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

Gender, genetics, and analgesia: understanding the differences in response to pain relief

Senthil Packiasabapathy, Senthilkumar Sadhasivam Department of Anesthesia, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA Abstract: Genetic variations and gender contribute significantly to the large interpatient variations in opioid-related serious adverse effects and differences in pain relief with other analgesics. Opioids are the most commonly used analgesics to relieve moderate-to-severe postoperative pain. Narrow therapeutic index and unexplained large interpatient variations in opioid-related serious adverse effects and analgesia negatively affect optimal perioperative outcomes. In surgical, experimental, chronic, and neuropathic pain models, females have been reported to have more pain than males. This review focuses on literature evidence of differences in pain relief due to multiple genetic variations and gender of the patient. Keywords: pain, analgesia, pain genomics, pharmacogenomics, pharmacokinetics, pharmacodynamic

Effect of dexmedetomidine as an adjuvant to bupivacaine in femoral nerve block for perioperative analgesia in patients undergoing total knee replacement arthroplasty: A dose–response study

Context: Dexmedetomidine is being increasingly used in nerve blocks. However, there are only a few dose determination studies. Aims: To compare two doses of dexmedetomidine, in femoral nerve block, for postoperative analgesia after total knee arthroplasty (TKA). Settings and Design: A prospective, randomized, controlled trial was conducted in the Department of Anesthesia at AIIMS, a Tertiary Care Hospital. Materials and Methods: Sixty American Society of Anesthesiologists I–II patients undergoing TKA under subarachnoid block were randomized to three Groups A, B, and C. Control Group A received 20 ml (0.25%) of bupivacaine in femoral nerve block. Groups B and C received 1 and 2 μg/kg dexmedetomidine along with bupivacaine for the block, respectively. Outcomes measured were analgesic efficacy measured in terms of visual analog scale (VAS) score at rest and passive motion, duration of postoperative analgesia, and postoperative morphine consumption. Adverse effects of dexmedetomidine were also studied. Statistical Analysis Used: All qualitative data were analyzed using Chi-square test and VAS scores using Kruskal–Wallis test. Comparison of patient-controlled analgesia (PCA) morphine consumption and time to first use of PCA were done using ANOVA followed by Least Significant Difference test. A P < 0.05 was considered statistically significant. Results: The VAS score at rest was significantly lower in Group C compared to Groups A and B (P < 0.05). There was no difference in VAS score at motion between Groups B and C. The mean duration of analgesia was significantly longer in Group C (6.66 h) compared to Groups A (4.55 h) and B (5.70 h). Postoperative mean morphine consumption was significantly lower in Group C (22.85 mg) compared to Group A (32.15 mg) but was comparable to Group B (27.05 mg). There was no significant difference in adverse effects between the groups. Conclusion: The use of dexmedetomidine at 2 μg/kg dose in femoral nerve block is superior to 1 μg/kg for providing analgesia after TKA, although its role in facilitating early ambulation needs further evaluation