Dario Bugada

Genetic variability at COMT but not at OPRM1 and UGT2B7 loci modulates morphine analgesic response in acute postoperative pain

PurposeTo investigate interindividual variability in response to pain treatment, we characterized postoperative patients for morphine metabolism and for COMT, OPRM1 and UGT2B7 polymorphisms.MethodsA total of 109 patients treated with morphine were genotyped by DNA sequencing for 12 DNA polymorphisms of the COMT, OPRM1 and UGT2B7 genes. The plasma concentration of morphine and of M3G/M6G metabolites were evaluated by means of reversed phase high-performance liquid chromatography coupled with mass spectrometry.ResultsAn association between average morphine consumption during the first 24 postoperative hours by patient-controlled analgesia (PCA) and COMT haplotypes was found. Specifically, patients with the diplotype for average pain intensity (APS/APS) required the lowest morphine doses compared to the other subjects (p = 0.011). The APS haplotype contains an adenine corresponding to methionine, instead of valine, at position 158 of the COMT protein. Met/Met homozygous patients consumed significantly lower morphine doses than other subjects (p = 0.014); accordingly, Val158Met genotyping alone might be used in the clinical setting to predict PCA morphine need. Considering both COMT Val158Met and OPRM1 A118G polymorphisms, carriers of both the Met/Met and AA genotypes required less morphine than other subjects, although the difference was not significant. The analysis of UGT2B7 revealed the occurrence of two common haplotypes (G_C_C_A_C and A_T_T_G_T) that did not prove to be related with plasma morphine and M3G/M6G concentration.ConclusionsBy considering COMT, OPRM1, and UGT2B7 genotypes, as well as pharmacokinetic results, only COMT polymorphisms appear to be predictive of morphine need in postoperative pain therapy.

Inflammation-based scores: a new method for patient-targeted strategies and improved perioperative outcome in cancer patients.

Systemic inflammatory response (SIR) has actually been shown as an important prognostic factor associated with lower postoperative survival in several types of cancer. Thus, the challenge for physicians is to find specific, low-cost, and highlyreliable inflammatory markers, clearly correlated with prognosis and able to preoperatively stratify patients risk. Inflammation is a promising target to improve perioperative outcome, and data show that anti-inflammation techniques have a great potential in the perioperative period of cancer surgery. Inflammation scores could be useful to stratify patients with a potential better response to anti-inflammation strategies. Furthermore, inflammation scores could prevent failure of clinical trials by a better definition of patients to be included in such trials; inflammation scoring could clarify the real role of different drugs and techniques on outcome after cancer surgery, defining if different therapies are required for different patients. The role of this review is to focus on the currently available scores, in order to clarify their rationale and to analyze the actual evidence and limits, providing physicians with an updated overview of the possible inflammation-based prognostic scores for cancer patients undergoing surgery.

Changes in total plasma and serum N-glycome composition and patient-controlled analgesia after major abdominal surgery

Systemic inflammation participates to the complex healing process occurring after major surgery, thus directly affecting the surgical outcome and patient recovery. Total plasma N-glycome might be an indicator of inflammation after major surgery, as well as an anti-inflammatory therapy response marker, since protein glycosylation plays an essential role in the inflammatory cascade. Therefore, we assessed the effects of surgery on the total plasma N-glycome and the association with self-administration of postoperative morphine in two cohorts of patients that underwent major abdominal surgery. We found that plasma N-glycome undergoes significant changes one day after surgery and intensifies one day later, thus indicating a systemic physiological response. In particular, we observed the increase of bisialylated biantennary glycan, A2G2S[3,6]2, 12 hours after surgery, which progressively increased until 48 postoperative hours. Most changes occurred 24 hours after surgery with the decrease of most core-fucosylated biantennary structures, as well as the increase in sialylated tetraantennary and FA3G3S[3,3,3]3 structures. Moreover, we observed a progressive increase of sialylated triantennary and tetraantennary structures two days after surgery, with a concomitant decrease of the structures containing bisecting N-acetylglucosamine along with bi- and trisialylated triantennary glycans. We did not find any statistically significant association between morphine consumption and plasma N-glycome.

Postoperative Analgesia after Laparoscopic Ovarian Cyst Resection: Double-blind Multicenter Randomized Control Trial Comparing Intraperitoneal Nebulization and Peritoneal Instillation of Ropivacaine

STUDY OBJECTIVE To compare the effects of local anesthetic intraperitoneal nebulization with intraperitoneal instillation during laparoscopic ovarian cystectomy on postoperative morphine consumption and pain. DESIGN Multicenter, randomized, case-control trial. DESIGN CLASSIFICATION Canadian Task Force Classification I. SETTING University hospitals in Italy. PATIENTS One hundred forty patients scheduled for laparoscopic ovarian cystectomy. INTERVENTIONS Patients were randomized to receive either nebulization of ropivacaine 150 mg before surgery or instillation of ropivacaine 150 mg before surgery. Nebulization was performed using the Aeroneb Pro device (Aerogen, Galway, Ireland). MEASUREMENTS AND MAIN RESULTS One hundred forty patients were enrolled, and 123 completed the study. There was no difference between the 2 groups in average morphine consumption (7.3 ± 7.5 mg in the nebulization group vs 9.2 ± 7.2 mg in the instillation group; p = .17). Eighty-two percent of patients in the nebulization group required morphine compared with 96% in the instillation group (p < .05). Patients receiving nebulization had a lower dynamic Numeric Ranking Scale compared with those in the instillation group in the postanesthesia care unit postanesthesia care unit and 4 hours after surgery (p < .05). Ten patients (15%) in the nebulization group experienced shivering in the postanesthesia care unit compared with 2 patients (4%) in the instillation group (p = .035). CONCLUSION Nebulization of ropivacaine prevents the use of morphine in a significant proportion of patients, reduced postoperative pain during the first hours after surgery, and was associated with a higher incidence of postoperative shivering when compared with instillation.

Effect of Preoperative Inflammatory Status and Comorbidities on Pain Resolution and Persistent Postsurgical Pain after Inguinal Hernia Repair.

Poor acute pain control and inflammation are important risk factors for Persistent Postsurgical Pain (PPSP). The aim of the study is to investigate, in the context of a prospective cohort of patients undergoing hernia repair, potential risk factors for PPSP. Data about BMI, anxious-depressive disorders, neutrophil-tolymphocyte ratio (NLR), proinflammatory medical comorbidities were collected. An analysis for correlation between comorbidities and PPSP was performed in those patients experiencing chronic pain at 3 months after surgery. Tramadol resulted less effective in pain at movement in patients with a proinflammatory status. Preoperative hypertension and NLR > 4 were correlated with PPSP intensity. Regional anesthesia was significantly protective on PPSP when associated with ketorolac. Patients with pain at 1 month were significantly more prone to develop PPSP at 3 months. NSAIDs or weak opioids are equally effective on acute pain and on PPSP development after IHR, but Ketorolac has better profile in patients with inflammatory background or undergoing regional anesthesia. Drug choice should be based on their potential side effects, patients profile (comorbidities, preoperative inflammation, and hypertension), and type of anesthesia. Close monitoring is necessary to early detect pain conditions more prone to progress to a chronic syndrome.

Future Perspectives of ERAS: A Narrative Review on the New Applications of an Established Approach

ERAS approach (Enhanced Recovery After Surgery) is a multimodal, perioperative pathway designed to achieve early recovery after surgery. ERAS has shown documented efficacy in elective surgery, and the concept of “multimodal” and “multidisciplinary” approach seems still to be of higher importance than each single item within ERAS protocols. New perspectives include the use of ERAS in emergency surgery, where efficacy and safety on outcome have been documented, and flexibility of traditional items may add benefits for traditionally high-risk patients. Obstetric surgery, as well, may open wide horizons for future research, since extremely poor data are currently available, and ERAS benefits may translate even on the baby. Finally, the concept of “outcome” may be extended when considering the specific setting of cancer surgery, in which variables like cancer recurrence, early access to adjuvant therapies, and, finally, long-term survival are as important as the reduced perioperative complications. In this perspective, different items within ERAS protocols should be reinterpreted and eventually integrated towards “protective” techniques, to develop cancer-specific ERAS approaches keeping pace with the specific aims of oncologic surgery.

Effect of postoperative analgesia on acute and persistent postherniotomy pain: a randomized study

STUDY OBJECTIVE The study objective is to identify differences in postoperative pain management according to different analgesic treatments, targeting 2 main pathways involved in pain perception. DESIGN The design is a randomized, parallel groups, open-label study. SETTING The setting is in an operating room, postoperative recovery area, and surgical ward. PATIENTS There are 200 patients undergoing open inguinal hernia repair (IHR) with tension-free technique (mesh repair). INTERVENTIONS The intervention is a randomization to receive ketorolac (group K) or tramadol (group T) for 3 days after surgery. MEASUREMENTS The measurements are differences in analgesic efficacy (numeric rating scale [NRS]) in the postoperative (up to 5 days) period, chronic pain incidence (1 and 3 months), side effects, and complications. MAIN RESULTS We found no differences in analgesic efficacy (NRS value ≥4 in the first 96 hours: 26% in group K vs 32% in group T, P = .43); the proportion of patients with NRS ≥4 was similar in both groups, and the time trajectories were not significantly different (P for interaction = .24). Side effects were higher (12% vs 6%) in the tramadol group, although not significantly (P = .14), with a case of bleeding in the ketorolac group and higher incidence of constipation in tramadol group. One patient in each group developed chronic pain. CONCLUSIONS Ketorolac or weak opioids are equally effective on acute pain and on persistent postsurgical pain development after IHR, and drug choice should be based on their potential side effects and patients comorbidities. Further studies are needed to standardize the most rational approach to prevent persistent postsurgical pain after IHR.

Surgical spacer placement prior carbon ion radiotherapy (CIRT): an effective feasible strategy to improve the treatment for sacral chordoma

BackgroundSacral chordoma (SC) is a neoplasm arising from residual notochordal cells degeneration. SC is difficult to manage mainly because of anatomic location and tendency to extensive spread. Carbon ion radiotherapy (CIRT) is highly precise to selectively deliver high biological effective dose to the tumor target sparing the anatomical structure on its path even if when SC is contiguous to the intestine, and a surgical spacer might be an advantageous tool to create a distance around the target volume allowing radical curative dose delivery with a safe dose gradient to the surrounding organs. This paper describes a double approach—open and hand-assisted laparoscopic—for a silicon spacer placement in patients affected by sacral chordoma undergoing carbon ion radiotherapy.MethodsSix consecutive patients have been enrolled for surgical spacer placement—open (three) or hand-assisted (three)—prior carbon ion radiotherapy treatment in order to increase efficacy of carbon ion radiotherapy minimizing its side effects.ResultsResults showed that silicon spacer placement for SC treatment is feasible both via laparoscopic and laparotomic approach.ConclusionsIts use might improve CIRT safety and thus efficacy for SC treatment.

Peritoneal nebulization of ropivacaine during laparoscopic cholecystectomy: Dose finding and pharmacokinetic study

Background. Intraperitoneal nebulization of ropivacaine reduces postoperative pain and morphine consumption after laparoscopic surgery. The aim of this multicenter double-blind randomized controlled trial was to assess the efficacy of different doses and dose-related absorption of ropivacaine when nebulized in the peritoneal cavity during laparoscopic cholecystectomy. Methods. Patients were randomized to receive 50, 100, or 150 mg of ropivacaine 1% by peritoneal nebulization through a nebulizer. Morphine consumption, pain intensity in the abdomen, wound and shoulder, time to unassisted ambulation, discharge time, and adverse effects were collected during the first 48 hours after surgery. The pharmacokinetics of ropivacaine was evaluated using high performance liquid chromatography. Results. Nebulization of 50 mg of ropivacaine had the same effect of 100 or 150 mg in terms of postoperative morphine consumption, shoulder pain, postoperative nausea and vomiting, activity resumption, and hospital discharge timing (>0.05). Plasma concentrations did not reach toxic levels in any patient, and no significant differences were observed between groups (P > 0.05). Conclusions. There is no enhancement in analgesic efficacy with higher doses of nebulized ropivacaine during laparoscopic cholecystectomy. When administered with a microvibration-based aerosol humidification system, the pharmacokinetics of ropivacaine is constant and maintains an adequate safety profile for each dosage tested.

Continuous regional anesthesia: A review of perioperative outcome benefits

Routine use of regional anesthesia for patients having surgery is supported by general safety and proven effectiveness as a targeted modality in the prevention and treatment of acute pain. Recently, perioperative physicians have become much more interested in improving long-term outcomes after surgery rather than focusing on the well-established short-term benefits of regional anesthesia. This interest has raised important questions regarding the potential influence of regional anesthesia on morbidity and mortality, persistent pain and cancer prognosis. Tissue injury is responsible for the inflammatory reaction and physiologic stress response observed during the perioperative period and can influence a patients recovery trajectory. Regional anesthesia can modulate the inflammatory response through the direct anti-inflammatory effect of local anesthetics, blocking neural afferents, and blunting sympathetic activation. Moreover, continuous techniques (e.g., epidural and perineural catheters) that provide longer duration and titratable pain relief in the perioperative period may be protective against the development of persistent post-surgical pain by providing effective acute pain management and decreasing exposure to opioids. To maximize the potential for long-term outcome benefits to surgical patients, continuous regional anesthesia techniques are preferred over single injection techniques. Although the data are not yet definitive, some studies have demonstrated better functional recovery after joint replacement and lower rates of cancer recurrence in patients treated with continuous regional anesthesia. Future research studies in regional anesthesia will have to focus on these long-term patient-centered outcomes and may need to incorporate novel study designs and analyses of big data.