01.NAJ.0000737312.95932.4d -
Forensic Science International Aug 2019Brain tissue is a useful supplement to blood in postmortem investigations, but reference concentrations are scarce for many opioids. Heroin cases may be difficult to...
Brain tissue is a useful supplement to blood in postmortem investigations, but reference concentrations are scarce for many opioids. Heroin cases may be difficult to distinguish from morphine cases as heroin and its metabolites are rapidly degraded. We present concentrations from brain and blood and brain-blood ratios of 98 cases where morphine was quantified. These cases were grouped according to the cause of death: A: The compound was solely assumed to have caused a fatal intoxication. B: The compound presumably contributed to a fatal outcome in combination with other drugs, alcohol or disease. C: The compound was not regarded to be related to the cause of death. The cases were further classified as heroin cases if 6-acetyl-morphine or noscapine were detected. The analyses were carried out using solid-phase extraction or protein precipitation followed by ultra high-performance liquid chromatography coupled to mass spectrometry. The average brain-blood ratios of morphine were 1.2 and 1.8 for 69 morphine and 29 heroin cases, respectively. Differences in the brain-blood ratios were found for cases where heroin and morphine were involved in the cause of death, either in combination or on its own (P<0.001 and P=0.004, respectively). However, the overlap between morphine and heroin cases precludes the use of the brain-blood ratio to distinguish heroin from morphine intake. Morphine-6-glucuronide and 6-acetyl-morphine were quantified in brain and blood in a subset of the samples, yielding median brain-blood ratios of 5.1 and 8.3, respectively. The brain concentrations may aid the toxicological investigation in cases where heroin or morphine intoxications are suspected, but blood is not available.
Topics: Brain Chemistry; Chromatography, Liquid; Drug Overdose; Forensic Toxicology; Heroin; Humans; Mass Spectrometry; Morphine; Morphine Derivatives; Narcotics; Noscapine; Poisoning
PubMed: 31226641
DOI: 10.1016/j.forsciint.2019.06.007 -
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 Palliative Medicine Nov 2022Equianalgesic tools are commonly utilized to guide dose of analgesic therapy, but there is no national consensus on equianalgesic calculations in the United States. To...
Equianalgesic tools are commonly utilized to guide dose of analgesic therapy, but there is no national consensus on equianalgesic calculations in the United States. To propose a summary of current opioid equianalgesic data that include variations and trends among national institutions. Opioid equianalgesic tools were obtained between May and September 2021. For meperidine, tramadol, codeine, hydrocodone, morphine, oxycodone, oxymorphone, hydromorphone, levorphanol, fentanyl, and tapentadol, details of adjustment for incomplete tolerance, opioid equianalgesic ratios, and formulation types were collected and analyzed. Baseline opioid pharmaco kinetic data were obtained through manufacturer labels on FDA databases, including half-life (), volume of distribution (), clearance (Cl), area under the curve (AUC), max concentration (), and time to max concentration (). Thirty-two institutions' equianalgesic tools were included with each study opioid appearing on an average of 23 institutions' tools. Few tools contained guidance on levorphanol or tapentadol; or included minimum and maximum recommended doses. All tools included guidance on fentanyl, hydromorphone, oxycodone, morphine, and hydrocodone. A minority of tools included guidance on cross-tolerance considerations ( = 12, 37.5%). Oral-tramadol-to-oral-morphine and oral-hydromorphone-to-intravenous (IV)-hydromorphone had the largest variances across equianalgesic tools (6.7 ± 2.8 and 4.06 ± 1.2 mg, respectively). Opioid equianalgesia tools from across the United States demonstrated significant variation in their inclusion of guidance on adjustment for incomplete cross-tolerance, oral-to-IV, and oral-to-oral opioid equianalgesic ratios, and which opioids and formulations were listed. Tramadol and hydromorphone had the most variation in their equianalgesic guidance among the opioids.
Topics: Humans; Analgesics, Opioid; Hydromorphone; Oxycodone; Tapentadol; Tramadol; Levorphanol; Hydrocodone; Administration, Oral; Fentanyl; Morphine
PubMed: 35559657
DOI: 10.1089/jpm.2021.0678 -
Neuropharmacology Feb 2023Morphine tolerance (MT) caused by long-term use of morphine is a major medical problem. The underlying molecular mechanisms of morphine tolerance remain unclear. Here,...
Morphine tolerance (MT) caused by long-term use of morphine is a major medical problem. The underlying molecular mechanisms of morphine tolerance remain unclear. Here, we establish the morphine tolerance model in mice and verify whether a novel circRNA, circRalgapa1 is involved in morphine tolerance and its specific molecular mechanism. We show that the expression of circRalgapa1 in the spinal cord is significantly down-expressed in the spinal cord of morphine-tolerant mice. CircRalgapa1 is mainly located in the neuronal cytoplasm and co-localizes with miR-873a-5p. Mechanically, circRalgapa1 acts as competing endogenous RNAs (ceRNAs) to regulate the inhibitory of miR-873a-5p on A20 (also known as tumor necrosis factor α-induced protein 3, TNFAIP3). Functionally, overexpression of circRalgapa1 by intrathecal injection of adeno-associated virus (AAV- circRalgapa1) attenuated the formation of morphine tolerance and partially reversed the development of morphine tolerance. Moreover, overexpression of miR-873a-5p blocked the effect of AAV-circRalgapa1 on alleviating morphine tolerance in mice. In conclusion, chronic morphine administration-mediated down-regulation of circRalgapa1 in the spinal cord contributes to morphine tolerance via miR-873a-5p/A20 axis in mice. Overexpression of circRalgapa1 may be a promising RNA-based therapy for morphine tolerance.
Topics: Animals; Mice; Cytoplasm; Down-Regulation; MicroRNAs; Morphine; Spinal Cord; RNA, Circular; Drug Tolerance
PubMed: 36455645
DOI: 10.1016/j.neuropharm.2022.109353 -
Journal of Veterinary Pharmacology and... Jul 2023The metabolism and pharmacokinetics of intravenous (i.v.) morphine in the horse have been described; however, administration of therapeutic doses has also been...
The metabolism and pharmacokinetics of intravenous (i.v.) morphine in the horse have been described; however, administration of therapeutic doses has also been associated with neuroexcitation and adverse gastrointestinal effects. In this study, we hypothesized that oral administration would lead to comparable concentrations of morphine and its presumed active metabolite, morphine 6-glucuronide (M6G) without the adverse effects associated with i.v. administration. Eight horses were administered a single i.v. dose of 0.2 mg/kg morphine and oral doses of 0.2, 0.6, and 0.8 mg/kg of morphine in a four-way balanced crossover design, with a 2-week washout period between doses. Concentrations of morphine and metabolites were determined, and pharmacokinetic parameters determined. Physiologic and behavioral outcomes including the number of steps taken, changes in heart rate, and gastrointestinal borborygmi were assessed. Oral administration of morphine resulted in higher concentrations of morphine metabolites, including M6G (C : 11.6-37.8 ng/mL (0.6 mg/kg); 15.8-42.6 ng/mL (0.8 mg/kg)), compared with i.v. Bioavailability was 36.5%, 27.6% and 28.0% for 0.2, 0.6 and 0.8 mg/kg, respectively. Behavioral and physiologic changes were noted in all groups but were less prominent with oral compared with i.v. administration. Results of the current study are encouraging for further study, specifically anti-nociceptive effects of morphine following oral administration.
Topics: Animals; Administration, Oral; Analgesics, Opioid; Biological Availability; Horses; Morphine; Morphine Derivatives; Cross-Over Studies
PubMed: 36883679
DOI: 10.1111/jvp.13122 -
Journal of Palliative Care Apr 2022Previous research unambiguously establishes the importance of knowledge and education about opioids and pain management in medical care. This article aimed at...
Previous research unambiguously establishes the importance of knowledge and education about opioids and pain management in medical care. This article aimed at describing the perception of the general public on the uses and the risks of morphine in palliative care in an Ecuadorian sample, where training and access to those services is limited. We used an online recruited sample of 257 participants for this cross-sectional descriptive study. Participants responded to an online self-report survey regarding morphine's effects and its relationship with addiction and death in a palliative care context. Analyses indicate that there is a lack of understanding about the effectiveness of morphine and that, overall, participants did not associate morphine with death and dying. Results also show that people in health-related occupations did not differ from the general public in beliefs about the addiction and the effectiveness of morphine. However, occupation and education effects were noted for several other items, as well as whether the participants had direct experiences with palliative care as either a patient or a caregiver. There is still misinformation about opioids such as morphine in the general public and health professionals in Ecuador. Although personal experiences with pain control and palliative care are linked to better knowledge about opioids, education is still necessary to overcome the myths around them. Future research could address the found misconceptions to increase health literacy through education policies and interventions.
Topics: Analgesics, Opioid; Cross-Sectional Studies; Ecuador; Humans; Morphine; Palliative Care
PubMed: 34128421
DOI: 10.1177/08258597211026398 -
Chemical Record (New York, N.Y.) Sep 2021The morphinans are an important class of structurally fascinating and physiologically important natural products as exemplified by the famous opium alkaloids of the... (Review)
Review
The morphinans are an important class of structurally fascinating and physiologically important natural products as exemplified by the famous opium alkaloids of the morphine family. Although this class of secondary metabolites from the juice of the opium poppy capsule was already used for medicinal purposes thousands of years ago, chemical modifications are still being applied to the core structure today in order to achieve the most specific effect on the various receptor subtypes possible with the fewest possible side effects. The unusual architecture of the morphinan core has also proven to be a highly challenging target for total synthesis. This review highlights electrosynthetic approaches towards natural and semisynthetic morphinan alkaloids. The historical progress in applying anodic aryl-aryl couplings to the construction of the morphinan framework is described in chronological order while particular benefits and challenges concerning the electrochemical transformations are grouped together, including the influence of substitution patterns, protecting groups, and reaction conditions.
Topics: Morphinans; Morphine; Papaver
PubMed: 33955153
DOI: 10.1002/tcr.202100078