B. Guignard

BACKGROUND: Rapid development of acute opioid tolerance is well established in animals and is more likely to occur with large doses of short-acting drugs. The authors therefore tested the hypothesis that intraoperative remifentanil administration results in acute opioid tolerance that is manifested by increased postoperative pain and opioid requirement. METHODS: Fifty adult patients undergoing major abdominal surgery were randomly assigned to two anesthetic regimens: (1) desflurane was kept constant at 0.5 minimum alveolar concentrations and a remifentanil infusion was titrated to autonomic responses (remifentanil group); or (2) remifentanil at 0.1 microg. kg-1. min-1 and desflurane titrated to autonomic responses (desflurane group). All patients were given a bolus of 0.15 mg/kg morphine 40 min before the end of surgery. Morphine was initially titrated to need by postanesthesia care nurses blinded to group assignment. Subsequently, patients-who were also blinded to group assignment-controlled their own morphine administration. Pain scores and morphine consumption were recorded for 24 postoperative h. RESULTS: The mean remifentanil infusion rate was 0.3 +/- 0.2 microg. kg-1. min-1 in the remifentanil group, which was significantly greater than in the desflurane group. Intraoperative hemodynamic responses were similar in each group. Postoperative pain scores were significantly greater in the remifentanil group. These patients required morphine significantly earlier than those in the desflurane group and needed nearly twice as much morphine in the first 24 postoperative h: 59 mg (25-75% interquartile range, 43-71) versus 32 mg (25-75% interquartile range, 19-59; P < 0.01). CONCLUSIONS: Relatively large-dose intraoperative remifentanil increased postoperative pain and morphine consumption. These data suggest that remifentanil causes acute opioid tolerance and hyperalgesia.

BACKGROUND: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia. METHODS: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 microg x kg(-1) x min(-1) (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 microg x kg(-1) x min(-1) until skin closure and then 2 microg x kg(-1) x min(-1) for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h. RESULTS: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects. CONCLUSION: A relatively large dose of intraoperative remifentanil triggers postoperative secondary hyperalgesia. Remifentanil-induced hyperalgesia was prevented by small-dose ketamine, implicating an N-methyl-d-aspartate pain-facilitator process.

UNLABELLED: In order to examine whether changes in the bispectral index (BIS) may be an adequate monitor for the analgesic component of anesthesia, we evaluated the effect of remifentanil on the BIS change and hemodynamic responses to laryngoscopy and tracheal intubation. Fifty ASA physical status I patients were randomly assigned, in a double-blinded fashion, to one of five groups (n = 10/group) according to the remifentanil target effect compartment site concentration (0, 2, 4, 8, or 16 ng/mL). The target-controlled infusion (TCI) of remifentanil was initiated 3 min after the TCI of propofol that was maintained at the effect-site concentration of 4 microg/mL throughout the study. After the loss of consciousness and before the administration of vecuronium 0.1 mg/kg, a tourniquet was applied to one arm and inflated above the systolic blood pressure in order to detect any gross movement within the first minute after tracheal intubation, which was performed 3 min after remifentanil TCI began. A BIS value was generated every 10 s. Arterial blood pressure and heart rate (HR) were measured every minute, noninvasively. Measures of mean arterial pressure (MAP), HR, and BIS were obtained before the induction, before the start of remifentanil TCI, before laryngoscopy, and 5 min after intubation. The relationships between remifentanil effect-site concentrations and BIS change or hemodynamic responses (changes in MAP and HR) to intubation were determined by logarithmic regression. BIS values were not affected by remifentanil before laryngoscopy. During this period, MAP and HR decreased significantly (P < 0.01) in the remifentanil 8 and 16 ng/mL groups. Changes in BIS, MAP, and HR were negatively correlated with remifentanil effect-site concentration (P < 0.0001). The number of movers in the remifentanil 0-, 2-, 4-, 8-, and 16-ng/mL groups was, respectively, 10, 9, 7, 1, and 0. Hypotensive episodes (MAP < 60 mm Hg) were noted in 1, 2, and 5 patients in the remifentanil 4-, 8-, and 16-ng/mL groups, respectively. We conclude that the addition of remifentanil to propofol affects BIS only when a painful stimulus is applied. Moreover, remifentanil attenuated or abolished increases in BIS and MAP after tracheal intubation in a comparable dose-dependent fashion. IMPLICATIONS: Bispectral index change is as sensitive as hemodynamic responses after a painful stimulus for detecting deficits in the analgesic component of anesthesia. It may, therefore, be a useful monitor of the depth of anesthesia in patients who are incapable of HR and MAP responses to noxious stimuli because of medications or cardiovascular disease.

Gabapentin has antihyperalgesic and anxiolytic properties. We thus tested the hypothesis that premedication with gabapentin would decrease preoperative anxiety and improve postoperative analgesia and early postoperative knee mobilization in patients undergoing arthroscopic anterior cruciate ligament repair under general anesthesia. Forty patients were randomly assigned to receive 1200 mg oral gabapentin or placebo 1-2 h before surgery; anesthesia was standardized. Patients received morphine, 0.1 mg/kg, 30 min before the end of surgery and postoperatively via a patient-controlled pump. Pain scores and morphine consumption were recorded over 48 h. Degrees of active and passive knee flexion and extension were recorded during physiotherapy on days 1 and 2. Preoperative anxiety scores were less in the gabapentin than control group (visual analog scale scores of 28 +/- 16 mm versus 66 +/- 15 mm, respectively; P < 0.001). The gabapentin group required less morphine than the control group (29 +/- 22 mg versus 69 +/- 40 mg, respectively; P < 0.001). Visual analog scale pain scores at rest and after mobilization were significantly reduced in the gabapentin group. First and maximal passive and active knee flexions at 24 and 48 h were significantly more extensive in the gabapentin than in the control group. In conclusion, premedication with 1200 mg gabapentin improved preoperative anxiolysis, postoperative analgesia, and early knee mobilization after arthroscopic anterior cruciate ligament repair.

UNLABELLED: In a randomized, double-blinded study with three parallel groups, we assessed the analgesic effect of intraoperative ketamine administration in 45 ASA physical status I or II patients undergoing elective arthroscopic anterior ligament repair under general anesthesia. The patients received either IV ketamine 0.15 mg/kg after the induction of anesthesia and before surgical incision and normal saline at the end of surgery (PRE group); normal saline after the induction of anesthesia and before surgical incision and IV ketamine at the end of surgery (POST group); or normal saline at the beginning and the end of surgery (CONT group). Anesthesia was performed with propofol (2 mg/kg for induction, 60-200 microg x kg(-1) x min(-1) for maintenance), sufentanil (0.2 microg/kg 10 min after surgical incision, followed by an infusion of 0.25 microg x kg(-1) x h(-1) stopped 30 min before skinclosure), vecuronium (0.1 mg/kg), and 60% N2O in O2 via a laryngeal mask airway. Postoperative analgesia was initially provided with IV morphine in the postanesthesia care unit, then with IV patient-controlled analgesia started before discharge from the postanesthesia care unit. Pain scores, morphine consumption, side effects, and degree of knee flexion were recorded over 48 h and during the first and second physiotherapy periods, performed on Days 1 and 2. Patients in the ketamine groups required significantly less morphine than those in the CONT group over 48 h postoperatively (CONT group 67.7+/-38.3 mg versus PRE group 34.3+/-23.2 mg and POST group 29.5+/-21.5 mg; P < 0.01). Better first knee flexion (CONT group 35+/-10 degrees versus PRE group 46+/-12 degrees and POST group 47+/-13 degrees; P < 0.05) and lower morphine consumption (CONT group 3.8+/-1.7 mg versus PRE group 1.2+/-0.4 mg and POST group 1.4+/-0.4 mg; P < 0.05) were noted at first knee mobilization. No differences were seen between the PRE and POST groups, except for an increase in morphine demand in the PRE versus the POST group (P < 0.05) in the second hour postoperatively. IMPLICATIONS: We found that intraoperative small-dose ketamine reduced postoperative morphine requirements and improved mobilization 24 h after arthroscopic anterior ligament repair. No differences were observed in the timing of administration. Intraoperative small-dose ketamine may therefore be a useful adjuvant to perioperative analgesic management.