Pain is a common component of inflammatory bowel disease. The substances involved in visceral hyperalgesia are present throughout the gastrointestinal tract and their synthesis is increased during acute clinical episodes of inflammatory bowel disease [1-3]. On the other hand, opioid binding proteins such as α1-glycoprotein acid are involved as acute phase reactants and their concentrations are elevated in inflammatory bowel disease [4,5]. Inflammatory bowel disease could influence opioid requirements during major abdominal surgery through interference with both pharmacokinetic and pharmacodynamic factors. Only one previous study  has compared opioid requirements in Crohn's disease and control patients. The authors demonstrated increased alfentanil requirements linked to pharmacodynamics alteration. However, in this study control patients underwent abdominal surgery, which was not exclusively bowel surgery.
The aims of our study were to compare opioid requirements in Crohn's disease and ulcerative colitis patients during an acute episode requiring bowel surgery to controls benefiting from similar surgery; and to determine whether pharmacokinetics or pharmacodynamics were concerned when an opioid such as sufentanil was used.
Our hospital Ethics Committee approved this study and informed consent was obtained from our patients. Thirty-six patients, aged 18-65 yr, ASA I-II, undergoing major abdominal surgery were included in the study and allocated to three groups. Based on Gesinkvan der Veer and colleagues'  study (12 patients with Crohn's disease and 10 in a control group), it was estimated that inclusion of 12 patients comprising an inflammatory bowel disease group would be sufficient. We then prospectively included all of our patients meeting the entry criteria over a period of 2 years. Patients with clinical evidence of acute episode of Crohn's disease (Crohn's disease activity index : CDAI > 150) and patients with clinical evidence of acute episode of ulcerative colitis (criteria of Edwards and Truelove  > 2) were considered. Patients without inflammatory process served as controls. Patients with clinical or biochemical evidence of renal or hepatic dysfunction or who were taking opioids on a regular basis were excluded. Preoperatively, erythrocyte sedimentation rate (ESR) and plasma concentration of C-reactive protein were measured as laboratory indicators of inflammatory activity.
Thirty minutes before operation all patients received midazolam 0.1 mg kg−1. Before anaesthesia, an internal jugular vein was cannulated for measurement of central venous pressure (CVP). Crystalloid and/or colloid was given to reach a CVP of 8-10 mmHg. Anaesthesia was induced with sufentanil 0.5 μg kg−1, supplemented with propofol 2 mg kg−1. Atracurium was given to facilitate tracheal intubation. Immediately after induction sufentanil was started as a continuous infusion (0.3 μg kg−1 h−1). Muscle relaxation was maintained by continuous infusion of atracurium. Patients' lungs were ventilated with 50% nitrous oxide in oxygen and 0.5 MAC isoflurane; the minute ventilation was adjusted to maintain an end-tidal PCO2 at 4.7 kPa. The electrocardiogram and non-invasive arterial pressure were recorded every 5 min. Urine output and blood loss were recorded every 30 min. Fluid loss was replaced by crystalloid, colloid or patched red cells, as indicated, to maintain adequate urine output (0.5 mL kg−1 h−1), central venous pressure at 8-10 mmHg and haemoglobin concentration above 8 g dL−1.
The infusion rate of sufentanil was adjusted to maintain adequate anaesthesia. Inadequate anaesthesia was defined by the following criteria or combinations of them: (a) an increase in systolic arterial pressure, lasting more than 1 min, of more than 20% baseline systolic blood pressure - defined as the mean of three lowest systolic blood pressure measurements from day 1, with the patient at rest; (b) an increase of heart rate >20% of the normal value lasting more than 1 min in the absence of hypovolaemia. Normal heart rate was defined as the average of the three lowest heart rate measurements from day 1 obtained with patient at rest; (c) other autonomic signs of inadequate anaesthesia, such as lacrymation, flushing or sweating. If inadequate anaesthesia was detected sufentanil 0.2 μg kg−1 was given as a bolus and the infusion rate was increased by 0.1 μg kg−1 h−1. This protocol was repeated every minute, until values returned to normal. The sufentanil infusion was decreased by 0.2 μg kg−1 h−1 rate when haemodynamic variables fell more than 20% of the preoperative values. The sufentanil infusion was discontinued 20 min before skin closure, and nitrous oxide administration was stopped at the end of the surgery.
A subgroup of patients served for pharmacokinetic analysis of sufentanil. We decided to include a minimum number of seven patients per group to achieve adequate statistical analysis. In each group, patients were consecutively included. Once patients were unconscious, a 20-G cannula was placed in the radial artery of the non-dominant arm for blood sampling. Before the sufentanil infusion was started, arterial blood samples were obtained for measurement of sufentanil and plasma concentrations of α1-glycoprotein acid. Plasma sufentanil concentrations were measured from arterial blood samples in heparinized syringes before and 5, 15 and 30 min after each variation of the sufentanil infusion as well as 30 min after it was stopped. Plasma α1-glycoprotein acid concentration and the degree of sufentanil protein binding were also determined in arterial blood drawn just before the sufentanil infusion was stopped. Plasma was separated by centrifugation and stored at −20°C until analysis. The plasma sample was proceeded 1 day after the plasma α1-glycoprotein acid concentration was measured by immunonephelometry (Dade Berhing, Paris, France). The plasma protein binding of sufentanil was assessed by equilibrium dialysis using 3H sufentanil (Dianorm®; Diachema AG, Zurich, Switzerland). Plasma sufentanil concentration was measured in duplicate by radioimmunoassay  (Janssen Research Foundation, Val de Reuil, France). The coefficients of variation in the concentration ranges encountered in the study were <5% for both α1-glycoprotein acid and sufentanil.
During the study, all patients were cared for by anaesthesiologists using the definition of inadequate anaesthesia used in this study. All surgical procedures were performed by the same surgical team.
The average total sufentanil consumption (μg kg−1 h−1), including the loading dose, was calculated for each patient. Additional sufentanil requirements (excluding loading dose and continuous infusion rate at 0.3 μg kg−1 h−1) were calculated for each patient during surgery for the following periods:
• Add 1 - additional sufentanil requirements during the time from induction until incision;
• Add 2 - additional sufentanil requirements during the time from incision until abdominal wall retraction;
• Add 3 - additional sufentanil requirements during the time from wall retraction until bowel resection;
• Add 4 - additional sufentanil requirements during the time from bowel resection until skin closure.
Total plasma sufentanil clearance was calculated by the trapezoidal rule, from the area under the plasma sufentanil concentration-time curve to the last measured plasma sufentanil concentration.
Data were presented as median (25-75%) and were compared by the Kruskal-Wallis test and the Bonferoni-Holm post hoc test; P < 0.05 was assumed as significant. Linear regression was used to assess a possible relationship between the average sufentanil requirement and the α1-glycoprotein acid concentration, C-reactive protein concentration and ESR values.
Thirty-six patients were included: there was no difference in patient characteristics data between the three groups (Table 1). In the group with inflammatory bowel disease, the indication for surgery was an acute inflammatory episode not responding to medical treatment. In the control group, surgery was performed for dolichocolon (an abnormally long colon or megacolon), polyposis, colic adenoma and adenocarcinoma. Twelve patients in the group with inflammatory bowel disease received corticosteroid therapy. In four patients in the Crohn's disease group, and two patients in the ulcerative colitis group, this therapy was tapered and discontinued within 4 weeks before surgery. In one patient with Crohn's disease and five patients with ulcerative colitis, corticosteroid therapy was continued perioperatively. Seven Crohn's disease patients and five ulcerative colitis patients received sulphasalazine. No inflammatory bowel disease group patients received antibiotics or salicylates during the preoperative period. Patients in the control group did not receive any medication. C-reactive protein plasma concentrations were greater in inflammatory bowel disease group patients than in control group (Table 1). ESR plasma values were not different between the three groups. There was no correlation between the average sufentanil requirement and the α1-glycoprotein acid concentration and C-reactive protein concentration and the ESR value.
All the patients underwent comparable surgery that consisted of median abdominal wall incision and bowel resection. The duration of surgery was similar between the three groups (Table 1).
The duration of sufentanil administration did not differ significantly between the three groups (Table 1). Intraoperative sufentanil consumption was greater in inflammatory bowel disease patients than in the controls (Table 1). Opioid consumption varied according to the group and according to the time of period of surgery. During skin incision and abdominal wall retraction (Add 2) and at peritoneum and skin closure (Add 4), a larger opioid requirement was noticed in the inflammatory bowel disease group compared to the control group (Fig. 1). During intestinal dissection (Add 3), additional sufentanil requirement was greater in the inflammatory bowel disease group than in control patients; this was significant only between ulcerative colitis and control patients (Fig. 1). In the control group, no major additional sufentanil opioid requirement was observed (Fig. 1). Moreover, in four control patients the sufentanil administration had to be decreased and stopped before the end of surgery. This was never observed in the inflammatory bowel disease group.
Inadequate blood sampling precluded formal pharmacokinetic analysis in two Crohn's disease patients. Eighteen patients were assessed for pharmacokinetic analysis. They were distributed in three groups: Crohn's disease (n = 5), ulcerative colitis (n = 7) and control (n = 6). We ensured that these patients were representative of the entire population. These three groups were comparable for patient characteristics data and ASA status, indication and duration of surgery (Table 1). As observed for the entire population, intraoperative sufentanil consumption was larger in the Crohn's disease and the ulcerative colitis groups than in the control group (Table 2). Plasma concentrations of α1-glycoprotein acid in the samples collected before induction were significantly higher in the inflammatory bowel disease group than in the control group. There was no correlation between sufentanil requirement and α1-glycoprotein acid concentration in the three groups. The maximal sufentanil concentration was not different between the three groups. Total plasma sufentanil clearance was significantly increased in the inflammatory bowel disease group compared to controls (Table 2).
Our study clearly demonstrates an increased opioid requirement for patients with inflammatory bowel disease, whether they had Crohn's disease or ulcerative colitis. This was especially observed during abdominal wall incision and closure. Our protocol was based upon sufentanil titration according to variation of clinical parameters, other anaesthesia components being unchanged. The titration was conducted by a select team of anaesthetists. We did not monitor depth of anaesthesia, but we assumed that haemodynamic differences were mainly related to pain and visceral hyperalgesia associated with inflamed tissue. One important aspect of our findings is that the largest increased opioid requirement was observed during abdominal wall incision, suggesting that it corresponds to the referred dermatomes of inflamed small and large intestines. During surgical incision, pain stimulation was comparable in each patient, and inflammatory bowel disease patients were the only ones requiring additional analgesic infusion. All patients, including those in the control group, underwent the same surgical procedures with a midline incision and intestinal resection therefore allowing appropriate comparison. Increased C-reactive protein plasma concentrations in the inflammatory bowel disease patients (Table 1) served as a biological marker of inflammatory activity in our patients. In contrast, the ESR did not help to identify inflammation. Even if the ESR is included in some scores to predict relapses in Crohn's disease  and ulcerative colitis , C-reactive protein concentrations have been shown to correspond better with clinical and pathological indices of relapse, remission and response to therapy in inflammatory bowel disease [11,12]. Inflammatory activity was therefore the only clinical difference between the inflammatory bowel disease group and the control patients.
The inflammatory process may influence sufentanil requirements through pharmacokinetics. α1-glycoprotein acid is the major binding protein for sufentanil and is one of acute phase reactant. According to previous studies [4-6], α1-glycoprotein acid concentrations were increased in inflammatory bowel disease in our pharmacological study. However, this increased α1-glycoprotein acid concentration was not associated with an altered degree of protein binding; the free sufentanil fraction did not differ from that in the control patients. Furthermore, there was no correlation between α1-glycoprotein acid concentrations and opioid requirements. The plasma concentration of sufentanil was not different between the three groups, but sufentanil clearance was significantly increased in patients with inflammatory bowel disease compared to the control group (Table 2). An explanation for an increased sufentanil metabolic clearance remains to be found.
Concurrent medication could influence pharmaco-kinetic or pharmacodynamic drug parameters. In this respect, the three groups were different. Patients with inflammatory bowel disease received glucocorticosteroids in contrast to controls who did not. All patients with inflammatory bowel disease received prednisolone or methylprednisolone, which are not inducers of major enzymes responsible for metabolizing sufentanil . Glucocorticosteroids have ability to reduce inflammatory swelling [14,15] and contribute to pain relief. One would expect, therefore, that patients receiving glucocorticosteroids preoperatively would require less opioids for postoperative pain relief. However, we found that the six patients with inflammatory bowel disease, receiving glucocorticosteroids, required much more opioid than did patients in the control group. We speculate that the glucocorticosteroids were not directly involved in this increased opioid requirement but was related to a more severe inflammatory process. Twelve patients with inflammatory bowel disease received sulphasalazine. We are not aware of any study documenting the influence of these drugs on the pharmacodynamics of opioids. To our knowledge sulphasalazine does not affect the perception of pain.
A second important result from our study is the variation of opioid requirement during the different stages of surgery (Fig. 1). We observed the largest opioid consumption in inflammatory bowel disease during the skin and abdominal wall incisions (Add 2) and during skin closure (Add 4) - this is in contrast to the control group in which no increased requirement was observed. During these two stages of surgery, pain stimulation did not result from the inflammatory bowel but from the abdominal wall. Over the last decade, many experimental and clinical studies have shown that increased gut inflammatory mediators generate visceral hyperalgesia [16,17] associated with somatic hyperalgesia in lumbosacral-referred dermatomes [18-20]. We speculate that increased opioid requirement during abdominal wall pain stimulation is linked to this somatic hyperalgesia in referred dermatomes.
The increased sufentanil requirement in patients with Crohn's disease and ulcerative colitis, which we observed in our study, confirms that inflammation interferes with analgesia through both pharmacokinetic and pharmacodynamic components.
The authors thank Patrick Devos (Department of Biostatistics, University Hospital of Lille) for his help in conducting statistical analyses, and our staff of anaesthesia nurses (Department of Anaesthesiology, University Hospital of Lille).
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