Intrathecal administration of MCRT produced potent antinociception in chronic inflammatory pain models via µ-δ heterodimer with limited side effects.

An important goal in the opioid field is to discover effective analgesic drugs with minimal side effects. MCRT demonstrated potent antinociceptive effects with limited side effects, making it a promising candidate. However, its pharmacological properties and how it minimizes side effects remain unknown. Various mouse pain and opioid side effect models were used to evaluate the antinociceptive properties and safety at the spinal level. The targets of MCRT were identified through cAMP measurement, isolated tissue assays, and pharmacological experiments. Immunofluorescence was employed to visualize protein expression. MCRT displayed distinct antinociceptive effects between acute and chronic inflammatory pain models due to its multifunctional properties at the µ opioid receptor (MOR), µ-δ heterodimer (MDOR), and neuropeptide FF receptor 2 (NPFFR2). Activation of NPFFR2 reduced MOR-mediated antinociception, leading to bell-shaped response curves in acute pain models. However, activation of MDOR produced more effective antinociception in chronic inflammatory pain models. MCRT showed limited tolerance and opioid-induced hyperalgesia in both acute and chronic pain models and did not develop cross-tolerance to morphine. Additionally, MCRT did not exhibit addictive properties, gastrointestinal inhibition, and effects on motor coordination. Mechanistically, peripheral chronic inflammation or repeated administration of morphine and MCRT induced an increase in MDOR in the spinal cord. Chronic administration of MCRT had no apparent effect on microglial activation in the spinal cord. These findings suggest that MCRT is a versatile compound that provides potent antinociception with minimal opioid-related side effects. MDOR could be a promising target for managing chronic inflammatory pain and addressing the opioid crisis.

Intrathecal Morphine Enhances Postoperative Analgesia and Recovery in Robotic-Assisted Laparoscopic Partial Nephrectomy: A Retrospective Study of 272 Patients.

BACKGROUND Robot-assisted laparoscopic partial nephrectomy (RAPN) has been increasingly used for treating renal tumors due to its advantages over other approaches. However, RAPN can induce acute incisional, peritoneal, visceral, and referred pain. Therefore, acute pain control in robotic surgery is a concern. This retrospective study aimed to evaluate the efficacy of intrathecal morphine (ITM) for postoperative analgesia and recovery after RAPN. MATERIAL AND METHODS We retrospectively investigated consecutive patients who underwent RAPN at our institute between 2020 and 2021. Among the 272 patients who met the inclusion criteria, 135 patients were administered 200 µg of ITM preoperatively (ITM group), while 137 patients were not (control group). Postoperative pain assessments using the numeric rating scale (NRS), opioid requirements, and recovery profiles during the first postoperative 24 h were compared between the 2 groups. RESULTS As the primary endpoint, the incidence of moderate-to-severe pain (24-h average NRS pain score ≥4) was significantly lower in the ITM group than in the control group (36.3% vs 61.3%, P<0.001). Pain scores and cumulative opioid requirements were also significantly lower in the ITM group for all assessments (P<0.001). Moreover, the ITM group had a higher score on the Quality of Recovery-15 questionnaire on the first postoperative day (129 vs 120, P=0.003) despite an increased rate of postoperative nausea/vomiting (27.4% vs 13.1%, P=0.003). CONCLUSIONS Our findings indicate that ITM provided superior pain control during the early period following RAPN, with reduced postoperative opioid requirements. Moreover, ITM improved patient satisfaction with recovery.

The effectiveness and outcomes of epidural analgesia in patients undergoing open liver resection: a propensity score matching analysis.

BACKGROUND: Open liver resection necessitates a substantial upper abdominal inverted-L incision, resulting in severe pain and compromising patient recovery. Despite the efficacy of epidural analgesia in providing adequate postoperative analgesia, the potential epidural-related adverse effects should be carefully considered. This study aims to compare the efficacy and safety of continuous epidural analgesia and intravenous analgesia in open liver resection. METHODS: A retrospective study was conducted, collecting data from patients who underwent open liver resection between 2007 and 2017. Propensity score matching was implemented to mitigate confounding variables, with patients being matched in a 1:1 ratio based on propensity scores. The primary outcome was the comparison of postoperative morphine consumption at 24, 48, and 72 hours between the two groups. Secondary outcomes included pain scores, postoperative outcomes, and epidural-related adverse effects. RESULTS: A total of 612 patients were included, and after matching, there were 204 patients in each group. Opioid consumption at 24, 48, and 72 hours postoperatively was statistically lower in the epidural analgesia group compared to the intravenous analgesia group (p < 0.001). However, there was no significant difference in pain scores (p = 0.422). Additionally, perioperative hypotension requiring treatment, as well as nausea and vomiting, were significantly higher in the epidural analgesia group compared to the intravenous analgesia group (p < 0.001). CONCLUSIONS: Epidural analgesia is superior to intravenous morphine in terms of reducing postoperative opioid consumption within the initial 72 h after open liver resection. Nevertheless, perioperative hypotension, which necessitates management, should be approached with consideration and vigilance. TRIAL REGISTRATION: The study was registered in the Clinical Trials Registry at www. CLINICALTRIALS: gov/ , NCT number: NCT06301932.

Immunological effects of post-operative epidural analgesia versus oral opioids in VATS.

INTRODUCTION: Anaesthetic choices in cancer surgery, including the use of epidural analgesia, may affect immune function during the perioperative period and might play an important role in subsequent cancer spread and recurrence. METHODS: This was a prospective, randomised, controlled, double-blinded, single-centre study allocating patients scheduled for video-assisted thoracoscopic surgery (VATS) lobectomy to post-operative pain management using either thoracic epidural analgesia or oral morphine. We compared pre-, per-, and post-operative plasma levels of interleukin (IL)-6, IL-10, IL-12, and interferon (IFN)-γ using regression analysis, and conducted a two-year survival follow-up. RESULTS: A total of 66 patients were randomised. Fifty-six received the allocated treatment and were analysed. None of the investigated cytokines exhibited significant between-group differences in plasma concentrations when adjusted for the chosen covariates (p ≥ 0.204). A two-year follow-up showed no difference in survival between the two groups (p = 0.5). CONCLUSION: Our study found no differences in the impact on the innate, non-specific immune system related to epidural analgesia for pain management in VATS. FUNDING: The Danish Cancer Society (R150-A10139). Oberstinde Kirsten Jensa la Cours Mindelegat (JSP-25076). University of Southern Denmark, Region of Southern Denmark and Department of Anaesthesia and Intensive Care, Odense University Hospital. TRIAL REGISTRATION: NCT02359175 (ClinicalTrials.gov).

Effects of anterior quadratus lumborum block versus erector spinae plane block on postoperative acute pain in percutaneous nephrolithotomy: a prospective, observational study.

BACKGROUND: The study aimed to compare the pain-relieving effectiveness of anterior quadratus lumborum block (QLB3) and erector spinae plane block (ESPB), both of which have been documented to provide relief during abdominal surgery. METHODS: This prospective observational study, conducted between February and July 2023, included 96 patients who had undergone percutaneous nephrolithotomy (PCNL). Patients were divided into three groups: QLB3, ESPB, and control (no block) and received the corresponding nerve block in the preanesthetic room for regional block. Cumulative morphine consumption during the initial 24 h after PCNL, numerical rating scale resting/movement scores, intraoperative remifentanil usage, rescue analgesic requirements, time when the first analgesic was requested, and postoperative nausea and vomiting scores were documented and compared between the groups. RESULTS: Total median morphine consumption in the first 24 h postoperatively was similar in the QLB3 and ESPB groups but higher in the control group (QLB3, 7 mg [(Q1-Q3) 7-8.5]; ESPB, 8 mg [6.5-9]; control, 12.5 [10-17]; P < 0.001). Similarly, median intraoperative remifentanil consumption did not differ between the block groups but was higher in the control group (QLB3, 1082 µg [IQR 805.5-1292.7]; ESPB, 1278 µg [940.2-1297.5]; control, 1561 µg [1315-2068]; P < 0.001). The number of patients receiving rescue analgesic medication was similar in the block groups but higher in the control group (QLB3, n = 9 [30%]; ESPB, n = 14 [46.7%]; control, n = 21 [70%]; P = 0.008). CONCLUSIONS: QLB3 and ESPB were adequate and comparable in providing postoperative analgesia as part of multimodal analgesia after PCNL. TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov (Identifier: NCT05822492).

The autoimmune nature of morphine addiction.

The onset of the disease as a morphine addiction is associated with the appearance in the patient's body of antibodies directed against opiate receptors (ORs). Once anti-opiate receptor antibodies (anti-OR antibodies) appear in the blood they will tend to bind to ORs. Such binding will cause blocking of physiological functions of OR. The blockage is felt by a morphine addict as withdrawal syndrome. To get rid of this harmful condition, the addict increases the dose of morphine taken. This is where tolerance manifests itself. The drug addict is forced to increase the dose of morphine from time to time because of the body responds by producing the more and more anti-OR antibodies. The immunological nature of morphine addiction is the reason for lifelong changes in the body's reactivity to the drug. An addict can be cured if he gets rid of B- and T-memory cells, which specifically react to ORs.

Chronic morphine treatment induces sex- and synapse-specific cellular tolerance on thalamo-cortical mu opioid receptor signaling.

How cellular adaptations give rise to opioid analgesic tolerance to opioids like morphine is not well understood. For one, pain is a complex phenomenon comprising both sensory and affective components, largely mediated through separate circuits. Glutamatergic projections from the medial thalamus (MThal) to the anterior cingulate cortex (ACC) are implicated in processing of affective pain, a relatively understudied component of the pain experience. The goal of this study was to determine the effects of chronic morphine exposure on mu-opioid receptor (MOR) signaling on MThal-ACC synaptic transmission within the excitatory and feedforward inhibitory pathways. Using whole cell patch-clamp electrophysiology and optogenetics to selectively target these projections, we measured morphine-mediated inhibition of optically evoked postsynaptic currents in ACC layer V pyramidal neurons in drug-naïve and chronically morphine-treated mice. We found that morphine perfusion inhibited the excitatory and feedforward inhibitory pathways similarly in females but caused greater inhibition of the inhibitory pathway in males. Chronic morphine treatment robustly attenuated morphine presynaptic inhibition within the inhibitory pathway in males, but not females, and mildly attenuated presynaptic inhibition within the excitatory pathway in both sexes. These effects were not observed in MOR phosphorylation-deficient mice. This study indicates that chronic morphine treatment induces cellular tolerance to morphine within a thalamo-cortical circuit relevant to pain and opioid analgesia. Furthermore, it suggests this tolerance may be driven by MOR phosphorylation. Overall, these findings improve our understanding of how chronic opioid exposure alters cellular signaling in ways that may contribute to opioid analgesic tolerance.NEW & NOTEWORTHY Opioid signaling within the anterior cingulate cortex (ACC) is important for opioid modulation of affective pain. Glutamatergic medial thalamus (MThal) neurons synapse in the ACC and opioids, acting through mu opioid receptors (MORs), acutely inhibit synaptic transmission from MThal synapses. However, the effect of chronic opioid exposure on MThal-ACC synaptic transmission is not known. Here, we demonstrate that chronic morphine treatment induces cellular tolerance at these synapses in a sex-specific and phosphorylation-dependent manner.

Negative allosteric modulation of CB1 cannabinoid receptor signalling decreases intravenous morphine self-administration and relapse in mice.

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that negative allosteric modulation of CB1R signalling would reduce the reinforcing properties of morphine and decrease behaviours associated with opioid misuse. By employing intravenous self-administration in mice, we studied the effects of GAT358, a functionally-biased CB1R negative allosteric modulator (NAM), on morphine intake, relapse-like behaviour and motivation to work for morphine infusions. GAT358 reduced morphine infusion intake during the maintenance phase of morphine self-administration under a fixed ratio 1 schedule of reinforcement. GAT358 also decreased morphine-seeking behaviour after forced abstinence. Moreover, GAT358 dose dependently decreased the motivation to obtain morphine infusions under a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self-administration was reward specific. Furthermore, GAT58 did not produce motor ataxia in the rotarod test. Our results suggest that CB1R NAMs reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease misuse of opioids.

TMEM132C rs7296262 Single-Nucleotide Polymorphism Is Significantly Associated with Nausea Induced by Opioids Administered for Cancer Pain and Postoperative Pain.

Opioids are almost mandatorily used for analgesia for cancer pain and postoperative pain. Opioid analgesics commonly induce nausea as a side effect. However, the genetic factors involved are still mostly unknown. To clarify the genetic background of individual differences in the occurrence of nausea during opioid administration, the incidence of nausea was investigated in 331 patients (Higashi-Sapporo Hospital [HS] group) who received morphine chronically for cancer pain treatment and in 2021 patients (Cancer Institute Hospital [CIH] group) who underwent elective surgery under general anesthesia. We conducted a genome-wide association study of nausea in HS samples. Among the top 20 candidate single-nucleotide polymorphisms (SNPs), we focused on the TMEM132C rs7296262 SNP, which has been reportedly associated with psychiatric disorders. The rs7296262 SNP was significantly associated with nausea in both the HS and CIH groups (TT+TC vs. CC; HS group, p = 0.0001; CIH group, p = 0.0064). The distribution of nausea-prone genotypes for the rs7296262 SNP was reversed between HS and CIH groups. These results suggest that the TMEM132C rs7296262 SNP is significantly associated with nausea during opioid use, and the effect of the SNP genotype on nausea is reversed between chronic and acute phases of opioid use.

Non-pulmonary complications of intrathecal morphine administration: a systematic review and meta-analysis with meta-regression.

BACKGROUND: Intrathecal morphine provides effective analgesia for a range of operations. However, widespread implementation into clinical practice is hampered by concerns for potential side-effects. We undertook a systematic review, meta-analysis, and meta-regression with the primary objective of determining whether a threshold dose for non-pulmonary complications could be defined and whether an association could be established between dose and complication rates when intrathecal morphine is administered for perioperative or obstetric analgesia. METHODS: We systematically searched the literature for randomised controlled trials comparing intrathecal morphine vs control in patients undergoing any type of surgery under general or spinal anaesthesia, or women in labour. Primary outcomes were rates of postoperative nausea and vomiting, pruritus, and urinary retention within the first 24 postoperative hours, analysed according to doses (1-100 µg; 101-200 µg; 201-500 µg; >500 µg), type of surgery, and anaesthetic strategy. Trials were excluded if doses were not specified. RESULTS: Our analysis included 168 trials with 9917 patients. The rates of postoperative nausea and vomiting, pruritus, and urinary retention were significantly increased in the intrathecal morphine group, with an odds ratio (95% confidence interval) of 1.52 (1.29-1.79), P<0.0001; 6.11 (5.25-7.10), P<0.0001; and 1.73 (1.17-2.56), P=0.005, respectively. Meta-regression could not establish an association between dose and rates of non-pulmonary complications. There was no subgroup difference according to surgery for any outcome. The quality of evidence was low (Grading of Recommendations Assessment, Development, and Evaluation [GRADE] system). CONCLUSIONS: Intrathecal morphine significantly increased postoperative nausea and vomiting, pruritus, and urinary retention after surgery or labour in a dose-independent manner. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023387838).

Opioid Dosing Deviation and Dose Banding Development in Young Hospitalized Children.

BACKGROUND AND OBJECTIVES: Individualized, weight-based opioid dosing poses safety risks and contributes to inefficient medication delivery processes. Dose banding is a patient safety strategy to reduce dosing errors through standardized doses based on weight ranges. Study objectives were (1) determine the frequency of dosing deviation from reference ranges of common intravenous (IV) and oral opioid medications, (2) evaluate the differences in dosing deviations by age, and (3) determine the potential reduction in dose variation that could be achieved by dose banding. METHODS: We conducted a cross-sectional analysis of hospitalized children ≥2 months to ≤24 months old who received IV morphine, oral methadone, or oral oxycodone at a single center. Dosing was categorized as no dosing deviation (within ±5% of the reference range), negative dosing deviation (>5% below the reference range), or positive dosing deviation (>5% above the reference range). Descriptive and bivariate analyses were conducted. RESULTS: A total of 3361 opioid doses met the inclusion criteria. A total of 2663 (79.2%) had no dosing deviation, 214 (6.3%) demonstrated negative deviations, and 484 (14.4%) demonstrated positive deviations. Dosing deviations were more frequent among subjects ≥2 months to ≤6 months old for oral methadone and oxycodone (P < .0001) and more frequent among older age group for IV morphine (P < .0001). Dose banding has the potential to reduce the number of unique doses prescribed for all medications by 75% while eliminating unintended dosing deviations. CONCLUSIONS: A total of 20% of opioid doses prescribed to children ≤24 months of age are outside the recommended ranges. Dose banding represents a promising method for simplifying opioid prescribing in the pediatric inpatient setting.

Clinical Analysis of Different Anesthesia and Analgesia Methods for Patients Undergoing Uniportal Video-assisted Lung Surgery.

PURPOSE: The purpose of this study was to compare 3 intraoperative modalities to determine the best and most convenient one for pain control for uniportal lung surgery. This study compared general anesthesia with serratus plane block, general anesthesia with epidural, and general anesthesia alone to examine postoperative pain scores in patients. METHODS: Eighty patients were enrolled and statistically analyzed. Three interventions were studied: general anesthesia with serratus plane block (group S), general anesthesia with thoracic epidural (group E), and general anesthesia only (group G). Outcome measures compared among the 3 groups included demographic characteristics; surgical types; anesthesia and operative time; postoperative pain scores; vital signs; morphine consumption at 0, 2, and 6 hours and day 1 and day 2 after surgery; incidence of opioid-related adverse events and chronic pain; hospital length of stay (LOS); and overall expenses. The numerical rating scale was used to assess the degree of pain on the first and second postoperative days. Postoperative morphine consumption, incidence of opioid-related side effects, hospital LOS, and overall hospital expenses were documented, as well as incidence of chronic postoperative pain. FINDINGS: There was no difference in the incidence of opioid-related adverse events and chronic pain, hospital LOS, and overall expenses among the 3 groups. After investigating factors that may influence hospital LOS and overall expenses, the multivariable analysis indicated that only longer operative time was associated with longer hospital stay and more hospital expenses. IMPLICATIONS: This prospective study found that general anesthesia alone offers an easy and efficient approach resulting in similar postoperative pain scores and morphine consumption compared with nerve block and epidural. Longer operative time was associated with longer hospital stay and more hospital expenses. CLINICALTRIALS: gov identifier: NCT03839160. (Clin Ther. 2024;XX:XXX-XXX) © 2024 Elsevier HS Journals, Inc.

The Effects of Eating a Traditional High Fat/High Carbohydrate or a Ketogenic Diet on Sensitivity of Female Rats to Morphine.

Patients diagnosed with obesity are prescribed opioid medications at a higher rate than the general population; however, it is not known if eating a high fat diet might impact individual sensitivity to these medications. To explore the hypothesis that eating a high fat diet increases sensitivity of rats to the effects of morphine, 24 female Sprague-Dawley rats (n = 8/diet) ate either a standard (low fat) laboratory chow (17% kcal from fat), a high fat/low carbohydrate (ketogenic) chow (90.5% kcal from fat), or a traditional high fat/high carbohydrate chow (60% kcal from fat). Morphine-induced antinociception was assessed using a warm water tail withdrawal procedure, during which latency (in seconds) for rats to remove their tail from warm water baths was recorded following saline or morphine (0.32-56 mg/kg, i.p.) injections. Morphine was administered acutely and chronically (involving 18 days of twice-daily injections, increasing in 1/4 log dose increments every 3 days: 3.2-56 mg/kg, i.p., to induce dependence and assess tolerance). The adverse effects of morphine (i.e., tolerance, withdrawal, and changes in body temperature) were assessed throughout the study. Acute morphine induced comparable antinociception in rats eating different diets, and all rats developed tolerance following chronic morphine exposure. Observable withdrawal signs and body temperature were also comparable among rats eating different diets; however, withdrawal-induced weight loss was less severe for rats eating ketogenic chow. These results suggest that dietary manipulation might modulate the severity of withdrawal-related weight loss in ways that could be relevant for patients.