Impact Of Opioids Research Articles

Abstract B042: The impact of opioids on the pancreatic tumor immune microenvironment

Abstract Pancreatic cancer is a highly lethal malignancy with a 5-year survival rate of 12.8%. Due to the high prevalence of cancer-related pain, 75% of pancreatic cancer patients are prescribed opioids. Opioids, which signal through the G protein-coupled receptor (GPCR) mu-opioid receptor (MOR), have peripheral effects outside of their analgesic function. Importantly, several studies have correlated opioids with worsened survival of patients receiving immunotherapy. However, the mechanism behind this is unknown. Immunotherapy is largely ineffective in pancreatic cancer, due in part to the tumor microenvironment (TME) characterized by dense, desmoplastic stroma, with cancer-associated fibroblasts (CAFs) comprising up to 90% of the tumor volume. CAFs play a large role in immunosuppression and therapy resistance, such as through promoting infiltration of immunosuppressive cells, resulting in reduced presence of antitumor immune cells and impaired immunotherapy efficacy. While the role of CAFs in promoting immunosuppression in the tumor microenvironment is well characterized, the effect of opioids on this phenomenon is unknown. We now provide evidence that MOR directly regulates CAF function. Specifically, knockdown of MOR in CAFs reduces gene expression of alpha-smooth muscle actin (aSMA) and leukemia inhibitory factor. MOR knockdown in CAFs also decreases protein expression of aSMA and type 1a collagen. We hypothesize that opioids promote MOR-dependent CAF activation and secretion of pro-inflammatory cytokines, resulting in a more immunosuppressive TME, and thus impaired immunotherapy response. The long-term goal of this work is to determine the role of opioids on CAFs in the pancreatic TME, as well as the role of MOR in promoting immunosuppression and the resulting value of MOR as a target to improve immunotherapy efficacy. This research is clinically significant because it could uncover a novel mechanism driving immunosuppression caused by a medication commonly prescribed to almost all pancreatic cancer patients. Citation Format: Kathryn Maraszek, Michael Feigin. The impact of opioids on the pancreatic tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B042.

The impact of opioids on the hallmarks of ageing

Opioids rank among the most hazardous substances of abuse, leading to opioid use disorders (which greatly diminish life quality) and contributing to the highest drug-related mortality rates. Nonetheless, both the therapeutic and recreational use of opioids is escalating globally. Interestingly, chronic opioid users often exhibit signs consistent with accelerated ageing, suggesting that they likely interfere with well-characterized ageing mechanisms (e.g., telomere shortening, epigenetic changes, mitochondrial dysfunction, cellular senescence). Here, we review the most recent advances regarding the impact of opioids on well-characterized hallmarks of ageing, to ascertain a potential association between opioid use and accelerated ageing. Our findings indicate that there is accumulating evidence supporting a close association between the use of opioids and the early onset of some ageing hallmarks, namely mitochondrial dysfunction, genomic instability, or telomere shortening. However, there is still limited data available regarding how opioids specifically impact other ageing hallmarks, like nutrient sensing, cellular senescence, or loss of proteostasis. Taking into consideration the high prevalence of opioid use, strengthening the understanding of the mechanisms underlying opioids’ impact on ageing assumes utmost relevance, both in terms of improving risk assessment, as well as to help researchers and clinicians prevent or mitigate these effects in clinical settings.

Opioid-induced adrenal insufficiency: diagnostic and management considerations.

The dramatic rise in opioid use over the last two decades has led to a surge in their harmful health effects. Lesser known among clinicians is the impact of opioids on the endocrine system, especially with regard to cortisol. Opioids can suppress the hypothalamus-pituitary-adrenal (HPA) axis and may result in clinically significant adrenal insufficiency, especially in those treated at higher doses and for a longer time. A high clinical suspicion is necessary in this population for early diagnosis of opioid-induced adrenal insufficiency (OAI). Diagnosis of OAI is challenging, as the symptoms are often vague and overlap with those due to opioid use or the underlying pain disorder. Traditional assays to diagnose adrenal insufficiency have not been widely studied in this population, and more investigation is needed to determine how opioids might affect assay results. Once a diagnosis of adrenal insufficiency has been made, glucocorticoid replacement in the form of hydrocortisone is likely the mainstay of treatment, and effort should be made to taper down opioids where possible. Cortisol levels should be retested periodically, with the goal of stopping glucocorticoid replacement once the HPA axis has recovered. In this review, we provide context for diagnostic challenges in OAI, suggest diagnostic tools for this population based on available data, and offer recommendations for the management of this disorder. There is a paucity of literature in this field; given the widespread use of opioids in the general population, more investigation into the effects of opioids on the HPA axis is sorely needed.

The impact of opioids on the transcriptional landscape of human villous trophoblasts

IntroductionOpioid use disorder (OUD) is implicated in major obstetrical diseases such as fetal growth restriction. Whether or not opioids directly impact placental trophoblast development and function remains unclear. We sought to examine the expression of opioid receptors (OPRs) in villous trophoblasts and the effect of opioids on placental transcriptomics. MethodsTrophoblast stem (TS) cells and primary human trophoblast (PHT) cells from healthy term placentas were used to assess OPR expression in conditions that enhance trophoblast stemness vs differentiation. Placental RNAseq was conducted using our retrospective cohorts of pregnant people with OUD vs controls, both without major obstetrical complications. RT-qPCR was used to determine the effect of fentanyl on the expression of putative opioid targets and stemness or differentiation-associated genes in TS and PHT cells. ResultsThree main OPRs, including OPRM1, OPRD1, and OPRK1 were expressed in term PHT cells cultured in the stemness medium, whereas only OPRD1 and OPRK1 were expressed in TS cells. Interestingly, upon induction of differentiation, the expressed OPR mRNAs in TS or in PHT cells were downregulated. We found 286 differentially expressed long RNAs in placentas from the OUD participants vs controls. While three putative opioid targets differed their expression in stemness vs differentiation states of trophoblasts, fentanyl had no effect on their expression or the expression of major stemness or differentiation-relevant genes in TS and PHT cells. DiscussionTrophoblastic expression of OPRs and opioid RNA targets is impacted by cell differentiation, suggesting differential susceptibility of villous trophoblasts to the effect of opioids.

Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs.

People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic.

Investigation of the Effects of Opioids on Microglial Nitrite and Nitric Oxide Synthase (iNOS) Production and Phagocytosis during Inflammation.

This study aimed to investigate how opioids affect phagocytosis and microglial nitrite and nitric oxide synthase (iNOS) production during inflammation. Opioids are a group of chemicals that are naturally found in the opium poppy plant and exert a variety of effects on the brain, including pain alleviation in some cases. They are commonly used in surgery and perioperative analgesia. However, research on the impact of opioids on microglial inflammatory factor production and phagocytosis is limited. This study was designed to investigate the effects of opioids on inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) generation. Moreover, the influence of opioids on the engulfment of C8-B4 microglial cells after stimulation with LPS was also examined. C8-B4 mouse microglial cells were exposed to various concentrations of opioids after stimulation with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Nitrite production was assayed. The iNOS and Cox-2 were determined by Western blotting, and fluorescent immunostaining was performed to assess the percentage of microglia that engulfed fluorescent microspheres in total microglia cultivating with opioids after being activated by LPS. After LPS and IFN-γ stimulation, microglia produced lower amounts of nitric oxide (NO) production with buprenorphine, salvinorin A, and naloxone (P<0.05). When combined with naloxone, no significant differences were found than buprenorphine. It was observed that buprenorphine and salvinorin A could suppress iNOS expression activated by LPS and IFN-γ. Phagocytosis was greatly increased after LPS stimulation, and a significant increase was observed after adding salvinorin A. Buprenorphine and salvinorin A were found to reduce NO production and iNOS induction in microglial cells activated by LPS and IFN-γ. Salvinorin A promoted the phagocytosis of microglia cells treated by LPS.

Fracture risk and opioid use in patients aged 17-64 years: An analysis of administrative claims data.

The objective of this work is to describe the risk of fracture in adults aged 17 to 64 years across categories of daily opioid dose. A retrospective analysis of insurance claims data. Information from a private health insurance provider for the years 2003-2014 for enrolled individuals living in Iowa. Patients who were aged 17 to 64 years and prescribed an opioid were followed for the length of opioid treatment plus 30 days to determine whether a fracture occurred. Average daily morphine milligram equivalent (MME) was determined for patients who received a prescription for opioids. The outcome of interest was incident fracture following opioid treatment initiation. Cox proportional hazard models were used to compare the risk of fracture across categorical groups of average daily MME. Inverse probability weighting was used to control for patient-level variables. In total, 316,024 individual patients were identified in the administrative claims data as having an opioid prescription from 2003 to 2014, and 3038 fractures occurred during follow-up (9.6 fractures per 1000 opioid-prescribed patients). Relative to the lowest quartile of prescribed opioid (⟨22 MME), patients in each higher prescribed level were more likely to experience a fracture (22-36 MME Hazard Ratio (HR) = 1.35, 95% Confidence Interval (CI): 1.21-1.51; 37-50 MME HR = 1.38, 95% CI: 1.24-1.54; ⟩50 MME HR = 1.35, 95% CI: 1.20-1.52). We observed an increased fracture risk in all three higher categories of opioid exposure relative to the lowest category (⟨22 MME). The risk of a fracture should be considered in opioid treatment decisions.

Chronic opioid use is associated with higher flu vaccine induced Ab response in HIV+ and HIV− individuals.

Abstract Opioid dependence is frequent in people with HIV (PWH), but impact of opioids on immune system of PWH is unknown. This study tested the hypothesis that chronic opioid use exacerbates known impairment of flu vaccine responses in PWH. Chronic opioid users were compared to non-opioid users in HIV+ and HIV− groups termed HIV+OP+ (n=28), HIV-OP+ (n=55), HIV+OP− (n=53), HIV-OP− (controls, n=58). HIV+ individuals were on ART with plasma virus load &amp;lt;200 copies/mL. Flu antibody titers were determined at pre- (T0) and 4 weeks post (T2) seasonal quadrivalent influenza vaccinations (2020–2022) by hemagglutination inhibition (HAI) along with a plasma cytokine score at T0. Vaccine response (VR) was defined as a 4-fold change (FC) in titer from T0 to T2. In Kruskal Wallis analysis, all 4 groups had increases in HAI titer from T0 to T2 (p&amp;lt;0.01 to p&amp;lt;0.0001) for antigens (H1N1, H3N2, B Victoria) and whole vaccine. HIV+ status was associated with decreased responses to all antigens but OP+ status in HIV+ and HIV− had higher response than HIV+OP−, both in T2/T0 FC and T2 titer for one or more vaccine antigens (p&amp;lt;0.05 to p&amp;lt;0.001). In regression analysis controlling for demographics, opioid use was associated with increased response to H1N1 and B Yamagata antigens. In a random forest model, predicted probability of VR was lower for HIV+ status and higher for OP+ status. Cytokine score was highest in HIV+OP+. Results of quantitative Ab response to flu vaccine refute our hypothesis that flu vaccine response would be impaired in PWH who chronically use opioids. Qualitative assessments of Ab and mechanism of opioid intersection with B cell function are ongoing to understand if opioid use overcomes humoral immune deficits in PWH.

Impact of opioids on esophageal motility

Opioids are well known to cause adverse effects on the gastrointestinal tract including nausea, vomiting, and constipation. Data regarding how opioids affect the esophagus are more limited. Opioid-induced esophageal dysfunction (OIED) is a clinical syndrome defined by chronic opioid use (≥3 months), esophageal symptoms (mainly dysphagia), and esophageal motility abnormalities diagnosed by manometry including achalasia type III, hypercontractile esophagus, distal esophageal spasm, and esophagogastric junction outflow obstruction. Up until now, the effect of opioids on esophageal motility assessed by the functional lumen imaging probe (FLIP) had not been described. In this issue of NGM, Patel et al. report that FLIP assessment in patients with esophageal symptoms showed that chronic opioid users have a significant increase in repetitive retrograde contractions, but no significant reduction in distensibility at the esophagogastric junction compared to non-users. Additionally, perceptive symptoms were higher, and quality of life metrics were lower in the chronic opioid users. This review article will discuss our current understanding of OIED and provide context for this latest study in chronic opioid users. Further investigation with larger prospective studies is needed to understand the pathophysiology, diagnosis, and management of OIED.

Impact of opioids on treatment response among idiopathic esophagogastric junction outflow obstruction patients: A retrospective cohort study.

Esophageal dysmotility has been attributed to opioid use. The goal was to assess the differences in pre- and post-treatment timed-barium esophagram (TBE) barium heights at 1 and 5minutes and symptomatic response to treatment in esophagogastric junction outflow obstruction (EGJOO) patients according to opioid use status. We performed a retrospective cohort study. Consecutive patients with EGJOO were eligible for inclusion. Data were collected on demographics, pre and post-treatment 1 and 5 minutes TBE barium heights and symptom outcomes. Groups were compared according to opioid use. Thirty-one EGJOO patients met the inclusion criteria. All patients were treated with pneumatic dilation. Of the 31 patients, 11 (35%) had opioid exposure and 20 (65%) did not. The median follow-up post-treatment was twomonths (range 1-47months). There was no statistically significant difference in post-treatment outcomes for opioid exposed vs. unexposed groups. The median per cent decrease in the TBE barium height at 1minute was 100% for the opioid exposed vs. 71% for the unexposed group (p = 0.92). The median per cent decrease in the TBE barium height at 5minutes was zero % for the opioid exposed and unexposed groups (p = 0.67). The incidence of symptomatic improvement was 82% (9/11) for the opioid exposed group vs 95% (19/20) for the unexposed group (p = 0.28). Patients with EGJOO seem to respond to treatment similarly regardless of being on opioids.

Cannabis Use and Its Association With Thirty- and Ninety-Day Hospital Readmissions for Patients Admitted for an Inflammatory Bowel Disease Exacerbation.

Though viewed as a potentially safer palliative alternative to opioids, studies of cannabis use for inflammatory bowel disease (IBD) are limited. The impact of opioids on hospital readmissions for IBD has been extensively examined, but cannabis has not been similarly studied. Our goal was to examine the relationship between cannabis use and the risk of 30- and 90-day hospital readmissions. We conducted a review of all adults admitted for an IBD exacerbation from January 1, 2016 to March 1, 2020 within the Northwell Health Care system. Patients with an IBD exacerbation were identified by primary or secondary ICD10 code (K50.xx or K51.xx) and administration of intravenous (IV) solumedrol and/or biologic therapy. Admission documents were reviewed for the terms "marijuana", "cannabis", "pot" and "CBD". A total of 1,021 patient admissions met inclusion criteria, of whom 484 (47.40%) had Crohn's disease (CD) and 542 (53.09%) were female. Pre-admission cannabis use was reported by 74 (7.25%) patients. Factors found to be associated with cannabis use included younger age, male gender, African American/Black race, current tobacco and former alcohol use, anxiety, and depression. Cannabis use was found to be associated with 30-day readmission among patients with ulcerative colitis (UC), but not among patients with CD, after respectively adjusting each final model by other factors (odds ratio (OR): 2.48, 95% confidence interval (CI): 1.06 - 5.79 and OR: 0.59, 95% CI: 0.22 - 1.62, respectively). Cannabis use was not found to be associated with 90-day readmission on univariable analysis (OR: 1.11, 95% CI: 0.65 - 1.87) nor in the final multivariable model after adjusting for other factors (OR: 1.19, 95% CI: 0.68 - 2.05). Pre-admission cannabis use was found to be associated with 30-day readmission among patients with UC, but not with 30-day readmission for patients with CD nor with 90-day readmission, following an IBD exacerbation.

Impact of Opioids and Paracetamol after Liver Resection for Colorectal Cancer Metastasis

Impact of Opioids and Paracetamol after Liver Resection for Colorectal Cancer Metastasis

HIV-1 Tat reduces apical dendritic spine density throughout the trisynaptic pathway in the hippocampus of male transgenic mice

Nearly one-third of persons infected with HIV-1 (PWH) develop HIV-associated neurocognitive disorders (HAND), which can be exacerbated by exposure to opioids. The impact of opioids on HIV-induced alterations in neuronal plasticity is less well understood. Both morphine exposure and HIV have been shown to disrupt synaptic growth and stability in the hippocampus suggesting a potential site of convergence for their deleterious effects. In the present study, we examined the density of dendritic spines in CA1 and CA3 pyramidal neurons, and granule neurons within the dentate gyrus representing the hippocampal trisynaptic pathway after short-term exposure to the HIV transactivator of transcription (Tat) protein and morphine. We exposed inducible male, HIV-1 Tat transgenic mice to escalating doses of morphine (10–40 mg/kg, b.i.d.) and examined synaptodendritic structure in Golgi-impregnated hippocampal neurons. HIV-1 Tat, but not morphine, systematically reduced the density of apical, but not basilar, dendrites of CA1 and CA3 pyramidal neurons, and granule neuronal apical dendrites, suggesting the coordinated loss of specific synaptic interconnections throughout the hippocampal trisynaptic pathway.

The Impact of Pediatric Opioid-Related Visits on U.S. Emergency Departments.

Background: While there is significant research exploring adults’ use of opioids, there has been minimal focus on the opioid impact within emergency departments for the pediatric population. Methods: We examined data from the Agency for Healthcare Research, the National Emergency Department Sample (NEDS), and death data from the Centers for Disease Control and Prevention. Sociodemographic and financial variables were analyzed for encounters during 2014–2017 for patients under age 18, matching diagnoses codes for opioid-related overdose or opioid use disorder. Results: During this period, 59,658 children presented to an ED for any diagnoses involving opioids. The majority (68.5%) of visits were related to overdoses (poisoning), with a mean age of 11.3 years and a majority female (53%). There was a curvilinear relationship between age and encounters, with teens representing the majority of visits, followed by infants. The highest volume was seen in the Southern U.S., with over 58% more opioid visits than the next highest region (Midwest). Charges exceeded USD 157 million, representing 2% of total ED costs, with Medicaid responsible for 54% of the total. Conclusions: With increases in substance use among children, there is a growing need for pediatric emergency physicians to recognize, refer, and initiate treatments.

Preoperative Opioid Dose and Surgical Outcomes in Colorectal Surgery.

The worsening opioid epidemic has led to an increased number of surgical patients with chronic preoperative opioid use. However, the impact of opioids on perioperative outcomes has yet to be fully elucidated. The purpose of this study was to assess the association between preoperative opioid dose and surgical outcomes among colectomy patients. Adult colectomy patients in the IBM MarketScan database (2010-2017) were stratified based on preoperative opioid dose, calculated as the average opioid dose in morphine milligram equivalents (MME) in the 90 days prior to surgery: 0 MME, 1 to 49 MME, and 50 or more MME. The association between preoperative opioid dose and anastomotic leak, the primary outcome of interest, as well as other postoperative complications, was assessed using multivariable regression. Among 45,515 adult colectomy patients, 71.4% did not use opioids (0 MME), 27.4% had an opioid dose between 1 and 49 MME, and 1.2% had an opioid dose at or above 50 MME. Patients with preoperative opioid use exhibited a higher incidence of anastomotic leak (0 MME: 4.8%, 1-49 MME: 5.5%, ≥50 MME: 8.3%; p trend = 0.001). Multivariable analysis demonstrated a dose-response relationship between preoperative opioids and surgical outcomes, as the odds of anastomotic leak worsened with increasing opioid dose (1-49 MME: OR 1.19, 95% CI 1.08-1.31, p < 0.001; ≥50 MME: OR 1.64, 95% CI 1.20-2.24, p = 0.002). Similar dose-response relationships were seen after risk-adjustment for lung complications, pneumonia, delirium, and 30-day readmission (p < 0.05 for all). Providers should exercise caution when prescribing opioids preoperatively, as increasing doses of preoperative opioids were associated with worse surgical outcomes and higher 30-day readmission among adult colectomy patients.

The Impact of Opioids on the Labor Market

The Impact of Opioids on the Labor Market

Comparison of the Impacts of Under-Treated Pain and Opioid Pain Medication on Cognitive Impairment.

Purpose: To guide clinicians in balancing the risks and benefits of opioids when treating pain, we conducted two systematic reviews: 1) the impact of pain on cognitive function, and 2) the impact of opioids on cognitive function.Methods: Part one addressed the impact of pain on cognitive impairment; Part two considered the impact of opioids on cognitive impairment. PubMed was used to search for eligible articles. For part one, 1786 articles were identified, of which 23 met our eligibility criteria. For part two, among 584 articles, 18 were found eligible.Results: For part one, 16 studies concluded that patients with chronic pain showed impaired cognitive function; six studies found that chronic pain does not worsen cognitive function; one study concluded that the impact of pain on cognitive function differs based on the underlying cognitive status. For part two, 15 studies found that using opioids to control pain did not cause significant cognitive impairment, while three studies concluded the opposite. Studies evaluating older subjects did not observe different results from those in the whole population for both reviews.Conclusion: The published literature indicates that moderate to severe pain can impair cognitive function, and that careful use of opioid analgesics in such subjects does not necessarily worsen cognition. Although our results are insufficient to support clear guidance due to heterogeneity of cohorts and outcomes, this study may assist primary care providers by rendering explicitly the factors to be considered by providers caring for this population with pain when opioids are considered.

Editors' Note: Automated Quantitative Pupillometry in the Critically Ill: A Systematic Review of the Literature

In “Automated Quantitative Pupillometry in the Critically Ill: A Systematic Review of the Literature,” Opic et al. summarized 58 articles (10 randomized trials) published from 1990 to 2019 on the use of automated pupillometry in adult critically ill patients. They reported that increased intracranial pressure (ICP), traumatic brain injury (TBI), ischemic brain damage, opioids and hypoxemia, and hypercarbia are potential confounders for pupillometry. Taccone et al. commented that increased ICP, TBI, and hypoxic ischemic brain injury (HIBI) should not be considered confounders of pupillometry (circumstances in which the test may be unreliable) but rather injuries that can cause pupillary abnormalities and that altered pupillary responses in these settings could be indicative of poor prognosis. In response, Opic et al. reinforced that medications can confound the pupillary assessment in certain circumstances but did not address the distinction between whether increased ICP, TBI, and HIBI typically confound or cause pupillary abnormalities. Larson commented that although opioids cause pupillary constriction, they do not affect the strength of the pupillary light reflex (PLR). They also pointed out that the systematic review did not include an article by Rollins et al., which described the persistence of a robust quantifiable PLR in the setting of opioid-induced hypoxia and hypercarbia. Opic et al. noted that they eliminated some articles based on the exclusion criteria of studies that used nonhandheld devices, but it is worth noting that Rollins et al. did, in fact, use a handheld device (the Neuroptics ForSite).[1][1],[2][2] Opic et al. acknowledged that although the PLR involves both static and dynamic parameters, most of the studies they reviewed regarding the impact of opioids on pupillometry discussed their confounding impact on static parameters. Opic et al. and Larson reinforced that pupillometry always requires interpretation by a clinician based on an individual patient's circumstances. In “Automated Quantitative Pupillometry in the Critically Ill: A Systematic Review of the Literature,” Opic et al. summarized 58 articles (10 randomized trials) published from 1990 to 2019 on the use of automated pupillometry in adult critically ill patients. They reported that increased intracranial pressure (ICP), traumatic brain injury (TBI), ischemic brain damage, opioids and hypoxemia, and hypercarbia are potential confounders for pupillometry. Taccone et al. commented that increased ICP, TBI, and hypoxic ischemic brain injury (HIBI) should not be considered confounders of pupillometry (circumstances in which the test may be unreliable) but rather injuries that can cause pupillary abnormalities and that altered pupillary responses in these settings could be indicative of poor prognosis. In response, Opic et al. reinforced that medications can confound the pupillary assessment in certain circumstances but did not address the distinction between whether increased ICP, TBI, and HIBI typically confound or cause pupillary abnormalities. Larson commented that although opioids cause pupillary constriction, they do not affect the strength of the pupillary light reflex (PLR). They also pointed out that the systematic review did not include an article by Rollins et al., which described the persistence of a robust quantifiable PLR in the setting of opioid-induced hypoxia and hypercarbia. Opic et al. noted that they eliminated some articles based on the exclusion criteria of studies that used nonhandheld devices, but it is worth noting that Rollins et al. did, in fact, use a handheld device (the Neuroptics ForSite).1,2 Opic et al. acknowledged that although the PLR involves both static and dynamic parameters, most of the studies they reviewed regarding the impact of opioids on pupillometry discussed their confounding impact on static parameters. Opic et al. and Larson reinforced that pupillometry always requires interpretation by a clinician based on an individual patient's circumstances. [1]: #ref-1 [2]: #ref-2

Opioids and Breast Cancer Recurrence: A Systematic Review.

Simple SummaryOpioids are one of the therapeutic and palliative options for breast cancer, a tumor with a strong epidemiological impact. Studies have been extensively reported in the literature that show a connection between the administration of opioids and the recurrence of the disease, both during surgery and subsequently in the management of cancer pain. This argument, in consideration of the strong impact of this cancer, is of great interest. Therefore, we decided, through the study of the existing literature, to describe the state of the art on this topic, to outline the best therapeutic approach to be adopted in these delicate patients.Breast cancer has the greatest epidemiological impact in women. Opioids represent the most prescribed analgesics, both in surgical time and in immediate postoperative period, as well as in chronic pain management as palliative care. We made a systematic review analyzing the literature’s evidence about the safety of opioids in breast cancer treatment, focusing our attention on the link between opioid administration and increased relapses. The research has been conducted using the PubMed database. Preclinical studies, retrospective and prospective clinical studies, review articles and original articles were analyzed. In the literature, there are several preclinical in vitro and in vivo studies, suggesting a possible linkage between opioids administration and progression of cancer disease. Nevertheless, these results are not confirmed by clinical studies. The most recent evidence reassures the safety of opioids during surgical time as analgesic associated with anesthetics drugs, during postoperative period for optimal cancer-related pain management and in chronic use. Currently, there is controversial evidence suggesting a possible impact of opioids on breast cancer progression, but to date, it remains an unresolved issue. Although there is no conclusive evidence, we hope to arouse interest in the scientific community to always ensure the best standards of care for these patients.

The dynamics of morphological changes of structural components of the intervertebral disc at the end of the thirty-fifth and forty-second days while applying the experimental opioid impact

Background. According to the WHO, the diseases of the musculoskeletal system, which cause disability and mortality, rank fourth in the world following cardiovascular disease, cancer and diabetes. Due to the statistics, every fifth person suffers from back pain. Chronic diseases of musculoskeletal system are also one of the most urgent problems in Ukraine, and about 3.5 million people encountered the problem of musculoskeletal system. Objective. The aim of the study was to investigate the impact of opioids on changes of structural components of the intervertebral disc at the end of the fifth and sixth weeks of the experiment. Methods. The materials of the study were 32 sexually mature, outbred male rats, weighing from 125 to 135 g, aged 4.5 months. Animals were injected with nalbuphine intramuscularly daily in the same intervals (at 10-11 am) for 42 days. This aim was achieved by using microscopic techniques of visualization of cellular components of the rat’s intervertebral disc. Histological specimens were prepared according to the common methods using the dye hematoxylin, eosin, azan according to Heidenhain method, PAS reaction according to McManus and Alcian blue according to Steedman. Results. As a result of experimental opioid exposure for 35 and 42 days, we discovered that in 35 days the gelatinous nucleus was reduced and deformed. Notochondral cells were rare. Mostly cell-free zones with a somewhat compacted matrix were localized in the gelatinous nucleus. In 42 days, there were significant structural changes in the gelatinous nucleus, as well as in the structural elements of the fibrous ring and cartilaginous locking plates. The amount of notochondral cells was reduced. The cytoplasm of some notochondral cells was compacted. Conclusion. Pathomorphological changes in the structural components of the intervertebral disc while applying the experimental opioid effect at the end of the 35th and 42nd days will serve as a basis for further study and comparison of the manifestations of opioid chondropathy in the longer periods applying experimental opioid impact.