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

Implementation of Max Principle with PCA in Image Fusion for Surveillance and Navigation Application

Image fusion is the combination of two or more different images by using suitable algorithms to form an output image. It provides a useful tool to integrate multiple images into a composite image. In this paper, we present an approach that uses the principle component analysis (PCA) along with the selection of maximum pixel intensity to perform fusion. The entropy, mutual information and the universal index based measure are used to evaluate the performance of this fusion algorithm

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

Perceived Stress, Resilience, and Wellbeing in Seasoned Isha Yoga Practitioners Compared to Matched Controls During the COVID-19 Pandemic

Background: Yoga practices, including breathing, meditation, and posture protocols (asanas), have been shown to facilitate physical and mental wellbeing. Methods: Seasoned yoga practitioners were recruited from the Isha Foundation. Recruitment of the comparison group was achieved using snowball sampling and were not yoga practitioners. Participants in the non-yoga group were randomized to a 3-min Isha practice or a comparator group asked to perform 15-min of daily reading. Participants completed a series of web-based surveys (REDCap) at baseline, 6, and 12 weeks. These surveys include validated scales and objective questions on COVID-19 infection and medical history. The validated questionnaires assess for: perceived stress (PSS), mood states [anxiety and depression (PHQ-4), joy (DPES-Joy subscale)], mindfulness attention and awareness (MAAS), resilience (BRS), mental wellbeing (WEMWBS) and recovery from traumatic event (PTGI). Weekly activity diaries were employed as a tool for collecting compliance information from study participants. Perceived stress scale scores were identified as primary outcome for this study. Findings: The median Perceived Stress Scale (PSS) score for the yoga practitioners compared to the active and placebo comparators was significantly lower at all time-points: baseline: 11 [IQR 7–15] vs. 16 [IQR 12–21] in both the active and placebo comparators (p \u3c 0.0001); 6 weeks: 9 [IQR 6–13] vs. 12 [IQR 8–17] in the active comparator and 14 [IQR 9–18] in the placebo comparator (p \u3c 0.0001); and 12 weeks: 9 [IQR 5–13] vs. 11.5 [IQR 8–16] in the active comparators and 13 [IQR 8–17] in the placebo comparator (p \u3c 0.0001). Among the randomized participants that were compliant for the full 12 weeks, the active comparators had significantly lower median PSS scores than the placebo comparators 12 weeks [10 (IQR 5–14) vs. 13 (IQR 8–17), p = 0.017]. Further, yoga practitioners had significantly lower anxiety at all three-time points (p \u3c 0.0001), lower depression at baseline and 6 weeks (p \u3c 0.0003), and significantly higher wellbeing (p \u3c 0.0001) and joy (p \u3c 0.0001) at all three-time points, compared to the active and placebo comparator groups. Interpretation: The lower levels of stress, anxiety, depression, and higher level of wellbeing and joy seen in the yoga practitioners compared to the active and placebo comparators illustrate the impact of regular yoga practices on mental health even during the pandemic

Pharmacogenomics of methadone: a narrative review of the literature

Background: Methadone, a synthetic opioid with longer duration of action and lower abuse potential compared with morphine, is used to prevent opioid withdrawal, as well as to manage chronic and acute surgical pain. The variability in response to methadone has been widely recognized. The purpose of this article is to review the literature on the pharmacogenetic factors underlying this variability. Materials & methods: This is a narrative overview of the literature on the genetic variants affecting pharmacodynamics and pharmacokinetics of methadone, retrieved from searches of databases such as PubMed and google scholar. Discussion: Clinical responses to methadone may be affected by genetic variants in the opioidergic, dopaminergic and neurotrophic pathways. Polymorphisms in genes related to disposition and elimination of methadone alter the pharmacokinetics, and possibly pharmacodynamics of methadone. Cytochrome P450 enzymes and P-glycoprotein variants contribute to the interindividual variability in methadone pharmacokinetics. Evidence for single gene variants affecting methadone response remains weak. Multiple genetic variants must be considered in conjunction to improve predictive ability. Conclusion: Evidence remains scarce at this time, to recommend pharmacogenetic testing before methadone administration. Well-powered clinical studies are needed with population pharmacokinetic-pharmacodynamic modeling and multigenetic signature-based predictions to enable tailored use of methadone in clinical practice

Methadone-based Multimodal Analgesia Provides the Best-in-class Acute Surgical Pain Control and Functional Outcomes With Lower Opioid Use Following Major Posterior Fusion Surgery in Adolescents With Idiopathic Scoliosis

Introduction: Posterior spinal fusion for idiopathic scoliosis is extremely painful, with no superior single analgesic modality. We introduced a methadone-based multimodal analgesia protocol, aiming to decrease the length of hospital stay (LOS), improve pain control, and decrease the need for additional opioids. Methods: We analyzed 122 idiopathic scoliosis patients with posterior instrumented spinal fusion. They were matched by age, sex, surgeon, and the number of levels fused before and after the implementation of the new protocol. This analysis included 61 controls (intrathecal morphine, gabapentin, intravenous opioids, and adjuncts) and 61 patients on the new protocol (scheduled methadone, methocarbamol, ketorolac/ibuprofen, acetaminophen, and oxycodone with intravenous opioids as needed). The primary outcome was LOS. Secondary outcomes included pain scores, total opioid use (morphine milligram equivalents), time to a first bowel movement, and postdischarge phone calls. Results: New protocol patients were discharged earlier (median LOS, 2 days) compared with control patients (3 days; P < 0.001). Total inpatient morphine consumption was lower in the protocol group (P < 0.001). Pain scores were higher in the protocol group on the day of surgery, similar on postoperative day (POD) 1, and lower by POD 2 (P = 0.01). The new protocol also reduced the median time to first bowel movement (P < 0.001), and the number of postdischarge pain-related phone calls (P < 0.006). Conclusion: Methadone-based multimodal analgesia resulted in significantly lower LOS compared with the conventional regimen. It also provided improved pain control, reduced total opioid consumption, and early bowel movement compared with the control group

Pharmacokinetic modeling of R and S-Methadone and their metabolites to study the effects of various covariates in post-operative children

Methadone is a synthetic opioid used as an analgesic and for the treatment of opioid abuse disorder. The analgesic dose in the pediatric population is not well-defined. The pharmacokinetics (PKs) of methadone is highly variable due to the variability in alpha-1 acid glycoprotein (AAG) and genotypic differences in drug-metabolizing enzymes. Additionally, the R and S enantiomers of methadone have unique PK and pharmacodynamic properties. This study aims to describe the PKs of R and S methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in pediatric surgical patients and to identify sources of inter- and intra-individual variability. Children aged 8-17.9 years undergoing orthopedic surgeries received intravenous methadone 0.1 mg/kg intra-operatively followed by oral methadone 0.1 mg/kg postoperatively every 12 h. Pharmacokinetics of R and S methadone and EDDP were determined using liquid chromatography tandem mass spectrometry assays and the data were modeled using nonlinear mixed-effects modeling in NONMEM. R and S methadone PKs were well-described by two-compartment disposition models with first-order absorption and elimination. EDDP metabolites were described by one compartment disposition models with first order elimination. Clearance of both R and S methadone were allometrically scaled by bodyweight. CYP2B6 phenotype was a determinant of the clearance of both the enantiomers in an additive gene model. The intronic CYP3A4 single-nucleotide polymorphism (SNP) rs2246709 was associated with decreased clearance of R and S methadone. Concentrations of AAG and the SNP of AAG rs17650 independently increased the volume of distribution of both the enantiomers. The knowledge of these important covariates will aid in the optimal dosing of methadone in children

Isha Yoga Practices and Participation in Samyama Program are Associated with Reduced HbA1C and Systemic Inflammation, Improved Lipid Profile, and Short-Term and Sustained Improvement in Mental Health: A Prospective Observational Study of Meditators

Background: Meditation is gaining recognition as a tool to impact health and well-being. Samyama is an 8-day intensive residential meditation experience conducted by Isha Foundation requiring several months of extensive preparation and vegan diet. The health effects of Samyama have not been previously studied. The objective was to assess physical and emotional well-being before and after Samyama participation by evaluating psychological surveys and objective health biomarkers. Methods: This was an observational study of 632 adults before and after the Isha Samyama retreat. All participants were invited to complete surveys. Controls included household significant others. Surveys were completed at baseline (T1), just before Samyama (T2), immediately after Samyama (T3), and 3 months later (T4) to assess anxiety, depression, mindfulness, joy, vitality, and resilience through validated psychometric scales. Voluntary blood sampling for biomarker analysis was done to assess hemoglobin (Hb), HbA1c, lipid profile, and C-reactive protein (CRP). Primary outcomes were changes in psychometric scores, body weight, and blood biomarkers. Results: Depression and anxiety scores decreased from T1 to T3, with the effect most pronounced in participants with baseline depression or anxiety. Scores at T4 remained below baseline for those with pre-existing depression or anxiety. Vitality, resilience, joy, and mindfulness increased from T1 to T3 (sustained at T4). Body weight decreased by 3% from T1 to T3. Triglycerides (TG) were lower from T2 to T3. Participants had lower HbA1c and HDL at T2, and lower CRP at all timepoints compared with controls. Conclusions: Participation in the Isha Samyama program led to multiple benefits. The 2-month preparation reduced anxiety, and participants maintained lower anxiety levels at 3 months post-retreat. Physical health improved over the course of the program as evidenced by weight loss and improved HbA1C and lipid profile. Practices associated with the Samyama preparation phase and the retreat may serve as an effective way to improve physical and mental health. Future studies may examine their use as an alternative therapy in patients with depression and/or anxiety