Development Of Opioid Tolerance Research Articles

A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model.

The ligands of chemokine receptors 2 and 5 (CCR2 and CCR5, respectively) are associated with the pathomechanism of neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, the aim of our study was to examine the function of these factors in the hypersensitivity accompanying diabetes. Additionally, we analyzed the analgesic effect of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, and its influence on the effectiveness of morphine. An increasing number of experimental studies have shown that targeting more than one molecular target is advantageous compared with the coadministration of individual pharmacophores in terms of their analgesic effect. The advantage of using bifunctional compounds is that they gain simultaneous access to two receptors at the same dose, positively affecting their pharmacokinetics and pharmacodynamics and consequently leading to improved analgesia. Experiments were performed on male and female Swiss albino mice with a streptozotocin (STZ, 200 mg/kg, i.p.) model of diabetic neuropathy. We found that the blood glucose level increased, and the mechanical and thermal hypersensitivity developed on the 7th day after STZ administration. In male mice, we observed increased mRNA levels of Ccl2, Ccl5, and Ccl7, while in female mice, we observed additional increases in Ccl8 and Ccl12 levels. We have demonstrated for the first time that a single administration of cenicriviroc relieves pain to a similar extent in male and female mice. Moreover, repeated coadministration of cenicriviroc with morphine delays the development of opioid tolerance, while the best and longest-lasting analgesic effect is achieved by repeated administration of cenicriviroc alone, which reduces pain hypersensitivity in STZ-exposed mice, and unlike morphine, no tolerance to the analgesic effects of CVC is observed until Day 15 of treatment. Based on these results, we suggest that targeting CCR2 and CCR5 with CVC is a potent therapeutic option for novel pain treatments in diabetic neuropathy patients.

Biasing Gβγ Downstream Signaling with Gallein Inhibits Development of Morphine Tolerance and Potentiates Morphine-Induced Nociception in a Tolerant State.

Opioid analgesics are widely used as a treatment option for pain management and relief. However, the misuse of opioid analgesics has contributed to the current opioid epidemic in the United States. Prescribed opioids such as morphine, codeine, oxycodone, and fentanyl are mu-opioid receptor (MOR) agonists primarily used in the clinic to treat pain or during medical procedures, but development of tolerance limits their utility for treatment of chronic pain. Here we explored the effects of biasing Gβγ signaling on tolerance development after chronic morphine treatment in vivo. We hypothesized that biasing Gβγ signaling with gallein could prevent activation of regulatory signaling pathways that result in tolerance to antinociceptive effects of MOR agonists. Gallein has been shown to bind to Gβγ and inhibit interactions of Gβγ with phospholipase-Cβ3 (PLCβ3) or G-protein-coupled receptor kinase 2 (GRK2) but not G-protein inwardly rectifying potassium (GIRK) channels. In mice, morphine-induced antinociception was evaluated in the 55°C warm water tail withdrawal assay. We used two paradigms for gallein treatment: administration during and after three times-daily morphine administration. Our results show that gallein cotreatment during repeated administration of morphine decreased opioid tolerance development and that gallein treatment in an opioid-tolerant state enhanced the potency of morphine. Mechanistically, our data suggest that PLCβ3 is necessary for potentiating effects of gallein in an opioid-tolerant state but not in preventing the development of tolerance. These studies demonstrate that small molecules that target Gβγ signaling could reduce the need for large doses of opioid analgesics to treat pain by producing an opioid-sparing effect. SIGNIFICANCE STATEMENT: Biasing Gβγ signaling prevents tolerance to repeated morphine administration in vivo and potentiates the antinociceptive effects of morphine in an opioid-tolerant state. Mechanistically, phospholipase-Cβ is necessary for potentiating effects of gallein in an opioid-tolerant state but not in preventing the development of tolerance. This study identifies a novel treatment strategy to decrease the development of tolerance to the analgesic effects of mu-opioid receptor agonists, which are necessary to improve pain treatment and decrease the incidence of opioid use disorder.

Relationship between intraoperative requirement for anesthetics and postoperative analgesic consumption in laparoscopic colectomy: a randomized controlled double-blinded study.

This study investigated the relationship between intraoperative requirement for an inhalational anesthetic (sevoflurane) or an opioid (remifentanil) and postoperative analgesic consumption. The study included 200 adult patients undergoing elective laparoscopic colectomy. In the sevoflurane group, the effect-site concentration of remifentanil was fixed at 1.0 ng/ml, while the inspiratory sevoflurane concentration was adjusted to maintain an appropriate anesthetic depth. In the remifentanil group, the end-expiratory sevoflurane concentration was fixed at 1.0 vol.%, and the remifentanil concentration was adjusted. Pain scores and cumulative postoperative analgesic consumptions were evaluated at 2, 6, 24, and 48 h after surgery. Average end-tidal concentration of sevoflurane and effect-site concentration of remifentanil were 2.0 ± 0.4 vol.% and 3.9 ± 1.4 ng/ml in the sevoflurane and remifentanil groups, respectively. Cumulative postoperative analgesic consumption at 48 h postoperatively was 55 ± 26 ml in the sevoflurane group and 57 ± 33 ml in the remifentanil group. In the remifentanil group, the postoperative cumulative analgesic consumptions at 2 and 6 h were positively correlated with intraoperative remifentanil requirements (2 h: r = 0.36, P < 0.001; 6 h: r = 0.38, P < 0.001). However, there was no significant correlation in the sevoflurane group (r = 0.04, P = 0.691). The amount of intraoperative requirement of short acting opioid, remifentanil, is correlated with postoperative analgesic consumption within postoperative 6 h. It may be contributed by the development of acute opioid tolerance. However, intraoperative sevoflurane requirement had no effect on postoperative analgesic consumption.

Development of opioid analgesic tolerance in rat to extended-release buprenorphine formulated for laboratory subjects.

Buprenorphine in an extended-release formulation intended for use in laboratory subjects is frequently administered to rats to provide extended analgesia without repeated handling. While levels of buprenorphine may persist in serum once extended-release buprenorphine has been introduced, exposure to opioids can cause opioid tolerance or opioid-induced hypersensitivity. This work examined the analgesic duration and efficacy of a single administration of extended-release buprenorphine intended for use in laboratory subjects in models of inflammatory pain and post-operative pain and the development of opioid tolerance in rat. After subcutaneous administration of 1 mg/kg extended-release buprenorphine, analgesic efficacy did not persist for the expected 72 hours. No changes were observed in mechanical thresholds in the hindpaws that were contralateral to the injury, suggesting a lack of centrally mediated opioid-induced hypersensitivity. To determine whether opioid tolerance arose acutely after one exposure to extended-release buprenorphine, we conducted the warm water tail flick assay; on Day 1 we administered either saline or extended-release buprenorphine (1 mg/kg) and on Day 3 we quantified the standard buprenorphine dose-response curve (0.1-3 mg/kg). Rats previously given extended-release buprenorphine displayed decreased analgesic responses after administration of standard buprenorphine as compared to the robust efficacy of standard buprenorphine in control subjects. Males appeared to show evidence of acute opioid tolerance, while females previously exposed to opioid did not demonstrate a decreased response at the doses examined. Taken together, these results suggest that opioid tolerance arises quickly in male rats after exposure to the extended-release formulation of buprenorphine. This tolerance may account for the brief period of antinociception observed.

Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance.

The development of opioid tolerance in patients on long-term opioid analgesic treatment is an unsolved matter in clinical practice thus far. Dose escalation is required to restore analgesic efficacy, but at the price of side effects. Intensive research is ongoing to elucidate the underlying mechanisms of opioid analgesic tolerance in the hope of maintaining opioid analgesic efficacy. N-Methyl-D-aspartate receptor (NMDAR) antagonists have shown promising effects regarding opioid analgesic tolerance; however, their use is limited by side effects (memory dysfunction). Nevertheless, the GluN2B receptor remains a future target for the discovery of drugs to restore opioid efficacy. Mechanistically, the long-term activation of µ-opioid receptors (MORs) initiates receptor phosphorylation, which triggers β-arrestin-MAPKs and NOS-GC-PKG pathway activation, which ultimately ends with GluN2B receptor overactivation and glutamate release. The presence of glutamate and glycine as co-agonists is a prerequisite for GluN2B receptor activation. The extrasynaptic localization of the GluN2B receptor means it is influenced by the glycine level, which is regulated by astrocytic glycine transporter 1 (GlyT1). Enhanced astrocytic glycine release by reverse transporter mechanisms as a consequence of high glutamate levels or unconventional MOR activation on astrocytes could further activate the GluN2B receptor. GlyT1 inhibitors might inhibit this condition, thereby reducing opioid tolerance.

Adeno-associated virus-mediated gene transfer of arginine decarboxylase to the central nervous system prevents opioid analgesic tolerance.

Agmatine, a decarboxylated form of L-arginine, prevents opioid analgesic tolerance, dependence, and self-administration when given by both central and systemic routes of administration. Endogenous agmatine has been previously detected in the central nervous system. The presence of a biochemical pathway for agmatine synthesis offers the opportunity for site-specific overexpression of the presumptive synthetic enzyme for local therapeutic effects. In the present study, we evaluated the development of opioid analgesic tolerance in ICR-CD1 mice pre-treated with either vehicle control or intrathecally delivered adeno-associated viral vectors (AAV) carrying the gene for human arginine decarboxylase (hADC). Vehicle-treated or AAV-hADC-treated mice were each further divided into two groups which received repeated delivery over three days of either saline or systemically-delivered morphine intended to induce opioid analgesic tolerance. Morphine analgesic dose-response curves were constructed in all subjects on day four using the warm water tail flick assay as the dependent measure. We observed that pre-treatment with AAV-hADC prevented the development of analgesic tolerance to morphine. Peripheral and central nervous system tissues were collected and analyzed for presence of hADC mRNA. In a similar experiment, AAV-hADC pre-treatment prevented the development of analgesic tolerance to a high dose of the opioid neuropeptide endomorphin-2. Intrathecal delivery of anti-agmatine IgG (but not normal IgG) reversed the inhibition of endomorphin-2 analgesic tolerance in AAV-hADC-treated mice. To summarize, we report here the effects of AAV-mediated gene transfer of human ADC (hADC) in models of opioid-induced analgesic tolerance. This study suggests that gene therapy may contribute to reducing opioid analgesic tolerance.

Dealing with "complex" pain patients in eye surgery : Perioperative management of patients with pre-existing chronic pain, opioid consumption and opioid use disorder

The quality of postoperative pain management is still considered insufficient in many cases, also in surgical ophthalmology. Complex constellations and comorbidities, such as pre-existing chronic pain, opioid consumption and opioid use disorders represent aspecial challenge due to psychosocial influencing factors and sometimes psychological and psychiatric comorbidities but also due to pharmacological effects, such as the development of opioid tolerance, the opioid-induced hyperalgesia. This review article aims to impart knowledge on aspects of these comorbidities and the perioperative management to improve the treatment skills of ophthalmologists in the management of pain in these complex patients.

Repurposing EGFR Inhibitors for Oral Cancer Pain and Opioid Tolerance.

Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how repurposing EGFR inhibitors typically used for cancer treatment could be an effective pharmacological strategy to treat oral cancer pain and to prevent or delay the development of opioid tolerance. We also propose that EGFR interaction with the µ-opioid receptor and glutamate N-methyl-D-aspartate receptor could be two novel downstream mechanisms contributing to pain and morphine tolerance. Most data presented here support that repurposing EGFR inhibitors as non-opioid analgesics in oral cancer pain is promising and warrants further research.

Noncoding RNAs: Novel Targets for Opioid Tolerance.

As a global health problem, chronic pain is one of the leading causes of disability, and it imposes a huge economic and public health burden on families and society. Opioids represent the cornerstone of analgesic drugs. However, opioid tolerance caused by long-term application of opioids is a major factor leading to drug withdrawal, serious side effects caused by dose increases, and even the death of patients, placing an increasing burden on individuals, medicine, and society. Despite efforts to develop methods to prevent and treat opioid tolerance, no effective treatment has yet been found. Therefore, understanding the mechanism underlying opioid tolerance is crucial for finding new prevention and treatment strategies. Noncoding RNAs (ncRNAs) are important parts of mammalian gene transcriptomes, and there are thousands of unique noncoding RNA sequences in cells. With the rapid development of high-throughput genome technology, research on ncRNAs has become a hot topic in biomedical research. In recent years, studies have shown that ncRNAs mediate physiological and pathological processes, including chromatin remodeling, transcription, posttranscriptional modification and signal transduction, which are key regulators of physiological processes in developmental and disease environments and have become biomarkers and potential therapeutic targets for various diseases. An increasing number of studies have found that ncRNAs are closely related to the development of opioid tolerance. In this review, we have summarized the evidence that ncRNAs play an important role in opioid tolerance and that ncRNAs may be novel targets for opioid tolerance.

Gut Brain axis: The gut microbiome in peri-operative medicine.

Sir, The human body is inhabited by a multitude of bacteria, viruses, fungi, phages constituting the microbiota, and their gene pool called the microbiome which is essential for human well-being.[1] The role of gut microbiome in peri-operative medicine is recently being explored. However, most of the literature available is that of animal studies and more extensive research would be needed in humans to establish an association. The mechanism of action of gut-microbiome on various systems of the human body can be explained by the “gut-brain axis.” This is a two-way interaction between the enteric nervous system (ENS) and central nervous system (CNS) [Figure 1]. The gut microbiota secrete various metabolites and products like-short chain fatty acids (SCFA), enzymes, polysaccharides, cytokines, and neurotransmitters, which are released in to the circulation to act on the CNS. The vagus nerve also carries inputs from ENS to CNS. The brain in-turn acts on the gut through the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system.[2] Immune mediated interaction and alteration of microglial activity are other proposed mechanisms of gut-brain interaction. All these mechanisms have been proven only by preclinical animal studies.[1]Figure 1: Gut brain axis. HPA = Hypothalamic pituitary adrenal axisAnaesthetic agents-like propofol and volatile anaesthetics have been found to alter the gut microbiota composition in animal studies. Han et al. studied gut microbiota of mice after sevoflurane exposure and found that microbiome composition was reduced on day-1, 3, 7, and 14 after sevoflurane anaesthesia compared to the control group. They also noted a significant difference in fecal metabolites of the experimental and control groups.[3] Also an infusion of propofol for 3 hours in rats was found to decrease the number of certain bacterial species for 14 days.[4] Postoperative delirium (POD) and post-surgical pain (PSP) have also been attributed to the gut-microbiome by animal studies. This means, why certain patients have more POD or PSP than others can be determined by their gut-microbiome constitution and may be pre-treatment with pre-biotics, post-biotics, or fecal microbiota transplantation reduces the risk of POD and PSP in these patients. However, this association between POD/PSP and gut-microbiome has been shown mostly in animal studies and human association is yet to be established.[1] Zhang et al. compared the gut-microbiota of rats who developed POD and those who did not develop POD after abdominal surgery. The composition of microbiota was significantly different between the groups. They also conducted fecal microbiota transplantation from rats with POD to antibiotic treated rats, which then developed POD.[5] A human study has proved association of gut microbiome with chronic PSP, where Yao et al. had preoperatively collected gut-microbiome samples for 132 patients undergoing breast cancer surgery. The gut microbiota of 66 patients who developed chronic PSP (CPSP) was significantly different from those who did not develop PSP. Fecal microbiome transplantation from CPSP patients to mice led to development of hyperalgesia in these mice.[6] The gut microbiome composition has been attributed to development of opioid tolerance. Chronic opioid exposure leads to activation of opioid receptors on gut epithelium and destruction of gut mucosal barrier, allowing translocation of gut bacteria leading to an inflammatory response and pain exacerbation.[1] The gut microbiota composition influences many chronic pain conditions like fibromyalgia, headache, neuropathic, visceral, and chronic pelvic pain. The mediators of gut microbiota can alter the neuronal excitability at the dorsal root ganglia and mediate neuro inflammation leading to central sensitization and peripheral sensitization in chronic pain. Thus, targeting the gut-microbiota seems to be a promising treatment of chronic pain.[1,2] In future, gut microbiome analysis might help to screen patients at risk of postoperative cognitive dysfunction, postoperative pain, chronic pain and opioid tolerance and alteration of gut microbiota by use of prebiotics, postbiotics, dietary, and life-style changes might provide therapeutic benefit in such patients. However, this hypothesis is based majorly on animal studies and gut microbiome still needs to be explored in humans. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Oxycodone-Naloxone Combination Hinders Opioid Consumption in Osteoarthritic Chronic Low Back Pain: A Retrospective Study with Two Years of Follow-Up.

Chronic low back pain (CLBP) due to osteoarthritis represents a therapeutic challenge worldwide. Opioids are extensively used to treat such pain, but the development of tolerance, i.e., less susceptibility to the effects of the opioid, which can result in a need for higher doses to achieve the same analgesic effect, may limit their use. Animal models suggest that ultra-low doses of opioid antagonists combined with opioid agonists can decrease or block the development of opioid tolerance. In this retrospective study, we tested this hypothesis in humans. In 2019, 53 patients suffering from CLBP were treated with either Oxycodone and Naloxone Prolonged Release (27 patients, OXN patients) or Oxycodone Controlled Release (26 patients, OXY patients). The follow-up period lasted 2 years, during which 10 patients discontinued the treatment, 5 out of each group. The remaining 43 patients reached and maintained the targeted pain relief, but at 18 and 24 months, the OXY patients showed a significantly higher oxycodone consumption than OXN patients to reach the same level of pain relief. No cases of respiratory depression or opioid abuse were reported. There were no significant differences in the incidence of adverse effects between the two treatments, except for constipation, more common in OXY patients. From our results, we can affirm that a long-term opioid treatment with oxycodone-naloxone combination, when compared with oxycodone only, may significantly hinder the development of opioid tolerance. We were also able to confirm, in our cohort, the well known positive effect of naloxone in terms of opioid-induced bowel dysfunction incidence reduction.

Changes in the development of opioid tolerance on re-exposure among people who use heroin: A qualitative study.

This qualitative study aimed to explore how the development of tolerance to both the psychoactive and respiratory depressant effects of heroin on re-exposure are experienced by people who use heroin. Semi-structured one-to-one interviews were conducted with 20 adults who currently or previously used heroin (for at least 6 months), with any type of administration (injected, smoked) and experience of abstinence (at least 2 weeks) and relapse. Topic guides explored the participants understanding of tolerance, their experience of developing tolerance to heroin and of tolerance following relapse. Interviews were audio-recorded and transcribed. Thematic analysis was used to generate salient themes. The analysis produced three broad themes: lay understanding of tolerance; tolerating tolerance; and rapid tolerance development following relapse. Tolerance was defined as the body adapting to regular drug use, so that the drug no longer produced the same level of effect. Tolerance was experienced as interacting and co-developing with physical dependence and the symptoms of withdrawal. Indeed, several participants did not differentiate between tolerance and dependence. Most participants did not notice tolerance to respiratory depression. Tolerance levels fluctuated-increasing over periods of regular use and reducing when abstinent. Using more drug was the most common response to increasing tolerance to the desired effects. On re-use following abstinence, tolerance was experienced as developing more quickly in the most recent relapse compared to the first. Tolerance was also perceived to return more quickly with each abstinence-relapse cycle. Qualitative accounts of tolerance report that tolerance returns more quickly with each relapse episode. By elucidating the mechanism(s) involved and potentially discovering how they could be switched on prior to relapse occurring we might be able to develop a beneficial harm reduction treatment for people in abstinence that would protect against overdose occurring on subsequent relapse.

Current and Future Therapeutic Optionsin Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation.

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

Opioid and Multimodal Analgesia Use Following Urological Trauma

ObjectiveTo examine opioid use following Urological trauma. Increased opioid use is associated with inferior outcomes and risk of dependence, particularly in vulnerable populations. In contrast, multimodal analgesia following trauma allows decreased pain and readmission. Currently there is a paucity of data describing opioid usage following urological trauma. The purpose of this study was to assess utilization of opioids and multimodal pain regimens following urologic trauma. MethodsWe retrospectively examined 116 patients hospitalized following urologic trauma from 2016-2021. Inpatient and discharge utilization of opioids, multimodal analgesia and length of stay were stratified by affected organ. Analyses were performed in STATA with p<0.05 reaching significance. Results116 patients were assessed; 84 (72.4%) required surgery. In the first 10 days, bladder injuries incurred higher mean and median OMEQ than other urological injuries. In nearly all groups, OMEQ prescribed at discharge is less than average inpatient OMEQ. Eighty-six (74.1%) patients received at least 2 different opioid medications while inpatient. Those with a history of opioid use received a significantly higher OMEQ dose per day (p<0.001). There were no significant differences between opioid prescribing patterns or average OMEQ dosages prescribed at discharge between those patients managed either surgically or non-operatively. Only 24 (20.7%) patients met the criteria for utilization of multimodal analgesia. ConclusionMultimodal analgesia is severely underutilized following urological trauma. Combined with the development of opioid tolerance over long hospital stays, this creates an avenue for opioid misuse following discharge and provides an opportunity for improvement.

MP20-01 OPIOID AND MULTIMODAL ANALGESIA USE FOLLOWING UROLOGICAL TRAUMA

You have accessJournal of UrologyCME1 May 2022MP20-01 OPIOID AND MULTIMODAL ANALGESIA USE FOLLOWING UROLOGICAL TRAUMA Mary Rostom, Andrew Gabrielson, Ryan Fransman, Shirley Wang, Albert Holler, Isabella Pan, Nikita Gupta, Joseph Sakran, and Andrew Cohen Mary RostomMary Rostom More articles by this author , Andrew GabrielsonAndrew Gabrielson More articles by this author , Ryan FransmanRyan Fransman More articles by this author , Shirley WangShirley Wang More articles by this author , Albert HollerAlbert Holler More articles by this author , Isabella PanIsabella Pan More articles by this author , Nikita GuptaNikita Gupta More articles by this author , Joseph SakranJoseph Sakran More articles by this author , and Andrew CohenAndrew Cohen More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002553.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Following trauma, increased opioid use is associated with inferior outcomes and increased risk of opioid dependence, particularly in vulnerable populations. In contrast, multimodal analgesia following trauma results in decreased pain and readmission. Currently there is a paucity of data describing opioid usage following urological trauma. We assess utilization of opioids and multimodal pain regimens following urologic trauma. METHODS: We retrospectively examined 121 patients hospitalized following urologic trauma from 2016-2021. Inpatient and discharge utilization of opioids, multimodal analgesia and length of stay were stratified by affected organ. Analyses were performed in STATA with p<0.05 reaching significance. RESULTS: 121 patients were assessed; affected organ and mechanism of injury are shown in Table 1. Displayed in Figure 1, though differences in average opioid morphine equivalence (OMEQ) per day are not significant (p=0.368), bladder injuries incurred higher mean OMEQ than other urological injuries with 14 (88%) requiring surgery and 8 (50%) associated with pelvic fracture. ISS’s were significantly different between trauma groups (p=0.011) with multiorgan trauma having the highest average. In nearly all groups, OMEQ prescribed at discharge is less than average inpatient OMEQ. Shown in Table 2, 87 (73%) patients were given acetaminophen in the hospital, but only 12 (10%) used non-opioid NSAIDs despite significantly lower average OMEQ prescriptions per day with acetaminophen use (p=0.009). CONCLUSIONS: Multimodal analgesia is severely underutilized following urological trauma. Combined with the development of opioid tolerance over long hospital stays, this creates an avenue for opioid misuse following discharge and opportunities for improvement. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e317 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mary Rostom More articles by this author Andrew Gabrielson More articles by this author Ryan Fransman More articles by this author Shirley Wang More articles by this author Albert Holler More articles by this author Isabella Pan More articles by this author Nikita Gupta More articles by this author Joseph Sakran More articles by this author Andrew Cohen More articles by this author Expand All Advertisement PDF DownloadLoading ...

Opioid-Induced Pronociceptive Signaling in the Gastrointestinal Tract Is Mediated by Delta-Opioid Receptor Signaling.

Opioid tolerance (OT) leads to dose escalation and serious side effects, including opioid-induced hyperalgesia (OIH). We sought to better understand the mechanisms underlying this event in the gastrointestinal tract. Chronic in vivo administration of morphine by intraperitoneal injection in male C57BL/6 mice evoked tolerance and evidence of OIH in an assay of colonic afferent nerve mechanosensitivity; this was inhibited by the δ-opioid receptor (DOPr) antagonist naltrindole when intraperitoneally injected in previous morphine administration. Patch-clamp studies of DRG neurons following overnight incubation with high concentrations of morphine, the µ-opioid receptors (MOPr) agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin (DAMGO) or the DOPr agonist [D-Ala2, D-Leu5]-Enkephalin evoked hyperexcitability. The pronociceptive actions of these opioids were blocked by the DOPr antagonist SDM25N but not the MOPr antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 The hyperexcitability induced by DAMGO was reversed after a 1 h washout, but reapplication of low concentrations of DAMGO or [D-Ala2, D-Leu5]-Enkephalin restored the hyperexcitability, an effect mediated by protein kinase C. DOPr-dependent DRG neuron hyperexcitability was blocked by the endocytosis inhibitor Pitstop 2, and the weakly internalizing DOPr agonist ARM390 did not cause hyperexcitability. Bioluminescence resonance energy transfer studies in HEK cells showed no evidence of switching of G-protein signaling from Gi to a Gs pathway in response to either high concentrations or overnight incubation of opioids. Thus, chronic high-dose opioid exposure leads to opioid tolerance and features of OIH in the colon. This action is mediated by DOPr signaling and is dependent on receptor endocytosis and downstream protein kinase C signaling.SIGNIFICANCE STATEMENT Opioids are effective in the treatment of abdominal pain, but escalating doses can lead to opioid tolerance and potentially opioid-induced hyperalgesia. We found that δ-opioid receptor (DOPr) plays a central role in the development of opioid tolerance and opioid-induced hyperalgesia in colonic afferent nociceptors following prolonged exposure to high concentrations of MOPr or DOPr agonists. Furthermore, the role of DOPr was dependent on OPr internalization and activation of a protein kinase C signaling pathway. Thus, targeting DOPr or key components of the downstream signaling pathway could mitigate adverse side effects by opioids.

Effects of Ultramicronized N-Palmitoylethanolamine Supplementation on Tramadol and Oxycodone Analgesia and Tolerance Prevention.

Chronic pain management requires increasing doses of opioids, the milestone of painkillers, which may result in the onset of tolerance with exacerbated side effects. Maintaining stable analgesia with low doses of opioids is thus imperative. N-palmitoylethanolamine (PEA) is an endogenous lipid compound endowed with pain-relieving as well as anti-inflammatory properties. The ultramicronized formulation of PEA was recently demonstrated to be able to modulate morphine’s effects, delaying tolerance and improving efficacy. To evaluate the possible application to other opioids, in this study, we analysed the capacity of ultramicronized PEA to regulate analgesia and tolerance induced by oxycodone and tramadol. Pre-emptive and continuative treatment with ultramicronized PEA (30 mg kg−1, daily, per os) delayed the onset of opioid tolerance and enhanced opioid analgesia when it was acutely administered in association with tramadol (20 mg kg−1, daily, subcutaneously) or oxycodone (0.5 mg kg−1, daily, subcutaneously). Moreover, PEA exerted antinociceptive effects on tolerant rats, suggesting the use of PEA together with opioids for stable, long-lasting analgesia. To that purpose, the oxycodone dose needed to be increased from 0.3 mg kg−1 (day 1) up to 1 mg kg−1 (day 31) in the oxycodone + vehicle group; the tramadol dose was progressively enhanced from 15 mg kg−1 to 50 mg kg−1 in 31 days in the tramadol + vehicle group. Acute oral co-treatment with PEA (120 mg kg−1) achieved the same analgesia without increasing the dose of both opioids. The behavioural effects of PEA on opioid chronic treatment paralleled a decrease in astrocyte activation in the dorsal horn of the spinal cord (a marker of the development of opioid tolerance) and with a modulation of mRNA expression of IL-6 and serpin-A3. In conclusion, pre- and co-administration of ultramicronized PEA delayed the development of tramadol tolerance, potentiating either oxycodone or tramadol analgesia and allowing a long-lasting analgesic effect with a low opioid dose regimen. The use of PEA is suggested for clinical purposes to support the opioid-based management of persistent pain.

Old and New Hypothesis to The Mechanism Underlying Opioid Addiction and A Novel Treatment – A Review

Previously we presented experimental evidence that the severity of drugs of abuse withdrawal behaviors is correlated with drug-related changes in baseline neuronal firing patterns in 14 regions of the brain that we studied. These 14 areas of the brain participate in reward and pain sensations as well in response to drugs of abuse. Based on these experiments we came to the following hypothesis: Repeated morphine exposure elicits a chain of molecular and cellular events that results in the modulation (disruption) of the baseline (spontaneous) neuronal activities from the initial state to the opioid-induced state which requires continuous morphine use to keep this new baseline (BL). Cessation of morphine consumption disrupts this new morphine modified BL. This BL neuronal activity disruption leads to the expression of the withdrawal. Activation of these brain areas by noninvasive transcranial current stimulation (NTCS) will provide a novel efficacious intervention to diminish the development of opioid tolerance and the severe symptoms of opioid withdrawal. NTCS, when applied to addicted animals when the morphine consumption is discontinued rewires the disrupted neuronal circuits activities and facilitates a return to the initial BL. This will lessen or eliminate the behavioral expression of the withdrawal symptoms. NTCS have the potential to obviate and/or supplement significantly the common treatments of addiction that employ medications with drugs in the opioid family and prolonged behavioral therapies. New approaches to the opioid crisis are badly needed since the current drug treatments require lengthy investments of times.

The Expression and Function of Nitric Oxide Synthase Enzyme in Atorvastatin Effects on Morphine-Induced Dependence in Mice

Background: Atorvastatin exerts neuroprotective effects on the treatment of central nervous system disorders. Morphine analgesic tolerance and dependence remain as major concerns in medicine. Nitric oxide (NO) pathway mediates the development of opioid analgesic tolerance and dependence, as well as atorvastatin neuroprotection. Objectives: The present study aimed to assess the possible involvement of the NO/cGMP pathway in the process of the effects of atorvastatin on morphine physical dependence. Methods: Dependence was induced by repetitive injection of morphine sulfate. Naloxone was injected at the dose of 4 mg/kg on the last day of the experiment to assess withdrawal signs. Animals received atorvastatin (1, 5, 10, and 20 mg/kg, orally). Nitric oxide synthase (NOS) inhibitors and ODQ were injected before protective dose of atorvastatin. The gene expression of NOS isoforms was evaluated by real-time PCR. Thereafter, the hippocampal levels of cGMP and nitrite were measured. Results: Treatment with atorvastatin 10 mg/kg significantly attenuated naloxone-induced withdrawal behaviours. The administration of L-NAME, aminoguanidine, and ODQ before atorvastatin enhanced its effects. The treatment with atorvastatin significantly decreased the nitrite and cGMP levels as well as NOS gene expression in the hippocampus of dependent animals. Conclusions: It can be concluded that atorvastatin, possibly, through inducible NOS, could alleviate morphine dependence and withdrawal signs.

Opioid Effects on the Central Nervous System and the Peripheral Immune System: Implications for Opioid Tolerance

Opioids exert differential effects in the central nervous system (CNS) and the peripheral immune system. Both systems may play a role in the development of opioid tolerance. This review provides a brief overview of the opioid effects on the CNS and peripheral immune system and discusses the potential roles of the connections between the two systems in opioid tolerance. Opioids induced pro-inflammatory response of the CNS immune cells through several mechanisms that involve mu-opioid receptor and Toll-like receptor 4. This neuroinflammation leads to enhanced neuron excitability and opioid tolerance and/or hyperalgesia. Opioid-exposed neuronal cells also contributed to CNS stress and inflammatory responses, further resulted in neuroinflammation. On the contrary, most studies have shown that opioids exert immunosuppressive effects in the peripheral immune system. There are, however, some evidence suggested that opioids may induce dose-, time-, and opioid agent-dependent pro-inflammatory responses. Though opioids have the opposite effects in the CNS and the peripheral immune system, newer evidence have suggested that the peripheral immune system plays a significant role in neuroinflammation and opioid tolerance. Opioid effects on the CNS and the peripheral immune system have been studied extensively; however, the integrated effects of opioids on tolerance development are yet to be explored. Further understanding of the integrated/interactive effects of opioids on peripheral immune cells and the CNS is required so that their interactions may be exploited for the identification of new therapeutics and biomarkers.