Effects Of Opioid Exposure Research Articles

In utero effects of opioids on fetal growth

Background Studies indicate antenatal opioid use is associated with birth size deficits, as evidenced by reductions in birth weight and head circumference. However, there remains a limited understanding of how early this growth restriction occurs, and what specific parameters are affected. This novel study evaluated global and specific growth deficits associated with prenatal opioid exposure between 18–22 weeks’ gestation as assessed during anatomy ultrasounds. Methods Pregnant women who completed an anatomy ultrasound were identified via electronic medical records from a large academic obstetric practice. The study group used opioids, with tobacco and/or marijuana use permitted (n = 41). The control group could have used tobacco and/or marijuana, but not opioids (n = 308). Neither group had alcohol or other drug exposure. Records were reviewed for medical history and ultrasound size parameters, coded as percentiles for gestational age. Results Demographics and medical histories were compared with several significant differences noted. After controlling for these differences, significant (p < 0.05) growth deficits were identified in opioid-exposed fetuses. Specifically, reductions >10 percentile points were observed in head circumference, biparietal diameter, and humerus length for opioid-exposed fetuses compared to controls. Additionally, intrauterine growth restriction (IUGR) was diagnosed five times more often. Femur length was significantly reduced in opioid-exposed fetuses prior to adjustment for confounding (p = .016), but this reduction was not significant (p = .072) after controlling for background differences. Estimated fetal weight (p = .274) and abdominal circumference (p = .633) were not significantly different between exposure groups. Conclusion Fetal opioid exposure predicted various bone growth deficits during routine anatomy ultrasound, indicating the effects of opioid exposure on size deficits may be evident as early as 18–22 weeks’ gestation. These findings may also suggest that in utero opioid exposure negatively impacts bone growth specifically rather than weight or fat/muscle mass. Additional studies with larger sample sizes may also reveal significantly reduced femur length, further supporting a negative impact on bone growth. Future studies evaluating bone health and immune function in children after antenatal opioid exposure may help clarify this specific effect of opioids on bone development.

A Systematic Review of Opioid Use and Multimodal Strategies in Solid Organ Transplant Recipients and Living Donors.

The opioid epidemic has impacted analgesia in the post-operative period for solid organ transplant (SOT) donors and recipients. However, optimal pain management and opioid stewardship strategies have not been identified across this unique population. the purpose of this systematic review is to evaluate the impact of perioperative opioid use and to describe multimodal analgesic strategies to reduce opiate use in SOT recipients and living donors. A systematic review was conducted. Electronic searches were performed in Medline, Embase, Google Scholar, and Web of Science through December 31, 2021. Title and abstracts were screened. Relevant articles underwent full text review. Literature was separated into effects of opioid exposure on post-transplant outcomes, recipient pain management strategies, and living donor pain management strategies. Search yielded 25,190 records, and 63 were ultimately included. The impact of opioid use on post-transplant outcomes were assessed in 19 publications. The risk of graft loss in pre-transplant opioid users was assessed in six reports and was found to be higher in the majority (66%) of publications. Opioid minimization strategies were reported in 20 studies in transplant recipients. Twenty-four studies evaluated pain management strategies in living donors. Both populations used a combination of multimodal strategies to minimize opioid use throughout the hospitalization and on discharge. 1.1.1. OPIOIDS ARE ASSOCIATED WITH SELECT NEGATIVE OUTCOMES IN POST-TRANSPLANT RECIPIENTS. TO MINIMIZE THEIR USE WHILE ALSO MAINTAINING APPROPRIATE ANALGESIA, MULTIMODAL PAIN REGIMENS SHOULD BE CONSIDERED IN SOT RECIPIENTS AND DONORS.

Reciprocity between IL-4 and opioid immune regulation: IL-4 primes human CD4+ T cells for opioid receptor driven MAP kinase signaling

Abstract Opioid receptor (OR) signaling induces transcriptomic and functional changes in human T cell responses at both a molecular and cellular level, yet the signaling pathways initiated by OR engagement in human T cells are poorly characterized. ORs are G-protein coupled receptors with three subtypes: MuOR, KappaOR, and DeltaOR. Using the human lymphoma Jurkat T cell line and negatively selected human peripheral blood CD4 +T cells, the effects of opioid exposure on the activation kinetics of the MAP kinases ERK 1/2, JNK, and p38, scored as their level of phosphorylation, was followed by immunoblot. Opioid-driven phosphorylation of the MAPKs was dependent on IL-4 pretreatment of Jurkat cells, but not blood-derived CD4+ T cells. After Jurkat cells were primed with a 3-day exposure to IL-4, a series of opioid agonists selective for each OR subtype induced the phosphorylation of all three MAPKs (ERK, JNK, p38) within 2 min. Phosphorylation of the MAPKs was independent of OR subtype and opioid agonist. Notably, the kinetics were different than that observed in neurons. When primary human CD4 +T cells were treated with opioids, only p38 MAPK, not ERK or JNK, was activated with similar kinetics and OR subtype independence as that seen in Jurkat cells. This difference between primary cells and Jurkat cells suggests an additional level of regulation of opioid signaling in primary cells not found in Jurkat cells. The requirement for IL-4 pretreatment suggests that opioids may play a role in Th2 biology. Preliminary data indicate that morphine modestly increases the expression of IL-4 mRNA. Overall, these results reveal that p38 functions as a primary effector of opioid receptor signal transduction in human T cells. Supported by grants from NIH / NIDA (R01 DA 043253, )

Co-occurrence of preconception maternal childhood adversity and opioid use during pregnancy: Implications for offspring brain development

Understanding of the effects of in utero opioid exposure on neurodevelopment is a priority given the recent dramatic increase in opioid use among pregnant individuals. However, opioid abuse does not occur in isolation—pregnant individuals abusing opioids often have a significant history of adverse experiences in childhood, among other co-occurring factors. Understanding the specific pathways in which these frequently co-occurring factors may interact and cumulatively influence offspring brain development in utero represents a priority for future research in this area. We highlight maternal history of childhood adversity (CA) as one such co-occurring factor that is more prevalent among individuals using opioids during pregnancy and which is increasingly shown to affect offspring neurodevelopment through mechanisms beginning in utero. Despite the high incidence of CA history in pregnant individuals using opioids, we understand very little about the effects of comorbid prenatal opioid exposure and maternal CA history on fetal brain development. Here, we first provide an overview of current knowledge regarding effects of opioid exposure and maternal CA on offspring neurodevelopment that may occur during gestation. We then outline potential mechanistic pathways through which these factors might have interactive and cumulative influences on offspring neurodevelopment as a foundation for future research in this area.

Epigenetic Alterations in Prescription Opioid Misuse: New Strategies for Precision Pain Management.

Prescription opioids are used for some chronic pain conditions. However, generally, long-term therapy has unwanted side effects which may trigger addiction, overdose, and eventually cause deaths. Opioid addiction and chronic pain conditions have both been associated with evidence of genetic and epigenetic alterations. Despite intense research interest, many questions about the contribution of epigenetic changes to this typology of addiction vulnerability and development remain unanswered. The aim of this review was to summarize the epigenetic modifications detected in specific tissues or brain areas and associated with opioid prescription and misuse in patients who have initiated prescribed opioid management for chronic non-cancer pain. The review considers the effects of opioid exposure on the epigenome in central and peripheral tissues in animal models and human subjects and highlights the mechanisms in which opioid epigenetics may be involved. This will improve our current understanding, provide the basis for targeted, personalized pain management, and thus balance opioid risks and benefits in managing chronic pain.

Effect of Opioid Exposure on Efficacy and Tolerability of Sublingual Fentanyl and Subcutaneous Morphine for Severe Cancer Pain Episodes. Secondary Analysis From a Double-Blind Double-Dummy, Randomized Trial

ContextFew studies have addressed the impact of previous opioid exposure on the effect of opioids for the treatment of severe cancer pain episodes. ObjectivesWe aimed to test whether previous exposure to higher opioid doses was associated with a reduced analgesic effect of fentanyl sublingual tablets (FST) and subcutaneous morphine (SCM) and whether it had an influence on their relative effect. MethodsThis is a secondary analysis of a placebo-controlled randomized trial comparing 100 μg FST with 5 mg SCM for the acute treatment of severe cancer pain episodes. The effect of previous opioid exposure (oral morphine equivalent daily dose from 20 to 120 mg) on pain intensity difference (PID) and side effects at 30 and 60 minutes after administration (PID 0–30 minutes, PID 0–60 minutes, and adverse events 30–60 minutes) and on re-medication for inefficacy, was studied by multivariable linear and logistic regression models and statistical tests for interaction. ResultsA total of 114 patients were enrolled. Results indicate modest and nonstatistically significant effect of previous opioid exposure on all the outcomes examined (P = 0.11, P = 0.35, P = 0.07, and P = 0.52, respectively, for PID 0–30 minutes, re-medication, PID 0–60 minutes, and adverse events 30–60 minutes). Nonstatistically significant tests for interaction for all models indicated a lack of impact of previous opioid exposure on the difference in the analgesic effect between treatments. ConclusionIn this study, we could not demonstrate an effect of previous opioid exposure, from 20 to 120 mg oral morphine equivalent daily dose, on the absolute and relative efficacy and tolerability of 100 μg FST and 5 mg SCM for severe cancer pain episodes.

342: The effect of opioid exposure in utero on neonatal body composition

Opioid use in pregnancy has been associated with low birth weight as well as reduced head circumference. Whether these differences are due to changes neonatal body composition (i.e. lean mass and fat mass) has not been established. The goal of this study is to investigate the differences in body composition among neonates exposed to opioids in utero, compared with those who are not exposed. This is a retrospective cohort study of singleton pregnancies delivered at term. Subjects with opioid exposure during pregnancy were identified and subjects without opioid exposure were used for comparison. Exposed subjects were matched 1:2 with unexposed subjects for variables known to affect neonatal body composition; this included gestational age at delivery (±7 days), neonatal sex, smoking, and maternal race. Neonatal anthropometric measurements and skin fold data were used to determine neonatal percent body fat. Anthropometric data was expressed as mean ± SD and analyzed by Mann-Whitney U test. Demographic data was compared using Student’s t test and chi-squared analysis where appropriate. All statistical analysis performed using R statistical software. P <0.05 was considered significant. 24 neonates exposed to opioids in utero were identified and matched with 48 unexposed neonates. The groups were similar in terms of maternal age, race, neonatal sex, and gestational age at delivery. The exposed versus unexposed subjects differed in maternal BMI at delivery (28.4 vs 35.3, p = 0.001), gestational weight gain (14.3 lb vs 28.6 lb, p = <0.05), nulliparity (17% vs 48%, p = 0.02) and smoking status (66% vs 33%, p = 0.02). The analysis of our results did not demonstrate a statistically significant difference in birth weight, skin fold measurement, fat mass, lean mass, or percent body fat between the two groups. However, we found birth length and head circumference to be significantly different (p = 0.03 for both, Table 1). In this cohort, opioid exposure in utero was not associated with changes in neonatal body composition. However, we identified statically significant decreases in birth length and head circumference when compared with unexposed neonates. This work suggests that opioid exposure does not affect neonatal body composition but may impact other neonatal anthropometric measures.

Delayed villous maturation in term placentas exposed to opioid maintenance therapy: a retrospective cohort study

Opioid use disorder among pregnant women is associated with adverse perinatal outcomes and is increasing in the United States. The standard of care for pregnant women with opioid use disorder is opioid maintenance therapy including either methadone or buprenorphine, which can be initiated at any time during pregnancy. These medications are known to cross the placenta but their placental and fetal effects have not been well characterized. Delayed villous maturation, a placental finding associated with stillbirth, was observed in placentas exposed to opioid maintenance therapy. Given the association of delayed villous maturation with stillbirth, and the possible relationship between opioid maintenance therapy and delayed villous maturation, this study was undertaken to explore the association between opioid maintenance therapy and this placental finding. Delayed villous maturation was not previously reported in placentas exposed to opioids or opioid maintenance therapy. This study sought to compare risk of delayed villous maturation in term placentas exposed and unexposed to opioid maintenance therapy with buprenorphine or methadone. This was a retrospective cohort study conducted between 2010 through 2012 at Magee-Womens Hospital comparing delayed villous maturation in placentas of women with opioid use disorder exposed to either buprenorphine (n= 86) or methadone (n= 268) versus women without opioid use disorder (n= 978). Potential covariates were assessed in univariate analyses with none significantly associated with delayed villous maturation. The final model used conditional logistic regression adjusting for smoking status alone. Among women without opioid use disorder (and therefore not exposed to opioid maintenance therapy), delayed villous maturation was identified in 5.7% of placentas while the prevalence among women treated with buprenorphine or methadone was 8.1% and 10.8%. Overall, the crude odds of being diagnosed with delayed villous maturation were significantly greater in those exposed to opioid maintenance therapy compared to those not exposed (odds ratio, 1.86; 95% confidence interval, 1.20-2.89). When considered separately, women treated with methadone had significantly greater odds of having a placenta with delayed villous maturation than women without exposure to opioid maintenance therapy (odds ratio, 2.00; 95% confidence interval, 1.52-3.20). Women treated with buprenorphine did not have significantly greater odds of this placental diagnosis when compared to the women unexposed to opioid maintenance therapy (odds ratio, 1.46; 95% confidence interval, 0.64-3.31). Results were similar after accounting for smoking. Delayed villous maturation was more common in the placentas of women exposed to opioid maintenance therapy. Further studies are required to characterize rates and extent of delayed villous maturation in the general population as well as to differentiate between possible effects of opioid exposure (eg, heroin, illicit use of prescription opioids) vs those of opioid maintenance therapy (buprenorphine and methadone).

Impact of opioid use on survival in patients with newly diagnosed stage IV non-hematologic malignancies.

188 Background: Pain is a challenging problem in patients with advanced cancers. Opioids are commonly required to treat cancer-related pain, but may be associated with tumor progression and shorter survival. We recently reported that high opioid use during the first 90 days after diagnosis is associated with shorter survival in patients with advanced lung cancer. Methods: We identified 1386 newly diagnosed stage IV non-hematologic malignancies from 2005-2013 and gathered pain and opioid utilization within 90 days of treatment using data from electronic medical records and the tumor registry. Opioid utilization was stratified into low opioid exposure (LOE; no opioid prescriptions or one prescription for a short-acting opioid) and high opioid exposure (HOE; any long-acting opioid prescription or 2 or more short-acting opioid prescriptions). Pain was analyzed by the proportion of time patients reported levels of moderate-severe pain (i.e., pain level ≥ 4). The effects of opioid exposure, prognosis of tumor type ( &lt; 1 year vs ≥ 1 year), and gender on overall survival were analyzed in univariable and multivariable models. Results: Patients in the HOE (n = 887) and LOE (n = 499) groups were well matched for age, gender, and tumor type. Moderate-severe pain was higher in the HOE group compared to the LOE group (29.3% vs 14.0%). HOE was associated with shorter median survival compared to LOE (7.2 vs 13.2 months, p-value &lt; 0.0001). On multivariable analysis, HOE was associated with shorter overall survival after adjusting for age, gender and tumor prognosis (HR 1.4, 95% CI 1.2- 1.6) (Table). Conclusions: Results support prior studies of advanced prostate and lung cancers, and show early utilization of opioids is a strong prognostic factor for survival. Further prospective investigation on the role of opioid receptors and opioid utilization is urgently needed. [Table: see text]

Effect of opioids on CXCL-8 production in healthy cats

The aim of this study was to evaluate the effect of opioid exposure on CXC chemokine ligand (CXCL)-8 production in cats using whole blood culture. Morphine, buprenorphine, fentanyl, and saline control were administered intravenously to five cats and whole blood pathogen associated molecular pattern motif-induced CXCL-8 production capacity was evaluated. Morphine potentiated CXCL-8 production. To further characterize this effect of morphine, morphine was incubated with whole blood ex vivo and pathogen associated molecular pattern motif-induced CXCL-8 production capacity was measured. There was a time and concentration dependent effect on CXCL-8 production, suggesting the proinflammatory effect of morphine is at least partially mediated by direct stimulatory effects on leukocytes. Additional investigation is indicated to assess the implications of the immunomodulatory actions of opioids in cats.