Oliceridine as a Novel Selective mu-receptor G-protein Pathway Modulator: A Narrative review

Objective: To review the literature on equianalgesic efficacy and better safety(less respiratory depression and gastrointestinal dysfunction) of oliceridine versus opioid analgesic in moderate to severe postoperative pain. Methodology: A comprehensive literature search was conducted in PubMed (January 2021 to March 2021) using keywords as ‘oliceridine’, ‘ligand biased mu receptor agonist’, ‘acute postoperative pain’, ‘conventional opioids’ and ‘morphine’. All English language full text pre-clinical and clinical research articles were searched. In addition, other data source was from ClinicalTrial. Gov. Data Synthesis: Oliceridine is a novel selective µ (mu)-receptor G-protein pathway modulator. G protein biased mu receptor agonists are a new class of opioids exhibiting analgesic properties at par to morphine with less respiratory depressant properties. Oliceridine a first-in-class intravenous (IV) analgesic has received the US FDA approval in August 2020, for management of moderate to severe acute pain in adults. The drug can be administered in cases where the pain is severe enough to require an intravenous opioid and when alternative treatments become inadequate. Oliceridine is an opioid agonist with a rapid onset of action within two to five minutes, was administered via clinician-administered bolus dosing, patient-controlled analgesia (PCA), or a combination of the two. Bolus dosing was initiated at 1 to 2 mg, with supplemental doses of 1 to 3 mg every one to three hours, as needed, based on individual patient need and previous response to oliceridine in management of acute post-operative pain. If oliceridine was administered via PCA, the loading dose was 1.5 mg, the demand dose was 0.5 mg, and the lockout interval (repeat dose)was six minutes. The clinically relevant concentration range of 0 to 35 ng/ml. It is indicated for short-term use only & limited to hospitals or other controlled clinical settings. Oliceridine requires no dosage adjustments in patients with renal impairment as well as in patient with significant medical complications. Therefore, opioids that bias towards G-protein and away from β arrestin signaling should produce analgesia with reduced side effects.

Efficiency of primary spine care as compared to conventional primary care: a retrospective observational study at an Academic Medical Center

Background Primary Spine Care (PSC) is an innovative model for the primary management of patients with spine-related disorders (SRDs), with a focus on the use of non-pharmacological therapies which now constitute the recommended first-line approach to back pain. PSC clinicians serve as the initial or early point of contact for spine patients and utilize evidence-based spine care pathways to improve outcomes and reduce escalation of care (EoC; e.g., spinal injections, diagnostic imaging, hospitalizations, referrals to a specialist). The present study examined 6-month outcomes to evaluate the efficiency of care for patients who received PSC as compared to conventional primary care. We hypothesized that patients seen by a PSC clinician would have lower rates of EoC compared to patients who received usual care by a primary care (PC) clinician. Methods This was a retrospective observational study. We evaluated 6-month outcomes for two groups seen and treated for an SRD between February 01, 2017 and January 31, 2020. Patient groups were comprised of N = 1363 PSC patients (Group A) and N = 1329 PC patients (Group B). We conducted Pearson chi-square and logistic regression (adjusting for patient characteristics that were unbalanced between the two groups) to determine associations between the two groups and 6-month outcomes. Results Within six months of an initial visit for an SRD, a statistically significantly smaller proportion of PSC patients utilized healthcare resources for spine care as compared to the PC patients. When adjusting for patient characteristics, those who received care from the PSC clinician were less likely within 6 months of an initial visit to be hospitalized (OR = .47, 95% CI .23–.97), fill a prescription for an opioid analgesic (OR = .43; 95% CI .29–.65), receive a spinal injection (OR = .56, 95% CI .33–.95), or have a visit with a specialist (OR = .48, 95% CI .35–.67) as compared to those who received usual primary care. Conclusions Patients who received PSC in an academic primary care clinic experienced significantly less escalation of their spine care within 6 months of their initial visit. The PSC model may offer a more efficient approach to the primary care of spine problems for patients with SRDs, as compared to usual primary care.

High concentration of Dezocine induces immune escape of lung cancer and promotes glucose metabolism through up-regulating PD-L1 and activating NF-κB pathway

Background: Dezocine is an opioid analgesic that can affect the immune system. Here, we explored the synergy of high concentration of Dezocine and Programmed death-ligand 1 (PD-L1) with regards to immune escape and glucose metabolism in lung cancer (LC). Methods: PD-L1 level in human LC cell lines was determined and the influence of Dezocine at different concentrations for the proliferation of LC cells was identified. Next, LC cells were transfected to alter PD-L1 level, and exposed to Dezocine at 8 μg/mL to explore their effects on cell proliferation, production of interferon-γ (IFN-γ), contents of glucose, lactate and NADPH/NADP+ and activation of the nuclear factor-κB (NF-κB) pathway. Results: PD-L1 level was increased in LC cells and Dezocine (8 μg/mL) impaired the proliferation of LC cells. Down-regulating PD-L1 inhibited cell proliferation, enhanced production of IFN-γ and reduced the contents of glucose, lactate and NADPH/NADP+ while up-regulating PD-L1 caused the opposite results. Dezocine (8 μg/mL) induced immune escape and glucose metabolism in LC, and Dezocine-induced effects were reversed by down-regulating PD-L1. Dezocine (8 μg/mL) up-regulated PD-L1 by activating the NF-κB pathway. Conclusion: Dezocine at 8 μg/mL promotes immune escape and glucose metabolism in LC through up-regulating PD-L1 and activating the NF-κB pathway.

Morphometric characteristics of the mucous membrane and the cartilaginous component of the larynx are normal at different times during the experimental opioid effect and during withdrawal

Background. The problem of uncontrolled use of opioid drugs is extremely relevant based on the data of domestic and world statistics which are covered in the scientific literature. That is why the study of indicators of morphometric characteristics of the laryngeal mucosa under opioid exposure under experimental opioid exposure will be of interest to both morphologists and practical otorhinolaryngologists. Objective: To study the morphometric parameters of the laryngeal mucosa in normal at different times of the experimental opioid effect and its cancellation. Methods. The material of the study were sexually mature, outbred rats - males in the amount of 61 animals, weighing 80 - 135 g, aged 4.5 - 7.5 months. Histological specimens were prepared according to conventional methods. All morphometric studies were performed using primary (unedited) photographs taken on a Meiji MT4300 LE microscope, Canon EOS 550D x100 lens. All statistical calculations were performed using RStudio v. 1.2.5042. Results. Throughout the experiment, the change of morphometric parameters of the laryngeal mucosa with signs of wavy growth and decline was clearly observed at all times. More positive was the dynamics of morphometric parameters after the abolition of the opioid analgesic, which hypothetically suggests the process of recovery of the mucosa, even after prolonged administration of the opioid.

Opioid Analgesic Prescription in French Children: A National Population-Based Study

Codeine use was restricted in 2013 and is currently contraindicated for children below the age of 12 years. We examined how the prescription of opioid analgesics in children in France evolved between 2012 and 2018. Our population-based study from the SNIIRAM database (National System of Health Insurance Inter-Regime Information) was designed to determine trends in opioid prescription from 2012 to 2018 in all French children. The number of children who received at least one opioid prescription gradually declined from 452,665 in 2012 (347.5 children per 10,000) to 169,338 in 2018 (130.3 children per 10,000). This decrease was especially marked for codeine (36 children per 10,000 in 2018 vs. 308.5 children per 10,000 in 2012), whereas the number of tramadol prescriptions increased by 171% in 2018 (94.6 children per 10,000). Despite the increase, strong opioids still formed only a small proportion of prescriptions (2.6 children per 10,000 given opioids in 2018). Overall opioid prescriptions in French children dramatically decreased between 2012 and 2018, probably owing to restrictions on the use of codeine. Codeine has been partly replaced by tramadol. Morphine is still probably underused. This suggests that opioids are being used less often for pain management in children.

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats

A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t, and AUC0–∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0–t of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0–t, and AUC0–∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.

Mixture toxicity of six pharmaceuticals towards Aliivibrio fischeri, Daphnia magna, and Lemna minor

As the knowledge on the joint effects of pharmaceuticals towards different non-target organisms is still limited, the aim of our study was to evaluate the toxicity of mixtures of pharmaceuticals, as well as their baseline toxicity towards three selected organisms, namely the bioluminescent bacteria Aliivibrio fischeri, the crustacean Daphnia magna, and the duckweed Lemna minor. Different mixtures composed of three up to five pharmaceuticals having the same or different mechanisms of action in terms of their therapeutic activity (non-steroidal anti-inflammatory drugs, opioid analgesic, antibacterial and anti-epileptic drugs) were investigated. The observed EC50s were compared with those predicted using the concentration addition (CA) and independent action (IA) models. In general, the EC50 values for mixtures predicted with the CA model were lower than those obtained with the IA model, although, in some cases, test predictions of these two models were almost identical. Most of the experimentally determined EC50 values for the specific mixtures were slightly higher than those predicted with the CA model; hence, a less than additive effect was noted. Based on the obtained results, it might be concluded that the CA model assumes the worst-case scenario and gives overall closer predictions; therefore, it should be recommended also for modeling the mixture toxicity of pharmaceuticals with different modes of action.

The Opioid Analgesic Reduction Study (OARS): A Comparison of Opioid vs. Non-Opioid Combination Analgesics for Management of Post-Surgical Pain Study Protocol for a Double-Blind Randomized Multi-Center Clinical Trial

Background: Everyday people die unnecessarily from opioid overdose-related addiction. Dentists are among the leading prescribers of opioid analgesics. Opioid seeking behaviors have been linked to receipt of initial opioid prescriptions following the common dental procedure of third molar extraction. With each opioid prescription a patient’s risk for opioid misuse or abuse increases. With an estimated 56 million tablets of 5 mg hydrocodone annually prescribed after third molar extractions in the United States, 3.5 million young adults may be unnecessarily exposed to opioids by dentists who are inadvertently increasing their patient’s risk for addiction.Methods: A double blind, stratified randomized, multi-center clinical trial has been designed to evaluate whether a combination of over-the-counter non-opioid containing analgesics is not inferior to the most prescribed opioid analgesic. The impacted 3rd molar extraction model is being used due to the predictable severity of the post-operative pain and generalizability of results. Within each site/clinic and gender type (male/female), patients are randomized to receive either OPIOID (hydrocodone/acetaminophen 5/300 mg) or NON-OPIOID (ibuprofen/acetaminophen 400/500 mg). Outcome data include pain levels, adverse events, overall patient satisfaction, ability to sleep, and ability to perform daily functions. To develop clinical guidelines and a clinical decision making tool, pain management, extraction difficulty and number of tablets taken is being collected enabling an experimental decision making tool to be developed. Discussion: The proposed methods address the short comings of other analgesic studies. Although prior studies have tested short-term effects of single doses of pain medications, patients and their dentists are interested in managing pain for the entire post-operative period, not just the first 12 hours. After surgery, patients expect to be able to perform normal daily functions without feeling nauseous or dizzy and they desire a restful sleep at night. Parents of young people are concerned with the risks of opioid use and misuse, either related to treatments received or to subsequent use of leftover pills. Upon successful completion of this clinical trial, dentists, patients, and their families will be better able to make informed decisions regarding post-operative pain management.Trial registration: ClinicalTrials.gov NCT04452344. Registered on June 20, 2020

Tackling the opioid crisis - development of kappa-opioid receptor peptide agonists for safer analgesic therapy

The kappa opioid receptor (KOPr) has exceptional potential as an analgesic target, seemingly devoid of the many peripheral side-effects of Mu receptors. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side effects have the limited their clinical translation. Here, we modify an active endogenous Dynorphin peptide with the aim of improving drug-likeness and developing safer KOPr agonists for clinical use. Using rational, iterative design and modern peptide chemistry, we developed a series of potent, selective and metabolically stable peptides from Dynorphin 1-7. Peptides were assessed for cAMP-modulation against Kappa, Mu and Delta opioid receptors, metabolic stability, KOPr specificity and binding, and interrogated for in vitro desensitisation and pERK signalling capability. Finally, lead peptides were evaluated for efficacy in Freund’s complete adjuvant rat model of inflammatory nociception. A library of 70 peptides was synthesised and assessed for pharmacological and metabolic stability factors. At least 10 peptide candidates showed low nanomolar activity (˂50 nM) in a cAMP assay, specificity for KORr, and plasma half-life >60 min, with 6 candidates also stable in trypsin. None of the selected peptides showed pERK activity, with a bias towards cAMP signalling. In vivo, KA305 and KA311 showed anti-nociception opioid receptor-specific activity comparable to morphine and U50 844. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are biased peptide KOPr agonists, it is plausible they lack many of the most significant side effects, such as tolerance, addiction, sedation and euphoria/dysphoria, common to opioid analgesics.