Dominique Fletcher

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.

BACKGROUND: Chronic postsurgical pain (CPSP) is an important clinical problem. Prospective studies of the incidence, characteristics and risk factors of CPSP are needed. OBJECTIVES: The objective of this study is to evaluate the incidence and risk factors of CPSP. DESIGN: A multicentre, prospective, observational trial. SETTING: Twenty-one hospitals in 11 European countries. PATIENTS: Three thousand one hundred and twenty patients undergoing surgery and enrolled in the European registry PAIN OUT. MAIN OUTCOME MEASURES: Pain-related outcome was evaluated on the first postoperative day (D1) using a standardised pain outcome questionnaire. Review at 6 and 12 months via e-mail or telephonic interview used the Brief Pain Inventory (BPI) and the DN4 (Douleur Neuropathique four questions). Primary endpoint was the incidence of moderate to severe CPSP (numeric rating scale, NRS ≥3/10) at 12 months. RESULTS: For 1044 and 889 patients, complete data were available at 6 and 12 months. At 12 months, the incidence of moderate to severe CPSP was 11.8% (95% CI 9.7 to 13.9) and of severe pain (NRS ≥6) 2.2% (95% CI 1.2 to 3.3). Signs of neuropathic pain were recorded in 35.4% (95% CI 23.9 to 48.3) and 57.1% (95% CI 30.7 to 83.4) of patients with moderate and severe CPSP, respectively. Functional impairment (BPI) at 6 and 12 months increased with the severity of CPSP (P < 0.01) and presence of neuropathic characteristics (P < 0.001). Multivariate analysis identified orthopaedic surgery, preoperative chronic pain and percentage of time in severe pain on D1 as risk factors. A 10% increase in percentage of time in severe pain was associated with a 30% increase of CPSP incidence at 12 months. CONCLUSION: The collection of data on CPSP was feasible within the European registry PAIN OUT. The incidence of moderate to severe CPSP at 12 months was 11.8%. Functional impairment was associated with CPSP severity and neuropathic characteristics. Risk factors for CPSP in the present study were chronic preoperative pain, orthopaedic surgery and percentage of time in severe pain on D1. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01467102.

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.