PHARMACOKINETICS AND ANALGESIC EFFECT OF ROPIVACAINE DURING CONTINUOUS EPIDURAL INFUSION FOR POSTOPERATIVE PAIN RELIEF

Background: The pharmacokinetics and clinical efficacy of ropivacaine (2.5 mg/ml) during a 24-h continuous epidural infusion for postoperati ve pain relief in 20 patients scheduled for abdominal hysterectomy wer e characterized using an open-label, increasing-dose design. Methods: Through an epidural catheter inserted at T10-T12, a test dose of 7.5 m g ropivacaine was given 3 min before a bolus dose of 42.5 mg and immed iately followed by a 24-h continuous epidural infusion with either 10 or 20 mg/h. Peripheral venous plasma samples were collected up to 48 h after infusion, and urinary excretion was followed up to the end of i nfusion. Postoperative pain at rest, on coughing, and at mobilization was assessed by means of a visual analog scale 2, 4, 6, 8, 12, and 24 h after the end of surgery. Sensory (pinprick) and motor block (modifi ed Bromage scale) were assessed at the same intervals. Results: The to tal plasma concentrations of ropivacaine increased markedly and consis tently during the 24-h epidural infusion, in contrast to stable unboun d concentrations. Both total and unbound plasma concentrations at the end of infusion were proportional to the total dose, although only the latter was proportional to the infusion rate, The total and unbound p lasma clearance was Independent of dose. Total mean clearance decrease d on average by 21% (P < 0.001) during the last 12 h of epidural infus ion, i.e., from 539 +/- 191 ml/min to 418 +/- 138 ml/min, indicating t ime-dependent kinetics. The unbound clearance also varied between esti mates after 8 h of infusion and the end of treatment, i.e., a 5.3% dec rease from 10.4 +/- 5.3 l/min to 9.5 +/- 3.9 l/min (P < 0.05). The unb ound fraction of ropivacaine in plasma decreased during treatment, and this was related to the increase in alpha(1)-acid glycoprotein concen tration Pain was generally well controlled, and median visual analog s cale scores during mobilization were less than 30 mm in patients recei ving ropivacaine at 20 mg/h. Conclusions: The pharmacokinetics of ropi vacaine were independent of dose, but total clearance decreased with t ime over 24 h, The consistent increase in total plasma concentration d uring the postoperative epidural infusion contrasted to much less vari ation in the unbound plasma concentrations of ropivacaine.