Formation of chronic morphine withdrawal memories requires C1QL3-mediated regulation of PSD95 in the mouse basolateral amygdala.

Chronic morphine withdrawal memory formation is a complex process influenced by various molecular mechanisms. In this study, we aimed to investigate the contributions of the basolateral amygdala (BLA) and complement component 1, q subcomponent-like 3 (C1QL3), a secreted and presynaptically targeted protein, to the formation of chronic morphine (repeat dosing of morphine) withdrawal memory using conditioned place aversion (CPA) and chemogenetic methods. We conducted experiments involving the inhibition of the BLA during naloxone-induced withdrawal to assess its impact on CPA scores, providing insights into the significance of the BLA in the chronic morphine memory formation process. We also examined changes in C1ql3/C1QL3 expression within the BLA following conditioning. Immunofluorescence analysis revealed the colocalization of C1QL3 and the G protein-coupled receptor, brain-specific angiogenesis inhibitor 3 (BAI3) in the BLA, supporting their involvement in synaptic development. Moreover, we downregulated C1QL3 expression in the BLA to investigate its role in chronic morphine withdrawal memory formation. Our findings revealed that BLA inhibition during naloxone-induced withdrawal led to a significant reduction in CPA scores, confirming the critical role of the BLA in this memory process. Additionally, the upregulation of C1ql3 expression within the BLA postconditioning suggested its participation in withdrawal memory formation. The colocalization of C1QL3 and BAI3 in the BLA further supported their involvement in synaptic development. Furthermore, downregulation of C1QL3 in the BLA effectively hindered chronic morphine withdrawal memory formation, emphasizing its pivotal role in this process. Notably, we identified postsynaptic density protein 95 (PSD95) as a potential downstream effector of C1QL3 during chronic morphine withdrawal memory formation. Blocking PSD95 led to a significant reduction in the CPA score, and it appeared that C1QL3 modulated the ubiquitination-mediated degradation of PSD95, resulting in decreased PSD95 protein levels. This study underscores the importance of the BLA, C1QL3 and PSD95 in chronic morphine withdrawal memory formation. It provides valuable insights into the underlying molecular mechanisms, emphasizing their significance in this intricate process.

Evaluating the Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Patients with Cancer.

The Commercially Insured health Plan Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (CIP-RIOSORD) is an evidence-based tool to determine serious opioid-induced respiratory depression (OIRD) or overdose risk. The CIP-RIOSORD total score determines a risk class and estimates the probability for an OIRD event within the next 6 months. We performed a single-center, retrospective analysis to determine CIP-RIOSORD baseline scores and the most common predictive factors in patients with cancer. Patients (n = 160) were split into new consultations (n = 83, Group 1) versus the first documented follow-up consultation (n = 77, Group 2). Most patients were Caucasian women with metastatic gastrointestinal cancer. CIP-RIOSORD scores for Group 1 patients were 14.8 ± 15.2 (mean ± SD, risk class 4). Group 2 patients had higher CIP-RIOSORD scores (16.6 ± 14.9, risk class 4). For Group 1, the most common CIP-RIOSORD predictive factors were use of a long-acting opioid formulation (n = 24, 29%) and daily oral morphine equivalent (OME) ≥100 (n = 20, 24%); for Group 2, predictive factors were use of an antidepressant (n = 34, 44%) and a long-acting opioid formulation (n = 27, 35%). Based on the CIP-RIOSORD, there is a 15% probability of experiencing a serious OIRD event or overdose within the next 6 months.

Behavioral and pharmacological characterization of planarian nociception.

Introduction: Pain mostly arises because specialized cells called nociceptors detect harmful or potentially harmful stimuli. In lower animals with less convoluted nervous system, these responses are believed to be purely nociceptive. Amongst invertebrate animal models, planarians are becoming popular in a wide range of pharmacological and behavioral studies beyond the field of regeneration. Recent publications led the way on pain studies by focusing on nociceptive behaviors such as the 'scrunching' gait displayed under various noxious stimuli, as opposed to the 'gliding' gait planarians usually adopt in normal conditions. Methods: In this study, we adapted commonly used nociceptive tests to further explore nociception in planarians of the species Girardia dorotocephala. By using behavioral analysis in open fields and place preferences, we managed to set up chemical, thermal and mechanical nociceptive tests. We also adapted RNA interference protocols and explored the effects of knocking down TRPA1 ion channels, one of the main effectors of chemically and thermally-induced nociceptive responses in vertebrates. Results: Consequently, we demonstrated the reliability of the scrunching gait in this planarian species, which they displayed in a dose-dependent manner when exposed to the irritant AITC. We also showed that suppressing the expression of TRPA1 ion channels completely suppressed the scrunching gait, demonstrating the involvement of TRPA1 nociceptors in this nociceptive reaction. Besides, we also explored the effects of two common analgesics that both displayed strong antinociceptive properties. First, morphine reduced the chemically-induced nociceptive scrunching gaits by more than 20% and shifted the EC50 of the dose-response curve by approximately 10 µM. Secondly, the NSAID meloxicam drastically reduced chemically-induced scrunching by up to 60% and reduced heat avoidance in place preference tests. Discussion: Thus, we managed to characterize both behavioral and pharmacological aspects of G. dorotocephala's nociception, further developing the use of planarians as a replacement model in pain studies and more globally the study of invertebrate nociception.

Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders.

RATIONALE: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. OBJECTIVE: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. METHODS: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. RESULTS: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at µ-opioid (MOP) receptors (Ki = 11 nM; lacking ß-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. CONCLUSIONS: ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.

Immunosuppressive effects of morphine on macrophage polarization and function.

Macrophages play a pivotal role in safeguarding against a broad spectrum of infections, from viral, bacterial, fungal to parasitic threats and contributing to the immune defense against cancer. While morphine's immunosuppressive effects on immune cells are extensively documented, a significant knowledge gap exists regarding its influence on macrophage polarization and differentiation. Hence, we conducted a study that unveils that prior exposure to morphine significantly impedes the differentiation of bone marrow cells into macrophages. Furthermore, the polarization of macrophages toward the M1 phenotype under M1-inducing conditions experiences substantial impairment, as evidenced by the diminished expression of CD80, CD86, CD40, iNOS, and MHCII. This correlates with reduced expression of M1 phenotypical markers such as iNOS, IL-1ß, and IL-6, accompanied by noticeable morphological, size, and phagocytic alterations. Further, we also observed that morphine affected M2 macrophages. These findings emphasize the necessity for a more comprehensive understanding of the impact of morphine on compromising macrophage function and its potential ramifications for therapeutic approaches.

Low-dose short infusion ketamine as adjunct to morphine for acute long bone fracture in the emergency department: a randomized controlled trial.

BACKGROUND: Ketamine is recognized as an alternative for pain management; however, concerns about emergent adverse reactions have limited its widespread adoption. This study aimed to assess the efficacy of a short infusion of low-dose ketamine (LDK) compared to intravenous morphine (MOR) as adjunctive analgesia for acute long bone fracture pain. METHODS: This single-blinded, randomized controlled trial was conducted in a single emergency department. Patients with acute long bone fractures and numerical rating scale (NRS) pain scores ≥ 6 following an initial dose of intravenous morphine were assigned to receive either a LDK (0.3 mg/kg) over 15 min or intravenous MOR at a dose of 0.1 mg/kg administered over 5 min. Throughout a 120-min observation period, patients were regularly evaluated for pain level (0-10), side effects, and the need for additional rescue analgesia. RESULTS: A total of 58 subjects participated, with 27 in the MOR group and 31 in the LDK group. Demographic variables and baseline NRS scores were comparable between the MOR (8.3 ± 1.3) and LDK (8.9 ± 1.2) groups. At 30 min, the LDK group showed a significantly greater mean reduction in NRS scores (3.1 ± 2.03) compared to the MOR group (1.8 ± 1.59) (p = 0.009). Similarly, at 60 min, there were significant differences in mean NRS score reductions (LDK 3.5 ± 2.17; MOR mean reduction = 2.4, ± 1.84) with a p-value of 0.04. No significant differences were observed at other time intervals. The incidence of dizziness was higher in the LDK group at 19.4% (p = 0.026). CONCLUSION: Short infusion low-dose ketamine, as an adjunct to morphine, is effective in reducing pain during the initial 30 to 60 min and demonstrated comparability to intravenous morphine alone in reducing pain over the subsequent 60 min for acute long bone fractures. However, it was associated with a higher incidence of dizziness. TRIAL REGISTRATION: NMRR17318438970 (2 May 2018; www.nmrr.gov.my ).

Large field-of-view metabolic profiling of murine brain tissue following morphine incubation using label-free multiphoton microscopy.

BACKGROUND: Although the effects on neural activation and glucose consumption caused by opiates such as morphine are known, the metabolic machinery underlying opioid use and misuse is not fully explored. Multiphoton microscopy (MPM) techniques have been developed for optical imaging at high spatial resolution. Despite the increased use of MPM for neural imaging, the use of intrinsic optical contrast has seen minimal use in neuroscience. NEW METHOD: We present a label-free, multimodal microscopy technique for metabolic profiling of murine brain tissue following incubation with morphine sulfate (MSO4). We evaluate two- and three-photon excited autofluorescence, and second and third harmonic generation to determine meaningful intrinsic contrast mechanisms in brain tissue using simultaneous label-free, autofluorescence multi-harmonic (SLAM) microscopy. RESULTS: Regional differences quantified in the cortex, caudate, and thalamus of the brain demonstrate region-specific changes to metabolic profiles measured from FAD intensity, along with brain-wide quantification. While the overall intensity of FAD signal significantly decreased after morphine incubation, this metabolic molecule accumulated near the nucleus accumbens. COMPARISON WITH EXISTING METHODS: Histopathology requires tissue fixation and staining to determine cell type and morphology, lacking information about cellular metabolism. Tools such as fMRI or PET imaging have been widely used, but lack cellular resolution. SLAM microscopy obviates the need for tissue preparation, permitting immediate use and imaging of tissue with subcellular resolution in its native environment. CONCLUSIONS: This study demonstrates the utility of SLAM microscopy for label-free investigations of neural metabolism, especially the intensity changes in FAD autofluorescence and structural morphology from third-harmonic generation.

Morphine-Driven m6A Epitranscriptomic Neuroadaptations in Primary Cortical Cultures.

Opioid overdose is the leading cause of accidental death in the United States and remains a major public health concern, despite significant resources aimed at combating opioid misuse. Neurobiological research to elucidate molecular and cellular consequences of opioid exposure is required to define avenues to explore for reversal of opioid-induced neuroadaptations. Opioids impart well-documented regulation of the transcriptome and epigenetic modifications in the brain, but opioid-induced epitranscriptomic posttranscriptional regulation of RNA is vastly understudied. N6-methyladenosine (m6A) RNA methylation is significantly enriched in the brain and involved in learning, memory, and reward. m6A modifications have not been studied in opioid use disorder, despite being the most common RNA modification. We detected significant regulation of m6A-modifying enzymes in rat primary cortical cultures following morphine treatment, including AlkB Homolog 5 (Alkbh5). The m6a demethylase ALKBH5 functions as an m6A eraser, removing m6A modifications from mRNA. We hypothesized that chronic opioid treatment regulates m6A modifications through modulation of Alkbh5 and profiled m6A modifications in primary cortical cultures following chronic morphine treatment and Alkbh5 knock-down. We observed differential regulation of m6A modifications for a common set of transcripts following morphine or Alkbh5 knock-down, and the two treatments elicited concordant m6A epitranscriptomic profiles, suggesting that a subset of morphine-driven m6A modifications may be mediated through downregulation of Alkbh5 in cortical cultures. Gene Ontology terms of commonly regulated transcripts included serotonin secretion, synapse disassembly, neuron remodeling, and immune response. Thus, we conclude that morphine can drive epitranscriptomic changes, a subset of which may occur in an Alkbh5-dependent manner.

Hospital and long-term opioid use according to analgosedation with fentanyl vs. morphine: Findings from the ANALGESIC trial.

Objectives: Opioid use disorder is extremely common. Many long-term opioid users will have their first exposure to opioids in hospitals. We aimed to compare long-term opioid use in patients who received fentanyl vs. morphine analgosedation and assess ICU related risk factors for long-term opioid use. Design: We performed a post-hoc analysis of the Assessment of Opioid Administration to Lead to Analgesic Effects and Sedation in Intensive Care (ANALGESIC) cluster randomised crossover trial of fentanyl and morphine infusions for analgosedation in mechanically ventilated patients. Setting: Two mixed, adult, university affiliated intensive care units in Melbourne, Australia. Participants: Adult patients who were mechanically ventilated and received fentanyl or morphine for analgosedation in the ANALGESIC trial. Main outcome measures: We assessed discharge and long-term (90-365 days) opioid use in opioid-naïve patients at hospital admission according to the agent used for analgosedation. Results: We studied 477 patients (242 fentanyl and 235 morphine). There were no differences between discharge (16.5% vs. 14.0%, p = 0.45), 90-180 day post-discharge use (3.7% vs 2.1%, p = 0.30) or 180-365 day post-discharge use (3.4% vs 1.3%, p = 0.22) of opioids when comparing those patients who received fentanyl vs. those who received morphine. Surgical diagnosis and one chronic condition were associated with increased hospital discharge prescription of opioids, whereas increasing APACHE II score was associated with decreased discharge prescription. No ICU-related factors were associated with long-term opioid use. Conclusions: Approximately one in seven opioid-naïve patients who receive analgosedation for mechanical ventilation in ICU will be prescribed opioid medications at hospital discharge. There was no difference in discharge prescription or long-term use of opioids depending on whether fentanyl or morphine was used for analgosedation.

Effects of Intrathecal Morphine Administration in Patients Undergoing Primary Total Hip Arthroplasty Under Spinal Anesthesia With Quadratus Lumborum Block for Postoperative Analgesia.

Introduction Quadratus lumborum (QL) block has previously been shown to provide improved analgesia in patients undergoing primary total hip arthroplasty (THA) under spinal anesthesia when compared to spinal anesthesia alone. Additionally, recent studies have shown the addition of intrathecal morphine (ITM) to provide superior postoperative analgesia in patients undergoing various surgical interventions including total knee arthroplasty under spinal anesthesia with peripheral nerve blockade. At this time, however, there has not been a study evaluating the effects of intrathecal morphine in patients undergoing THA under spinal anesthesia with QL block. This study aims to assess if the addition of intrathecal morphine can provide adequate or even superior postoperative analgesia in patients undergoing primary THA. Methods This retrospective study included 26 patients in the spinal/QL block/intrathecal morphine (SA+QLB+ITM) group, 31 patients in the spinal/QL block group (SA+QLB), and 28 patients in the spinal only (SA or control) group. Twenty-six patients undergoing primary THA under a combination of spinal anesthesia and peripheral nerve blockade (quadratus lumborum block) were given a dose of 100 mcg of intrathecal morphine. Various parameters were evaluated including Post-Anesthesia Care Unit (PACU) and 24-hour visual analog scale (VAS) scores, time to first opioid use, 24- and 48-hour total opioid use as oral morphine equivalents (OME), 24-hour ambulation distance, and time from block placement to hospital discharge. The results were analyzed and compared to patients undergoing primary THA under spinal anesthesia with QL block (no intrathecal morphine) and compared to a control group of patients undergoing primary THA under spinal anesthesia only. Results The study analysis included 26 patients in the SA+QLB+ITM group, 31 patients in the SA+QLB group, and 28 patients in the SA (control) group. When compared with the control group, the SA+QLB+ITM had lower 24-hour total opioid usage (mean difference 20.80 OME, CI 6.454 to 35.15, p-value 0.0025), longer time to 1st opioid use (mean difference -20.51 hours later, p-value .0052), lower 24-hr VAS (difference 2.421, p-value 0.0012, CI 0.8559 to 3.987), and faster time to discharge (16.00 hr earlier, p-value 0.0459). When compared to the SA+QLB group, the SA+QLB+ITM group only showed a statistically significant difference in faster time to discharge (19.46 hr earlier, p-value 0.0068). However, while there was no statistically significant difference in time to 1st opioid use between the control and SA+QLB group, the difference did become significant when comparing the control to the SA+QLB+ITM group (mean difference -20.51 hours later (p-value .0052). There was no significant difference in either of the three groups in ambulation distance at 24 hours, PACU VAS, or 48-hour total opioid use. Conclusion Our study concludes that the addition of 100 mcg ITM for total hip arthroplasty under spinal anesthesia improved postoperative analgesia compared to the control group. Also, the ITM group did better with respect to delay in first opioid use and decreased hospital stay compared to the control and block-only groups. Our study warrants no more concerns of PONV, pruritus, or respiratory depression with this dose of ITM and requires standard postoperative care.

Morphine timing-dependent modulation of TRPV1 phosphorylation correlates with differential morphine effects on myocardial ischemia/reperfusion injury.

Opioids are used for pain relief in patients suffering from acute myocardial ischemia or infarction. Clinical and laboratory studies demonstrate that morphine treated patients or the experimental animal model suffering acute myocardial ischemia and reperfusion, may worsen myocardial viability. As transient receptor potential vanilloid 1 (TRPV1) plays important roles in pain sensation and cardio-protection, we query whether opioids may exacerbate myocardial viability via interaction with TRPV1 activity in the pain relief. We found the co-expressions of TRPV1 and opioid µ, δ and κ receptors in adult rat cardiomyocytes. Intravenous injection of morphine (0.3 mg/kg) at 20 min after induction of myocardial ischemia, in the rat model of acute myocardial ischemia and reperfusion, induced significant reduction of phosphorylated TRPV1 (p-TRPV1) in the ventricular myocardium and increase in serum cardiac troponin I (cTnI), compared with the ischemia/reperfusion controls (all P < 0.05). The effects of morphine were completely reversed by selective opioid µ, δ and κ receptor antagonists. While significant upregulation of p-TRPV1 (P < 0.05) and improvement of ±dP/dt max (all P < 0.05) were detected in the animals giving the same dose of morphine before induction of myocardial ischemia. The changes in p-TRPV1 correlate with the alterations of cTnI (r = -0.5840, P = 0.0283) and ±dP/dt max (r = 0.8084, P = 0.0005 and r = -0.8133, P = 0.0004, respectively). The findings of this study may indicate that potentiation and attenuation of TRPV1 sensitivity correlate with the improvement of the cardiac performance and the aggravation of myocardial viability, respectively, by giving morphine before and during myocardial ischemia and reperfusion.

Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial.

BACKGROUND: To determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0-3 years after cardiac surgery with cardiopulmonary bypass. METHODS: Multi-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016-July 2020. Children aged 0-3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if numeric rating scale (NRS) pain scores exceeded predetermined cutoff values. Primary outcome was median weight-adjusted cumulative morphine dose in mcg/kg in the first 48 h postoperative. For the comparison of the primary outcome between groups, the nonparametric Van Elteren test with stratification by center was used. For comparison of the proportion of patients with one or more NRS pain scores of 4 and higher between the two groups, a non-inferiority analysis was performed using a non-inferiority margin of 20%. RESULTS: In total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. Fourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median weight-adjusted cumulative morphine consumption in the first 48 h postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0-432.5) mcg/kg vs 692.6 (IQR, 532.7-856.1) mcg/kg; P < 0.001). The rescue morphine consumption was similar between the groups (p = 0.38). Non-inferiority of IV paracetamol administration in terms of NRS pain scores was proven; difference in proportion - 3.1% (95% CI - 16.6-10.3%). CONCLUSIONS: In children aged 0-3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the median weight-adjusted cumulative morphine consumption in the first 48 h after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic. Trial Registration Clinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20.

[Pharmacological pain management in cancer patients]. / Medikamentöse Schmerztherapie bei Patienten mit Tumorerkrankungen.

Pharmacological pain therapy in cancer patients is based on guideline recommendations, which, however, do not fully coincide in all aspects due to varying weighting of evidence. The present article discusses current issues including the decreasing significance of the World Health Organization (WHO) analgesic ladder, with its distinction between step 2 and 3 being increasingly questioned. Risks of nonopioid analgesics such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), particularly in older populations, are discussed. Paracetamol may potentially reduce the effectiveness of immunotherapies. Aspects of administering analgesics via a feeding tube are considered. Recommendations for the treatment of episodic pain, transitioning between different opioids, and some relevant interactions are also discussed.

Inhibition of endoplasmic reticulum stress attenuates morphine protracted abstinence-induced anxiety-like behaviors in the male mice.

The anxiety caused by morphine protracted abstinence is considered to be an important factor contributes to drug-seeking and relapse. Endoplasmic reticulum (ER) stress plays important roles in many kinds of mental disorders including drug addiction and anxiety, but it is unclear whether ER stress is involved in anxiety-like behaviors induced by morphine withdrawal. In this study, by using behavioral test, western blot, immunofluorescence, electron transmission microscope, we found that: (1) Inhibition of endoplasmic reticulum stress by 4-Phenylbutyric acid (4-PBA) could attenuate anxiety-like behaviors induced by morphine withdrawal. (2) The endoplasmic reticulum stress-related proteins in the lateral habenula (LHb) but not in the nucleus accumbens (NAc), ventral pallidum (VP), basolateral amygdala (BLA) and CA1 of hippocampus was upregulated by morphine withdrawal, upregulation of endoplasmic reticulum stress-related proteins in the lateral habenula induced by morphine withdrawal was inhibited by 4-PBA. (3) Endoplasmic reticulum stress-related protein CHOP and eIF2α were expressed in neurons but not in microglia in the LHb. (4) Morphine withdrawal induced neuronal morphological change in the LHb, which was attenuated by 4-PBA.

Intravenous administration of recombinant Phα1ß: Antinociceptive properties and morphine tolerance reversal in a cancer-associated pain model.

Cancer-related pain is considered one of the most prevalent symptoms for those affected by cancer, significantly influencing quality of life and treatment outcomes. Morphine is currently employed for analgesic treatment in this case, however, chronic use of this opioid is limited by the development of analgesic tolerance and adverse effects, such as digestive and neurological disorders. Alternative therapies, such as ion channel blockade, are explored. The toxin Phα1ß has demonstrated efficacy in blocking calcium channels, making it a potential candidate for alleviating cancer-related pain. This study aims to assess the antinociceptive effects resulting from intravenous administration of the recombinant form of Phα1ß (r-Phα1ß) in an experimental model of cancer-related pain in mice, tolerant or not to morphine. The model of cancer-induced pain was used to evaluate these effects, with the injection of B16F10 cells, followed by the administration of the r-Phα1ß, and evaluation of the mechanical threshold by the von Frey test. Also, adverse effects were assessed using a score scale, the rotarod, and open field tests. Results indicate that the administration of r-Phα1ß provoked antinociception in animals with cancer-induced mechanical hyperalgesia, with or without morphine tolerance. Previous administration of r-Phα1ß was able to recover the analgesic activity of morphine in animals tolerant to this opioid. r-Phα1ß was proved safe for these parameters, as no adverse effects related to motor and behavioral activity were observed following intravenous administration. This study suggests that the concomitant use of morphine and r-Phα1ß could be a viable strategy for pain modulation in cancer patients.

Advances in animal models of prenatal opioid exposure.

Neonatal opioid withdrawal syndrome (NOWS) is a growing public health concern. The complexity of in utero opioid exposure in clinical studies makes it difficult to investigate underlying mechanisms that could ultimately inform early diagnosis and treatments. Clinical studies are unable to dissociate the influence of maternal polypharmacy or the environment from direct effects of in utero opioid exposure, highlighting the need for effective animal models. Early animal models of prenatal opioid exposure primarily used the prototypical opioid, morphine, and opioid exposure that was often limited to a narrow period during gestation. In recent years, the number of preclinical studies has grown rapidly. Newer models utilize both prescription and nonprescription opioids and vary the onset and duration of opioid exposure. In this review, we summarize novel prenatal opioid exposure models developed in recent years and attempt to reconcile results between studies while critically identifying gaps within the current literature.

Neuropsychiatric Effects Associated with Opioid-Based Management for Palliative Care Patients.

PURPOSE OF REVIEW: The abundance of opioids administered in the palliative care setting that was once considered a standard of care is at present necessitating that providers evaluate patients for unintentional and deleterious symptomology related to aberrant opioid use and addiction. Polypharmacy with opioids is dynamic in affecting patients neurologically, and increased amounts of prescriptions have had inimical effects, not only for the individual, but also for their families and healthcare providers. The purpose of this review is to widen the perspective of opioid consequences and bring awareness to the numerous neuropsychiatric effects associated with the most commonly prescribed opioids for patients receiving palliative care. RECENT FINDINGS: Numerous clinical and research studies have found evidence in support for increased incidence of opioid usage and abuse as well as undesirable neurological outcomes. The most common and concerning effects of opioid usage in this setting are delirium and problematic drug-related behavioral changes such as deceitful behavior towards family and physicians, anger outbursts, overtaking of medications, and early prescription refill requests. Other neuropsychiatric effects detailed by recent studies include drug-seeking behavior, tolerance, dependence, addictive disorder, anxiety, substance use disorder, emotional distress, continuation of opioids to avoid opioid withdrawal syndrome, depression, and suicidal ideation. Opioid usage has detrimental and confounding effects that have been overlooked for many years by palliative care providers and patients receiving palliative care. It is necessary, even lifesaving, to be cognizant of potential neuropsychiatric effects that opioids can have on an individual, especially for those under palliative care. By having an increased understanding and awareness of potential opioid neuropsychiatric effects, patient quality of life can be improved, healthcare system costs can be decreased, and patient outcomes can be met and exceeded.

Comparative effects of epidural analgesia and intramuscular morphine on maternal and neonatal outcomes: a retrospective cohort study.

BACKGROUND: The global practice of pain management during labor involves the use of epidural analgesia or intramuscular morphine. However, the impact of these methods on maternal and neonatal short-term outcomes remains uncertain. OBJECTIVE: This study aimed to evaluate the effect of labor exposure to epidural analgesia and intramuscular morphine on neonatal intensive care unit admission rates and other associated maternal and neonatal outcomes such as sepsis, respiratory distress, instrumental delivery, birth trauma, low Apgar score, and chorioamnionitis. STUDY DESIGN: A study at the Women's Wellness and Research Center in Qatar analyzed 7721 low-risk normal vaginal deliveries from January 2017 to April 2018. Results were analyzed using descriptive and backward stepwise multinomial regression analysis, categorizing outcomes on the basis of pain management during active labor. RESULTS: Of the 7607 participants in the final sample, 2606 received epidural analgesia, 1338 received intramuscular morphine, 286 received both, and 3304 received neither. Multinomial regression analysis revealed no difference in neonatal intensive care unit admission in the epidural analgesia group or in the intramuscular morphine group compared with the group that received neither intervention. However, the analysis showed a significant association between the combined use of epidural analgesia and intramuscular morphine and neonatal intensive care unit admission due to respiratory depression (adjusted odds ratio, 8.63; 95% confidence interval, 1.07-69.46; P=.04). Moreover, there was a significant association between prolonged duration of the second stage of labor and receiving epidural analgesia alone (adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.02; P<.001) or the combination of epidural analgesia and intramuscular morphine (adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.03; P<.001). In addition, the combined use of epidural analgesia and intramuscular morphine was associated with gestational age (adjusted odds ratio, 1.86; 95% confidence interval, 1.19-2.90; P=.01) and infant sex (adjusted odds ratio, 3.72; 95% confidence interval, 1.54-9.01; P=.003). Intramuscular morphine alone was only linked to low Apgar score at 1 minute (adjusted odds ratio, 6.29; 95% confidence interval, 1.33-29.83; P=.02). CONCLUSION: In low-risk mothers, combining epidural analgesia and intramuscular morphine during labor increases NICU admission risk due to respiratory depression. However, the individual use of either method shows distinct clinical profile. Further research is warranted to enhance understanding and optimize pain management protocols.

Effectiveness of Erector Spinae Muscle Block in Vertebral Oncologic Fracture.

Objectives An observational, retrospective, longitudinal, and analytical study aimed to evaluate the effectiveness of the erector spinae plane (ESP) block in managing pain in patients with vertebral fractures secondary to tumoral activity. This study included patients treated at the Pain Clinic who underwent ESP block. The objectives were to describe demographic characteristics, oncological diagnosis, vertebral fracture features, imaging techniques, medications used, and the level of ESP block. Additionally, pain levels were assessed using a numerical analog scale, and the consumption of opioid analgesic medications before and after the ESP block, during follow-up consultations, along with patient satisfaction. Methodology This retrospective, observational, and analytical study was conducted at the Pain Clinic of the National Cancer Institute of Mexico. Patients with vertebral fractures secondary to tumor activity were included, with data collected from March 2020 to September 2023. A consecutive non-probabilistic sampling method was employed, and specific inclusion and exclusion criteria were applied. Data were analyzed using descriptive statistics and the Wilcoxon signed-rank test for quantitative variables, with a significance level of p ≤ 0.05. IBM SPSS Statistics v. 26.0 (IBM Corp., Armonk, NY) software was utilized. Results A sample comprising 16 individuals was obtained, with an equal distribution between males and females. Fracture levels displayed variation, with L3 (12.5%) and T6 (12.5%) being the most prevalent. The ESP approach was primarily conducted using ultrasound (68.8%), while fluoroscopy and computed tomography were utilized in 25.0% and 6.3% of cases, respectively. Predominantly, methylprednisolone and ropivacaine (75.0%) were administered, with phenol used in 18.8% and a combination of methylprednisolone and bupivacaine in 6.3%. Patient satisfaction levels were reported at 81.3% (satisfied or very satisfied). Statistically significant disparities were noted between baseline and incidental pain reduction and oral opioid equivalent dosage in milligrams of morphine per day (MME/day) before and after ESP block (p ≤ 0.05). Conclusions This research provides promising preliminary evidence supporting the effectiveness of ESP block for pain management in vertebral fractures secondary to tumoral activity, enhancing the quality and safety of care for oncology patients. The absence of complications, significant improvement in pain, and reduction in opioid dependence underscore the clinical relevance of this therapeutic approach. An observational, retrospective, longitudinal, and analytical study aimed to evaluate the effectiveness of the ESP block in managing pain in patients with vertebral fractures secondary to tumoral activity. This study included patients treated at the Pain Clinic who underwent ESP block. The objectives were to describe demographic characteristics, oncological diagnosis, vertebral fracture features, imaging techniques, medications used, and the level of ESP block. Additionally, pain levels were assessed using a numerical analogue scale, and the consumption of opioid analgesic medications before and after the ESP block, during follow-up consultations, along with patient satisfaction.