Effects Of Opioids Research Articles

Low opioid and opioid-free anesthesia - a review of current data

Introduction: Opioids are one of the most frequently used drugs during anesthesia. Due to the side effects anesthesiologists try to limit their number during anesthesia. They use low-opioid and opioid-free anesthesia. 
 Purpose: The purpose of this work is to present the current state of knowledge and recent reports on low-opioid and non-opioid anesthesia and their use. 
 Materials and Methods: The search was conducted using PubMed and GoogleScholar databases. Articles were searched in English using the following keywords: "low-opioid anesthesia," "non-opioid anesthesia," "OFA," "LOA" 
 Key words: "low-opioid anesthesia", "non-opioid anesthesia", "OFA", "LOA", "opioids". 
 Conclusion: low-opioid anesthesia techniques are being used more and more frequently and reduce the incidence of opioid side effects: respiratory depression, postoperative nausea and vomiting. This helps ensure greater patient safety and shortens the postoperative recovery period.

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

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

The Practice of Multimodal Analgesia Technique for Patients Undergoing Surgery under General Anaesthesia in Debre Markos Compersive Specialized Hospital Debre Markos, East Gojjam, Ethiopia, 2022. A Cross-Sectional Study

Background: Practice guidelines for preoperative pain management recommend that multimodal analgesic therapy should be used for postsurgical patients. This method uses different analgesic agents, which may target different components of pain transmission to improve post-operative analgesia and decrease reliance on opiate-based medication. The practice of Multimodal analgesia includes the combined use of neuraxial blockage regional anesthesia and systemic medications and has been shown to reduce opioid use and side effects in surgical patients. However, the proportion of patients who receive this evidence-based approach is unknown. To assess the practice of multimodal analgesia among patients undergoing surgery under general anesthesia at Debere Markos Compressive Specialized Hospital, Northwest Ethiopia, 2022. Methods: After obtaining ethical approval a hospital-based cross-sectional study was conducted from February 22 to May 10, 2022, in Debere Markos Compressive specialized hospital. Data was collected, prospectively using questionnaires from anesthetists, nurses in the recovery room, and anesthesia record sheets. Patients were considered to have multimodal analgesia if they received two or more analgesics. Descriptive statistics were performed to identify the practice of multimodal analgesia. Results: A total of 200 participated in our study. We observed the practice of multimodal analgesia in patients who had undergone surgery under general anesthesia in the study period was 47%. Opiod is the most widely administered analgesia. It was given to 81.5% of patients. The practice of multimodal analgesia in emergency surgery was found to be 61.7%. During the study period, multimodal analgesia was more practiced among Bsc anesthetists and it was found to be 42.5%. The practice of multimodal analgesia in PACU was found to be 9%. Conclusion and Recommendation: The practice of multimodal analgesia for surgical patients in Debre Markos Specialized Compressive Hospital is underutilized. Anesthesia professionals should use a multimodal approach for preoperative pain management for all surgical patients. The Department of Anesthesia should develop a guideline for the treatment of perioperative pain.

Analgesic Efficacy of Epidural Patient-Controlled Analgesia on Cancer Pain: A Retrospective Observational Study

BACKGROUND: In patients with severe cancer pain, systemic analgesics are often refractory or have limited application due to the side effects of opioids. In these cases, epidural analgesia may be effective. However, data on the effects of epidural patient-controlled analgesia (PCA) on cancer pain are limited. OBJECTIVES: To evaluate the analgesic efficacy of epidural PCA in patients with cancer pain through a retrospective chart review. STUDY DESIGN: Retrospective analysis. SETTING: A single academic center in Daegu, South Korea. METHODS: The analgesic efficacy of epidural PCA on cancer pain was analyzed in patients who underwent epidural PCA using a disposable balloon pump with a flow regulator between 2012 and 2021. The pump was filled with a 600-mL mixture of 6 ampoules of 0.2% ropivacaine, 1 mg fentanyl, and normal saline. For the first use of epidural PCA, the basal rate, bolus dose, and lockout time were set as 4 mL/h, 2 mL, and 15 min, respectively. The basal rate was increased and decreased depending on the degree of pain relief effect and occurrence of side effects, respectively. To increase the usage time of epidural PCA and reduce the patient’s cost burden, the fentanyl dose was increased by 1 mg when the disposable balloon pump was replaced with a new one after exhaustion of the drug if no side effects from the previous dose were observed. Analgesic efficacy was confirmed by comparing the number of types and the total amount of opioids used in patients before and after epidural PCA application in terms of the equivalent dose of oral morphine. RESULTS: Epidural catheterization was performed 105 times, and PCA was refilled 257 times in 88 patients. On average, epidural catheterization was performed 1.2 ± 0.4 (1–3) times, and epidural PCA was refilled 3.2 ± 2.3 (1–11) times per patient. The mean duration of PCA use was 15.6 ± 13.4 (1–82) days. The mean number of opioid types used the day before the procedure and the mean smallest number of opioids used per day up to 5 days after the procedure were 3.4 ± 1.2 and 2.4 ± 1.4, respectively (P < 0.05). The total amount of opioids used the day before the procedure and the smallest total amount of opioids used per day up to 5 days after the procedure were converted into oral morphine equivalent doses, respectively, and the mean doses were 449.5 ± 555.9 and 331.9 ± 462.8 mg, respectively (P < 0.05). LIMITATIONS: The study results are the author’s observations from a single center. Epidural PCA was performed only on hospitalized patients. Individual differences were not considered in the composition of drugs for PCA. Transmucosal immediate-release fentanyl was not accurately converted to oral morphine; thus, it was excluded from the analysis of the total amount used, and the effect of adjuvant analgesics could not be considered. CONCLUSION: Epidural PCA using subcutaneous tunneling is a useful cancer pain control method. Furthermore, it can be safely used for a longer duration owing to its low infection risk. KEY WORDS: Cancer pain, epidural, epidural analgesia, fentanyl, pain, patient-controlled analgesia, ropivacaine, tunneling

Analgesic and Opioid Sparing Effects of Tramadol, Ketamine, and Bupivacaine Following Wound Infiltration After Caesarean Section

Analgesic and Opioid Sparing Effects of Tramadol, Ketamine, and Bupivacaine Following Wound Infiltration After Caesarean Section

People who use drugs show no increase in pre-existing T-cell cross-reactivity toward SARS-CoV-2 but develop a normal polyfunctional T-cell response after standard mRNA vaccination.

People who use drugs (PWUD) are at a high risk of contracting and developing severe coronavirus disease 2019 (COVID-19) and other infectious diseases due to their lifestyle, comorbidities, and the detrimental effects of opioids on cellular immunity. However, there is limited research on vaccine responses in PWUD, particularly regarding the role that T cells play in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we show that before vaccination, PWUD did not exhibit an increased frequency of preexisting cross-reactive T cells to SARS-CoV-2 and that, despite the inhibitory effects that opioids have on T-cell immunity, standard vaccination can elicit robust polyfunctional CD4+ and CD8+ T-cell responses that were similar to those found in controls. Our findings indicate that vaccination stimulates an effective immune response in PWUD and highlight targeted vaccination as an essential public health instrument for the control of COVID-19 and other infectious diseases in this group of high-risk patients.

Brain oxygen responses induced by opioids: focus on heroin, fentanyl, and their adulterants.

Opioids are important tools for pain management, but abuse can result in serious health complications. Of these complications, respiratory depression that leads to brain hypoxia is the most dangerous, resulting in coma and death. Although all opioids at large doses induce brain hypoxia, danger is magnified with synthetic opioids such as fentanyl and structurally similar analogs. These drugs are highly potent, act rapidly, and are often not effectively treated by naloxone, the standard of care for opioid-induced respiratory depression. The goal of this review paper is to present and discuss brain oxygen responses induced by opioids, focusing on heroin and fentanyl. In contrast to studying drug-induced changes in respiratory activity, we used chronically implanted oxygen sensors coupled with high-speed amperometry to directly evaluate physiological and drug-induced fluctuations in brain oxygen levels in awake, freely moving rats. First, we provide an overview of brain oxygen responses to physiological stimuli and discuss the mechanisms regulating oxygen entry into brain tissue. Next, we present data on brain oxygen responses induced by heroin and fentanyl and review underlying mechanisms. These data allowed us to compare the effects of these drugs on brain oxygen in terms of their potency, time-dependent response pattern, and potentially lethal effect at high doses. Then, we present the interactive effects of opioids during polysubstance use (alcohol, ketamine, xylazine) on brain oxygenation. Finally, we consider factors that affect the therapeutic potential of naloxone, focusing on dosage, timing of drug delivery, and contamination of opioids by other neuroactive drugs. The latter issue is considered chiefly with respect to xylazine, which strongly potentiates the hypoxic effects of heroin and fentanyl. Although this work was done in rats, the data are human relevant and will aid in addressing the alarming rise in lethality associated with opioid misuse.

Possible unusual presentation of opioid side effect in a child: a case report

Atypical presentations are commonly encountered in the Pediatric intensive care unit (PICU) but having a high index of suspicion is crucial to prevent or treat severe and life-threatening conditions. This case describes the clinical presentation and course of a 14-month-old girl with congenital heart disease who was admitted to the PICU after cardiac repair and remained agitated, irritable, in hysteria and delirium despite adequate sedation. Different measures to relieve her condition were attempted but to no avail. All the common causes of this atypical presentation including pain, ventilator induced agitation, low cardiac output syndrome (LCOS), opioid side effects, toxicity, opioid induced neurotoxicity (OIN) as well as withdrawal syndrome were ruled out. However, the use of naloxone as a last resort after exhausting all the other options has led to immediate and successful reversal of her symptoms.

Placental cytochrome P450 methylomes in infants exposed to prenatal opioids: exploring the effects of neonatal opioid withdrawal syndrome on health horizons.

Background: Neonatal opioid withdrawal syndrome (NOWS), arises due to increased opioid use during pregnancy. Cytochrome P450 (CYP) enzymes play a pivotal role in metabolizing a wide range of substances in the human body, including opioids, other drugs, toxins, and endogenous compounds. The association between CYP gene methylation and opioid effects is unexplored and it could offer promising insights. Objective: To investigate the impact of prenatal opioid exposure on disrupted CYPs in infants and their anticipated long-term clinical implications. Study Design: DNA methylation levels of CYP genes were analyzed in a cohort of 96 placental tissues using Illumina Infinium MethylationEPIC (850k) BeadChips. This involved three groups of placental tissues: 32 from mothers with infants exposed to opioids prenatally requiring pharmacologic treatment for NOWS, 32 from mothers with prenatally opioid-exposed infants not needing NOWS treatment, and 32 from unexposed control mothers. Results: The study identified 20 significantly differentially methylated CpG sites associated with 17 distinct CYP genes, with 14 CpGs showing reduced methylation across 14 genes (CYP19A1, CYP1A2, CYP4V2, CYP1B1, CYP24A1, CYP26B1, CYP26C1, CYP2C18, CYP2C9, CYP2U1, CYP39A1, CYP2R1, CYP4Z1, CYP2D7P1 and), while 8 exhibited hypermethylation (CYP51A1, CYP26B1, CYP2R1, CYP2U1, CYP4X1, CYP1A2, CYP2W1, and CYP4V2). Genes such as CYP1A2, CYP26B1, CYP2R1, CYP2U1, and CYP4V2 exhibited both increased and decreased methylation. These genes are crucial for metabolizing eicosanoids, fatty acids, drugs, and diverse substances. Conclusion: The study identified profound methylation changes in multiple CYP genes in the placental tissues relevant to NOWS. This suggests that disruption of DNA methylation patterns in CYP transcripts might play a role in NOWS and may serve as valuable biomarkers, suggesting a future pathway for personalized treatment. Further research is needed to confirm these findings and explore their potential for diagnosis and treatment.

Opioid/Dopamine Receptor Binding Studies, NMR and Molecular Dynamics Simulation of LENART01 Chimera, an Opioid-Bombesin-like Peptide.

The design and development of hybrid compounds as a new class of drug candidates remains an excellent opportunity to improve the pharmacological properties of drugs (including enzymatic stability, efficacy and pharmacokinetic and pharmacodynamic profiles). In addition, considering various complex diseases and/or disorders, the conjugate chemistry approach is highly acceptable and justified. Opioids have long been recognized as the most potent analgesics and serve as the basic pharmacophore for potent hybrid compounds that may be useful in pain management. However, a risk of tolerance and physical dependence exists. Since dopamine receptors have been implicated in the aforementioned adverse effects of opioids, the construction of a hybrid with dual action at opioid and dopamine receptors is of interest. Herein, we present nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation results for LENART01, an opioid-ranatensin hybrid peptide. Apart from molecular docking, protein-ligand interactions were also assessed in vitro using a receptor binding assay, which proved LENART01 to be bound to mu-opioid and dopamine receptors, respectively.

Opioid-free anaesthesia.

Adverse effects of perioperative opioids have led to the pursuit of 'opioid-free anaesthesia'. While early studies have shown that effective analgesia can be achieved without using opioids, with some reduction in unwanted effects, further research is needed to elucidate which patients may benefit most and how.

The Role of Endogenous Opioids in Cardioprotection.

The opioid system involves opioid receptors (OPRs) and endogenous opioid peptides.This chapter will focus on the distribution of OPRs in the cardiovascular system, the expression pattern in the heart, the activation by opioid peptides, and the effects of OPRs activation with potential relevance in cardiovascular performance. In the heart, OPRs are co-expressed with beta adrenergic receptors (β-ARs) in the G-protein-coupled receptor (GPCR) superfamily, functionally cross-talk with β-Ars and modify catecholamine-induced effects. They are involved in cardiac contractility, energy metabolism, myocyte survival or death, vascular resistance. The effects of the opioid system in the regulation of systemic circulation at both the central and peripheral level are presented. The pathways are discussed under physiological (i.e., aging) and pathological conditions (atherosclerosis, heart failure, essential hypertension, ischemic stress). Stimulation of OPRs not only inhibits cardiac excitation-contraction coupling, but also protects the heart against hypoxic and ischemic injury. An enhanced sensitivity to opioids of endocrine organs and neuronal systems is operative in hypertensive patients. The opioid system can be pharmacologically engaged to selectively mimic these responses via cardiac and nervous signaling. The clinical opportunities for the use of cardioprotective effects of opioids require future investigations to provide more specific details of the impact on cardiac performance and electrophysiological properties.

Comparison of the Effectiveness and Satisfaction of Different Opioids Combined with Etomidate-Propofol in Painless Gastroenteroscopy Anaesthesia

Comparison of the Effectiveness and Satisfaction of Different Opioids Combined with Etomidate-Propofol in Painless Gastroenteroscopy Anaesthesia

Kratom as a potential substance use disorder harm reduction agent.

Substance use disorders contribute to considerable U.S. morbidity and mortality. While effective pharmacotherapy options are available to treat opioid and alcohol use disorders, for a variety of reasons, many patients lack access to treatment or may be reluctant to seek care due to concerns such as perceived stigma or a current lack of desire to completely curtail their substance use. Furthermore, treatment options are limited for patients with stimulant or polysubstance use disorders. Thus, there is considerable need to expand the substance use disorder harm reduction armamentarium. Kratom (Mitragyna speciosa Korth.) is an herbal substance that can produce both opioid and stimulant-like effects, and its use in the US is growing. Though there are concerns regarding adverse effects, dependence risk, and limited regulation of its manufacturing and sale, the pharmacology of kratom and early preclinical studies suggest a potential role as a harm reduction agent for various substance use disorders, and it has historically been used in Southeast Asia for such purposes. The goal of this review is to describe kratom's history of use, pharmacology, and early pre-clinical and observational research regarding its therapeutic potential in opioid use disorder, as well as alcohol, stimulant, and polysubstance use disorders, while also highlighting current concerns around its use, existing gaps in the literature, and directions for future research.

Endogenous Opioid Activity as the Mechanism of Action for Mitragyna speciosa (Kratom): The Current State of the Evidence.

Kratom (Mitragyna speciosa) is a substance derived from botanical compounds native to Southeast Asia. This substance has been cultivated predominantly in Thailand, Malaysia, Vietnam, and Myanmar, where it has historically been used in traditional medicine as a near panacea for several health problems. Such ritualistic use of kratom has been present for centuries; however, recreational use appears to have increased globally, especially in the United States. Pharmacodynamic and pharmacokinetic studies have found that kratom demonstrates a unique parabolic, dose-dependent pattern of effects ranging from stimulation to opioid and analgesic effects. Pharmacological research indicates that kratom is both a mu opioid receptor (μ-OR; MOR) and a kappa opioid receptor (κ-OR; KOR) agonist, which mediates its analgesic effects. Other research suggests that kratom may simultaneously act on dopaminergic and serotonergic receptors, which mediate its stimulant effects. This chapter reviews the literature related to the structural, functional, and cultural characteristics of kratom use. We begin with an overview of current and historical patterns of kratom, followed by a review of data on the pharmacodynamics and pharmacokinetics of kratom thus far.

Opioids and the kidney: two sides of the same coin.

Renal dysfunction, including acute renal failure (ARF) and chronic kidney disease (CKD), continues to present significant health challenges, with renal ischemia-reperfusion injury (IRI) being a pivotal factor in their development and progression. This condition, notably impacting kidney transplantation outcomes, underscores the urgent need for innovative therapeutic interventions. The role of opioid agonists in this context, however, remains a subject of considerable debate. Current reviews tend to offer limited perspectives, focusing predominantly on either the protective or detrimental effects of opioids in isolation. Our review addresses this gap through a thorough and comprehensive evaluation of the existing literature, providing a balanced examination of the dualistic nature of opioids' influence on renal health. We delve into both the nephroprotective and nephrotoxic aspects of opioids, dissecting the complex interactions and paradoxical effects that embody the "two sides of the same coin" phenomenon. This comprehensive analysis is vital for understanding the intricate roles of opioids in renal pathophysiology, potentially informing the development of novel therapeutic strategies for preventing or treating hypoxic kidney injury.

Pain Management Strategies before Pan-Retinal Photocoagulation for Diabetic Retinopathy: A Systematic Review.

This systematic review aims to consolidate key findings regarding the efficacy of pain relief medications administered prior to pan-retinal photocoagulation (PRP) for diabetic retinopathy (DR). A comprehensive search of major databases from 1993 to 2023 was conducted. Clinical trials comparing pain relief drugs before PRP in patients diagnosed with DR requiring PRP treatment were eligible for inclusion. The assessment of pain scores involved the use of various scales, such as the visual analog scale (VAS), numerical rating scale (NRS), verbal rating scale (VRS), and other ordinal pain scales. In addition, laser parameters were taken into consideration during the analysis. Twenty-two clinical trials from initial 150 studies were included in the review. Nine studies evaluated the pain relief effects of nonsteroidal anti-inflammatories NSAIDs (selective NSAID and nonselective NSAID), two studies compared the effects of opioids (conventional opioids and atypical opioids), and eleven studies investigated the effects of benzodiazepines, lidocaine, and other sedatives. This review synthesizes findings from multiple studies reporting pain as an adverse outcome of PRP in patients with advanced DR. Based on the evidence from reviewed clinical trials, the administration of lidocaine 2% via transconjunctival, retrobulbar, or peribulbar block along with specific NSAIDs, such as topical ketorolac administrated 24 hours before treatment or oral diclofenac potassium (50 mg) prior to PRP, demonstrated beneficial effects among patients with DR.

Metamizole outperforms meloxicam in sepsis: insights on analgesics, survival and immunomodulation in the peritoneal contamination and infection sepsis model.

Limited availability and side effects of opioids have led to an increased use of non-opioid analgesia in animal disease models. However, by affecting the immune-inflammatory reactions, analgesia may disrupt the resolution of the host inflammation and modulate the survival in septic animals. This study used a clinically relevant sepsis mouse model of peritoneal contamination and infection (PCI) to investigate the antinociceptive and anti-inflammatory properties of two non-opioid analgesics. Adult C57BL/6J mice were intraperitoneally injected with a human feces suspension and received either no analgesics (Non-A), Meloxicam, or Metamizole orally. The mice were monitored for pain and illness. Mortality was assessed at 7 days post-PCI. A separate group of mice was sacrificed 24 hours after infection. Blood, peritoneal lavage fluid (PLF), liver, and spleen were harvested for pathogen load quantification via qPCR, macrophage phenotyping, neutrophil infiltration/activation, and systemic/tissue cytokine release by flow cytometry. Meloxicam but not Metamizole reduced the mortality of septic mice by 31% on day 7 compared to the Non-A group. Both analgesics effectively alleviated pain but did not affect illness severity, body weight, and temperature. Meloxicam quadrupled the bacterial burden in the blood and PLF. In high IL-6 responders, Meloxicam treatment was associated with reduced circulating IL-10 and IL-1β compared to the Non-A septic group. In low IL-6 responders, Meloxicam increased circulating MCP-1 levels and decreased PGE2 levels compared to Non-A septic mice. Notably, Meloxicam reduced spleen neutrophil infiltration by 20% compared to two other sepsis groups. Metamizole and Meloxicam effectively relieved pain and increased the animals' basal activity in the PCI sepsis model. Meloxicam prolonged survival yet triggered maladaptive responses due to its immunosuppressive features that decreased tissue bacterial clearance during sepsis. In contrast, Metamizole constitutes a safe and effective non-opioid alternative for analgesic control in the non-surgical PCI sepsis model.

Opioid Induced Adrenal Insufficiency Complicated by Adrenal Crisis-A Case Report

Introduction: 1 in 5 people experience chronic pain that limits their ability to carry out activities of daily living. Opioid analgesics are one of the pharmaceutical interventions utilized to treat chronic pain. In fact, chronic pain is one of the most common reasons opioids are prescribed. Although many of the secondary effects of opioids are well known, a lesser-known side effect is opioid induced adrenal insufficiency (OIAI). OIAI can cause significant morbidity and has the potential to result in adrenal crisis, profound hypotension, and potential cardiovascular collapse, resulting in death. With sparse literature on OIAI, we present a case of OIAI complicated by adrenal crisis to expand awareness and discussion on the topic. Methods: The patient was a 65-year-old female on chronic opioid therapy for back pain who presented to the emergency room for syncope. On presentation, patient was hypotensive, bradycardic, and had an inadequate fluid response requiring pressors. Traditional etiologies of shock were ruled out, but interestingly morning cortisol and adrenocorticotropic hormone (ACTH) levels were low. Additionally, the cosyntropin stimulation test was suboptimal. Results suggested central hypothalamic pituitary axis suppression, which after discussion with Endocrinology indicated OIAI given the patient’s history. Results: Shortly after steroid regimen initiation the patient was weaned off pressors, and after multiple taper trials was successfully sent home on a steroid taper with Endocrinology follow up. Conclusion: Long term opioid use to treat chronic pain can decrease cortisol production via HPA axis suppression resulting in OIAI. To date, there is limited investigation into OIAI despite its increased prevalence and widespread use of opioids. The case adds to the available literature on OIAI, and sheds light on adrenal crisis as its initial presentation.

Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone.

(R,S)-methadone ((R,S)-MTD) is a µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers. (S)-MTD is being developed as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. We compared the pharmacology of (R)-MTD and (S)-MTD and found they bind to MORs, but not NMDARs, and induce full analgesia. Unlike (R)-MTD, (S)-MTD was a weak reinforcer that failed to affect extracellular dopamine or induce locomotor stimulation. Furthermore, (S)-MTD antagonized motor and dopamine releasing effects of (R)-MTD. (S)-MTD acted as a partial agonist at MOR, with complete loss of efficacy at the MOR-galanin Gal1 receptor(Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use.One-sentence summary: (S)-MTD, like (R)-MTD, binds to and activates MORs in vitro, but (S)-MTD antagonizes the MOR-Gal1R heteromer, decreasing its abuse liability.