CYP2D6 phenotypes and opioid metabolism: the path to personalized analgesia.

INTRODUCTION: Opioids play a fundamental role in chronic pain, especially considering when 1 of 5 Europeans adults, even more in older females, suffer from it. However, half of them do not reach an adequate pain relief. Could pharmacogenomics help to choose the most appropriate analgesic drug? AREAS COVERED: The objective of the present narrative review was to assess the influence of cytochrome P450 2D6 (CYP2D6) phenotypes on pain relief, analgesic tolerability, and potential opioid misuse. Until December 2021, a literature search was conducted through the MEDLINE, PubMed database, including papers from the last 10 years. CYP2D6 plays a major role in metabolism that directly impacts on opioid (tramadol, codeine, or oxycodone) concentration with differences between sexes, with a female trend toward poorer pain control. In fact, CYP2D6 gene variants are the most actionable to be translated into clinical practice according to regulatory drug agencies and international guidelines. EXPERT OPINION: CYP2D6 genotype can influence opioids' pharmacokinetics, effectiveness, side effects, and average opioid dose. This knowledge needs to be incorporated in pain management. Environmental factors, psychological together with genetic factors, under a sex perspective, must be considered when you are selecting the most personalized pain therapy for your patients.

Blunt Chest Trauma and Regional Anesthesia for Analgesia of Multitrauma Patients in French Intensive Care Units: A National Survey.

BACKGROUND: Chest injuries are associated with mortality among patients admitted to the intensive care unit (ICU) and require multimodal pain management strategies, including regional anesthesia (RA). We conducted a survey to determine the current practices of physicians working in ICUs regarding RA for the management of chest trauma in patients with multiple traumas. METHODS: An online questionnaire was sent to medical doctors (n = 1230) working in French ICUs, using the Société Française d'Anesthésie Réanimation (SFAR) mailing list of its members. The questionnaire addressed 3 categories: general characteristics, practical aspects of RA, and indications and contraindications. RESULTS: Among the 333 respondents (response rate = 27%), 78% and 40% of 156 respondents declared that they would consider using thoracic epidural analgesia (TEA) and thoracic paravertebral blockade (TPB), respectively. The main benefits declared for performing RA were the ability to have effective analgesia, a more effective cough, and early rehabilitation. For 70% of the respondents, trauma patients with a theoretical indication of RA did not receive TEA or TPB for the following reasons: the ICU had no experience of RA (62%), no anesthesiologist-intensivist working in the ICU (46%), contraindications (27%), ignorance of the SFAR guidelines (19%), and no RA protocol available (13%). In this survey, 95% of the respondents thought the prognosis of trauma patients could be influenced by the use of RA. CONCLUSIONS: While TEA and TPB are underused because of several limitations related to the patterns of injuries in multitrauma patients, lack of both experience and confidence in combination with the absence of available protocols appear to be the major restraining factors, even if physicians are aware that patients' outcomes could be improved by RA. These results suggest the need to strengthen initial training and provide continuing education about RA in the ICU.

A possible future for anaesthesia in breast surgery: thoracic paravertebral block and awake surgery. A prospective observational study.

INTRODUCTION: Quadrantectomy is a surgical procedure traditionally performed under general anaesthesia with intraoperative and postoperative opioid-based analgesia. The use of locoregional anaesthesia techniques in breast surgery has become widespread and allows excellent management of intraoperative and postoperative pain with reduced opioid consumption. We chose thoracic paravertebral block as regional anaesthesia technique in breast surgery to investigate the possibility of carrying out this surgery with the patient awake. METHODS: A prospective observational study on 50 patients was designed. The primary outcome for this study was the possibility to carry out the surgery with only the paravertebral block associated with mild sedation without general anaesthesia. Forty minutes before the start of the surgery, an ultrasound-guided thoracic paravertebral block was performed at two thoracic levels, and for each level, 7 mL of ropivacaine 0.7% was injected. Sedation was obtained with target-controlled infusion of propofol. RESULTS: Forty-nine patients underwent the operation awake; in one case, we had to place an I-gel and perform general anaesthesia. No patient needed intraoperative or postoperative opioids. The numeric rating scale, recorded at 0, 2, 6, 12, 24, and 36 hours, was greater than 3 in only five patients. CONCLUSIONS: We believe that if in the future we try to make quadrantectomy an intervention in which the anaesthesia is exclusively regional, therefore with a patient awake and collaborating, it will not be possible to ignore the use of thoracic paravertebral block.

The role of regional analgesia in personalized postoperative pain management.

Pain management plays a fundamental role in enhanced recovery after surgery pathways. The concept of multimodal analgesia in providing a balanced and effective approach to perioperative pain management is widely accepted and practiced, with regional anesthesia playing a pivotal role. Nerve block techniques can be utilized to achieve the goals of enhanced recovery, whether it be the resolution of ileus or time to mobilization. However, the recent expansion in the number and types of nerve block approaches can be daunting for general anesthesiologists. Which is the most appropriate regional technique to choose, and what skills and infrastructure are required for its implementation? A multidisciplinary team-based approach for defining the goals is essential, based on each patient's needs, and incorporating patient, surgical, and social factors. This review provides a framework for a personalized approach to postoperative pain management with an emphasis on regional anesthesia techniques.

Current understanding of the fascial plane blocks for analgesia of the chest wall: techniques and indications update for 2020.

PURPOSE OF REVIEW: Thoracic myofascial plane blocks have gained popularity because of their ease of performance and relative safety. This review highlights current research demonstrating the efficacy of these blocks for specific surgical procedures and provides a brief description of how these techniques are performed. RECENT FINDINGS: Fascial plane blocks of the thorax and chest wall have been shown to be beneficial in providing perioperative analgesia for a variety of surgical procedures. Studies discussed in this review compare thoracic fascial plane blocks to systemic analgesia alone, contrast these novel methods of pain control to more traditional techniques, such as paravertebral nerve blocks and epidural anesthesia, and attempt to determine, which fascial plane blocks provide optimal postsurgical analgesia. SUMMARY: Thoracic fascial plane blocks provide the anesthesiologist a number of techniques to address postsurgical pain. The relative ease of performance and safety profile of these blocks make them an appealing option for pain control for many patients undergoing thoracic or chest wall surgery. Further research is needed to not only define additional indications for each of these blocks, but also explore optimal dosing including the use of continuous catheter techniques.

The relative analgesic value of a femoral nerve block versus adductor canal block following total knee arthroplasty: a randomized, controlled, double-blinded study.

BACKGROUND: Multiple comparative studies report that adductor canal blocks provide similar pain relief to femoral nerve blocks following total knee arthroplasty. However, adductor canal blockade fails to anesthetize several important femoral nerve branches that contribute to knee innervation. We sought to clarify this anatomic discrepancy by performing both blocks in sequence, using patients as their own controls. We hypothesized that patients would experience additional pain relief following a superimposed femoral nerve block, demonstrating that these techniques are not equivalent. METHODS: Sixteen patients received continuous adductor canal block before undergoing knee arthroplasty under general anesthesia. In the recovery room, patients reported their pain score on a numeric scale of 0-10. Once a patient reached a score of five or greater, he/she was randomized to receive an additional femoral nerve block using 2% chloroprocaine or saline sham, and pain scores recorded every 5 min for 30 min. Patients received opioid rescue as needed. Anesthesiologists performing and assessing block efficacy were blinded to group allocation. RESULTS: Patients randomized to chloroprocaine versus saline reported significantly improved median pain scores 30 min after the femoral block (2.0 vs. 5.5, P = 0.0001). Patients receiving chloroprocaine also required significantly fewer morphine equivalents during the 30 min post-femoral block (1.0 vs. 4.5 mg, P = 0.03). CONCLUSIONS: Adductor canal block is a useful technique for postoperative pain following total knee arthroplasty, but it does not provide equivalent analgesic efficacy to femoral nerve block. Future studies comparing efficacy between various block sites along the thigh are warranted.

Trends in opioid use before critical illness among elderly patients in Ontario.

PURPOSE: To assess temporal trends in pre-existing opioid exposure prior to hospitalization among elderly intensive care unit (ICU) patients and its association with adverse outcomes. MATERIALS AND METHODS: We performed a population-based retrospective cohort study using health administrative data from the province of Ontario, Canada. We included all older adult (> 65 years) admissions to an ICU between April 2002 and March 2015. The exposure was opioid use before admission categorized as chronic use, intermittent use, and non-use. RESULTS: The cohort included 711,312 elderly patient admissions to an ICU. Of these, 6.8% (n = 48,363) were chronic opioid users, 28.1% (n = 200,149) intermittent users, and 65.0% (n = 462,800) non-users. Compared with non-users, chronic opioid users and intermittent users had higher in-hospital mortality (adjusted odds ratio: 1.12, 95% CI, 1.09-1.15, p < 0.0001 for chronic users; adjusted odds ratio: 1.09, 95% CI, 1.07-1.11, p < 0.0001 for intermittent users), and a lower subdistribution hazard of time to hospital discharge, translating to a longer hospital length of stay (adjusted hazard ratio: 0.87, 95% CI, 0.85-0.88, p < 0.0001 for chronic users; adjusted hazard ratio: 0.93, 95% CI, 0.92-0.94, p < 0.0001 for intermittent users). CONCLUSIONS: Among elderly ICU patients, opioid exposure prior to admission is prevalent and use is associated with higher in-hospital mortality.

Penthrox: a breath of PHEC air for the military?

Prehospital analgesia is vital to good clinical care and inhaled methoxyflurane (Penthrox) would be a valuable addition to the armed forces medical armoury. Penthrox would provide strong, fast-acting, self-administered and safe analgesia to patients with moderate to severe injuries. In addition, it would provide an option for strong analgesia which would not be subject to the regulations that govern controlled or accountable drugs which gives it a unique position as the military moves its focus from large enduring operations to small short-term training teams supported by lone combat medics in remote locations across the globe.

Analgesic and Respiratory Depressant Effects of R-dihydroetorphine: A Pharmacokinetic-Pharmacodynamic Analysis in Healthy Male Volunteers.

BACKGROUND: There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the µ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception. METHODS: The authors performed a population pharmacokinetic-pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis. RESULTS: R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml. CONCLUSIONS: Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.

Technological Advances in Exotic Pet Anesthesia and Analgesia.

Even when performed by skilled operators, locating the nerves can be challenging in small exotic pets; in such cases, the use of an electrical nerve stimulator may be useful to confirm the correct identification of the target nerve. Exotic animal anesthesia and analgesia have dramatically progressed over the past decade and continue to do so as more research and technologies develop. Technological advancements such as airway devices, endoscopic intubation techniques, positive intermittent pressure ventilators, and invasive and noninvasive blood pressure monitors have played a significant role in improving patient safety and the anesthetic outcomes of exotic animals.

Updates on multimodal analgesia and regional anesthesia for total knee arthroplasty patients.

The subspecialty of regional anesthesiology and acute pain medicine (RAAPM) is in a position to lead changes that may impact the current opioid crisis. At the hospital level, RAAPM experts can implement evidence-based multimodal analgesic clinical pathways featuring regional anesthesia. Multimodal analgesia consists of using two or more analgesic modalities targeting pain pathways at various levels to improve pain control, while also aiming to reduce opioid utilization and related adverse effects. These types of pathways or protocols have been widely applied in the joint replacement population. This review focuses on the current state of the evidence regarding individual elements of a multimodal analgesic pathway for patients with total knee arthroplasty including new regional anesthesia techniques like the IPACK (Infiltration between the Popliteal Artery and Capsule of the Knee) block and suggests future research directions to improve the clinical care of this surgical population in the future.

Percutaneous peripheral nerve stimulation and other alternatives for perineural catheters for postoperative analgesia.

A perineural catheter with a continuous infusion of local anesthetic is an excellent option for postoperative analgesia; however, its limitations include limited duration of action (i.e., 3-7 days) as well as a risk of infection and dislodgement. Furthermore, these blocks may cause dense sensory and motor blockades that under certain circumstances may not be ideal. There is novel evidence that ultrasound-guided percutaneous peripheral nerve stimulation (pPNS) may serve as an alternative approach free of the limitations associated with peripheral nerve blocks. In this review, we discuss the evidence for pPNS on postoperative acute pain management. Subsequently, we briefly discuss additional alternatives to continuous peripheral nerve blocks, including cryoanalgesia and liposomal bupivacaine.

Analgesic efficacy and impact of caudal block on surgical complications of hypospadias repair: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: is commonly used for children undergoing hypospadias repair. However, the safety of caudal block for hypospadias repair in children is controversial in terms of surgical complications such as urethrocutaneous fistula and glans dehiscence. We sought to perform a meta-analysis to estimate the analgesic efficacy and relative complications of caudal block for hypospadias repair in children. METHODS: We identified comparative studies of caudal block versus peripheral nerve block or no caudal block; studies were published or presented through 1 January 2018, and reports of analgesic efficacy or surgical complications of hypospadias repair in children were identified. Peripheral nerve block includes dorsal nerve penile block and pudendal nerve block. Data were abstracted from studies comparing caudal block with peripheral nerve block or no caudal block; original source data were used when available. We prespecified separate assessments of randomized controlled trials (RCTs) and observational studies given the inherent differences between types of study designs. Data from 298 patients in four RCTs and from 1726 patients in seven observational studies were included. RCT and observational data were analyzed separately. RESULTS: In RCTs, caudal blocks (compared with peripheral nerve blocks) showed no detectable differences in terms of need for additional analgesia within 24 hours after the surgery (OR 10.49; 95% CI 0.32 to 343.24; p=0.19), but limited data showed lower pain scores 24 hours after the surgery (standardized mean difference (SMD) 1.57; 95% CI 0.29 to 2.84; p=0.02), a significantly shorter duration of analgesia (SMD -3.33; 95% CI -4.18 to -2.48; p<0.0001) and analgesics consumption. No significant differences were observed in terms of postoperative nausea and vomiting (OR 3.08; 95% CI 0.12 to 77.80; p=0.50) or motor weakness (OR 0.01; 95% CI -0.03 to 0.05; p=0.56). Only one randomized study showed that caudal blocks (compared with peripheral nerve blocks) were associated with detectable differences in urethrocutaneous fistula rate (OR 25.27; 95% CI 1.37 to 465.01; p=0.03) and parental satisfaction rate (OR 0.07; 95% CI 0.02 to 0.21; p<0.00001). In observational studies, caudal block was not associated with surgical complications in all types of primary hypospadias repair (OR 1.83; 95% CI 0.80 to 4.16; p=0.15). To adjust for confounding factors and to eliminate potential selection bias involving caudal block indication, we performed subgroup analysis including only patients with distal hypospadias. This analysis revealed similar complication rates in children who received a caudal block and in children not receiving caudal block (OR 1.02; 95% CI, 0.39 to 2.65; p=0.96). This result further confirmed that caudal block was not a risk factor for surgical complications in hypospadias repair. The direction of outcomes in all the other subgroup analyses did not change, suggesting stability of our results. CONCLUSIONS: In RCTs, only limited data showed peripheral nerve blocks providing better analgesic quality compared with caudal blocks. In real-world non-randomized observational studies with greater number of patients (but with admitted the potential for a presence of selection bias and residual confounders), caudal blocks were not associated with postoperative complications including urethrocutaneous fistula and glans dehiscence.

Opioid-Based Anesthesia and Analgesia for Adult Cardiac Surgery: History and Narrative Review of the Literature.

Opioids have played in a key role in cardiac anesthesia and analgesia since the early years of cardiac surgery. Today, opioids continue to be the primary mode for analgesia in cardiac surgery, yet there is considerable variability in the choice, dose and route of used. A history of the use of opioids in cardiothoracic anesthesia is presented, followed by an examination of the differences among current opioids in use and of outcome variables important in cardiac anesthesia, such as postoperative analgesia, extubation times, fast-track cardiac anesthesia, chronic neuropathic pain, and cardioprotection. Topical issues such as the role of perioperative opioid use in the global opioid crisis, opioid-sparing techniques and novel opioids in development are also discussed.

Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation: Neuromodulation of the Femoral Nerve for Postoperative Analgesia Following Ambulatory Anterior Cruciate Ligament Reconstruction: A Proof of Concept Study.

OBJECTIVES: The purpose of this prospective proof of concept study was to investigate the feasibility of using percutaneous peripheral nerve stimulation of the femoral nerve to treat pain in the immediate postoperative period following ambulatory anterior cruciate ligament reconstruction with a patellar autograft. MATERIALS AND METHODS: Preoperatively, an electrical lead (SPRINT, SPR Therapeutics, Inc., Cleveland, OH, USA) was percutaneously implanted with ultrasound guidance anterior to the femoral nerve caudad to the inguinal crease. Within the recovery room, subjects received 5 min of either stimulation or sham in a randomized, double-masked fashion followed by a 5-min crossover period, and then continuous active stimulation until lead removal postoperative Day 14-28. Statistics were not applied to the data due to the small sample size of this feasibility study. RESULTS: During the initial 5-min treatment period, subjects randomized to stimulation (n = 5) experienced a slight downward trajectory (decrease of 7%) in their pain over the 5 min of treatment, while those receiving sham (n = 5) reported a slight upward trajectory (increase of 4%) until their subsequent 5-min stimulation crossover, during which time they also experienced a slight downward trajectory (decrease of 11% from baseline). A majority of subjects (80%) used a continuous adductor canal nerve block for rescue analgesia (in addition to stimulation) during postoperative Days 1-3, after which the median resting and dynamic pain scores remained equal or less than 1.5 on the numeric rating scale, respectively, and the median daily opioid consumption was less than 1.0 tablet. CONCLUSIONS: This proof of concept study demonstrates that percutaneous femoral nerve stimulation is feasible for ambulatory knee surgery; and suggests that this modality may be effective in providing analgesia and decreasing opioid requirements following anterior cruciate ligament reconstruction. clinicaltrials.gov: NCT02898103.

Association between perioperative cholesterol level and analgesia after video-assisted thoracoscopic surgery.

BACKGROUND: Cholesterol plays an important role in the action of opioid analgesics, but its association with postoperative pain has not been clarified. Our study examined the association of pre- and postoperative total serum cholesterol (TSC), and change between the pre- and postoperative TSC levels with postoperative pain outcomes in patients with non-small cell lung cancer (NSCLC) who underwent video-assisted thoracoscopic surgery (VATS) lobectomy. METHODS: We retrospectively reviewed medical records of patients with NSCLC who underwent VATS lobectomy at the Seoul National University Bundang Hospital in South Korea. We sought to determine the association between preoperative TSC, TSC on postoperative day (POD) 0-1, and pre- and postoperative changes in TSC by comparing numeric rating scale (NRS) scores on POD 0, 1, and 2 and total morphine equivalent consumption on POD 0-2. Multivariate linear regression analyses were used, and P < 0.05 was considered statistically significant. RESULTS: A total of 1,720 patients with NSCLC who underwent VATS lobectomy were included in the analysis. The change in TSC, preoperative TSC, and postoperative TSC showed no associations with morphine equivalent consumption on POD 0-2 (P > 0.05). In addition, the changes in TSC, preoperative TSC, and postoperative TSC were not associated with postoperative NRS pain score on POD 0, 1, and 2 (P > 0.05). CONCLUSIONS: Our results indicated that no significant association was observed between pre- and postoperative TSC level and postoperative pain outcome after VATS lobectomy of the lung.

Sedaciones en procedimientos diagnósticos y/o terapéuticos: recomendaciones de calidad y seguridad / Sedations in diagnostic and/or therapeutic procedures: quality and safety recommendations

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Intraperitoneal Local Anesthetic Instillation and Postoperative Infusion Improves Functional Recovery Following Colectomy: A Randomized Controlled Trial.

BACKGROUND: Intraperitoneal local anesthetic is an analgesic technique for inclusion in the polypharmacy approach to postoperative pain management in enhanced recovery after surgery programs. Previously, augmentation of epidural analgesia with intraperitoneal local anesthetic was shown to improve functional postoperative recovery following colectomy. OBJECTIVE: This study determines whether intraperitoneal local anesthetic improves postoperative recovery in patients undergoing colectomy, in the absence of epidural analgesia, with standardized enhanced recovery after surgery perioperative care. DESIGN: This is a multisite, double-blinded, randomized, placebo-controlled trial (ClinicalTrials.gov Identifier NCT02449720). SETTINGS: This study was conducted at 3 hospital sites in South Australia. PATIENTS: Eighty-six adults undergoing colectomy were stratified by approach (35 open; 51 laparoscopic), then randomly assigned to intraperitoneal local anesthetic (n = 44) and control (n = 42) groups. INTERVENTIONS: Patients in the intraperitoneal local anesthetic group received an intraoperative intraperitoneal ropivacaine 100-mg bolus both pre- and postdissection and 20 mg/h continuous postoperative infusion for 48 hours. Patients in the control group received a normal saline equivalent. MAIN OUTCOME MEASURES: Functional postoperative recovery was assessed by using the surgical recovery scale for 45 days; postoperative pain was assessed by using a visual analog scale; and opioid consumption, use of rescue ketamine, recovery of bowel function, time to readiness for discharge, and perioperative complications were recorded. RESULTS: The intraperitoneal local anesthetic group reported improved surgical recovery scale scores at day 1 and 7, lower pain scores, required less rescue ketamine, and passed flatus earlier than the control group (p < 0.05). The improvement in surgical recovery scale at day 7 and pain scores remained when laparoscopic colectomy was considered separately. Opioid consumption and time to readiness for discharge were equivalent. LIMITATIONS: This study was powered to detect a difference in surgical recovery scale, but not the other domains of recovery, when the intraperitoneal local anesthetic group was compared with control. CONCLUSIONS: We conclude that instillation and infusion of intraperitoneal ropivacaine for patients undergoing colectomy, including by the laparoscopic approach, decreases postoperative pain and improves functional postoperative recovery. We recommend routine inclusion of intraperitoneal local anesthetic into the multimodal analgesia component of enhanced recovery after surgery programs for laparoscopic colectomy. See Video Abstract at http://links.lww.com/DCR/A698.