Morphine Side Effects Research Articles

Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial

Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis. The PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40-90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at ClinicalTrials.gov, NCT04429516, and has been completed. Between Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82% (17·3), and mean predicted diffusion capacity of carbon monoxide was 48% (10·9). Of the 44 patients who were randomised, 43 completed morphine treatment and 41 completed placebo treatment. In the intention-to-treat analysis, morphine reduced objective awake cough frequency by 39·4% (95% CI -54·4 to -19·4; p=0·0005) compared with placebo. Mean daytime cough frequency reduced from 21·6 (SE 1·2) coughs per h at baseline to 12·8 (1·2) coughs per h with morphine, whereas cough rates did not change with placebo (21·5 [SE 1·2] coughs per h to 20·6 [1·2] coughs per h). Overall treatment adherence was 98% in the morphine group and 98% in the placebo group. Adverse events were observed in 17 (40%) of 43 participants in the morphine group and six (14%) of 42 patients in the placebo group. The main side-effects of morphine were nausea (six [14%] of 43 participants) and constipation (nine [21%] of 43). One serious adverse event (death) occurred in the placebo group. In patients with cough related to idiopathic pulmonary fibrosis, low dose controlled-release morphine significantly reduced objective cough counts over 14 days compared with placebo. Morphine shows promise as an effective treatment to palliate cough in patients with idiopathic pulmonary fibrosis, and longer term studies should be the focus of future research. The Jon Moulton Charity Trust.

Zingerone Alleviates Morphine Tolerance and Dependence in Mice by Reducing Oxidative Stress-Mediated NLRP3 Inflammasome Activation.

Morphine (MPH) is widely used for pain management; however, long-term MPH therapy results in antinociceptive tolerance and physical dependence, limiting its clinical use. Zingerone (ZIN) is a natural phenolic compound with neuroprotective effects. We investigated the effects of single and repeated doses of ZIN on MPH-induced tolerance, dependence, and underlying biochemical mechanisms. After a dose-response experiment, tolerance was developed to MPH (10mg/kg, i.p.) for seven days. In the single-dose study, ZIN was administered on day seven. In the repeated-dose study, ZIN was administered for seven days. Naloxone (5mg/kg, i.p., 120min after MPH) was injected to assess withdrawal signs on day seven. The levels of thiobarbituric acid reactive substances (TBARS), nitric oxide (NO), total thiol (TT), and glutathione peroxidase (GPx) were measured in the prefrontal cortex. The protein levels of interleukin-1 beta (IL-1β) and NLRP3-ASC-Caspase-1 axis were assessed by ELISA and Western blotting, respectively. Results showed that ZIN (100mg/kg) had no antinociceptive activity, and subsequent experiments were performed at this dose. Repeated ZIN reversed MPH antinociceptive tolerance, whereas single ZIN did not. Single and repeated ZIN attenuated naloxone-induced jumping. In addition, repeated ZIN significantly inhibited weight loss. Repeated ZIN suppressed the MPH-induced increase in TBARS, NO, IL-1β, NLRP3, ASC, and Caspase-1. It also inhibited MPH-induced TT and GPx reduction. In contrast, single ZIN had no effect. Findings suggest that ZIN reduces MPH-induced tolerance and dependence by suppressing oxidative stress and NLRP3 inflammasome activation. This study provides a novel therapeutic approach to reduce the side effects of MPH.

Influence of pre-peritoneal vs. epidural levobupivacaine infusion on troponin I and BNP as predictors of cardiac injury in cancer patients undergoing major upper abdominal operations: A randomized controlled clinical trial

ABSTRACT Background Cancer patients undergoing major noncardiac surgery are more likely to experience perioperative morbidity and mortality due to myocardial damage. Methods Comparative study enrolled 80 patients with upper abdominal malignancies subjected to major abdominal surgeries. Of them, seventy-two patients were eligible and randomly assigned into two groups; Epidural catheter group (n = 37), received thoracic epidural infusion of levobupivacaine, and pre-peritoneal catheter group (n = 35), received preperitoneal infusion of levobupivacaine postoperatively. Primary endpoint was pain severity by NRS immediately after recovery, at 2, 4, 6, 12, 24, 36, and 48 hours. Secondary endpoints were: (1) Patient`s hemodynamics monitored for postoperative 48 hours. (2) Myocardial injury, confirmed by troponin I & BNP levels preoperatively and on postoperative day 1 and 2 (3) Time of first analgesic demand and total postoperative 48 h morphine consumption. (4) Cardiovascular side effects; hypotension, bradycardia & arrhythmia. (5) Morphine side effects; PONV Results NRS scores showed non-significant reduction at most study times between both groups with significant reduction in the ECI group at 6-, 12-, and 24-hour than other group. First analgesic demand was earlier in PCI group than ECI without significant difference, while total 48 h morphine consumption showed a significant reduction in ECI group than PCI group. Hemodynamics were comparable in both groups. Cardiac enzymes, Troponin I and BNP, showed non-significant differences over study time between both groups. Postoperative complications, PONV, were similar in both groups without any significance, but with more cases of hypotension and bradycardia in epidural group. No cases of myocardial injury or heart failure were reported. Conclusions Preperitoneal analgesia is an effective analgesic method comparable to epidural analgesia limiting the occurrence of major cardiovascular events in cancer patients undergoing major abdominal surgeries and can be utilized when epidural analgesia is not desired or forbidden.

Effects of Post Trauma Morphine On Dorsal Horn Neuron Excitability: Studies using cFOS and RNAscope

Previous research has shown that a 5-day course of morphine enhances nociceptive sensitivity and allodynia when given 10 days after chronic constriction injury (CCI) as measured by the Von Frey test, a test where the hindpaw is poked with force (measured in grams) calibrated filament. This increased sensitivity to touch suggests that post trauma morphine makes second order sensory dorsal horn neurons more excitable. Therefore, it is hypothesized that during morphine enhanced allodynia, dorsal horn neurons will be more excitable to nociceptive stimulus. It was found that morphine enhanced allodynia causes more excitable neurons across a larger spatial range of the spinal cord, both rostral-caudal and dorsal-ventral along the dorsal horn. Mechanisms for the increased excitability of the dorsal horn are proposed and explored. These findings add to a robust literature which has detailed the paradoxical pain amplifying effects of morphine. Further, this study predicts that hyperexcitability of pain and touch pathways may occur as a clinically unintended side effect of morphine when administered to treat ongoing neuropathic pain. Lay Summary When working on the body, opioids take effect on various cells- including cells of the nervous system known as Glia. These glial cells produce various inflammatory responses that are typically known to decrease inflammation in the body. However, prior literature has revealed that following an activated state, these cells enter a “primed” form. If a second immunological activation occurs during this primed state, glial cells have been shown to release proteins that actually potentiate the state of pain. This study examines this hypothesis through the context of peripheral nerve injury (modeling injury, surgery, or trauma), followed by an administration of morphine. Using advanced imaging techniques, we are able to visualize exactly what modulators are inducing this potentiated pain response, as well as where in the nervous system these cells are found. Morphine has a potent effect on various aspects of the nervous system which may be alleviated by other treatment routes that focus specifically on the cell type and location that release the molecules that initiate the healing process. By unveiling the details of this mechanism, we can better understand how to treat patients following injury or surgery without inducing a higher pain response that can be caused by a short-term administration of morphine. To see the complete thesis, please visit https://scholar.colorado.edu/concern/undergraduate_honors_theses/0k225c53t.

Protective Effect of Baclofen against Oxidative Stress in Dorsal Hippocampus of Rats with Morphine-Induced Ovarian Polycystic

Background and Objectives: Studies have shown that polycystic ovary (PCO) may be induced by morphine and CA1 may be damaged by PCO-related oxidative stress but can be protected by a potent GABAB receptor agonist. Therefore, this study aimed to investigate the protective effect of baclofen against oxidative stress in the dorsal hippocampus (DH) of morphine-treated rats with ovarian cysts. Materials and Methods: In total, 66 female Wistar rats were selected and randomly divided into control and experimental groups. The control group received saline (1 ml/kg, intraperitoneally [i.p.], once a day). Experimental groups were treated with morphine (5 mg/kg, i.p.), baclofen alone (10-30 mg/kg, i.p.), and baclofen (10, 20, 30 mg/kg, i.p.) before morphine (5 mg/kg, i.p.), once daily. One group received morphine (0.4 µg/rat) once in the ventromedial hypothalamus, and the last ovariectomized group was administered morphine (5 mg/kg, i.p.) after recovery. Then blood and hippocampus samples were prepared. Moreover, the levels of oxidative stress factors (GPX, MDA, SOD, and CAT), and the intensity of estrogen and glucocorticoid receptors in DH were evaluated. Ovaries and the uterus were also examined biometrically. Results: In the morphine-treated groups, regardless of the injection method, the development of follicles was rare, compared to the control group, instead, thick-walled follicular cysts were abundant. However, in the groups that received baclofen alone or baclofen together with morphine, the number of cysts decreased and the number of mature follicles increased significantly. Oxidative agents showed high levels in the DH of the morphine-treated group, which correlated with low estrogen receptors in DH. However, baclofen pretreatment improved these conditions. Besides, glucocorticoid receptors in DH did not show significant differences in different groups, and necrosis in the CA1 area was not observed either in the morphine-receiving group or in the other groups. The uterus did not show significant changes in any group. Conclusion: Prophylactic use of baclofen can protect against morphine side effects.

Spinal Morphine-Induced Hypothermia Syndrome: A Closer Look

While neuraxial opioids for post-op pain control came into common use in the early 1980s, it was not until a decade later, in 1992, when the first case report1 was published about an unusual side effect of the spinal morphine. It was a hypothermia that was not only profound [≤34℃], but refractory to usual rewarming methods, and delayed in onset [about 2.5 to 3 hours from initial dose] and resolved in 6-8 hours after onset. It also was associated with paradoxical signs and symptoms such as subjective hyperthermia or euthermia while hypothermic, and concurrent shivering and diaphoresis.

Analgesic effect of ketorolac added to lidocaine in surgery of traumatic arm injuries: A double-blind, randomized clinical trial.

Acute pain after surgery can cause harmful effects. There are many ways to treat pain after surgery. Bier block technique is also a type of intravenous regional anesthesia that is suitable for short and minor surgeries of the arm, wrist, and fingers, so this study aims to compare the analgesic effect of Ketorolac in intravenous injection and when the lidocaine is added to Bier block. In surgery, traumatic injuries to the upper limbs. This study was a clinical trial, randomized and double-blind. The target population was candidates for upper limb orthopedic surgery. The patients selected based on the entry and exit criteria were randomly assigned to one of the 3 study groups. The intensity of pain, the amount of morphine consumed through the intravenous PCA pump, the incidence of side effects of morphine and ketorolac, as well as the overall patient satisfaction regarding the anesthesia method and pain control were compared between the groups. Data analysis, both descriptive and analytical, was done using SPSS statistical software version 21. The three studied groups were identical and had no differences in terms of quantitative and qualitative demographic variables. The median tourniquet closing time is different between the control group and the intravenous ketorolac and topical ketorolac groups with P=0.002 and P=0.001, respectively. There was no significant difference between the three groups in terms of the time of the first request to receive painkillers after deflating the tourniquet, but the amount of morphine received between the groups was significantly different (P=0.02). Comparison of pain intensity based on NRS, considering Taking the measurement repetition times indicated the significance of the effect of pain intensity between the groups (P=0.001). In terms of overall satisfaction with the quality of analgesia and anesthesia method, no significant difference was observed between the three study groups. In terms of the occurrence of complications related to the use of ketorolac, no complications were observed in any of the groups receiving this drug. In general, by conducting this study, it can be said that the administration of Ketorolac reduces the intensity of postoperative pain in the recovery room and transfer to the inpatient ward, and reduces the amount of morphine received by patients, but the time of the first request for pain relief by the patient It does not significantly delay and does not affect the overall satisfaction of patients with the quality of analgesia during and after the operation and their satisfaction with the anesthesia method they received.

The Effects of Additional Intraoperative Epidural Morphine Bolus Followed by Postoperative Thoracic Epidural Analgesia in Patients Underwent Liver Resection: A Retrospective Study

Background: Liver resection is a major surgery that usually causes immense postoperative pain. Thoracic epidural analgesia is one of the effective methods for postoperative pain control. However, inadequate epidural analgesia in liver resection is still high. Objective: To compare the effectiveness of adding a bolus dose of morphine to epidural analgesia with the epidural analgesia alone in patients that underwent liver resection. Materials and Methods: A retrospective study collected the data from medical records of patients aged 18 to 80 who underwent liver resection between October 2018 and March 2021. Patients were divided into two groups, the conventional group and the epidural morphine bolus group that received additional epidural morphine bolus intraoperatively followed by continuous epidural analgesia. The numeric pain rating scale and the requirement for breakthrough pain were collected either at the post-anesthetic care unit (PACU) or on the first postoperative day (POD1) at the ward. The epidural morphine-related side effects were reviewed. Results: One hundred sixty-two patients that underwent liver resection and received thoracic epidural analgesia were reviewed. The eighty-four patients (51.8%) were in the epidural morphine bolus group. The median pain scores at PACU and POD1 in the epidural morphine bolus group and the conventional group were 2.5 (0 to 7) and 6 (1 to 8) (p=0.025), and 1 (1 to 6) and 6 (6 to 7) (p<0.001), respectively. Moreover, the requirement for rescue treatment of the epidural morphine bolus group at both PACU and POD1 was significantly lower than that of the conventional group. However, the incidence of pruritus in the epidural morphine bolus group was significantly higher. Conclusion: Additional epidural morphine bolus into epidural analgesia provided better postoperative pain control and decreased the need for rescue treatment of breakthrough pain compared with the conventional technique. At the same time, the incidence of pruritus was significantly higher in the epidural morphine bolus group. Keywords: Epidural analgesia; Epidural morphine; Hepatectomy; Morphine side effects; Postoperative pain

Comparison of Side Effects of Nalbuphine and Morphine in the Treatment of Pain in children with Cancer: A Prospective Study.

Simple SummaryIn the 2012 WHO guidelines for the treatment of chronic pain in children, the recommendation for the use of the weak opioids tramadol and codeine was removed, and in 2017 the indication for the use of these drugs for the treatment of postoperative pain in the paediatric population was also withdrawn. For the treatment of pain associated with cancer treatment, the recommendations of non-opioid analgesics and, in cases of insufficient analgesia, the use of strong opioids remained. Nalbuphine, a weak opioid commonly used in the treatment of perioperative pain in children, can also be used effectively in the treatment of cancer-related pain. Our study is the first to evaluate the quality of analgesia, side effects, and withdrawal syndrome in children receiving nalbuphine for the treatment of cancer pain. The results indicate that nalbuphine is an effective and safe analgesic that is less likely than morphine to cause adverse side effects when used to treat cancer-related pain in children.Contemporary pain management regimens in children do not include the use of the middle step of the analgesic ladder, i.e., weak opioids. The aim of this study was to analyse the comparison of side effects and the therapeutic efficacy of morphine and nalbuphine in pain management in children with cancer. We conducted an observational, prospective study and analysed medical records of patients treated at the Clinic of Paediatric Haematology and Oncology of the University Hospital in Wroclaw (Poland), who developed mucositis during treatment. The efficacy and safety of both drugs were analysed, and the efficacy of pain relief and the incidence of adverse effects characteristic of opioid drugs were compared. The cases of 96 of children treated with opioid drugs nalbuphine or morphine were analysed. Nalbuphine therapy was accompanied by a statistically significantly lower incidence of side effects such as skin pruritus, constipation, and micturition disorders compared to morphine (p < 0.05). After the discontinuation of nalbuphine, signs of withdrawal syndrome were much less frequent than after morphine (p < 0.05). In Conclusion, nalbuphine used as a pain killer in children with oncological disorder is a safe drug. It provides stable analgesia in most children. Compared to morphine, the side effects typical of opioid use are less common, and the incidence decreases over time.

Evaluation the Protective Effect of Withania somnifera Extract on the Level of Sex Hormone in Morphine Addicted Female Rats

Morphine is one of the most types of phenanthrene alkaloid opioid used to soothe the acute and chronic pain via narcotic and analgesic medical employment. Increasingly constantly used of opioid in the public and medication practical important knowledge improve that. Morphine show pernicious has effects on numerous tissue for instance ovary, liver and lung morphine side effects instruct for existence of oxidative role due to generation of reactive oxygen species in the affected tissue. Last decades researchers proved that natural substance provides protective role against toxic effect. Thus, withania somnifera consider as antioxidant substance provide protective versus the toxic substance as morphine. The present study wase aimed to evaluate the protective role of withania somnifera extract on the level of sex hormone in morphine addicted female rats. In conclusion, the present study confirmed a truth evidence of a protective roles of withania somnifera against the morphine addiction in female rats.

Patient-Controlled Analgesia After Cardiac Surgery With Median Sternotomy: No Advantages of Hydromorphone When Compared to Morphine

ObjectivesTo compare the efficacy, safety, and side effects of hydromorphone and morphine administered as patient-controlled analgesia (PCA) for postoperative pain therapy after cardiac surgery with median sternotomy. DesignA retrospective analysis of data from 2 prospective, single-blinded, randomized trials. SettingA single-center intensive care unit at a university hospital. ParticipantsForty-one adult patients undergoing cardiac surgery with median sternotomy. InterventionsPostoperative pain therapy at the intensive care unit was performed by PCA with intravenously administered bolus doses of 0.2 mg of hydromorphone (n = 21) or 2 mg of morphine (n = 20). Measurements and Main ResultsPain at rest and under deep inspiration regularly was assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, cardiac output, oxygen saturation, and respiratory rate were monitored, and adverse events were registered. The median (range) NRS rating at rest was 1.5 (0-5) after hydromorphone and 0.5 (0-5) after morphine, respectively (p = 0.41). The median NRS rating under deep inspiration was 3 (0-6) after hydromorphone and 4 (0-7) after morphine, respectively (p = 0.074). The dose ratio of morphine to hydromorphone during PCA was 5.7 (95% confidence interval: 2.9-7.6). Hemodynamics and respiration were stable and did not differ significantly. Postoperative nausea and vomiting were the most frequent adverse events, which were observed in 29% of the patients after hydromorphone and in 35% after morphine, respectively (p = 0.74). ConclusionsThere were no significant differences in analgesic efficacy and safety between hydromorphone and morphine when used for postoperative pain therapy with PCA after cardiac surgery with median sternotomy.

Assessing the synergistic effects of morphine and MP‐III‐024 co‐administration: enhanced antinociception with reduced side effects

Opioid analgesics are critical for acute and chronic pain management, but important side effects—including tolerance, constipation, respiratory depression, and abuse liability—limit their safety and utility. To provide patients with safer analgesic options, it is critically important to identify of new pharmacotherapeutic strategies to treat pain. Activation of µ‐opioid receptors (MORs) in central and peripheral nociceptive pathways mediates opioid analgesia and their critical side effects. Antinociception can also be achieved via selective enhancement of GABAergic signaling at ionotropic GABAA receptors. α2 and α3 subunit‐containing GABAA receptors (α2/α3GABAA), which are co‐expressed with MORs in dorsal horn spinal pathways important to nociceptive transmission, can be selectively targeted with novel imidazodiazepine positive allosteric modulators (PAMs), such as MP‐III‐024, which produces antinociceptive effects with limited behavioral disruption. MP‐III‐024 co‐administered with morphine produces synergistic antinociceptive and anti‐hyperalgesic effects. In this study, we evaluated whether MP‐III‐024/morphine co‐administration produces sub‐additive or synergistic effects in behavioral tests sensitive to morphine side effects. Herein we report that co‐administration of MP‐III‐024/morphine at a 0.94/1 ratio (synergistic in models of antinociception) produced sub‐additive effects in morphine‐induced hyperlocomotion and in measures of behavioral disruption in food‐maintained operant responding. Ongoing studies are evaluating the effects of MP‐III‐024/morphine co‐administration on tolerance in the hot plate test and in conditioned place preference. These experiments are the first comprehensive preclinical analyses of a dual MOR‐α2/α3GABAA pharmacotherapy strategy which may increase the therapeutic window between desirable opioid analgesic effects and side effects.

The effect of posterior tibial and sural nerve blocks on postoperative pain of patients following open reduction and internal fixation of calcaneal fractures

IntroductionPostoperative pain control and achieving opioid-free anesthesia are major issues for surgically treated patients with calcaneal fractures. We evaluated the potential role of posterior tibial and sural nerve blocks as a part of multimodal pain control techniques in patients underwent open reduction and internal fixation (ORIF) of calcaneal fractures via extensile lateral approach. MethodsForty-eight patients randomly allocated to receive either posterior tibial and sural nerve blocks with bupivacaine (peripheral nerve block (PNB) group) or normal saline, after induction of general anesthesia. Patients were assessed for pain intensity, Interval from entrance to the recovery room to the first request for analgesic, recovery room and ward morphine consumption, global satisfaction and morphine side effects. ResultsPNB group had less pain score compared to sham block (SB) group at each time point measurement during recovery room stay. There was also significant difference between the 2 groups regarding the pain scores after 2, 4 and 6 h of the operation in the ward. Time to the first request for analgesic was significantly prolonged in the PNB group (P < 0.001). The recovery room and ward morphine consumption was significantly lower in the PNB group (P < 0.001). Global satisfaction in PNB group was significantly more than that of SB group. No complication related to the nerve block was detected at the first postoperative visit in the outpatient clinic. ConclusionPeripheral nerve block could result in less postoperative pain especially in the early hours after ORIF of calcaneal fractures and reduce opioid administration within the first 24 h following the surgery.

Intrathecal morphine in planned gynecologic surgery: Recovery and postoperative pain control

BackgroundTo compare post-operative pain control and side effects of intrathecal morphine (ITM) given in two different doses in patients undergoing gynecological surgery. MethodsThis was a retrospective data base cohort study conducted between 2015 and 2017 at the Shaare Zedek Medical Center. Surgeries were divided into subgroups: vaginal, abdominal and oncological. A comparison was made between 2 distinct doses of ITM (standard – 150 mcg and high - 200 mcg) in terms of post-operative pain as reflected by visual analog scale (VAS) scores and side effects. Additional subgroup of the three surgical groups was made regardless of the ITM dose used. Multivariate analysis was carried out using appropriate tests. ResultsThe study included 156 patients. Forty five patients received a standard dose ITM and 111 received the high dose. Sixty three patients had vaginal surgery, 80 had benign abdominal surgery and 13 had a gynecologic oncology surgery. No difference was noted in VAS scores during the first 24 h of hospitalization. However, average and maximal VAS scores were higher among those who received high dose ITM. This difference did not remain significant in the multivariate analysis controlling for patient age and surgery type. Patients treated with high dose ITM had a higher incidence of pruritus. No difference was noted in respiratory depression as reflected by medically indicated oxygen consumption between those treated with high vs. standard dose ITM. ConclusionsITM dose higher than 150 mcg is associated with a higher rate of pruritus without any additional benefit on the analgesic effect as reflected by post-operative VAS scores.

The role of hippocampal glial glutamate transporter (GLT-1) in morphine-induced behavioral responses.

Opioid abuse modifies synaptic plasticity, which leads to behavioral changes, such as morphine dependence, but the mechanism remains poorly understood. Glial cells play an important role in the modulation of synaptic plasticity and are involved in addictive‐like behaviors. The indisputable role of glutamate in opiate addiction has been shown. Astrocytes, a type of glial cells, which are integral functional elements of synapses, modulate the concentration of glutamate in the synaptic space. One of the most important mechanisms for glutamate concentration regulation is its uptake from the synaptic cleft. In this study, we evaluated the role of hippocampal glial glutamate transporter (GLT‐1) in morphine dependence. Male rats received subcutaneous (s.c.) morphine sulfate (10 mg/kg) at an interval of 12 h for 9 days. In order to activate GLT‐1, animals received an intrahippocampal injection of ceftriaxone (0.5 mmol/0.5 μl) in the CA1 region of the hippocampus, 30 min before each morphine administration. Rats were assessed for morphine dependence by monitoring naloxone hydrochloride‐induced morphine withdrawal. Our results showed that hippocampal microinjection of ceftriaxone, as an activator of GLT‐1, reduced some signs of morphine withdrawal, such as activity, diarrhea, head tremor, freezing, and ptosis. It seems that hippocampal GLT‐1 can be affected by chronic morphine administration and involved in morphine dependence. Therefore, its activation may reduce morphine side effects by reducing hippocampal glutamate.

P-122 Gastrointestinal side effects of morphine in cancer pain: A comparison between the smoking and non-smoking patients

The use of morphine analgesics is associated with a number of side effects, especially morphine-induced gastrointestinal dysfunction. Gastrointestinal side effects of morphine have a negative impact on patient quality of life. The complex relationship between nicotine and opioids is a controversial one and still not well understood. Some animal studies suggest that nicotine binds some opioid receptors. The aim of this study was to prospectively compare the incidence of gastrointestinal side effects of morphine between smokers and non-smokers in cancer pain patients. The study was conducted in our institution between 2019 and 2021. We included all patients receiving oral morphine, at least 60 mg daily, for cancer pain, for a week or longer before inclusion. All patients received oral sustained-release morphine sulfate and morphine sulfate immediate release. We used a prospective survey with a questionnaire administered weekly for 4 weeks. The participants were free of psychiatric disturbance, substance abuse (other than nicotine), had no renal or hepatic disease failure, and had no gastrointestinal disease. Patients were divided into two groups: smokers (n=40) and non-smokers (n=40). Gastrointestinal side effects of morphine were recorded and compared between the two groups. Of the 96 patients, 80 completed the entire study by answering the questionnaire on 4 consecutive occasions. There were 40 smokers and 40 non-smokers. The group of smokers was all men and the group of non-smokers had 17 men and 23 women. The mean age was 50 years (range: 26-65). The gastrointestinal side effects in the smokers group were: constipation in 20%, nausea in 18%, dry mouth in 18%, reflux in 5%, dyspepsia in 4%, anorexia in 1%, and abdominal pain in 1%. The gastrointestinal side effects in the non-smokers group were: constipation in 65% nausea in 60%, vomiting in 20%, dry mouth in 20%, reflux in 7%, dyspepsia in 7%, anorexia in 6%, abdominal pain in 6%. The gastrointestinal side effects were often moderate in the two groups; we rotated morphine in just two patients in the group of non-smoker patients as a result of vomiting. Overall, gastrointestinal side effects of morphine in non-smokers were statistically higher than in smokers (77% vs. 27%, p=0.001). 60% of non-smokers had nausea versus 18% in smokers (p=0.001). 20% of non-smokers had vomiting versus 0% in smokers (p=0.003). 65% of non-smokers had constipation versus 20% in smokers (p=0.005). Although other gastrointestinal side effects were higher in non-smoking patients compared to smoker patients, they did not reach statistical significance. There was a significant difference in terms of gastrointestinal side effects between smoker and non-smoker patients. Higher levels of morphine-induced gastrointestinal adverse effects were observed in non-smoking patients. Specifically, non-smokers reported more nausea, vomiting, and constipation than smokers.

Efficacy of Intravenous Paracetamol and Ibuprofen on Postoperative Pain and Morphine Consumption in Lumbar Disc Surgery: Prospective, Randomized, Double-Blind, Placebo-Controlled Clinical Trial

ObjectivesEffective postoperative pain management after lumbar disc surgery reduces complications and improves postoperative care. The purpose of this prospective, randomized, double-blind, placebo-controlled clinical study is to evaluate the effects of IV paracetamol and ibuprofen on postoperative pain, morphine consumption and side effects of morphine in patients who underwent lumbar disc surgery. Materials and methodsSeventy-five patients aged 18-85 years scheduled for lumbar disk surgery with a single level laminectomy included in this study. All patients received morphine with an IV patient-controlled analgesia device during the first postoperative 24hour. The patients were divided randomly and double-blinded into three groups (control, paracetamol and ibuprofen). The demographic characteristics and procedure data, VAS score, cumulative morphine consumption, opioid-related side effects were recorded. ResultsThere was no significant difference regarding to demographic characteristics, comorbidities, and durations of anesthesia and surgery. There was a significant difference between all groups regarding to total morphine consumption (P<0.001). IV ibuprofen significantly reduced the total morphine consumption in comparison with control and paracetamol (P<0.001). Repeated measures ANOVA showed in all periods of the study that VAS score was significantly lower in ibuprofen (P<0.001), but not in paracetamol (P=0.394) in comparison with control. There was no difference between groups regarding postoperative heart rate, mean arterial pressure, nausea-vomiting, pruritus and urinary retention. ConclusionsThis study showed that pain scores and morphine consumption, but not the side effects of patient-controlled analgesia during 24hours after the lumbar disk surgery, were significantly reduced by IV ibuprofen as a supplemental analgesic when compared with controls and paracetamols.

The protective effect of zinc on morphine-induced testicular toxicity via p53 and Akt pathways: An in vitro and in vivo approach

BackgroundChronic use of morphine is associated with reproductive complications, such as hypogonadism and infertility. While the side effects of morphine have been extensively studied in the testis, much less is known regarding the effects of morphine on Sertoli cells and the effects of zinc on morphine-induced testicular injury as well as their underlying mechanisms. Therefore, the purpose of this study was to investigate the effect of morphine (alone and co-administered with zinc) on cell viability and apoptosis of the testicular (Sertoli) cells as well as the tumor suppressor p53 and phosphorylated-protein kinase B (p-Akt) protein levels in both in vitro and in vivo models. MethodsCultured Sertoli cells were exposed to morphine (23 μM), zinc (8 μM), and zinc prior to morphine and their effects on Sertoli cell viability and apoptosis were investigated. Morphine (3 mg/kg) and zinc (5 mg/kg, 1 h before morphine) were also injected intraperitoneally to rats and then the apoptotic changes in the testis were evaluated. ResultsCell viability and p-Akt protein levels decreased in morphine-treated cells, while apoptosis and p53 protein expression increased in these cells. Pretreatment with zinc recovered morphine-induced apoptotic effects, as well as over-expression of p53 and down-regulation of p-Akt. These findings were supported by a subsequent animal study. ConclusionThe present data indicated the protective effect of zinc against morphine-induced testicular (Sertoli) cell toxicity via p53/Akt pathways in both in vivo and in vitro models and suggested the clinical importance of zinc on infertility among chronic opioid users and addicted men.

Intrathecal Morphine Versus Intrathecal Hydromorphone for Analgesia After Cesarean Delivery: A Randomized Clinical Trial

(Anesthesiology. 2020;132:1382–1391) The effectiveness of intrathecal morphine for postcesarean analgesia is widely established, and is used throughout the United States and across the world. However, drug shortages have affected the supply of preservative-free morphine throughout the United States, leading to the exploration of alternative analgesic options. This study aimed to compare both the effectiveness and side effects of intrathecal morphine when compared with intrathecal hydromorphone. The authors hypothesized that equipotent doses would yield a superior result for intrathecal morphine following a 24-hour period.

The synergistic effects of opioid and neuropeptide B/W in rat acute inflammatory and neuropathic pain models

The use of morphine is controversial due to the incidence of rewarding behavior, respiratory depression, and tolerance, leading to increased drug dose requirements, advancing to morphine addiction. To overcome these barriers, strategies have been taken to combine morphine with other analgesics. Neuropeptide B23 and neuropeptide W23 (NPB23 and NPW23) are commonly used to relieve inflammatory pain and neuropathic pain. As NPB23 and NPW23 system shares similar anatomical basis with opioid system at least in the spinal cord we hypothesized that NPB23 or NPW23 and morphine may synergistically relieve inflammatory pain and neuropathic pain. To test this hypothesis, we demonstrated that μ opioid receptor and NPBW1 receptor (receptor of NPB23 and NPW23) are colocalized in the superficial dorsal horn of the spinal cord. Secondly, co-administration of morphine witheitherNPB23 or NPW23 synergistically attenuated inflammatory and neuropathic pain. Furthermore, either NPB23 or NPW23 significantly reduced morphine-induced conditioned place preference (CPP) and constipation. We also found that phosphorylation of extracellular-regulated protein kinase (ERK1/2) following morphine was profoundly potentiated by the application of NPB23 or NPW23. Hence, combination of morphine with either NPB23 or NPW23 reduced dose of morphine required for pain relief in inflammatory and neuropathic pain, while effectively prevented some side-effects of morphine.