Morphine Group Research Articles

The Effect of Memantine on the Expression of Dopamine Receptors in the Striatum of Male Rats With Morphine Addiction

Background and Objectives: Studies have indicated that the chronic use of morphine can result in physical and psychological dependence. Morphine dependence is associated with several cellular and molecular alterations in the mesocorticolimbic system, and striatal dopamine signaling is involved in this process. In the present study, we aim to investigate possible alterations in the level of dopamine receptors DRD2 and DRD4 in the striatum of male rats following chronic oral administration of morphine and assess the effect of subcutaneous injection of memantine on morphine-induced effects. Methods: In this experimental study, 16 male Wistar rats were randomly divided into four groups: Control, morphine, memantine, and morphine+memantine. The morphine group received increasing doses of morphine (0.1-0.4 mg/kg) via their drinking water for 21 consecutive days. The memantine groups, after receiving distilled water without morphine for 21 days, received a subcutaneous injection of 5 mg memantine. The morphine memantine group received 5 mg of memantine subcutaneously on day 21 and 30 minutes after the last oral administration of morphine. After collecting striatum tissue, dopamine receptor levels were evaluated by the western blotting method. Results: The chronic use of morphine increased the levels of DRD2 and DRD4 compared to the controls. Memantine administration also increased the level of these receptors compared to the controls. In addition, the expression of DRD2 and DRD4 increased in the morphine+ memantine group compared to the memantine group. Conclusion: Morphine affects the expression of dopamine receptors in the striatum. Treatment with memantine can increases dopamine receptors’ expression.

The Effect of Magnesium Sulfate plus Ketorolac versus Morphine plus Ketorolac on Pain Relief in Patients with Renal Colic: A Double-blind Randomized Clinical Trial

Abstract Background: It seems that magnesium sulfate (MgSO4) can be useful in reducing acute pain caused by stone passing through the ureter by reducing ureteral smooth muscle contractions. Aim: This study aimed to evaluate the effect of MgSO4 plus ketorolac versus morphine plus ketorolac on pain relief in renal colic. Methods: The present double-blind randomized clinical trial was performed on 70 patients with renal colic divided into two groups. Patients in the first group received 30 mg intravenous ketorolac plus 5 mg intravenous morphine while patients in the second group received 30 mg/kg MgSO4 plus 30 mg intravenous ketorolac. Then, patients’ hemodynamic parameters and pain scores were evaluated before and 20, 40, and 60 min after the intervention. Results: Within 60 min of administration, systolic blood pressure was significantly reduced in the morphine plus ketorolac group (P < 0.001) while there was no significant change in the MgSO4 plus ketorolac group in this regard (P = 0.576). In addition, the patients’ mean pain scores were not significantly different between the two groups in any of the studied times (P > 0.05). Conclusion: Given that the addition of MgSO4 to ketorolac, as compared with the addition of morphine (as a drug) to ketorolac, has been associated with fewer complications and greater stability of hemodynamic parameters, it can be stated that the use of MgSO4 as an adjunct can be a good choice for further pain relief in patients with contraindications for drug administrations.

Clonidine as Monotherapy for Neonatal Opioid Withdrawal Syndrome: A Randomized Trial.

We sought to determine whether clonidine, a non-opioid α-2-adrenergic agonist, would effectively treat neonatal opioid withdrawal syndrome (NOWS). This was an intention-to-treat randomized clinical trial. Enrollment criteria included prenatal opioid exposure, age ≤7 days, gestational age ≥35 weeks, no other medical condition, and need for pharmacotherapy. Primary outcomes were length of treatment and neurobehavioral performance. A total of 1107 patients were screened for enrollment (645 ineligible, 91 parents or staff unavailable, 216 declined, 155 consented). Of 155 infants, 120 required treatment and were randomized to receive oral clonidine (n = 60) at 1 µg/kg/dose or morphine (n = 60), 0.06 mg/kg/dose, every 3 hours. Infants with no improvement had their doses increased by 25% of the initial dose every 12 to 24 hours. Those without improvement by the fourth dose increase, received adjunct therapy. Length of treatment did not differ between morphine and clonidine, with median (95% confidence interval [CI]) days, respectively, of 15 (13-17) and 17 (15-19), P = .48. More clonidine-treated infants (45%) needed adjunct therapy versus 10% in the morphine group, adjusted odds ratio (95% CI) = 8.85 (2.87-27.31). After treatment completion, the NICU Network Neurobehavioral Scales summary scores did not differ between clonidine-treated and morphine-treated infants. Length of pharmacologic treatment and final neurobehavioral performance were not significantly different between the clonidine- and morphine-treated groups. Clonidine appears to be an effective non-opioid medication to treat NOWS. Future studies are needed to determine the optimal clonidine dosage for a quicker response and obviation of adjunct therapy.

Upregulation of HCN2 in ventral tegmental area is involved in morphine-induced conditioned place preference in rats.

Morphine is an opioid commonly used to treat pain in clinic, but it also has the potential to be highly addictive, which can lead to abuse. Despite these known risks, the cellular and molecular mechanism of morphine conditioned place preference (CPP) is still unclear. In this study, using a rat model of chronic morphine administration, we found that compared with the control group, the mRNA and protein expression of HCN2 channel in the ventral tegmental area (VTA) were upregulated. Further immunofluorescence analysis showed that the fluorescence intensity of HCN2 channel of VTA dopaminergic neurons in morphine group was significantly enhanced, while the patch clamp recording of brain slices showed that both the magnitude and the density of Ih (HCN channel current) of VTA neurons were significantly increased. Moreover, intra-VTA infusion of ZD7288, a selective inhibitor of HCN channel, into rats of the morphine group decreased morphine CPP. Taken together, our results show that chronic morphine administration induces an upregulation of HCN2 in VTA dopamine neurons, while HCN inhibition reduces morphine CPP, suggesting that HCN channel may be a potential target for the treatment of morphine addiction.

Comparative Analysis of Epidural Dexamethasone and Epidural Morphine (EM) for Postoperative Pain Control After Total Abdominal Hysterectomy: A Randomized Clinical Trial

Background: Epidural anesthesia is commonly utilized for pain management following lower abdominal surgeries; however, the search for an optimal analgesic additive continues. Objectives: This study aimed to compare the efficacy of epidural dexamethasone versus epidural morphine (EM) in managing postoperative pain after total abdominal hysterectomy. Methods: This randomized controlled trial enrolled patients undergoing total abdominal hysterectomy (TBAH) and assigned them to two groups: Group D (Dexamethasone), which received epidural dexamethasone (8 mg) with bupivacaine, and Group M (Morphine), which received epidural morphine (10 mg) with bupivacaine. Marcaine (bupivacaine) 0.25% was used in both groups. Baseline characteristics, surgical outcomes, physiological parameters, pain management, adverse effects, and blood sugar levels were analyzed and compared between the groups. Results: The groups exhibited similar initial characteristics and surgical outcomes. Vital signs, including heart rate (HR), mean arterial pressure, respiratory rate, and oxygen saturation, remained consistent before and after surgery. The Dexamethasone group (Group D) demonstrated superior pain control compared to the Morphine group (Group M). Patients in Group D required pain medication for a significantly shorter duration (24 hours vs. 36 hours, P < 0.05), representing a 50% reduction in medication duration. Additionally, Group D patients required fewer rescue analgesics (1.2 doses vs. 2.1 doses, P < 0.05), indicating a 43% decrease in the need for additional medication. The time to a visual analog scale (VAS) score exceeding 4 was significantly longer in Group D, indicating less intense pain for an extended period. Although no significant differences were observed in common postoperative side effects, Group D exhibited a lower incidence of these effects, albeit not statistically significant. Furthermore, Group D showed a significantly lower incidence of hyperglycemia at the 8th hour post-surgery compared to Group M (P < 0.05), suggesting a potential benefit of epidural dexamethasone in mitigating hyperglycemia risk. Conclusions: Epidural dexamethasone appears to offer superior analgesic efficacy compared to epidural morphine in postoperative pain management after total abdominal hysterectomy. The findings suggest that Group D (Dexamethasone) experienced improved pain management, reduced medication requirements, and a lower incidence of hyperglycemia. Further research with larger cohorts and extended follow-up is warranted to validate these findings and guide clinical practice.

FP4.13 - Intravenous morphine negatively affects length of stay following minimally invasive colorectal surgery

Abstract Aim Investigate the impact of intravenous (IV) morphine administered as patient controlled analgesia (PCA) following minimally invasive colorectal resections. Method Demographic, peri-operative and follow-up data from a prospectively maintained database were collected for all laparoscopic and robotic assisted colorectal procedures carried out at our centre. Results Our cohort included 38 colorectal resections completed with the DaVinci Xi (Intuitive Surgical, USA) robotic platform and 57 consecutive laparoscopic colorectal resections. 7 patients were excluded due to incomplete data. 51/88 (57.9%) of patients underwent a left sided resection and 24/88 (27.3%) had a stoma formed. We observed a median IV morphine dose of 15.5mg (IQR 15.5-43.5mg) and we sub-divided the cohort into those who received >15 mg of IV morphine and <15mg of morphine via PCA. Patients who received <15mg IV morphine were older (median age 75 Vs 67 years; p<0.001). There was no statistical difference in the body mass index, ASA grade, total operative time, or type of minimally invasive resection. The median length of stay was 4 days for the <15mg IV Morphine cases compared to 5 in the >15mg IV Morphine group (p<0.001). As expected, there was a quicker time to first flatus in the <15mg IV Morphine group (median 2 days Vs 3 days; p<0.001) and a shorter time to opening bowels (median 3 days Vs 4 days; p=0.003). There was no statistically significant difference in post-operative complications between the two groups. Conclusions Reducing postoperative IV Morphine dosing following minimally invasive colorectal resections may lead to prompter recovery.

Impact of chronic opioid on cognitive function and spermatogenesis in rat: An experimental study.

Opioid analgesics like morphine and methadone are widely used for managing severe pain; however, concerns over their potential misuse and adverse effects on the brain and reproductive system are significant. We aimed to investigate their impacts on spermatogenesis and cognitive function in male Norway rats. In this experimental study, 36 male Norway rats (250-300 gr, 6 months old) were divided into 6 groups: low-dose morphine, high-dose morphine, low-dose methadone, high-dose methadone, positive control (received normal saline at 5 mg/kg), and negative control (received no treatment). Morphine and methadone were administered intraperitoneally over 30 days at doses of 3 mg/kg and 7 mg/kg, respectively. Behavioral assessments evaluated anxiety, stress, and short- and long-term memory. Sperm parameters (viability, motility, morphology), hormonal analysis (testosterone, luteinizing hormone, follicle-stimulating hormone, estradiol), and gene expressions (Tp53, CatSper1) were assessed. A significant reduction in rat weight was observed in the high-dose morphine group (p = 0.0045), while testicular weights remained unchanged. Sperm abnormalities were observed with high doses of methadone and morphine. High-dose methadone significantly reduced offspring count (p = 0.0004). Levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol varied significantly across treatment groups. Gene expression was altered in response to treatments (p 0.05). Prolonged exposure to methadone and morphine resulted in memory dysfunction, chronic stress, hormonal disturbances, altered gene expression, and fertility complications. These effects were more pronounced at higher doses, highlighting the importance of careful dosage management in opioid therapy.

Postoperative Sedation in Free Microvascular Tissue Transfer in Head and Neck Cancer: A Comparison of Fentanyl and Morphine

Background and Aims: Head-and-neck cancer surgeries with microvascular free flap reconstruction require endotracheal tube retention for 24–48 h postoperatively. Many regimes have been used for analgesia and sedation. The efficacy of fentanyl and morphine for post-operative analgosedation was compared by evaluating the need for additional sedatives to achieve optimum sedation scores. The secondary objective included analgesia, haemodynamic stability and a re-exploration rate. Methods: This was an open-label prospective study. A sample size of 36 was calculated in each group with α = 0.05 and a power of 80% to detect a 50% difference between the groups. Ninety adult patients were allocated to receive either fentanyl (Group F) or morphine (Group M). The Richmond agitation sedation score, Behavioural pain scale score, requirement of rescue hypnotic drug, pulse rate, systolic and diastolic blood pressures and re-explorations were recorded postoperatively. Haemodynamic parameters and sedation were analysed by two-way repeated measures of analysis variances. Pain scores were analysed using the Chi-square test. Results: When titrating to optimal sedation, in Group M, more patients needed intravenous midazolam boluses (n = 42, 93.3%) as compared to Group F (n = 33, 73.3%) (P = 0.011). More subjects in Group M required propofol infusion (n = 15, 33.3%) than in Group F (n = 4, 8.9%) (P = 0.009). Mean behavioural pain scores were significantly higher in Group M (score 1: P = 0.005 and score 2: P =0.001). The difference in the mean systolic, diastolic blood pressure, pulse rate, respiratory rate and re-exploration rate between the two groups was statistically insignificant. Conclusion: For analgesia-based sedation of spontaneously breathing intubated patients after head-and-neck cancer reconstructive surgeries, fentanyl is more effective than morphine in terms of ease of titration, sedation quality and analgesia. Both are safe for post-operative sedation regarding haemodynamic stability, tube retention and maintenance of spontaneous respiration.

Modulatory Effects of Morphine and Xylopia aethioica Extract on Kappa Opiod Receptors (KOR), Delta Opioid Receptor (DOR), Pain Hypersensitivity and Motor Functions in Wistar Rats

This study investigates the modulatory effects of morphine and Xylopia aethiopica extract on kappa opioid receptors (KOR), delta opioid receptors (DOR), pain hypersensitivity, and motor functions in Wistar rats. We utilized three experimental groups: a control group receiving distilled water, a morphine group receiving either low (5 mg/kg) or high (10 mg/kg) doses after inducing pain, Xylopia aethiopica group received either 25 mg/kg or 50 mg/kg of hydromethanolic extract following similar pain induction. Pain perception was quantified using the tail flick test and Analgesy-Meter while motor functions were assessed through the Rotarod and Climbing/Beam Walk tests. Additionally, molecular docking studies were performed on selected compounds from Xylopia aethiopica to determine their binding affinities to opioid receptors using Vina. Results demonstrated that morphine and Xylopia aethiopica significantly increased tail flick response times, indicating notable analgesic effects, while improving motor functions particularly in animals treated with higher doses of Xylopia aethiopica. Molecular analysis revealed potential interactions between bioactive compounds and opioid receptors, suggesting further therapeutic applications. These findings highlight the potential of Xylopia aethiopica as a natural analgesic and its implications in managing pain and associated motor deficits, the findings further revealed that Morphine and not Xylopia aethiopica is implicated in pain hypersensitivity after long term exposure. Further research should pay attention on improving the pharmacological profiles of the identified compounds for clinical use.

Ibogaine administration following repeated morphine administration upregulates myelination markers 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and myelin basic protein (MBP) mRNA and protein expression in the internal capsule of Sprague Dawley rats.

Ibogaine is a psychedelic alkaloid being investigated as a possible treatment for opioid use disorder. Ibogaine has a multi-receptor profile with affinities for mu and kappa opioid as well as NMDA receptors amongst others. Due to the sparsity of research into ibogaine's effects on white matter integrity and given the growing evidence that opioid use disorder is characterized by white matter pathology, we set out to investigate ibogaine's effects on two markers of myelination, 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and myelin basic protein (MBP). Fifty Sprague Dawley rats were randomly assigned to five experimental groups of n = 10; (1) a saline control group received daily saline injections for 10 days, (2) a morphine control group received escalating morphine doses from 5 to 15 mg/kg over 10 days, (3) an ibogaine control group that received 10 days of saline followed by 50 mg/kg ibogaine hydrochloride, (4) a combination morphine and ibogaine group 1 that received the escalating morphine regime followed by 50 mg/kg ibogaine hydrochloride and (5) a second combination morphine and ibogaine group 2 which followed the same morphine and ibogaine regimen yet was terminated 72 h after administration compared to 24 h in the other groups. White matter from the internal capsule was dissected and qPCR and western blotting determined protein and gene expression of CNP and MBP. Morphine upregulated CNPase whereas ibogaine alone had no effect on CNP mRNA or protein expression. However, ibogaine administration following repeated morphine administration had an immediate effect by increasing CNP mRNA expression. This effect diminished after 72 h and resulted in a highly significant upregulation of CNPase protein at 72 h post administration. Ibogaine administration alone significantly upregulated protein expression yet downregulated MBP mRNA expression. Ibogaine administration following repeated morphine administration significantly upregulated MBP mRNA expression which increased at 72 h post administration resulting in a highly significant upregulation of MBP protein expression at 72 h post administration. These findings indicate that ibogaine is able to upregulate genes and proteins involved in the process of remyelination following opioid use and highlights an important mechanism of action of ibogaine's ability to treat substance use disorders.

Impact of Neuraxial Preservative-Free Morphine in Vaginal Delivery on Opiate Consumption and Recovery: A Randomized Control Trial.

Neuraxial opioids are commonly used after cesarean delivery (CD). However, they are not commonly used after vaginal delivery (VD) though some studies have suggested they may be beneficial from a pain perspective. However, they did not evaluate other potential benefits including patient satisfaction, impact on postpartum depression and breastfeeding (BF) success, or side effects such as pruritus. Parturients who delivered vaginally with epidural analgesia were randomized to receive either 2 mg of preservative-free morphine (4 mL) or saline (4 mL) via the epidural catheter within 1 hour of VD. Routine analgesics were unchanged and included q 6-hour dosing of acetaminophen 975 mg orally and ketorolac 30 mg intravenous (IV). Hydromorphone 2 mg or oxycodone 10 mg were offered for breakthrough pain. Our primary outcome was opiate consumption in the first 24 hours after drug administration. Secondary outcomes included pain scores at 24 hours and 1 week postpartum as well as opiate consumption up to 1 week postpartum. Additional end points such as obstetric quality of recovery score (OBS-QOR10) breast feeding success, and an Edinburgh Postnatal Depression Score (EPDS) were also obtained. Data were analyzed for 157 parturients, 80 in the morphine group and 77 in the saline group. No difference was observed in the EDPS score predelivery or intention to BF. We found a statistically significant difference in the use of opioids in the first 24 hours, 3.8% (95% confidence interval [CI], 0.9%-11.3%) vs 14.3% (7.7%-24.5%) in the morphine and saline groups, respectively; and in total opioid dose, median (interquartile range, IQR [range]) of morphine milligram equivalent vs 0 (0-0 [0-47.5]) vs 0 (0-0 [0-72]), P = .023, in the morphine and saline groups, respectively. Verbal pain scores (0-10) at 24 hours were lower in the morphine group (median (IQR [range): 2.0 (1-4 [0-10]) vs 3.0 (1.5-5.0 [0-10]), P = .043. There was a greater incidence of pruritus in the morphine group versus saline group, 37.5% (95% CI, 27.1%-49.1%) vs 18.2% (95% CI, 10.6%-29.0%), P = .008. We did not find any differences in the OBS-QOR10, BF success, or EPDS at 6 weeks PP (P < .05). A single epidural dose of 2 mg preservative-free morphine after VD was effective at decreasing pain and opioid use at 24 hours after VD but came at the cost of increased pruritus. We did not detect any differences in BF, recovery scores, or PPD. Future studies should focus on elucidating the role of neuraxial preservative-free morphine after VD.

Low dose of morphine to relieve dyspnea in acute respiratory failure: the OpiDys double-blind randomized controlled trial

BackgroundMorphine relieves dyspnea in various clinical circumstances. Whether or not this applies to patients admitted to intensive care units (ICUs) for acute respiratory failure (ARF) is unknown. We evaluated the efficacy and safety of low-dose morphine on dyspnea in patients admitted to the ICU for ARF.MethodsIn this single-center, double-blind, phase 2, randomized, controlled trial, we assigned non-intubated adults admitted to the ICU for ARF with severe dyspnea, defined by a visual analog scale for dyspnea (dyspnea-VAS) from zero (no dyspnea) to 100 mm (worst imaginable dyspnea) ≥40 mm, to receive a low dose of Morphine Hydrochloride (intravenous titration followed by subcutaneous relay) or Placebo. All patients received standard therapy, including etiological treatment and non-invasive respiratory support.ResultsTwenty-two patients were randomized, 11 in each group. The average dyspnea (median [interquartile range]) over 24 hours did not significantly differ between the two groups (40 [25 – 43] mm in the Morphine group vs. 40 [36 – 49] mm in the Placebo group, p=0.411). Dyspnea-VAS was lower in the Morphine group than in the Placebo group at the end of intravenous titration (30 [11 – 30] vs. 35 [30 – 44], p=0.044) and four hours later (18 [10 – 29] vs. 50 [30 – 60], p=0.043). The cumulative probability of intubation was higher in the Morphine group than in the Placebo group (p=0.046)ConclusionIn this phase 2 pilot trial, morphine did not improve 24-hour average dyspnea in adult patients with ARF, even though it had a statistically significant immediate effect. Of concern, Morphine use was associated with a higher intubation rate.Trial registrationThe protocol was declared on the ClinicalTrial.gov database (no. NCT04358133) and was published in September 2022.

Disrupted neuregulin 1-ErbB4 signaling: Consequences of prenatal morphine exposure in rat pups and molecular gateway to neurological impairment

ObjectiveMorphine exposure during pregnancy has detrimental effects on both the mother and her offspring, both during and after childbirth. This study aimed to investigate the impact of prenatal morphine exposure on rat pups and dams, specifically focusing on changes in Neuregulin-1 (Nrg-1)/ErbB4 gene expression, inflammation, and brain-derived neurotrophic factor (BDNF) levels. Materials and methodsTwenty female rats were randomized into two experimental groups:1-Morphine Group: Dams received morphine throughout pregnancy. 2-Control Group: Dams received no interventions.At the end of gestation, blood samples were collected from the dams. Subsequently, dams and their pups underwent tissue collection from the cortical area of the brain to evaluate the following parameters: Interleukin-6 (IL-6), Interleukin-10 (IL-10), total antioxidant capacity (TAC), Malondialdehyde (MDA), and Brain-derived neurotrophic factor (BDNF).Additionally, RNA was extracted from the pup's cortical brain tissue for the assessment of gene expression levels of Neuregulin-1 (NRG-1) and ErbB-4 using quantitative real-time polymerase chain reaction (qrt-PCR). ResultsThe molecular investigation revealed a decrease in NRG-1 and ErbB-4 expressions in the brain cortex of offspring exposed to morphine during prenatal development. Additionally, the levels of IL-6 and IL-10 in both the serum and brain of both the mothers and their offspring in the morphine group were significantly higher compared to the control group. The morphine-exposed group also exhibited significantly lower levels of TAC and higher levels of MDA, indicating increased oxidative stress. Furthermore, the levels of BDNF in the morphine group were significantly lower compared to the control group. ConclusionPrenatal morphine exposure in rats has detrimental effects on both the dams and their offspring. This study demonstrates that prenatal morphine exposure disrupts critical molecular pathways involved in neurodevelopment, inflammation, oxidative stress, and neurotrophic signaling. These findings suggest that prenatal morphine exposure can have long-lasting consequences for the offspring, potentially contributing to neurodevelopmental disorders and other health issues later in life.

Comparative Study of Morphine, Fentanyl or Nalbuphine Patient Controlled Analgesia (PCA) for Mucositis Pain in Pediatric Patients Undergoing Cancer Therapy. A Prospective Randomized Clinical Trial

Abstract Background Cancer treatment may cause several side effects, including severe oral mucositis (SOM). Oral mucositis is an inflammation of the oral mucosa that causes severe pain and ulceration. Children and adolescents are more prone to develop chemotherapy-induced SOM. Opiates have been the cornerstone of pain management for moderate to severe oral mucositis. The effective use of opiates requires balancing the desired effects of pain relief with undesired adverse effects Aim of the Work We evaluated the efficacy and safety of Nalbuphine (agonist – antagonist) in comparison with the pure agonist opioids (Morphine and Fentanyl) when used for oral mucositis pain in pediatric patients undergoing cancer therapy. Primary outcomes measures were Pain intensity self- assessment by using VAS, Number of active and total pushes of PCA buttons, Total opioid consumptions for each patient, and Patient satisfaction at the end of the 7 days using Patient Satisfaction Score PSS were assessed using a linear scale where 0 = very satisfied; 10 = very dissatisfied. Secondary outcomes measures were Adverse events including Respiratory depression, Bradycardia, Hypotension, Over sedation, Nausea and vomiting, Pruritus, Urinary retention. Patients and Methods This was a Randomized Clinical Trial conducted on 90 Pediatric patients who were diagnosed with cancer, admitted to Children Cancer Hospital -Egypt (CCHE-57357) and underwent cancer therapy that was complicated with Mucositis grade 3 and 4 (severe oral mucositis) according to the WHO scale for oral mucositis. Patients were randomly allocated into 3 equal groups each included 30 patients using of: PCA Morphine (Group M), PCA Nalbuphine (Group N) and PCA Fentanyl (Group F). Using equipotent doses of the three medications. Results Highly significant decrease in VAS score (7th day) and total opioid consumption (7th day), in Nalbuphine and Morphine groups; compared to Fentanyl group (p &amp;lt; 0.01 respectively). Significant increase in patient satisfaction score PSS in Nalbuphine drug group; compared to other drug groups (p = 0.032). Highly significant decrease in serious side effects (especially respiratory depression and sedation problems), in Nalbuphine and Morphine groups; compared to Fentanyl group (p = 0.0004). Conclusion Nalbuphine proven to be adequately effective, not inferior to Morphine in terms of improving pain relief, decreasing opioid consumptions in pediatric PCA users. However patients reported less satisfaction with Nalbuphine than Fentanyl or Morphine. In terms of safety profile, Nalbuphine had less adverse effects in pediatric patients with oral mucositis related to cancer therapy in comparison to Fentanyl or morphine.

Additive Anticonvulsive Effects of Sumatriptan and Morphine on Pentylenetetrazole-Induced Clonic Seizures in Mice.

Sumatriptan protects the brain from damage and enhance the anti-seizure effect of morphine. There is evidence that nitric oxide (NO) may mediate these effects of both drugs. In the present study, we investigated the effects of sumatriptan (0.1-20 mg/kg, intraperitoneal [i.p.]) and morphine (0.1-20 mg/kg, i.p.) alone or in combination on seizure thresholds in an in vivo model of seizure in mice. Using various NO synthase inhibitors as well as the NO precursor, we assessed possible involvement of NO signaling in these effects. Clonic seizures were induced in male Naval Medical Research Institute mice by intravenous administration of pentylenetetrazol (PTZ). Acute sumatriptan administration exerted anti-convulsive effects at 0.5 (p<0.01) and 1 mg/kg (p<0.05), but pro-convulsive effects at 20 mg/kg (p<0.05). Morphine had anti-convulsive effects at 0.5 (p<0.05) and 1 mg/kg (p<0.001), but exerted pro-convulsive effect at 20 mg/kg (p<0.05). Combination treatment with sub-effective doses of sumatriptan (0.1 mg/kg) and morphine (0.1 mg/kg) significantly (p<0.05) exerted an anti-convulsive effect. Co-administration of the NO precursor L-arginine (60 mg/kg) with sub-effective doses of sumatriptan and morphine significantly (p<0.05) increased seizure threshold compared with sumatriptan alone, but not sumatriptan+morphine group. While concomitant administration of either the non-selective NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (5 mg/kg) or the selective inducible NOS inhibitor aminoguanidine (50 mg/kg) with combined sub-effective doses of morphine and sumatriptan produced significant anticonvulsive effects, concomitant administration with the selective neuronal NOS inhibitor 7-nitroindazole (30 mg/kg) inhibited this effect. Our data suggest a possible role for the NO signaling in the anticonvulsive effects of combined sumatriptan and morphine on the PTZ-induced clonic seizures in mice.

Effects of ketamine on the severity of depression and anxiety following postoperative mechanical ventilation: a single-blind randomized clinical trial in Iran.

In this study, we compare the effects of ketamine and the combination of midazolam and morphine on the severity of depression and anxiety in mechanically ventilated patients after discharge from the intensive care unit (ICU). This randomized single-blind clinical trial included 50 patients who were candidates for craniotomy and postoperative mechanical ventilation in the ICU of 5 Azar Teaching Hospital in Gorgan City, North Iran, from 2021 to 2022. Patients were allocated to two groups by quadruple block randomization. In group A, 0.5 mg/kg of ketamine was infused over 15 minutes after craniotomy and then continued at a dose of 5 µ/kg/min during mechanical ventilation. In group B, midazolam was infused at a dose of 2-3 mg/hr and morphine at a dose of 3-5 mg/hr. After patients were discharged from the ICU, if their Glasgow Coma Scale scores were ≥14, Beck's anxiety and depression inventories were completed by a psychologist within 2 weeks, 2 months, and 6 months after discharge. The mean scores of depression at 2 months (P=0.01) and 6 months (P=0.03) after discharge were significantly lower in the ketamine group than in the midazolam and morphine group. The mean anxiety scores were significantly lower in the ketamine group 2 weeks (P=0.006) and 6 months (P=0.002) after discharge. Ketamine is an effective drug for preventing and treating anxiety and depression over the long term in patients discharged from the ICU. However, further larger volume studies are required to validate these results.

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

BackgroundKetamine 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.MethodsThis 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.ResultsA 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).ConclusionShort 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 registrationNMRR17318438970 (2 May 2018;www.nmrr.gov.my).

Assessing the Impact of Morphine on Adverse Outcomes in ACS Patients Treated with P2Y12 Inhibitors: Insights from Multiple Real-World Evidence.

Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators. Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis. Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted-P =3.55*10-209). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI. The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.

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

BackgroundTo 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.MethodsMulti-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%.ResultsIn 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%).ConclusionsIn 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.

Effectiveness of Intravenous Low-Dose Ketamine Versus Morphine for Procedural Burn Pain Management During Dressing Changes: A Randomized Clinical Trial

Background: There is limited literature on using low-dose intravenous ketamine as a single agent for procedural burn pain management during adult dressing changes. Aims &amp; Objectives: To determine the effectiveness of low-dose ketamine compared to morphine as a single analgesic agent in procedural burn pain management during dressing changes. Materials &amp; Methods: We performed an institutional review board-approved, randomized, prospective, double-blinded, controlled, non-inferiority trial. All adult patients 18 years and above scheduled for dressing change were screened. Patients who consented were randomized to receive low-dose ketamine infusion at 0.2mg/kg/hr. In the treatment group, morphine infusion at 0.1mg/kg/hr. In the control group. The primary endpoint was pain intensity, measured using a visual analog scale. Data were analyzed on an intention-to-treat (ITT) approach. Secondary endpoints included rescue analgesia requirements and the occurrence of adverse effects in both groups. Results: 82 patients were enrolled (ketamine 41 vs. morphine 41). We compared VAS scores at 5-minute intervals during the dressing changes. Overall, pain scores are similar in both groups (p-value=0.595). The pain control was homogenous. However, the morphine group required more rescue analgesia throughout the dressing changes than the low-dose ketamine group (p=0.013 at T15, p&lt;0.001 at T20, and p&lt;0.001 at T30). The occurrence of side effects was similar in both groups. Conclusion: This study suggests that low-dose ketamine provides as effective and more predictable procedural analgesia as morphine during dressing procedures for adult burn patients.