Naloxone Group Research Articles

Effects of Chronic Pain Following Unilateral Ureteral Obstruction on Hippocampal CA1 Pyramidal Neurons in Male Wistar Rats

Background: Chronic pain can adversely affect cognitive functions such as learning, memory, and attention. However, the precise mechanisms underlying cognitive impairment in chronic pain remain elusive. Objectives: This study aims to investigate the impact of chronic pain induced by unilateral ureteral obstruction (UUO) on hippocampal neurons. Methods: In the current case-control study, 27 male Wistar rats (230 - 280 g) were randomly assigned to three groups: 1-sham, 2-UUO, and 3-UUO treated with naloxone (i.p.; 1 mg/kg for 5 days). Following transcardial perfusion, the rats' brains were removed, and histological studies were performed to count the number of neurons using an optical microscope. Concurrently, TNF-α and NGF levels were measured in brain tissue homogenate. Results: The mean number of neurons in the CA1 region of the animals in the UUO group was 68.11 ± 1.34, which showed a significant decrease compared to the mean number of neurons in the sham-operated group (114.1 ± 1.77; P < 0.0001). In contrast, the mean number of neurons in the CA1 region of the UUO with naloxone group showed a significant increase compared to the animals in the UUO group (73.44 ± 1.37; P < 0.0001). TNF-α was 264.3 ± 2.6 pg/mL in the UUO animals and decreased significantly in the UUO animals treated with naloxone (P = 0.001). However, NGF was 115.2 ± 2.9 pg/mL in UUO animals and increased significantly in the UUO with naloxone group (P < 0.01). Conclusions: Unilateral ureteral obstruction, through inducing chronic pain and inflammation, resulted in neurodegeneration in the CA1 region of the hippocampus. The use of naloxone, an opioid antagonist, immediately after the surgery was able to provide neuronal protection and an anti-inflammatory effect.

Effects of perioperative low-dose naloxone on the immune system in patients undergoing laparoscopic-assisted total gastrectomy: a randomized controlled trial

BackgroundLow immune function after laparoscopic total gastrectomy puts patients at risk of infection-related complications. Low-dose naloxone (LDN) can improve the prognosis of patients suffering from chronic inflammatory diseases or autoimmune diseases. The use of LDN during perioperative procedures may reduce perioperative complications. The purpose of this study was to examine the effects of LDN on endogenous immune function in gastric cancer patients and its specific mechanisms through a randomized controlled trial.MethodsFifty-five patients who underwent laparoscopic-assisted total gastrectomy were randomly assigned to either a naloxone group (n = 23) or a nonnaloxone group (n = 22). Patients in the naloxone group received 0.05 µg/kg-1.h− 1naloxone from 3 days before surgery to 5 days after surgery via a patient-controlled intravenous injection (PCIA) pump, and patients in the nonnaloxone group did not receive special treatment. The primary outcomes were the rates of postoperative complications and immune function assessed by NK cell, CD3+ T cell, CD4+ T cell, CD8+ T cell, WBC count, neutrophil percentage, and IL-6 and calcitonin levels. The secondary outcomes were the expression levels of TLR4 (Toll-like receptor), IL-6 and TNF-α in gastric cancer tissue.ResultsCompared with the nonnaloxone group, the naloxone group exhibited a lower incidence of infection (in the incision, abdomen, and lungs) (P < 0.05). The numbers of NK cells and CD8+ T cells in the naloxone group were significantly greater than those in the nonnaloxone group at 24 h after surgery (P < 0.05) and at 96 h after surgery (P < 0.05). Compared with those in the nonnaloxone group, the CD3 + T-cell (P < 0.05) and CD4 + T-cell (P < 0.01) counts were significantly lower in the naloxone group 24 h after surgery. At 24 h and 96 h after surgery, the WBC count (P < 0.05) and neutrophil percentage (P < 0.05) were significantly greater in the nonnaloxone group. The levels of IL-6 (P < 0.05) and calcitonin in the nonnaloxone group were significantly greater at 24 h after surgery. At 24 h following surgery, the nonnaloxone group had significantly greater levels of IL-6 (P < 0.05) and calcitonin than did the naloxone group. Compared with those in the naloxone group, the expression levels of TLR4 (P < 0.05) in gastric cancer tissue in the naloxone group were greater; however, the expression levels of IL-6 (P < 0.01) and TNF-α (P < 0.01) in the naloxone group were greater than those in the nonnaloxone group.ConclusionLaparoscopic total gastrectomy patients can benefit from 0.05 ug/kg− 1. h− 1 naloxone by reducing their risk of infection. It is possible that LDN alters the number of cells in lymphocyte subpopulations, such as NK cells, CD3 + T cells, and CD4 + T cells, and the CD4+/CD8 + T-cell ratio or alters TLR4 receptor expression in immune cells, thereby altering immune cell activity.Trial registrationThe trial was registered at the Chinese Clinical Trial Registry on 24/11/2023 (ChiCTR2300077948).

Investigation of Melatonin Receptors Gene Expression Levels in the Hippocampus and Hypothalamus in Rats with an Experimental Morphine Dependence Model

Objective: Morphine is one of the important opioids used in chronic and acute pain management. However, it has many side effects, including the development of addiction, which seriously limits its use. Melatonin shows its physiological effects through melatonin receptor 1 (MT1), melatonin receptor 2 (MT2) and heterodimer receptors (MT1/MT2). No study has examined the presence of MT1/MT2 mRNA in the hypothalamus and hippocampus and its relationship with the addiction process. The aim of this study was to investigate the gene expression levels of MT1, MT2 and MT1/MT2 in rat hippocampus and hypothalamus during morphine addiction and morphine withdrawal. Materials and Methods: A total of 36 male Wistar rats were divided into 3 groups (n=12). Control (C) group received saline subcutaneously for 6 days. Morphine (M) and morphine+naloxone (M+N) groups received 10 mg/kg/day morphine subcutaneously for 6 days. On the seventh day, saline was injected intraperitoneally into C and M groups and 1 mg/kg naloxone was injected intraperitoneally into M+N group. 30 minutes later, hippocampus and hypothalamus tissues of rats were dissected. Melatonin receptor gene expression level was analysed by quantitative qPCR. Results: Both MT1 and MT1/MT2 gene expression levels in the hypothalamus were in the M+N group than in the C group (p&lt;0.05). There was no difference between the expression levels of MT2 receptors in the hypothalamus (p&gt;0.05). There was no difference in MT1, MT2 and MT1/MT2 gene expression in the hippocampus (p&gt;0.05). Conclusion: This is the first study to show the presence of MT1/MT2 in the hypothalamus and hippocampus, and it is possible that MT1 and MT1/MT2 receptors, especially in the hypothalamus, play a role in the addiction process.

Pharmacokinetics and pharmacodynamics of intranasal and intramuscular administration of naloxone in working dogs administered fentanyl.

Working dogs exposed to narcotics might require reversal in the field. To explore the pharmacokinetic and pharmacodynamic effects of naloxone administered intramuscularly (IM) or intranasally (IN) to reverse fentanyl sedation in working dogs. Ten healthy, working dogs aged 1.7 ± 1 year and weighing 26 ± 3 kg. In this randomized, controlled cross-over study dogs received either 4 mg of naloxone IN or IM 10 minutes after fentanyl (0.3 mg IV) administration. Sedation was assessed at baseline and 5 minutes after fentanyl administration, then at 5, 10, 15, 20, 25, 30, 60 and 120 minutes after reversal with naloxone. Blood samples for naloxone detection were obtained at 0, 5, 10, 30, 60 and 120 minutes. Pharmacokinetic parameters and sedation scores were compared between IM and IN naloxone groups. There was a significant increase in sedation score from baseline (0.25 [-4 to 1] IM; 0 [-2 to 1] IN) after fentanyl administration (11 [5-12] IM; 9.25 [4-11] IN), followed by a significant reduction at 5 (0.5 [-0.5 to 1.5] IM; 1.25 [-1.5 to 4.5] IN) through 120 minutes (-0.5 [-2 to 1] IM; 0 [-4.5 to 1] IN) after reversal with naloxone. Route of administration had no significant effect on sedation score. Maximum plasma concentration was significantly lower after IN administration (11.7 [2.8-18.8] ng/mL IN, 36.7 [22.1-56.4] ng/mL IM, P < .001) but time to reach maximum plasma concentration was not significantly different from IM administration. Although IM administration resulted in higher naloxone plasma concentrations compared to IN, reversal of sedation was achieved via both routes after administration of therapeutic doses of fentanyl.

Modifying naloxone to reverse fentanyl-induced overdose

Developing an effective antidote for fentanyl-induced overdose (OD) is an unmet medical need that requires both lipophilicity comparable to fentanyl and fast onset of overdose reversal. We synthesized and evaluated a bioreversible derivative of naloxone (NX-90) in silico, in vitro and in vivo to yield a robust reversal of fentanyl-induced OD in rats. All monitored reflexes along with the heart rate (HR) and respiratory rate (RR) were fully restored faster in the NX-90 groups than in naloxone groups on equimolar bases when given intranasally. In NX-90 treated rats RR over the time of observation (RR AUC) was significantly higher at all respective doses with no re-narcotization observed. Apart from the enhanced pharmacodynamics profile, NX-90 was found to have lower circulating levels of naloxone, clean profile in in vitro selectivity panels, as well as Ames and CYP450 counter screens. Finally, we demonstrated a robust release of the parent naloxone in brain matrix, as well as lower peripheral naloxone levels after NX-90 iv administration. With the demonstrated pharmacological profile superior yet congruent to naloxone we nominated NX-90 for preclinical development as an effective intranasal fentanyl antidote.

Effects of intracerebroventricularly administered opioid peptide antagonists on tissue glycogen levels in rats after exercise

Background/aim Physical exercise is a state of physiological stress that requires adaptation of the organism to physical activity. Glycogen is an important and essential energy source for muscle contraction. Skeletal muscle and liver are two important glycogen stores, and the energy required to maintain exercise in rodents are provided by destruction of this glycogen depot. In this study, the effects of endogenous opioid peptide antagonism at the central nervous system level on tissue glycogen content after exhaustive exercise were investigated. Materials and methods Rats had intracerebroventricularly (icv) received nonspecific opioid peptide receptor antagonist, naloxone (50 μg/10 μL in saline) and δ-opioid receptor-selective antagonist naltrindole (50 μg/10 μL in saline) and then exercised till exhaustion. After exhaustion, skeletal muscle, heart, and liver were excised immediately. Results Both opioid peptide antagonists decreased glycogen levels in skeletal muscle. Although, in soleus muscle, this decrease was not statistically significant (p > 0.05), in gastrocnemius muscle, it was significant in the icv naloxone administered group compared with control (p < 0.05). Heart glycogen levels increased significantly in both naloxone and naltrindole groups compared to control and sham-operated groups (p < 0.05). Heart glycogen levels were higher in the naloxone group than naltrindole (p < 0.05). Liver glycogen levels were elevated significantly with icv naloxone administration compared with the control group (p < 0.05). Glycogen levels in the naloxone group was also significantly higher than the naltrindole group (p < 0.05). Conclusion Our findings indicate that icv administered opioid peptide antagonists may play a role in glycogen metabolism in peripheral tissues such as skeletal muscle, heart, and liver.

Effect of naloxone hydrochloride on β-EP, CD4+, CD8+, IL2, MMP-9 and S100-B levels in peripheral blood after traumatic brain injury in rats

Purpose: To study the influence of naloxone hydrochloride on traumatic brain injury (TBI).&#x0D; Methods: Three groups of rats were used: normal control, TBI, and TBI + naloxone hydrochloride groups (12 rats/group). In the control group, only the osseous foramen was opened. Rats in TBI group were intraperitoneally injected with normal saline, while the naloxone group received naloxone hydrochloride injection at the same time. Changes in peripheral blood β-EP, CD4+, CD8+, IL-2, and S100-B levels; and brain tissue MMP-9 were assessed.&#x0D; Results: The levels of β-EP in the TBI- and naloxone-treated rats were higher than control values, while levels of CD4+ in TBI and naloxone groups were significantly lower than those of control group (p &lt; 0.01). At every time point, CD8+ level in naloxone group was significantly lower than that in TBI group (p &lt; 0.01). Compared with control group, the levels of IL-2 in the TBI and naloxone groups were significantly lower. Higher levels of S100-B were seen in TBI- and naloxone-treated rats, relative to control value. In the naloxone group, MMP-9 expression was downregulated, when compared to the expression TBI rats (p &lt; 0.05).&#x0D; Conclusion: Naloxone hydrochloride reduces β-EP, alleviates inflammation, protects nerve cells and reduces brain injury in TBI rats. There is, thus, a potential to develop naloxone for the management of brain injury

A Low Dose of Naloxone Added to Ropivacaine Prolongs Femoral Nerve Blockade: A Randomized Clinical Trial.

Femoral nerve blocks (FNBs) are used as safe and useful procedures to control severe postoperative pain from total knee arthroplasty (TKA). Various adjuvants have been used to prolong the duration of the local anesthetic blockade. This study evaluated whether a low dose of naloxone administered with local anesthetics prolongs the duration of FNB. A prospective, randomized double-blind controlled study was conducted with 74 patients undergoing unilateral TKA. Through a single-bolus administration guided by ultrasound, the control group (group C) received 20 mL of 0.375% ropivacaine, while the naloxone group (group N) received 20 mL of 0.375% ropivacaine with 100 ng of naloxone. The time elapsed before the first analgesia request, the total amount of opioids consumed at 24 h postoperatively, the onset time of the sensory blockade, the visual analog pain scale (VAS) scores after arriving at the recovery room, after 6, 12, 18, and 24 h at rest and after 12, 18, and 24 h of activity, the quadricep strength before the FNB procedure and at 12 and 24 h postoperatively, the quality of sleep on the first night after surgery, the satisfaction score, and the incidence of postoperative complications were recorded. The time elapsed before the first analgesia request was significantly longer in group N (735.5 ± 187.2 min) than that in group C (602.6 ± 210.4 min) (P=0.003). The total dose of supplementary opioids consumed at 24 h postoperatively was significantly lower in group N (312.4 ± 141.7 μg) than that in group C (456.5 ± 279.5 μg) (P=0.007). Lower VAS scores were recorded in group N than that in group C at rest and during knee activity (rest, 12 h, P=0.001, 18 h, P=0.043; activity, 12 h, P=0.001). The addition of a low dose of naloxone to ropivacaine for FNB significantly delayed the first request for rescue analgesia and decreased the opioid consumption within 24 h, without significant complications.

Naloxone Continuous Infusion for Spinal Cord Protection in Endovascular Aortic Surgery Leads to Higher Opioid Administration and More Pain

Compare total perioperative opioid use in patients receiving naloxone continuousinfusion (NCI) for spinal cord ischemia prophylaxis, versus patients not receiving NCI, in endovascular aortic repair. Single-center, retrospective cohort review. Academic medical center. Patients undergoing elective thoracic, thoracoabdominal, or abdominal aortic endovascular repair. Patients were separated based on the use of naloxone continuous infusion as part of a spinal protection protocol. Primary endpoint was opioid requirements, in milligram morphine equivalents (MME), during the first 48 hours or during NCI. Secondary endpoints included: postoperative pain scores during the same interval; opioid requirements during hours 48 to 72; and pain scores during hours 48 to 72. Ninety-five procedures were included; 43 received naloxone continuous infusion and 52 patients were in the non-naloxone group. Opioid use from a linear mixed model was elevated across the entire continuum in the naloxone group (18 MMEs, 95% CI 13-24), with the greatest difference seen at the 24-to-48-hour interval (51 MMEs, 95% CI 26-75) after adjustment for age, incisions, and prehospital opioid use. In the naloxone group, pain score estimates were elevated at each postoperative interval of evaluation, with similar adjustment. Across the continuum this was 0.7 higher (95% CI 0.2-1.3); the zero-six-hour and six-to-12-hour intervals were 0.9 (95% CI 0.4-1.4) and 1.2 higher (95% CI 0.7-1.7). Patients receiving anloxone continuous infusion to prevent spinal cord ischemia required greater quantities of opioids and had higher postoperative pain, compared with patients not requiring naloxone.

Co-Administration of Morphine and Naloxone: Histopathological and Biochemical Changes in the Rat Liver

Background: Co-administration of opioid agonists and antagonists at low doses has been reported to significantly enhance and/or prolong the analgesic effects and reduce or prevent tolerance to or dependence on opioids. Objectives: The current study aimed at evaluating the naloxone effect on morphine-induced histopathological and hematologic changes in rats. Materials and Mehods: Thirty mature male Wistar rats were categorized into three groups (n = 10) in a random manner, including the control group receiving normal saline, the morphine-sole group receiving morphine (5 mg/kg/day), and morphine + naloxone group receiving morphine and naloxone (5 and 0.4 mg/kg/day, respectively). After 50 days, the levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), triglyceride (TG), aspartate aminotransferase (AST), cholesterol, and high-density lipoprotein (HDL) were measured in the serum. Moreover, the levels of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione peroxidase (GPx) were measured to assess the serum antioxidant capacity. Histopathological changes were investigated via hematoxylin and eosin, Masson’s trichrome, and periodic acid-Schiff staining. Inter-group comparisons were made by GraphPad Prism software using one-way ANOVA and Tukey’s test. Results: The animals in the morphine + naloxone group showed higher AST, ALP, ALT, and CAT levels in comparison with the control and morphine-sole groups (P &lt; 0.05). Our findings revealed no changes in the cholesterol, TG, SOD, and GPx levels among the groups (P &gt; 0.05). However, the morphine-sole group exhibited higher serum levels of HDL compared with the controls (P &lt; 0.05). The morphine-sole group showed fibrosis, local necrosis, immune cell infiltration, and diminished intra-cytoplasmic carbohydrate storage. Conclusions: The findings suggest that apart from unchanged serum markers, morphine can potentially induce hepatotoxicity, and at the same time, naloxone is able to ameliorate morphine-induced histopathological damages.

Compound matrine injection reduces morphine tolerance of the mice with lung cancer by inhibiting expression of multidrug resistance gene 1 and P-glycoprotein

Objective: To investigate the effect of compound matrine injection on morphine tolerance in mice with lung cancer in situ and the expressions of multidrug resistance gene 1 (MDR1) and P-glycoprotein (P-gp). Methods: A mouse model of lung cancer in situ and morphine tolerance mode was established. The mice were injected with gradient concentration of compound matrine. The pain thresholds under different conditions were measured by thermal radiation tail-flick method. The mRNA level of MDR1 was tested by reverse transcription polymerase chain reaction (RT-PCR) and the protein level of P-gp was detected by western blot. The DNA binding activity of cyclophosphoadenosine response element binding protein (CREB) to the promoter of MDR1 gene was detected by electrophoretic mobility shift assay (EMSA). Results: The maximum analgesic percentage (MPE) of the mice in the morphine group was (85.21±6.53)% on the 8th day, and decreased to (38.45±5.52)% and (28.14±4.52)% on the 10th and 12th day, respectively, which indicated the morphine tolerance of mice with lung cancer in situ.The MPE of the mice in the group treated with morphine and compound matrine injection (300 mg/kg) was (79.34±6.50)% on the 8th day, and decreased to (62.16±5.53)% and (40.20±4.50)% on the 10th and 12th day, respectively.The results of RT-PCR assay showed that the relative expression levels of MDR1 mRNA in the brain tissues of mice in the morphine group, saline group, morphine combined with compound matrine injection (300 mg/kg) group and compound matrine injection (200 mg/kg) group were 2.33±0.79, 1.04±0.38, 1.37±0.38, and 1.43±0.53, respectively. There were statistically significant differences between the morphine group and the normal saline group, the morphine group and the morphine combined with compound matrine injection (300 mg/kg) group (P<0.05). There was no significant difference between the normal saline group and the compound matrine injection (200 mg/kg) group (P=0.05). The results of western blot showed that the relative expression levels of P-gp protein in the brain tissue of mice in the morphine group, saline group, and morphine combined with compound matrine injection (300 mg/kg) group were 1.86±0.40, 1.00±0.23, and 1.27±0.27, respectively. The expression of P-gp protein in the morphine group was significantly higher than those of the normal saline group and the morphine combined with compound matrine injection (300 mg/kg) group (P<0.05). The DNA-binding activity of CREB in the saline group was (0.23±0.07) Pu, significantly lower than (0.89±0.23) Pu of morphine combined with naloxone group and (0.80±0.23) Pu of morphine group (P<0.05). While the CREB DNA binding activity of morphine combined with compound matrine injection (300 mg/kg) group was (0.79±0.21) Pu, implicated that compound matrine had marginal effect on the DNA-binding activity of CREB (P>0.05). Conclusion: Compound matrine injection can significantly improve morphine tolerance and drug resistance of lung cancer through inhibiting the upregulations of MDR1 and P-gp induced by morphine.

Intranasal Versus Intravenous Naloxone in Opium Poisoning in Children, A Pilot Study

Background: Opioid poisoning is a common and fatal poisoning in children in our country. Objectives: This study was designed to compare the effects of intranasal (IN) dribbling with intravenous (IV) injection of naloxone in opioid poisoning in Loghman-Hakim Hospital, Tehran, Iran. Methods: This is a prospective, clinical trial study performed on children between the ages of one to 13 years with opioid poisoning from April 2018 to April 2019 compared to IN naloxone 0.01 mg/kg dribbling versus Intravenous naloxone 0.01 mg/kg injection. Patients with nasal congestion, severe poisoning and co-ingestion were excluded. The main outcomes included GCS, response time, respiratory rate, and O2 saturation. This study was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.RETECH.REC.1397.258) and was registered with the Iranian Registry of Clinical Trials (www.irct.ir) (IRCT20180226038869N1). Results: A total of 44 patients (22 IV and 22 IN) with a mean age of 38.2 ± 28.8 months in IV and 36.8 ± 19.7 months in the IN naloxone group, 14 methadone and eight opium poisoning in IV and 13 methadone and nine opium poisoning in the IN group. The male/female ratio was 14/8 in both groups. There were no statistically significant differences between the two groups in RR, GCS, and O2 saturation before naloxone administration. The IV and IN groups had similar average increases in RR, O2 saturation and GCS after naloxone administration. There was a significant difference in the time of response between the two groups (P < 0.008), 3.9 ± 3 minutes in IV group and 5.9 ± 2.9 minutes in the IN group. No complications were observed in this study. Conclusions: This study showed that Intranasal naloxone is safe, effective, and a well-tolerated needleless method for opioid poisoning in children. Although the time to response was longer in the IN groups, if we add the time needed for IV catheter insertion it seems that the IN route is faster.

Intra-articular ultra-low-dose naloxone for postoperative analgesia after knee arthroscopy

Background Naloxone has been used at low doses to enhance the analgesic effect; however, this application remains less well defined. It was added to local anesthetics for intrapleural, axillary brachial plexus block, and peribulbar anesthesia with good results but was not used before as an adjuvant in intra-articular injection. The aim of this prospective double-blinded randomized controlled study is to assess the effect of intra-articular ultra-low-dose naloxone when added to bupivacaine on postoperative pain after knee arthroscopy, with time to first analgesic request as the primary outcome and total analgesic requirement, severity of pain, and side effects as secondary outcomes. Patients and methods In all, 80 patients who underwent knee arthroscopic meniscectomy under general anesthesia were randomly allocated into two groups (40 patients each): the naloxone group received 100 ng naloxone added to 20 ml 0.25% bupivacaine, and the control group received 20 ml 0.25% bupivacaine. General anesthesia was standardized for all patients. At the end of surgery, the study solution was injected intra-articularly through the arthroscope. Visual analog scale was recorded at 1, 2, 4, 6, 8, 12, 18, and 24 h. An intravenous dose of 20 mg pethidine was given if visual analog scale greater than or equal to 3 or on patient request. The time to first analgesic request, total analgesic consumption, and side effects were recorded. Results The time to first analgesic request was significantly longer, and the total analgesic consumption was significantly lower in the naloxone group compared with the control group. Pain score was significantly higher after 6 and 8 h in the control group compared with the naloxone group. No side effects were reported. Conclusion Intra-articular ultra-low-dose naloxone enhanced postoperative analgesic effect of bupivacaine after knee arthroscopy without adverse effects.

The effect of a low-dose naloxone infusion on the incidence of respiratory depression after intrathecal morphine administration for major open hepatobiliary surgery: a randomised controlled trial.

Intrathecal morphine is an analgesic option for major hepatopancreaticobiliary procedures but is associated with a risk of respiratory depression. We hypothesised that a postoperative low-dose naloxone infusion would reduce the incidence of respiratory depression without an increase in pain scores. Patients scheduled for major open hepatopancreaticobiliary surgery and who were receiving 10μg.kg-1 intrathecal morphine were eligible for inclusion. Patients were allocated randomly to receive a postoperative infusion of naloxone 5μg.kg-1 .h-1 (naloxone group) or saline at an identical infusion rate (control group) until the morning after surgery. Clinicians, nursing staff and patients were blinded to group allocation. The primary outcome measure was the incidence of respiratory depression (respiratory rate <10 breaths.min-1 and/or oxygen saturation <90%). Secondary outcome measures included: arterial partial pressure of carbon dioxide; pain score; requirement for supplemental analgesic; and incidence of nausea and vomiting, pruritus and sedation. In total, data from 95 patients (48 in the naloxone group and 47 in the control group) were analysed. The incidence of respiratory depression was lower in the naloxone group compared with the control group (10/48 vs. 21/47 patients, respectively; p=0.037, relative risk 0.47 (95%CI 0.25-0.87). Maximum pain scores were greater for patients allocated to the naloxone group compared with control (median 5 (95%CI 4-6) vs. 4 (95%CI 2-4), respectively; p<0.001). A low-dose naloxone infusion decreases the incidence of respiratory depression following intrathecal morphine administration in patients having major hepatopancreaticobiliary surgery at the expense of a small increase in postoperative pain.

Effect of low dose naloxone on the immune system function of a patient undergoing video-assisted thoracoscopic resection of lung cancer with sufentanil controlled analgesia \u2014 a randomized controlled trial

BackgroundPerioperative immune function plays an important role in the prognosis of patients. Several studies have indicated that low-dose opioid receptor blockers can improve immune function.MethodsSixty-nine patients undergoing video-assisted thoracoscopic resection of the lung cancer were randomly assigned to either the naloxone group (n = 35) or the non-naloxone group (n = 34) for postoperative analgesia during the first 48 h after the operation. Both groups received sufentanil and palonosetron via postoperative analgesia pump, while 0.05 μg·kg− 1·h− 1 naloxone was added in naloxone group. The primary outcomes were the level of opioid growth factor (OGF) and immune function assessed by natural killer cells and CD4+/CD8+ T-cell ratio. Second outcomes were assessed by the intensity of postoperative pain, postoperative rescue analgesia dose, postoperative nausea and vomiting (PONV).ResultsThe level of OGF in the naloxone group increased significantly at 24 h (p<0.001) and 48 h after the operation (P < 0.01). The natural killer cells (P < 0.05) and CD4+/CD8+ T-cell ratio (P < 0.01) in the naloxone group increased significantly at 48 h after the operation. The rest VAS scores were better with naloxone at 12 and 24 h after operation(P < 0.05), and the coughing VAS scores were better with naloxone at 48 h after the operation(P < 0.05). The consumption of postoperative rescue analgesics in the naloxone group was lower (0.00(0.00–0.00) vs 25.00(0.00–62.50)), P < 0.05). Postoperative nausea scores at 24 h after operation decreased in naloxone group(0.00 (0.00–0.00) vs 1.00 (0.00–2.00), P < 0.01).ConclusionInfusion of 0.05 μg·kg− 1·h− 1 naloxone for patients undergoing sufentanil-controlled analgesia for postoperative pain can significantly increase the level of OGF, natural killer cells, and CD4+/CD8+ T-cell ratio compared with non-naloxone group, and postoperative pain intensity, request for rescue analgesics, and opioid-related side effects can also be reduced.Trial registrationThe trial was registered at the Chinese Clinical Trial Registry on January 26, 2019 (ChiCTR1900021043).

Effects of epidural infusion of morphine combined with small-dose naloxone on gastrointestinal interstitial cells of Cajal in rabbits.

To study the effect of epidural infusion of morphine combined with small-dose naloxone on gastrointestinal interstitial cells of Cajal (ICC) in rabbits. A total of 80 healthy New Zealand rabbits were selected as objects of study, and divided into normal saline control group (Group NS, n=20), morphine group (Group M, n=20), naloxone group (Group N, n=20), and morphine + naloxone group (Group NM, n=20). Rabbits in four the groups received epidural catheterization for continuous drug infusion for 7 d, and epidural analgesia pump was connected. Visual analogue scale (VAS) score, intestinal propulsion rate, c-kit expression, and ICC count were detected and compared among four groups of rabbits. No statistical differences of occurrence rates regarding constipation as well as expressions of c-kit and ICC count in the proximal colon were shown among rabbits in Group NS, Group N, and Group NM during drug administration (p>0.05). However, the occurrence rates of constipation of rabbits in Group M at 3-7 d were statistically higher than those in Group NS, Group N, and Group NM, and the differences were statistically significant (p<0.05). Moreover, the VAS scores in Group NS and Group N were significantly higher than those in Group M and Group NM, while the scores in Group M were also significantly increased compared to that in Group NM (p<0.05). The intestinal propulsion rates, expressions of c-kit and ICC counts of rabbits in Group NS, Group N, and Group NM were statistically higher than that in Group M (p<0.05). Epidural infusions of morphine combined with small-dose naloxone effectively inhibit the gastrointestinal motility of rabbits via the reduction of ICC in the proximal colon of the gastrointestinal tract of rabbits. Moreover, small-dose of naloxone enhances the analgesic effect and reduces the risk of adverse reactions.

Effect of ultra-low-dose naloxone with ultrasound-guided transversus abdominis plane block on postoperative pain relief in patients undergoing laparoscopic cholecystectomy

Introduction Transversus abdominis plane (TAP) blocks have been described as an effective component of multimodal postoperative analgesia for a wide variety of abdominal procedures such as bowel resection, open/laparoscopic appendectomy, cesarean delivery, hysterectomy, laparoscopic cholecystectomy, open prostatectomy, renal transplant surgery, and abdominoplasty. Various adjuvants have been added to augment the effect and prolong the duration of action of analgesia in TAP block. The mechanism of action of ultra-low-dose naloxone includes selective inhibition of the impulses from excitatory opioid receptors and release of encephalin. Aim This study investigated the effect of ultra-low-dose naloxone on intensity and duration of analgesia of transversus abdominis plane block (TAP block). The primary outcome of the work is to assess the quality of TAB block with addition of ultra-low-dose naloxone in terms of time to first analgesic request (rescue analgesia) and visual analogue score (VAS) score. The secondary outcome is to assess opioid consumption and occurrence of complications (nausea and vomiting). Patients and methods A total of 100 elective laparoscopic cholecystectomy patients were included in our study who were divided randomly into two groups: in the naloxone group (N) (50 patients), bilateral ultrasound-guided subcostal TAP block was done with injection of bupivacaine 0.25% in the plane +100 ng naloxone with total volume of 20 ml in each side, and in the control group (C) (50 patients), bilateral ultrasound-guided subcostal TAP block was done with injection of bupivacaine 0.25% in the plane with total volume 20 ml in each side. Then, the patients were assessed for postoperative pain after full recovery as baseline and then every 4 h for 24 h by VAS. Time to first analgesic request (rescue analgesia), postoperative opioid consumption for the first 24 h, and any adverse effects (nausea and vomiting) were noted. Results We found, a highly significant decrease in VAS scores at 12, 16, 20, and 24 h in naloxone group compared with the control group (P&lt;0.01). There was a nonsignificant difference regarding VAS scores at PACU, 4, and 8 h (P&gt;0.05). Moreover, there was a highly significant increase in time to first analgesic request in naloxone group compared with the control group (P&lt;0.01). Regarding secondary outcomes, there was a highly significant decrease in postoperative opioid consumption in naloxone group compared with the control group (P&lt;0.01), and nonsignificant difference regarding nausea and vomiting (P&gt;0.05). Conclusion Ultra-low-dose naloxone usage in TAP block helps in reducing postoperative pain scores and postoperative opioid consumption in patients who underwent laparoscopic cholecystectomy.

Does co-treatment with ultra-low-dose naloxone and morphine provide better analgesia in renal colic patients?

ObjectiveThis study attempted to evaluate the efficacy of ultra-low-dose intravenous (IV) naloxone combined with IV morphine, as compared to IV morphine alone, in terms of reducing pain and morphine-induced side effects in patients with renal colic. MethodsIn this double-blind clinical trial, 150 patients aged 34 to 60 years old who presented to the emergency department (ED) with renal colic were randomly allocated to either an intervention group that received ultra-low-dose IV naloxone combined with IV morphine or to a control group that received morphine plus a placebo. The severity of pain, sedation, and nausea were assessed and recorded for all patients at entrance to the ED (T1), then at 20 (T2), 40 (T3), 60 (T4), 120 (T5), and 180 (T6) minutes after starting treatment. The Numeric Rating Scale (NRS) was used for the assessment of pain and nausea intensities, and the Ramsay Sedation Scale (RSS) was used to assess sedation. ResultsA GEE model revealed that patients in the naloxone group had non-significantly reduced pain scores compared to those in the morphine group (coefficient = −0.68; 95% CI: −1.24 to −0.11, Wald X2 (1) = 5.41, p = 0.02). The sedation outcome demonstrated no statistically significant differences at T1 to T4 among patients with renal colic compared to the ones who only received morphine. At T5 and T6, 1.5% vs. 20% and 1.5% vs. 16.9% of subjects from the naloxone group versus the morphine group obtained RSS scores equal to 3, respectively (p = 0.001 and p = 0.004, respectively). ConclusionsCompared to patients who only received IV morphine, co-treatment of ultra-low-dose naloxone with morphine could not provide better analgesia and sedation/agitation states in renal colic patients.

Low-Dose Versus High-Dose Postoperative Naloxone Infusion Combined With Patient-Controlled Analgesia for Adolescent Idiopathic Scoliosis Surgery: A Randomized Controlled Trial

Study DesignRandomized controlled trial. ObjectivesThe aim of this prospective randomized clinical trial was to compare low (0.5 μg/kg/h) and high (2.5 μg/kg/h) dose naloxone infusion on the time to tolerate liquids and meals after surgery, patient-controlled analgesia (PCA) opioid requirements, nausea and pruritus ratings, and hospital length of stay. Summary of Background DataAdolescents undergoing posterior spinal fusion often receive PCA after surgery and may experience common opioid-associated side effects, including nausea and pruritus. Low-dose naloxone infusion has been shown to reduce the incidence of pruritus and nausea while preserving analgesia, although an ideal dose has not been determined. Less is known about the potential for naloxone to improve bowel function after surgery. MethodsEighty-four patients (age 10–21 years) were randomly allocated to receive low- or high-dose naloxone infusion postoperatively. Surgical anesthetic consisted of propofol and opioid infusion with intrathecal morphine (10–15 μg/kg) at the conclusion of surgery. A visual analog scale (VAS) was used to rate nausea and pruritus. ResultsThe groups had similar time to oral liquid intake after surgery and transition from PCA to oral pain medication. The VAS scores for pruritus and nausea were also similar, as was the need to treat these side effects. Morphine equivalents were similar between groups on postoperative day (POD) 0 and 1. On POD 2, the high-dose infusion group had significantly greater PCA bolus use (1.41±0.9 vs. 1.04±0.6; p<.05), although pain scores did not differ significantly. Hospital length of stay was similar for the two groups. ConclusionHigh-dose naloxone infusion was associated with similar rates of opioid side effects as low-dose. Increased PCA use noted on POD 2 may represent partial reversal of opioid analgesia in the high-dose naloxone group. Level of EvidenceLevel 1.

Effect of Endomorphin-1 on Maturation and Expression of TLR4 in Peripheral Blood Dendritic Cells Induced by High Glucose

To investigate the effects of endomorphin-1 (EM-1) on the maturation phenotype, cytokine secretion, T cell proliferation and TLR4 expression in human peripheral blood dendritic cells (PBDCs) stimulated and induced by high glucose, and to explore the regulatory mechanism of EM-1 on DC immune function. Peripheral blood mononuclear cells (PBMNCs) were induced into immature dendritic cells (imDCs). The high glucose was used as the stimulating factor, and the EM-1 was used as the interventional factor. Then, the experiments were divided into normal glucose group (NG group), high glucose group (HG group), high glucose plus EM-1 group (EM group) and high glucose plus EM-1 and naloxone group (Nal group), respectively. The PBDC's phenotype changes were detected by flow cytometry; ELISA was used to detect the changes of cytokines secreted by PBDCs co-cultured with autologous lymphocytes; CFSE was used to detect the proliferation of T lymphocytes. TLR4 expression on PBDC surface was detected by RT-PCR. Compared with HG group, the expression of PBDC surface molecules CD86, CCR7 and CD36 was up-regulated in EM group (P<0.01), while the change of CD83 expression was not statistically significant. However, IL-12 and IL-10 secreted by PBDCs and the proliferation index of T-lymphocytes stimulated by PBDCs were both decreased in EM group. Compared with EM group, the expression of CD86, CCR7 and CD36 was decreased in Nal group (P<0.01), while the expression of CD83 was almost unchanged (P>0.05). T-lymphocyte proliferation index was increased very significantly in Nal group (P<0.01). The gray ratio of TLR4 in HG group was higher than that in NG group, while the gray ratio in EM group's was very significantly lower than that in HG group's (P<0.01). These results indicate that the high glucose can promote the expression of PBDC TLR4, while the EM-1 inhibits the expression of TLR4. EM-1 up-regulates the expression of PBDC surface molecules CD86, CCR7 and CD36 stimulated and induced by high glucose, but inhibites the induction of PBDC to maturity by high glucose. And the secreted inflammatory cytokines IL-12 and IL-10 inhibites the proliferation of T lymphocytes derived from PBDCs, while naloxone inhibites the effect of EM-1. EM-1 inhibites the expression of TLR4 on PBDC surface induced by high glucose.