title: A Comparison of Differences Between the Systemic Pharmacokinetics of Levobupivacaine and Ropivacaine During Continuous Epidural Infusion: A Prospective, Randomized, Multicenter, Double-Blind Controlled Trial.
abstract: BACKGROUND
  Epidural infusion of levobupivacaine and ropivacaine provides adequate postoperative pain management by minimizing side effects related to IV opioids and improving patient outcome. The safety profile of different drugs can be better estimated by comparing their pharmacokinetic profiles than by considering their objective side effects. Because levobupivacaine and ropivacaine have different pharmacokinetic properties, our aim was to investigate whether there is a difference in the pharmacokinetic variability of the 2 drugs in a homogeneous population undergoing continuous epidural infusion. This double-blind, multicenter, randomized, controlled trial study was designed to compare the pharmacokinetics of continuous thoracic epidural infusion of levobupivacaine 0.125% or ropivacaine 0.2% for postoperative pain management in adult patients who had undergone major abdominal, urological, or gynecological surgery. This study is focused on the evaluation of the coefficient of variation (CV) to assess the equivalence in the systemic exposure and interindividual variability between levobupivacaine and ropivacaine and, therefore, the possible differences in the predictability of the plasmatic concentrations of the 2 drugs during thoracic epidural infusion.
  
  
  METHODS
  One hundred eighty-one adults undergoing major abdominal surgery were enrolled in the study. Patients were randomized to receive an epidural infusion of levobupivacaine 0.125% + sufentanil 0.75 μg/mL or of ropivacaine 0.2% + sufentanil 0.75 μg/mL at 5 mL/h for 48 hours. The primary end point of this study was to analyze the variability of plasma concentration of levobupivacaine and ropivacaine via an area under the curve within a range of 15% of the CV during 48 hours of continuous epidural infusion. The CV shows how the concentration values of local anesthetics are scattered around the median concentration value, thus indicating the extent to which plasma concentration is predictable during infusion. Secondary end points were to assess the pharmacologic profile of the local anesthetics used in the study, including an analysis of mean peak plasma concentrations, and also to assess plasma clearance, side effects, pain intensity (measured with a verbal numeric ranging score, i.e., static Numeric Rating Scale [NRS] and dynamic NRS]), and the need for rescue doses.
  
  
  RESULTS
  The comparison between the 2 CVs showed no statistical difference: the difference between area under the curve was within the range of 15%. The CV was 0.54 for levobupivacaine and 0.51 for ropivacaine (P = 0.725). The plasma concentrations of ropivacaine approached the Cmax significantly faster than those of levobupivacaine. Clearance of ropivacaine decreases with increasing patient age. There were no significant differences in NRS, dynamic NRS scores, the number of rescue doses, or in side effects between groups.
  
  
  CONCLUSIONS
  Considering the CV, the interindividual variability of plasma concentration for levobupivacaine and ropivacaine is equivalent after thoracic epidural infusion in adults. We found a reduction in clearance of ropivacaine depending on patient age, but this finding could be the result of some limitations of our study. The steady-state concentration was not reached during the 48-hour infusion and the behavior of plasma concentrations of ropivacaine and levobupivacaine during continuous infusions lasting more than 48 hours remains to be investigated, because they could reach toxic levels. Finally, no differences in the clinical efficacy or in the incidence of adverse effects between groups were found for either local anesthetic.
authors.affiliation: From the *Anesthesia and Intensive Care III, Cardiothoracic and Vascular Surgery Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; †Unit of Clinical Pharmacokinetics in Transplant and Autoimmune Diseases, Infectious Diseases Department, Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; ‡Department of Anesthesia, Montreal Children's Hospital, Alan Edwards Research Center for Pain, McGill University, Montreal, Canada; §Anesthesia and Intensive Care I, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; ∥Anesthesia and Intensive Care I. Ca'Granda Niguarda Hospital, Milano, and Università degli Studi of Milan Bicocca, Milan, Italy; ¶Anesthesia and Intensive Care I. San Gerardo Hospital, Monza, Italy; #Department of Experimental Medicine. University of Milan Bicocca, Milan, Italy; **Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; ††Department of Anesthesia, Critical Care and Pain Medicine, General University Hospital, Valencia, Spain; ‡‡Department of Anesthesiology, Critical Care and Pain Medicine, University of Parma, Parma, Italy; §§Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; ∥∥Unit of Clinical Pharmacokinetics in Transplant and Autoimmune Diseases, Infectious Diseases Department, Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; ¶¶Department of Surgical Sciences, University of Parma, Parma, Italy; and ##Anesthesia, Intensive Care and Pain Medicine Department, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; SIMPAR Group.
authors.forename: Luciano
authors.initials: L
authors.lastname: Perotti
authors.forename: Maria
authors.initials: M
authors.lastname: Cusato
authors.forename: Pablo
authors.initials: P
authors.lastname: Ingelmo
authors.forename: Thekla Larissa
authors.initials: TL
authors.lastname: Niebel
authors.forename: Marta
authors.initials: M
authors.lastname: Somaini
authors.forename: Francesca
authors.initials: F
authors.lastname: Riva
authors.forename: Carmine
authors.initials: C
authors.lastname: Tinelli
authors.forename: José
authors.initials: J
authors.lastname: De Andrés
authors.forename: Guido
authors.initials: G
authors.lastname: Fanelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Braschi
authors.forename: Mario
authors.initials: M
authors.lastname: Regazzi
authors.forename: Massimo
authors.initials: M
authors.lastname: Allegri
mesh_terms: D000005:Abdomen / Q000601:surgery*; D000368:Aged; D000577:Amides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002045:Bupivacaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D060186:Infusions, Spinal; D007558:Italy; D000077554:Levobupivacaine; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010147:Pain Measurement; D010149:Postoperative Pain / Q000175:diagnosis / Q000517:prevention & control*; D011446:Prospective Studies; D000077212:Ropivacaine; D013810:Therapeutic Equivalency; D016896:Treatment Outcome
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D000077212:Ropivacaine; D000077554:Levobupivacaine; D002045:Bupivacaine