Challenges of acute pain management in older patients.

Adequate management of acute pain in the older population is crucial. However, it is inherently complex because of multiple physiological changes that significantly impact both the pharmacokinetics and pharmacodynamics of medications. Current guidelines promote paracetamol as the first-line analgesic for acute pain in older adults, whereas opioids are advised cautiously for moderate to severe acute pain. However, opioids come with a significant array of side effects, which can be more pronounced in older individuals. Ketamine administered via intranasal (IN) and nebulised inhalation in the emergency department for managing acute pain in older patients shows promising potential for improving pain management and reducing opioid reliance Kampan, Thong-on, Sri-on (2024, Age Ageing, 53, afad255). Nebulised ketamine appears superior in terms of adverse event incidence. However, the adoption of IN or nebulised ketamine in older adult acute pain management remains unclear because of the lack of definitive conclusions and clear guidelines. Nevertheless, these modalities can be valuable options for patients where opioid analgesics are contraindicated or when intravenous morphine titration is impractical or contraindicated. Here, we review these concepts, the latest evidence and propose avenues for research.

Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial.

BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.

Antinociceptive and adverse effects of morphine:ketamine mixtures in rats.

Prescription opioids are the gold standard for treating moderate to severe pain despite their well-documented adverse effects. Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. One strategy for improving the margin of safety of opioids is combining them with non-opioid drugs to decrease the opioid dose needed for pain relief, thereby reducing adverse effects that occur with larger doses. The N-methyl-D-aspartate receptor antagonist ketamine has been used safely as an analgesic but only under a very limited range of conditions. The current studies characterized the antinociceptive, behavioral suppressant, and gastrointestinal effects of morphine and ketamine alone and in mixtures to determine their interaction in 24 adult male Sprague-Dawley rats (n = 8 per assay). Given alone, both morphine and ketamine produced antinociception, decreased responding for food, and reduced gastrointestinal transit (i.e. produced constipation). The effects of morphine:ketamine mixtures generally were additive, except for the antinociceptive effects of 1:1 mixtures for which the difference in slope (i.e. non-parallel shift) between the observed and predicted effects suggested synergy at smaller doses and additivity at larger doses. The potency of morphine to produce constipation was not enhanced by administration of morphine:ketamine mixtures with antinociceptive effects. The nature of the interaction between morphine and ketamine for adverse effects such as dependence, withdrawal, abuse, or respiratory depression remains unknown but also might be related to the ratio of each drug in mixtures. It will be important to identify conditions that produce the largest potential therapeutic window in humans.

Minimal important difference in postoperative morphine consumption after hip and knee arthroplasty using nausea, vomiting, sedation and dizziness as anchors.

BACKGROUND: Morphine-sparing effects are often used to evaluate non-opioid analgesic interventions. The exact effect that would warrant the implementation of these interventions in clinical practice (a minimally important difference) remains unclear. We aimed to determine this with anchor-based methods. METHODS: This was a post hoc analysis of three studies investigating pain management after hip or knee arthroplasty (PANSAID [NCT02571361], DEX-2-TKA [NCT03506789] and Pain Map [NCT02340052]). The overall population was median aged 70, median ASA 2, 54% female. We examined the correlation between 0 and 24 h postoperative iv morphine equivalent consumption and the severity of nausea, vomiting, sedation and dizziness. The anchor was different severity degrees of these opioid-related adverse events. The primary outcome was the difference in morphine consumption between patients experiencing no versus only mild events. Secondary outcomes included the difference in morphine consumption between patients with mild versus moderate and moderate versus severe events. We used Hodges-Lehmann median differences, exact Wilcoxon-Mann-Whitney tests and quantile regression. RESULTS: The difference in iv morphine consumption was 6 mg (95% confidence interval: 4-8) between patients with no versus only mild events, 5 mg (2-8) between patients with mild versus moderate events and 0 mg (-4 to 4) between patients with moderate versus severe events. CONCLUSIONS: In populations comparable to this post-hoc analysis (orthopaedic surgery, median age 70 and ASA 2), we suggest a minimally important difference of 5 mg for 0-24 h postoperative iv morphine consumption.

Prescription opioids induced microbial dysbiosis worsens severity of chronic pancreatitis and drives pain hypersensitivity.

Opioids, such as morphine and oxycodone, are widely used for pain management associated with chronic pancreatitis (CP); however, their impact on the progression and pain sensitivity of CP has never been evaluated. This report investigates the impact of opioid use on the severity of CP, pain sensitivity, and the gut microbiome. C57BL/6 mice were divided into control, CP, CP with morphine/oxycodone, and either morphine or oxycodone alone groups. CP was induced by administration of caerulein (50ug/kg/h, i.p. hourly x7, twice a week for 10 weeks). The mouse-to-pancreas weight ratio, histology, and Sirius red staining were performed to measure CP severity. Tail flick and paw pressure assays were used to measure thermal and mechanical pain. DNA was extracted from the fecal samples and subjected to whole-genome shotgun sequencing. Germ-free mice were used to validate the role of gut microbiome in sensitizing acute pancreatic inflammation. Opioid treatment exacerbates CP by increasing pancreatic necrosis, fibrosis, and immune-cell infiltration. Opioid-treated CP mice exhibited enhanced pain hypersensitivity and showed distinct clustering of the gut microbiome compared to untreated CP mice, with severely compromised gut barrier integrity. Fecal microbiota transplantation (FMT) from opioid-treated CP mice into germ-free mice resulted in pancreatic inflammation in response to a suboptimal caerulein dose. Together, these analyses revealed that opioids worsen the severity of CP and induce significant alterations in pain sensitivity and the gut microbiome in a caerulein CP mouse model. Microbial dysbiosis plays an important role in sensitizing the host to pancreatic inflammation.

Chronic Morphine Treatment and Antiretroviral Therapy Exacerbate HIV-Distal Sensory Peripheral Neuropathy and Induce Distinct Microbial Alterations in the HIV Tg26 Mouse Model.

Distal Sensory Peripheral Neuropathy (DSP) is a common complication in HIV-infected individuals, leading to chronic pain and reduced quality of life. Even with antiretroviral therapy (ART), DSP persists, often prompting the use of opioid analgesics, which can paradoxically worsen symptoms through opioid-induced microbial dysbiosis. This study employs the HIV Tg26 mouse model to investigate HIV-DSP development and assess gut microbiome changes in response to chronic morphine treatment and ART using 16S rRNA sequencing. Our results reveal that chronic morphine and ART exacerbate HIV-DSP in Tg26 mice, primarily through mechanical pain pathways. As the gut microbiome may be involved in chronic pain persistence, microbiome analysis indicated distinct bacterial community changes between WT and Tg26 mice as well as morphine- and ART-induced microbial changes in the Tg26 mice. This study reveals the Tg26 mouse model to be a relevant system that can help elucidate the pathogenic mechanisms of the opioid- and ART-induced exacerbation of HIV-associated pain. Our results shed light on the intricate interplay between HIV infection, ART, opioid use, and the gut microbiome in chronic pain development. They hold implications for understanding the mechanisms underlying HIV-associated pain and microbial dysbiosis, with potential for future research focused on prevention and treatment strategies.

A non-inferiority randomized controlled trial comparing nebulized ketamine to intravenous morphine for older adults in the emergency department with acute musculoskeletal pain.

OBJECTIVE: Our study aimed to investigate the analgesic efficacy of nebulized ketamine in managing acute moderate-to-severe musculoskeletal pain in older emergency department (ED) patients compared with intravenous (IV) morphine. METHODS: This was a non-inferiority, double-blind, randomized controlled trial conducted at a single medical centre. The patients aged 65 and older, who presented at the ED musculoskeletal pain within 7 days and had a pain score of 5 or more on an 11-point numeric rating scale (NRS), were included in the study. The outcomes were a comparison of the NRS reduction between nebulized ketamine and IV morphine 30 minutes after treatment, incidence of adverse events and rate of rescue therapy. RESULTS: The final study included 92 individuals, divided equally into two groups. At 30 minutes, the difference in mean NRS between the nebulized ketamine and IV morphine groups was insignificant (5.2 versus 5.7). The comparative mean difference in the NRS change from baseline between nebulized ketamine and IV morphine [-1.96 (95% confidence interval-CI: -2.45 to -1.46) and -2.15 (95% CI: -2.64 to -1.66) = 0.2 (95% CI: -0.49 to 0.89)] did not exceed the non-inferiority margin of 1.3. The rate of rescue therapy did not differ between the groups. The morphine group had considerably higher incidence of nausea than the control group (zero patients in the ketamine group versus eight patients (17.4%) in the morphine group; P = 0.006). CONCLUSIONS: Nebulized ketamine has non-inferior analgesic efficacy compared with IV morphine for acute musculoskeletal pain in older persons, with fewer adverse effects.

The µ-opioid receptor-mediated Gi/o protein and ß-arrestin2 signaling pathways both contribute to morphine-induced side effects.

The µ-opioid receptor-biased agonist theory holds that Gio protein signaling mediates the analgesic effect of opioids and the related side effects via the ß-arrestin2 signaling pathway. A series of µ-opioid-biased agonists have been developed in accordance with this theory, and the FDA has approved TRV130 (as a representative of biased agonists) for marketing. However, several reports have raised the issue of opioid side effects associated with the use of agonists. In this study, five permeable peptides were designed to emulate 11 S/T phosphorylation sites at the µ-opioid receptor (MOR) carboxyl-terminal. In vitro experiments were performed to detect the activation level of G proteins from the cAMP inhibition assay and the ß-arrestin2 recruitment by the BRET assay. Designed peptides might effectively interfere with the activation of the Gio and ß-arrestin2 pathways when combined with morphine. The resulting morphine-induced tolerance, respiratory inhibition, and constipation in mice showed that the ß-arrestin2 pathway was responsible for morphine tolerance while the Gio signaling pathway was involved with respiratory depression and constipation and that these side effects were significantly related to phosphorylation sites S363 and T370. This study may provide new directions for the development of safer and more effective opioid analgesics, and the designed peptides may be an effective tool for exploring the mechanism by which µ-opioid receptors function, with the potential of reducing the side effects that are associated with clinical opioid treatment.

Nalbuphine-6-glucuronide is a potent analgesic with superior safety profiles by altering binding affinity and selectivity for mu-/kappa-opioid receptors.

Although nalbuphine, a semi-synthetic analgesic compound, is less potent than morphine in terms of alleviating severe pain, our recent findings have revealed that nalbuphine-6-glucuronide (N6G), one of the glucuronide metabolites of nalbuphine, promotes a significantly more robust analgesic effect than its parent drug. Nevertheless, despite these promising observations, the precise mechanisms underlying the analgesic effects of nalbuphine glucuronides have yet to be determined. In this study, we aim to elucidate the mechanisms associated with the analgesic effects of nalbuphine glucuronides. Pharmacokinetic and pharmacodynamic studies were conducted to investigate the relationship between the central and peripheral compartments of nalbuphine and its derivatives. The analgesic responses of these compounds were evaluated based on multiple behavioral tests involving thermal and mechanical stimuli. Radioligand binding assays were also performed to determine the binding affinity and selectivity of these compounds for different opioid receptors. The results of these tests consistently confirmed that the heightened analgesic effects of N6G are mediated through its enhanced binding affinity for both mu- and kappa-opioid receptors, even comparable to those of morphine. Notably, N6G exhibited fewer side effects and did not induce sudden death, thereby highlighting its superior safety profile. Additionally, pharmacokinetic studies indicated that N6G could cross the blood-brain barrier when administered peripherally, offering pain relief. Overall, N6G provides great analgesic efficacy and enhanced safety. These findings highlight the potential value of nalbuphine glucuronides, particularly N6G, as promising candidates for the development of novel analgesic drugs.

The Effect of Prenatal and Neonatal Fluoride Exposure to Morphine-Induced Neuroinflammation.

Physical dependence is associated with the formation of neuroadaptive changes in the central nervous system (CNS), both at the molecular and cellular levels. Various studies have demonstrated the immunomodulatory and proinflammatory properties of morphine. The resulting neuroinflammation in drug dependence exacerbates substance abuse-related behaviors and increases morphine tolerance. Studies prove that fluoride exposure may also contribute to the development of neuroinflammation and neurodegenerative changes. Morphine addiction is a major social problem. Neuroinflammation increases tolerance to morphine, and neurodegenerative effects caused by fluoride in structures related to the development of dependence may impair the functioning of neuronal pathways, change the concentration of neurotransmitters, and cause memory and learning disorders, which implies this element influences the development of dependence. Therefore, our study aimed to evaluate the inflammatory state of selected brain structures in morphine-dependent rats pre-exposed to fluoride, including changes in cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) expression as well as microglial and astroglial activity via the evaluation of Iba1 and GFAP expression. We provide evidence that both morphine administration and fluoride exposure have an impact on the inflammatory response by altering the expression of COX-1, COX-2, ionized calcium-binding adapter molecule (Iba1), and glial fibrillary acidic protein (GFAP) in brain structures involved in dependence development, such as the prefrontal cortex, striatum, hippocampus, and cerebellum. We observed that the expression of COX-1 and COX-2 in morphine-dependent rats is influenced by prior fluoride exposure, and these changes vary depending on the specific brain region. Additionally, we observed active astrogliosis, as indicated by increased GFAP expression, in all brain structures of morphine-dependent rats, regardless of fluoride exposure. Furthermore, the effect of morphine on Iba1 expression varied across different brain regions, and fluoride pre-exposure may influence microglial activation. However, it remains unclear whether these changes are a result of the direct or indirect actions of morphine and fluoride on the factors analyzed.

Sensitization of human and rat nociceptors by low dose morphine is toll-like receptor 4-dependent.

While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4. And, sub-analgesic doses of several opioids have been shown to induce hyperalgesia in rodents by their action as TLR4 agonists. In the present in vitro patch-clamp electrophysiology experiments, we demonstrate that low dose morphine directly sensitizes human as well as rodent dorsal root ganglion (DRG) neurons, an effect of this opioid analgesic that is antagonized by LPS-RS Ultrapure, a selective TLR4 antagonist. We found that low concentration (100 nM) of morphine reduced rheobase in human (by 36%) and rat (by 26%) putative C-type nociceptors, an effect of morphine that was markedly attenuated by preincubation with LPS-RS Ultrapure. Our findings support the suggestion that in humans, as in rodents, OIH is mediated by the direct action of opioids at TLR4 on nociceptors.

Opioids in geriatric units in 14 Belgian hospitals: prevalence, dosage and associated factors.

Introduction: Adverse effects of opioids are common among older individuals, and undertreatment as well as overuse can be an issue. Epidemiological data on opioid use in older individuals are available, but scarce in hospitalized patients.Aims: The aim of this study is to examine the one-day prevalence of opioid use among older inpatients and identify the factors associated with both opioid use and dosage.Materials and methods: One-day cross-sectional study with data collected from geriatric units across 14 Belgian hospitals. The primary focus of the study is to assess the prevalence of opioid use and dosage, along with identifying associated factors. To achieve this, a multiple binary logistic regression model was fitted for opioid use, and a multiple linear regression model for opioid dose.Results: Opioids were used in 24.4% of 784 patients, of which 57.9% was treated with tramadol, 13.2% with oxycodone or morphine and 28.9% with transdermal buprenorphine or fentanyl. The odds for opioid use were 4.2 times higher in patients in orthogeriatric units compared to other patients (OR=4.2, 95% CI=2.50-7.05). The prevalence of opioid use was 34% higher in patients without dementia compared to patients with dementia (OR=0.66, 95% CI=0.46-0.95). The overall mean daily dosage was 14.07mg subcutaneous morphine equivalent. After adjustment for age, gender and dementia, dosage was only associated with type of opioid: the estimated mean opioid dose was 70% lower with tramadol (mean ratio=0,30,95% CI=0,23-0,39) and 67% lower with oxycodone and morphine (mean ratio=0,33, 95% CI=0,22-0,48) compared to transdermal buprenorphine and transdermal fentanyl.Conclusions: One in four patients received opioid treatment. It is not clear whether this reflects under- or overtreatment, but these results can serve as a benchmark for geriatric units to guide future pain management practices. The utilization of transdermal fentanyl and buprenorphine, resulting in higher doses of morphine equivalent, poses significant risks for side effects.

Comparison of different sustained-release opioids and acute respiratory conditions in patients with cancer and chronic kidney disease.

STUDY OBJECTIVE: Few data are available on the association between the use of oxycodone in patients with chronic kidney disease (CKD) and acute respiratory conditions. The aim of this study was to investigate whether oxycodone is associated with an increased risk of acute respiratory conditions in patients with cancer and CKD compared with other opioids. DESIGN AND SETTING: The data were obtained from a claims database in Japan. Patients with cancer and CKD who had received sustained-release opioids, including oral oxycodone, oral morphine, or transdermal fentanyl, between April 2014 and May 2021 were selected. The primary outcome was defined as an acute respiratory condition. Data for age and sex, morphine equivalent daily dose, concomitant use of specified medications, comorbidities defined based on the modified Charlson comorbidity index, substance use disorder, and lung cancer or metastatic lung cancer were investigated as covariates. Distribution of acute respiratory conditions was compared among the three sustained-release opioid groups using the log-rank test. Estimates of the incidence of acute respiratory conditions were compared among the groups using a Cox proportional hazards model with time-varying variables. MAIN RESULTS: A significant difference in the distribution of acute respiratory conditions was found among the three groups (p < 0.01). Cox regression analysis showed a significantly higher risk of acute respiratory conditions with morphine (hazard ratio [HR]: 3.04, 95% confidence interval [CI]: 1.07-8.65, p = 0.04) compared with oxycodone but no significant difference in risk with oxycodone (HR 0.67, 95% CI: 0.32-1.38, p = 0.27) compared with fentanyl. CONCLUSIONS: The findings suggest that the risk of acute respiratory conditions may be lower in patients with CKD who use oxycodone for cancer pain than in those who use morphine. Additionally, no difference in the risk of acute respiratory conditions was found between oxycodone and fentanyl use.

A systematic review and meta-analysis comparing the efficacy and safety of ketamine versus morphine for the treatment of acute pain.

INTRODUCTION: Ketamine is reported as a potent opioid alternative that provides significant reduction in pain with no severe adverse events. However, some studies didn't find its use satisfactory and reported less reduction in pain score with ketamine. The purpose of this study is to compare the efficacy and safety of ketamine versus morphine for the treatment of acute pain in emergency situations. EVIDENCE ACQUISITION: The PubMed, MEDLINE, PsycINFO EMBASE, Cochrane Library, PROSPERO registry platform, and ClinicalTrials.gov websites were queried in accordance with the PRISMA guidelines in order to locate relevant studies. According to the predefined PICOS criteria, articles were included and event data pertaining to changes in Visual Analog Scale or Numeric Rating Scale pain scales were extracted. Using RevMan and MedCalc, a meta-analysis was conducted to compare the effects of ketamine and morphine for the treatment of acute pain. EVIDENCE SYNTHESIS: Twelve studies met the criteria for inclusion in this meta-analysis. Ketamine was found to be more effective than morphine at reducing pain scores, with an odds ratio of 0.60 (95% CI 0.48 to 0.76). Similarly, no severe adverse events related to ketamine were reported in any study, and it has a low-risk ratio of 0.78 (95% CI 0.70 to 0.87). Egger's Test P values (0.3052) and Begg's Test P values (0.3869) indicate a low risk of bias, and the Bland-Altman plot demonstrates a high degree of concordance. CONCLUSIONS: Ketamine is a potent and effective alternative to morphine for the management of acute pain, and it reduces pain score significantly with minimal side effects.

Intrathecal drug-infusion system for treating pain in advanced cancer: New research in patient management.

Currently, the treatment of cancer pain in China mainly follows the three-step pain relief principles formulated by the World Health Organization. As research on subarachnoid drug diffusion has intensified, intrathecal drug delivery has been gradually applied in the treatment of diseases, and improved analgesia can be achieved via the continuous infusion of small doses of morphine-derived drugs. This method can not only effectively relieve pain and enhance quality of life but also significantly reduce the incidence of nausea, vomiting, constipation, and other adverse reactions caused by the long-term intensive use of drugs in patients with cancer pain. This study summarizes the development of the intrathecal drug-infusion system for treating cancer pain in patients with advanced cancer and describes the drugs used, the advantages in pain treatment, and key nursing factors before and after device placement to provide a basis for alleviating pain in patients with cancer.

Omission of perioperative morphine reduces postoperative pain in proctological interventions: a single-center analysis.

There is an increase in outpatient procedures and this trend will continue in the future. For hemorrhoidectomy, it is the standard of treatment in many health care systems. Perioperative management including adequate pain control is of paramount importance to ensure successful ambulatory surgery. This study investigates the role and effect of morphine compared to short-acting opiates applied before, during, or after proctological interventions and with focus on hemorrhoidectomy. A retrospective analysis of a prospective database was conducted comparing two populations. The control cohort received morphine (Yes-Mô) intra- and postoperatively, while the intervention group did not receive morphine (No-Mô) between January 2018 and January 2020. Both cohorts were balanced by propensity score matching. The outcomes were postoperative pain measured by numeric ratings scale (NRS) one hour postoperatively, pain 24 h postoperatively, success rate of outpatient management, and complication rate including postoperative nausea and vomiting as well as urinary retention. The intervention population comprised 54 patients and the control group contained 79 patients. One hour after surgery, patients in No-Mô reported lower NRS (1.44 ± 1.41) compared to Yes-Mô (2.48 ± 2.30) (p = 0.029). However, there was no difference in NRS 24 h postoperatively (No-Mô: 1.61 ± 1.41 vs Yes-Mô: 1.63 ± 1.72; p = 0.738). 100% of No-Mô was managed as outpatients while only 50% of Yes-Mô was dismissed on the day of the operation (p = < 0.001). There was no difference in postoperative complications (including postoperative nausea and vomiting (PONV) and urinary retention) between the two groups (PONV No-Mô 7.4% vs Yes-Mô 5.6%, p = 1.0 and urinary retention No-Mô 3.7% vs Yes-Mô 7.4%, p = 0.679). No-Mô received an oral morphine equivalent of 227.25 ± 140.35 mg intraoperatively and 11.02 ± 18.02 mg postoperatively. Yes-Mô received 263.17 ± 153.60 mg intraoperatively and 15.97 ± 14.17 mg postoperatively. The difference in received morphine equivalent between the groups was not significant after matching for the intraoperative (p = 0.212) and postoperative (p = 0.119) received equivalent. Omission of perioperative morphine is a viable but yet not understood method for reducing postoperative pain. Omission of morphine leads to a lower use of total morphine equivalent to attain satisfactory analgesia. The reduction of the overall opiate load and using opiates with a very short half-life potentially leads to a reduction of side effects like sedation. This in turn promotes discharge of the patient on the day of surgery. Omission of morphine is safe and does not increase postoperative complications.

Morphine aggravates inflammatory, behavioral, and hippocampal structural deficits in septic rats.

Although pain and sepsis are comorbidities of intensive care units, reported data on whether pain control by opioid analgesics could alter inflammatory and end-organ damage caused by sepsis remain inconclusive. Here, we tested the hypothesis that morphine, the gold standard narcotic analgesic, modifies behavioral and hippocampal structural defects induced by sepsis in male rats. Sepsis was induced with cecal ligation and puncture (CLP) and behavioral studies were undertaken 24 h later in septic and/or morphine-treated animals. The induction of sepsis or exposure to morphine (7 mg/kg) elicited similar: (i) falls in systolic blood pressure, (ii) alterations in spatial memory and learning tested by the Morris water maze, and (iii) depression of exploratory behavior measured by the new object recognition test. These hemodynamic and cognitive defects were significantly exaggerated in septic rats treated with morphine compared with individual interventions. Similar patterns of amplified inflammatory (IL-1ß) and histopathological signs of hippocampal damage were noted in morphine-treated septic rats. Additionally, the presence of intact opioid receptors is mandatory for the induction of behavioral and hemodynamic effects of morphine because no such effects were observed when the receptors were blocked by naloxone. That said, our findings suggest that morphine provokes sepsis manifestations of inflammation and interrelated hemodynamic, behavioral, and hippocampal deficits.

Chronic Voluntary Morphine Intake Is Associated with Changes in Brain Structures Involved in Drug Dependence in a Rat Model of Polydrug Use.

Chronic opioid intake leads to several brain changes involved in the development of dependence, whereby an early hedonistic effect (liking) extends to the need to self-administer the drug (wanting), the latter being mostly a prefrontal-striatal function. The development of animal models for voluntary oral opioid intake represents an important tool for identifying the cellular and molecular alterations induced by chronic opioid use. Studies mainly in humans have shown that polydrug use and drug dependence are shared across various substances. We hypothesize that an animal bred for its alcohol preference would develop opioid dependence and further that this would be associated with the overt cortical abnormalities clinically described for opioid addicts. We show that Wistar-derived outbred UChB rats selected for their high alcohol preference additionally develop: (i) a preference for oral ingestion of morphine over water, resulting in morphine intake of 15 mg/kg/day; (ii) marked opioid dependence, as evidenced by the generation of strong withdrawal signs upon naloxone administration; (iii) prefrontal cortex alterations known to be associated with the loss of control over drug intake, namely, demyelination, axonal degeneration, and a reduction in glutamate transporter GLT-1 levels; and (iv) glial striatal neuroinflammation and brain oxidative stress, as previously reported for chronic alcohol and chronic nicotine use. These findings underline the relevance of polydrug animal models and their potential in the study of the wide spectrum of brain alterations induced by chronic morphine intake. This study should be valuable for future evaluations of therapeutic approaches for this devastating condition.

Initiation and rapid titration of methadone and slow-release oral morphine (SROM) in an acute care, inpatient setting: a case series.

BACKGROUND: Methadone titration in an outpatient setting typically involves initiation with subtherapeutic doses with slow titration to mitigate the risks of respiratory depression and overdose. In pregnancy, and generally, subtherapeutic doses of methadone and slow titrations are associated with poorer outcomes in terms of treatment retention and ongoing illicit opioid use. We aim to describe rapid titration of OAT in an inpatient setting for pregnant injection opioid users with high opioid tolerance secondary to a fentanyl-based illicit drug supply. METHODS: Retrospective case series of patients admitted to a tertiary center with a primary indication of opioid withdrawal and treatment for severe opioid use disorder in pregnancy. RESULTS: Twelve women received rapid methadone titrations with or without slow-release oral morphine for opioid use disorder during a total of fifteen hospital admissions. All women included in the study were active fentanyl users (12/12). Methadone dosing was increased rapidly with no adverse events with a median dose at day 7 of 65 mg (IQR 60-70 mg) and median discharge dose of 85 mg (IQR 70-92.5 mg) during their admission for titration. Slow-release oral morphine was used in half of the titration admissions (8/15) with a median dose of 340 mg (IQR 187.5-425 mg) at discharge. The median length of admission was 12 days (IQR 9.5-15). CONCLUSIONS: A rapid titration of methadone was completed in an inpatient setting with or without slow-release oral morphine, without adverse events showing feasibility of this protocol for a pregnant population in an inpatient setting. Patients achieved therapeutic doses of methadone (and/or SROM) faster than outpatient counterparts with no known adverse events.