DNA methylation at the mu-1 opioid receptor gene (OPRM1) promoter predicts preoperative, acute, and chronic postsurgical pain after spine fusion.

INTRODUCTION:The perioperative pain experience shows great interindividual variability and is difficult to predict. The mu-1 opioid receptor gene (OPRM1) is known to play an important role in opioid-pain pathways. Since deoxyribonucleic acid (DNA) methylation is a potent repressor of gene expression, DNA methylation was evaluated at the OPRM1 promoter, as a predictor of preoperative, acute, and chronic postsurgical pain (CPSP). METHODS:A prospective observational cohort study was conducted in 133 adolescents with idiopathic scoliosis undergoing spine fusion under standard protocols. Data regarding pain, opioid consumption, anxiety, and catastrophizing (using validated questionnaires) were collected before and 2-3 months postsurgery. Outcomes evaluated were preoperative pain, acute postoperative pain (area under curve [AUC] for pain scores over 48 hours), and CPSP (numerical rating scale >3/10 at 2-3 months postsurgery). Blood samples collected preoperatively were analyzed for DNA methylation by pyrosequencing of 22 CpG sites at the OPRM1 gene promoter. The association of each pain outcome with the methylation percentage of each CpG site was assessed using multivariable regression, adjusting for significant (P<0.05) nongenetic variables. RESULTS:Majority (83%) of the patients reported no pain preoperatively, while CPSP occurred in 36% of the subjects (44/121). Regression on dichotomized preoperative pain outcome showed association with methylation at six CpG sites (1, 3, 4, 9, 11, and 17) (P<0.05). Methylation at CpG sites 4, 17, and 18 was associated with higher AUC after adjusting for opioid consumption and preoperative pain score (P<0.05). After adjusting for postoperative opioid consumption and preoperative pain score, methylation at CpG sites 13 and 22 was associated with CPSP (P<0.05). DISCUSSION:Novel CPSP biomarkers were identified in an active regulatory region of the OPRM1 gene that binds multiple transcription factors. Inhibition of binding by DNA methylation potentially decreases the OPRM1 gene expression, leading to a decreased response to endogenous and exogenous opioids, and an increased pain experience

Genetics of perioperative pain management

PURPOSE OF REVIEW: The current review will discuss the current literature on genetics of pain and analgesia, with special emphasis on perioperative setting. We will also discuss pharmacogenetics-based management guidelines, current clinical status and future perspectives. RECENT FINDINGS: Recent literature suggests that the interindividual variability in pain and postoperative analgesic response is at least in part because of one's genetic make-up. Some of the well characterized polymorphisms that are associated with surgical pain and opioid-related postoperative adverse outcomes are described in catechol-O-methyl transferase, CYP2D6 and μ-opioid receptor (OPRM1), ATP-binding cassette subfamily B member 1, ABCC3, organic cation transporter 1 genes. Clinical Pharmacogenetics Implementation Consortium has put forth recommendations on CYP2D6 genotype-based opioid selection and dosing. The list of drug-gene pairs studied continue to expand. SUMMARY: Pharmacogenetic approach marks the dawn of personalized pain medicine both in perioperative and chronic pain settings

Decreased brain volumes in infants with prenatal opioid exposure

Background/Objective: Previous small studies have shown that prenatal opioid-exposed (POE) infants and older children display decreased cerebral, cerebellar, or subcortical brain volumes. However, these studies are plagued by suboptimal reference standards or were unable to correct for the influence of other environmental factors in older children. Therefore, our goal was to study differences in brain volume of POE infants when compared to a geographically matched population. We hypothesized that there will be a significant decrease in total brain volume of the POE infants in comparison to the non-opioid exposed control infants, including a reduction in the cerebellar volume.    Methods: This was an IRB approved prospective study of mothers and infants with POE and controls without POE. All recruited infants underwent MRI scans of the brain before they reached a corrected age of 2 months. The T1-weighted MRI images were analyzed by Infant FreeSurfer and segmented into ROIs. The segmentations were manually checked and edited. An ANOVA analysis was performed to compare the cerebellar and total brain volume datasets. We corrected for gender, corrected gestational age at MRI scan, and total brain volume where necessary.     Results: 42 infants were included in the study, 21 with POE and 21 control infants. There was a significant difference in the mean gestational age of POE infants (38.28±2.13) compared to control infants (39.42±0.72). On quantitative analysis, the POE group had a significantly reduced total brain and supratentorial volume in comparison to the controls. The cerebellar volume was also significantly smaller in POE, but this significance did not persist when the total brain volume was included in the model.     Conclusion: The supratentorial region is affected disproportionately more than the cerebellum in POE. Specific reductions in cortical, subcortical, and white matter volume need to be further investigated and their influence on developmental outcomes need to be studied.&nbsp

Brain Resting State Functional Networks in Infants with Prenatal Opioid Exposure

Purpose: Infants of mothers with opioid and substance use can present with postnatal withdrawal symptoms and are at risk of poor neurodevelopmental outcomes in later childhood. Identifying methods to evaluate the consequences of substance exposure on the developing brain can help initiate proactive therapies to improve outcomes for opioid-exposed neonates. Additionally, early brain imaging in infancy has the potential to identify early brain developmental alterations that could prognosticate neurodevelopmental outcomes in these children. In this study, we aim to identify differences in global brain network connectivity in infants with prenatal opioid exposure compared to healthy control infants, using resting-state functional MRI performed at less than 2 months completed gestational age.   Materials and Methods: In this prospective, IRB-approved study, we recruited 20 infants with prenatal opioid exposure and 20 healthy, opioid naïve infants. Anatomic imaging and resting-state functional MRI were performed at less than 48 weeks corrected gestational age, and rs-fMRI images were co-registered to the UNC neonate brain template and 90 anatomic atlas-labelled regions. Covariate Assisted Principal (CAP) regression was performed to identify brain network functional connectivity that was significantly different among infants with prenatal opioid exposure compared to healthy neonates.   Results: Of the 5 significantly different CAP components identified, the most distinct component (CAP5, p= 3.86 x 10-6) spanned several brain regions, including the right inferior temporal gyrus, bilateral Hesch’s gyrus, left thalamus, left supramarginal gyrus, left inferior parietal lobule, left superior parietal gyrus, right anterior cingulate gyrus, right gyrus rectus, left supplementary motor area, and left pars triangularis. Functional connectivity in this network was lower in the infants with prenatal opioid exposure compared to non-opioid exposed infants.   Conclusion: This study demonstrates global network alterations in infants with prenatal opioid exposure compared to non-opioid exposed infants. Future studies should be aimed at identifying clinical significance of this altered connectivity

Resting State Functional MRI in Neonates with Prenatal Opioid Exposure: Analysis of Thalamocortical Functional Connectivity

Background/Objective: Prenatal opioid exposure (POE) is a growing public health issue that can result in premature birth, Neonatal Abstinence Syndrome (NAS), and adverse neurodevelopmental outcomes. However, the neural basis for these findings remains relatively unknown. In this study, we aimed to investigate the neural correlates of POE based on neonatal thalamocortical functional connectivity using resting state functional magnetic resonance imaging (rs-fMRI).     Methods: In this prospective, IRB-approved study, nineteen neonates with POE and twenty opioid naive (ON) controls underwent non-invasive MRI during natural sleep at mean post-menstrual age (PMA) of 44.7 ± 2.6 and 44.6 ± 2.6 weeks respectively. MR imaging included anatomic T2-weighted images and rs-fMRI. General Linear Model (GLM) seed-based whole brain functional connectivity analysis was performed for each subject, with the right and left thalamus as distinct seed regions. Unpaired mixed-effects group analyses between POE and ON groups were conducted for each seed region corrected for PMA and sex.    Results: Thalamic connectivity to cortical and subcortical structures differed in the POE group compared to the ON control group. The POE group exhibited higher functional connectivity to deep gray structures, frontal, medial prefrontal, parietal, occipital, and anterior temporal cortices compared to controls. The POE group exhibited lower connectivity to the nuclei accumbentes, bilateral caudate nuclei, posterior cingulate gyri, superior frontal gyri, insular, and dorsolateral prefrontal cortices.     Conclusion and Potential Impact: Overall, these novel results suggest the presence of opioid exposure-related alterations in thalamic functional connectivity. Given that the thalamus plays a crucial role in early brain development, the described alterations in thalamocortical and thalamic-subcortical connectivity may have implications in stratifying risk and informing treatment for the adverse neurodevelopmental outcomes associated with POE. Future studies should explore the relationship between POE-associated disruptions in thalamic connectivity and developmental outcomes.&nbsp

Personalized pediatric anesthesia and pain management: problem-based review

Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.' Although oncology spearheaded the clinical implementation of personalized medicine, other specialties are rapidly catching up. In anesthesia, classical examples of genetically mediated idiosyncratic reactions have been long known (e.g., malignant hyperthermia and prolonged apnea after succinylcholine). The last two decades have witnessed an expanding body of pharmacogenetic evidence in anesthesia. This review highlights some of the prominent pharmacogenetic associations studied in anesthesia and pain management, with special focus on pediatric anesthesia

Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children

Aim: Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics. Methods: This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV). Results:CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadone metabolism compared with normal/rapid metabolizers. The incidence of PONV was 4.7× greater with CYP2B6 rs1038376 variant. AG/GG variants of rs2279343 SNP had 2.86-fold higher incidence of PONV compared with the wild variant (AA). Nominal associations between rs10500282, rs11882424, rs4803419 and pain scores were observed. Conclusion: We have described novel associations between CYP2B6 genetic variants and perioperative methadone metabolism, and associations with pain scores and PONV

The effect of a one-time 15-minute guided meditation (Isha Kriya) on stress and mood disturbances among operating room professionals: a prospective interventional pilot study

Background: Operating room professionals are exposed to high levels of stress and burnout. Besides affecting the individual, it can compromise patient safety and quality of care as well. Meditation practice is getting recognized for its ability to improve wellness among various populations, including healthcare providers. Methods: Baseline stress levels of perioperative healthcare providers were measured via an online survey using a Perceived Stress Scale (PSS) questionnaire. An in-person meditation workshop was demonstrated during surgical grand rounds and an international anesthesia conference using a 15-minute guided Isha Kriya meditation. The participants were then surveyed for mood changes before and after meditation using a Profile of Mood States (POMS) questionnaire. Results: Surgeons and anesthesiologists were found to have higher median (interquartile range) Perceived Stress Scores as compared to nurses respectively (17 [12, 20] and 17 [12, 21] vs 14 [9, 19]; P = 0.01). Total mood disturbances were found to be significantly reduced after meditation in both the surgical grand rounds (pre-meditation median [IQR] 99 [85, 112] vs 87 [80, 93] post-meditation; P < 0.0001) and anesthesia conference cohorts (pre-meditation 92 [86, 106] vs 87 [81, 92] post-meditation; P < 0.0001). Conclusions: Isha Kriya, a guided meditation, is easy to learn and takes less than 15 minutes to complete. This meditation technique improves mood changes and negative emotions among operating room professionals and could be used as a potential tool for improving wellness

Inner Engineering Practices and Advanced 4-day Isha Yoga Retreat Are Associated with Cannabimimetic Effects with Increased Endocannabinoids and Short-Term and Sustained Improvement in Mental Health: A Prospective Observational Study of Meditators

Background Anxiety and depression are common in the modern world, and there is growing demand for alternative therapies such as meditation. Meditation can decrease perceived stress and increase general well-being, although the physiological mechanism is not well-characterized. Endocannabinoids (eCBs), lipid mediators associated with enhanced mood and reduced anxiety/depression, have not been previously studied as biomarkers of meditation effects. Our aim was to assess biomarkers (eCBs and brain-derived neurotrophic factor [BDNF]) and psychological parameters after a meditation retreat. Methods This was an observational pilot study of adults before and after the 4-day Isha Yoga Bhava Spandana Program retreat. Participants completed online surveys (before and after retreat, and 1 month later) to assess anxiety, depression, focus, well-being, and happiness through validated psychological scales. Voluntary blood sampling for biomarker studies was done before and within a day after the retreat. The biomarkers anandamide, 2-arachidonoylglycerol (2-AG), 1-arachidonoylglycerol (1-AG), docosatetraenoylethanolamide (DEA), oleoylethanolamide (OLA), and BDNF were evaluated. Primary outcomes were changes in psychological scales, as well as changes in eCBs and BDNF. Results Depression and anxiety scores decreased while focus, happiness, and positive well-being scores increased immediately after retreat from their baseline values (P 70% (P < 0.001). Increases of ≥20% in anandamide, 2-AG, 1-AG, and total AG levels after meditation from the baseline had weak correlations with changes in happiness and well-being. Conclusions A short meditation experience improved focus, happiness, and positive well-being and reduced depression and anxiety in participants for at least 1 month. Participants had increased blood eCBs and BDNF, suggesting a role for these biomarkers in the underlying mechanism of meditation. Meditation is a simple, organic, and effective way to improve well-being and reduce depression and anxiety