Pre-emptive effect of epidural sufentanil in abdominal hysterectomy

E. I. Akural*,1, T. E. Salomäki1, A. H. Tekay2, A. H. Bloigu3 and S. M. Alahuhta1

1Department of Anaesthesiology, University of Oulu. 2Department of Obstetrics and Gynaecology, University of Oulu. 3National Public Health Institute, Oulu, Finland*Corresponding author: Department of Anaesthesiology, University Hospital of Oulu, PO Box 5000, FIN-90014, University of Oulu, Oulu, Finland

Accepted for publication: January 28, 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Experimental studies suggest pre-emptive administration of analgesics is effective but clinical evidence is less convincing.

Methods. Forty-one patients undergoing abdominal hysterectomy were allocated randomly in a double-blind fashion to receive sufentanil 50 µg via a lumbar epidural catheter before or at the end of surgery.

Results. Sufentanil consumption from a patient-controlled epidural analgesia (PCEA) system and numerical pain scores at rest and during movement over the initial 72 h were similar in the two groups. When the study period was divided into five time intervals, sufentanil consumption in the pre-emptive group was significantly less than in the control group between 8 and 16 h after surgery (P=0.04). Furthermore, the number of failed bolus attempts from the PCEA device was significantly lower and patient satisfaction was significantly better in the pre-emptive group during the 72 h of PCEA treatment (P<0.05). In addition, the median decrease in ACTH and cortisol on the first postoperative morning relative to baseline values was greater in the pre-emptive group than in the control group (P<0.05). In subjects who had a Pfannenstiel incision, touch and pain sensitivity in the wound area were less in the pre-emptive group over the first 4 postoperative days (P<0.05).

Conclusions. We conclude that pre-emptive analgesia with epidural sufentanil was associated with a short-term sufentanil-sparing effect, and could have reduced stress hormone responses and wound sensitization after abdominal hysterectomy.

Br J Anaesth 2002; 88: 803–8

Keywords: analgesia, pre-emptive; pain, postoperative; pain, threshold; stress; surgery, gynaecological


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In animals, continued pain after injury is accompanied by functional changes in the nervous system, including reduced thresholds of tissue nociceptors and increased excitability of the central nervous system (CNS) (central sensitization).1 Pre-emptive analgesia describes the concept of being able to reduce pain perception and overall analgesic needs by using agents to inhibit CNS sensitization before the application of painful stimuli. Opioids can reduce central neurone activation by presynaptically inhibiting neurotransmitter release from primary afferent terminals2 or by postsynaptically reducing the firing of dorsal horn nociresponsive neurones,3 thereby inhibiting central sensitization. Some clinical trials on pre-emptive analgesia using the i.v.4 5 and epidural68 administration of opioids indicate that the pre-emptive administration of analgesics can lead to clinically appreciable analgesic effects. Possible long-term clinical benefits from pre-emptive analgesia remain controversial.9

We considered that pre-emptive lumbar epidural sufentanil could attenuate central sensitization, reduce the need for postoperative epidural sufentanil and reduce postoperative hormonal responses. To test this hypothesis, we compared the effects of epidural sufentanil given before or at the end of surgery in women undergoing abdominal hysterectomy.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
After obtaining approval from the local ethics committee and written informed consent from the patients, we studied 44 healthy women (ASA physical status I and II) undergoing elective total abdominal hysterectomy with or without salpingo-oophorectomy. A prospective, randomized (sealed envelopes), double-blind design was used, with both patients and postoperative assessors blinded to intraoperative management. Exclusion criteria were a previous history of a chronic pain condition or regular ingestion of analgesic drugs, a psychiatric history and any contraindication to epidural anaesthesia. None of the patients were narcotic addicts or had received any opioids for pain treatment.

On the day before surgery, patients were made familiar with the use of a numerical rating scale (NRS; 0=no pain, 10=worst pain imaginable)10 and instructed in the use of the patient-controlled epidural analgesia (PCEA) device. The patients were premedicated with diazepam 10 mg approximately 1 h before operation. An epidural catheter (18G epidural minipack; SIMS Portex, Hythe, UK) was inserted via a midline approach at the L1–L2 interspace using the loss of resistance technique before induction of general anaesthesia.

The patients were divided into two groups. Patients in the pre-emptive group received a fixed dose of sufentanil 50 µg dissolved in normal saline 20 ml as an infusion over 20 min, begun before the induction of general anaesthesia and ending just before surgical incision. This was followed by an epidural infusion of normal (0.9%) saline 20 ml over 20 min at the end of surgery, started after closure of the peritoneum. Patients in the control group received the same treatment but in reverse order.

Anaesthesia was induced in both groups using propofol 2–3 mg kg–1, glycopyrrolate 0.2 mg, isoflurane and vecuronium 0.1 mg kg–1 to facilitate orotracheal intubation with a cuffed tube. Anaesthesia was maintained with a continuous infusion of propofol 5–10 mg kg–1 h–1 and isoflurane 1–2% end-tidal concentration in an oxygen-air mixture. No supplementary analgesia was given during anaesthesia. All patients received an i.v. infusion of normal (0.9%) saline during surgery and until the first postoperative morning.

Surgery was performed via a Pfannenstiel (transverse lower abdominal) incision or a vertical midline incision.

After spontaneous respiration had been re-established, the patient was transferred to the postanaesthesia care unit and remained there overnight. Patients were immediately free to use the PCEA device. Postoperative analgesic requirements were measured using a PCEA system (Graseby 9300 PCA pump; SIMS Graseby, Watford, UK) programmed to deliver a bolus dose of sufentanil 4 µg at a concentration of 2 µg ml–1 at intervals of 6 min (the bolus dose was infused over 5 min with a subsequent lockout time of 1 min). There was no background infusion. Anaesthetist-administered bolus doses of sufentanil were also available in the recovery room at emergence for patients with inadequate analgesia. Acetaminophen was prescribed for fever or pain that did not result from the surgical wound (such as a headache) during the first 3 days. This regimen was continued for 3 days.

Pain and touch sensitivity were assessed during the 1st, 2nd, 3rd and 4th postoperative days in the morning, with von Frey hairs on the abdomen 10 cm above the wound in subjects who had been operated using a Pfannenstiel incision. Touch and pain thresholds were determined with 20 progressively rigid von Frey hairs weighing 0.008– 279.4 g (Semmes-Weinstein Von Frey Anesthesiometer Kit; North Coast Medical, San Jose, CA, USA). We examined the force (in grams) required to bend a von Frey hair on the patient’s skin. Touch threshold was the smallest pressure that could be detected. Pain threshold was the smallest pressure that produced a definite sensation of pain.5

Pain scores on a numerical rating scale (NRS; 0=no pain, 10=worst pain imaginable) were obtained at rest (NRS-R) and after movement (changing sides in the supine position on the operation day, the morning of the first postoperative day and walking on the other days) (NRS-M). Pain scores were recorded by trained nurses at the following times: 2, 4, 6, 8, 10 and 12 h after the operation, on the first postoperative day at 7 a.m. and 3 p.m., on the second postoperative day at 10 a.m. and 3 p.m. and on the third and fourth postoperative days at 10 a.m. Patient satisfaction with the quality of analgesia during PCEA treatment was rated using a category scale11 (excellent, good, satisfactory, poor) on discharge from the hospital. Questionnaires about pain (NRS-R, NRS-M) 2 and 4 weeks after surgery were given to each patient or mailed to the patients with stamped return envelopes.

Neuroendocrine stress responses were assessed by measuring plasma concentrations of ß-endorphin, adrenocorticotropin (ACTH), cortisol and glucose before insertion of the epidural catheter (baseline concentration), 4 h after surgery and between 7 and 8 a.m. on the first postoperative morning (first postoperative day concentration). Blood samples were obtained via a venous catheter inserted in the antecubital fossa. Blood samples for plasma ACTH, ß-endorphin and sufentanil analyses were collected into 10 ml tubes treated with EDTA (ethylenediamine tetraacetic acid) and transported in ice for centrifugation. The collected plasma was stored at –20°C until assayed. Glucose concentrations were determined by a routine glucose oxidase method (Glucose, Granutest 250; Merck) with a normal reference range of 3.9–5.6 mmol litre–1.

Plasma ACTH, ß-endorphin and serum cortisol were measured by radioimmunoassay. Details of these assays have been published previously.12 Blood samples for measurement of sufentanil concentration were drawn 4 h after surgery and between 7 and 8 a.m. on the first postoperative morning. Sufentanil concentrations were determined by radioimmunoassay at the Bioanalytical Laboratory of Janssen Pharmaceutica. The lowest detection limit for the assay was 0.010 ng ml–1.

The presence and intensity of side-effects and the respiratory rate were noted along with pain intensity assessments. Sedation was graded using a four-point drowsiness score (0=awake and alert, 1=awake but drowsy, 2=drowsy but rousable, 3=unrousable). Nausea and itching were noted as none, light, moderate or severe.

The sample size (44) was estimated to show a clinically useful difference in mean epidural sufentanil consumption over the first 24 h with 95% power at a significance level of 0.05. A difference of 25% in sufentanil consumption was considered to be clinically significant. The power calculation was based on results reported by Geller and colleagues.13

We used SPSS for Windows version 9.0 for statistical analysis and the CIA (Confidence Interval Analysis) version 1.2 software to calculate 95% confidence intervals (CI). Statistical analysis was with Student’s t-test for normally distributed data and the Mann–Whitney U-test for skewed data. The Wilcoxon signed rank test was used to analyse changes between baseline and postoperative values within the groups. NRS pain scores and the von Frey threshold were plotted against time and the area under the resulting curves were calculated (AUC NRS). The incidence of side-effects and patient satisfaction were compared using the {chi}2 test. Data are presented as mean (SD) and median [interquartile range (IQR)] where appropriate; a P value less than 0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Three of the initial 44 patients were not studied. The reasons for this were a wish to withdraw from the study, protocol violation and reoperation because of bleeding. After exclusions, there were 20 patients in the pre-emptive group and 21 in the control group. The two groups were similar with regard to patient data and operative procedures (Table 1). There were no significant differences between the groups in the NRS-R (Fig. 1A) and during mobilization (NRS-M) at any time during the study period (Fig. 1B), nor was there any difference in NRS-R and NRS-M pain scores, expressed as AUC over 3 days (Table 2). Sufentanil consumption via PCEA over time intervals is demonstrated in Figure 2. The pre-emptive group [42 µg (IQR 28–83)] used less sufentanil in the 8–16 h period compared with the control group [72 µg (IQR 48–102), P=0.04]. Sufentanil consumption during this period was also significantly less than in the first 8 h in the pre-emptive group but not in the control group (P=0.002 and P=0.7). However, postoperative PCEA sufentanil consumption over the first 24 and 72 h was similar in the two groups (Table 2).


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Table 1 Patient characteristics and clinical variables in the two groups. Data are median (interquartile range). There were no significant differences
 


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Fig 1 Postoperative NRS pain scores (median and interquartile range) at rest (NRS-R) (A) and during mobilization (NRS-M) (B) after abdominal hysterectomy in the pre-emptive, and control groups on the operation day (2, 4, 6, 8, 10 and 12 h after operation), the first (1 a.m., 1 p.m.), second (2 a.m., 2 p.m.), third (3 a.m.) and fourth (4 a.m.) postoperative days and 2 and 4 weeks after operation.

 

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Table 2 Area under curve (AUC) NRS pain scores at rest and at mobilization, plasma sufentanil concentration, total consumption of sufentanil via patient-controlled epidural analgesia (PCEA), number of successful (good demand) and failed bolus (bad demand) attempts from the PCEA device, patient assessment of the quality of postoperative pain relief during PCEA treatment (patient satisfaction) and AUC touch and pain thresholds on the abdomen. Data are median (interquartile range), mean (SD) or the percentage of patients. *Significantly different from 4 h value.
 


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Fig 2 Postoperative PCEA sufentanil consumption (median, range) for pre-emptive and control group. Sufentanil consumption in the early hours (0–8 h) after surgery includes both anaesthetist- and patient-administered doses. *Significant difference between groups (P<0.05).

 
The median plasma sufentanil concentration was significantly greater on the first postoperative morning compared with the 4-h concentrations after surgery in the control group but not in the pre-emptive group (Table 2). However, the median plasma concentration of sufentanil was similar between groups 4 h after surgery and on the first postoperative morning. The number of failed bolus attempts from the PCEA device (bad demands) was also significantly greater in the control group than in the pre-emptive group. Patient satisfaction with the quality of analgesia was significantly greater in the pre-emptive group compared with the control group at the 72 h PCEA treatment (Table 2).

Twelve patients in the pre-emptive group and 11 patients in the control group had a Pfannenstiel incision. In those patients with a Pfannenstiel incision, the touch detection and pain thresholds expressed as AUC over 4 postoperative days were significantly lower in the abdominal area in the control group than in the pre-emptive group (Table 2).

The baseline concentrations of cortisol, ACTH, ß-endorphin and glucose were similar in the two groups (Table 3). Both groups had statistically significant increases in plasma ACTH, ß-endorphin, glucose and serum cortisol concentrations 4 h after surgery compared with the baseline concentrations (Table 3). The plasma ACTH concentration on the first postoperative day [2.7 (IQR 2–4.4)] was significantly lower than the baseline concentration in the pre-emptive group, but concentrations at these two times were similar in the control group (Table 3). The median decreases in cortisol and ACTH concentrations on the first postoperative day relative to the preoperative baseline were greater in the pre-emptive group than in the control group (Table 3).


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Table 3 Plasma ACTH and ß-endorphin, serum cortisol and blood glucose concentrations before epidural catheter insertion (baseline concentrations), 4 h after surgery and on the first postoperative day, and the change on the first postoperative day (first postoperative day concentration minus baseline concentration). Values are expressed as median (interquartile range) compared with the baseline value. *Significant decrease from the baseline value in the same group; {dagger}significant increase from the baseline value in the same group
 
Acetaminophen consumption during PCEA treatment was similar in the pre-emptive [750 mg (IQR 0–1375)] and control [500 mg (IQR 0–2250)] groups. The frequency of side-effects was similar in the two groups: nine patients in the pre-emptive group and 10 in the control group complained of nausea or vomiting (95% CI of the difference, –33 to 28%), and four patients in the pre-emptive group and five patients in the control group complained of mild pruritus (95% CI of the difference, –29 to 22%).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We found that pre-emptive epidural sufentanil administration reduced wound touch and pain sensitivity in patients with a Pfannenstiel incision and reduced ACTH and cortisol concentrations compared with patients who received epidural sufentanil at the end of surgery. Pre-emptive epidural sufentanil administration was associated with a short-term opioid-sparing effect between 8 and 16 h after surgery during the 72 h study period.

The significantly greater consumption of sufentanil by the control group during the 8–16 h period after surgery supports the findings of previous studies comparing preincisional vs postincisional lumbar epidural fentanyl (4 µg kg–1) in patients undergoing lateral thoracotomy6 and pre-emptive vs postoperative epidural morphine (3 mg) in patients undergoing lumbar laminectomy.8 Katz and colleagues6 found a lower pain score 6 h after surgery and reduced patient-controlled i.v. morphine consumption between 12 and 24 h after operation during the 48 h study period. Kundra and colleagues8 observed lower pain scores 8, 12 and 24 h after surgery and less total i.v. morphine consumption over the 24 h period in the pre-emptive group. Postoperative pain is a multifactorial experience involving sensation generated from the peripheral inflammation that follows surgery and the central sensitization that occurs during surgery. Post-surgical treatments may act as pre-emptive treatments during the initial postoperative period. In both our study and the papers cited above, the benefits of postoperative analgesia in preventing central sensitization in the pre-emptive and control group patients might, in this sense, mask the long-term benefits of pre-emptive analgesia given before surgery. This may explain why total sufentanil consumption was similar in the two groups in our study.

The increase in plasma sufentanil concentration from 4 h after surgery to the first postoperative day was significant only in the control group, and these concentrations of sufentanil were well within the range of effective concentrations (0.01–0.56 ng ml–1) reported14 after major gynaecological surgery with i.v. patient-controlled analgesia. Recent studies speculated that analgesia with continuous infusions13 or PCEA15 with low-dose sufentanil was primarily mediated by systemic absorption of the drug, with subsequent recirculation to supraspinal centres. Therefore, an increase in the sufentanil concentration in the control group may reflect the level of analgesic consumption, and this may imply that more analgesia was consumed during this period in the control group of patients.

Although sufentanil consumption in the first 24 or 72 h was similar in the two groups, consumption during the period 8–16 h after surgery and the number of failed bolus attempts from the PCEA device (bad demands) over 72 h were significantly lower and patient satisfaction was significantly greater in the pre-emptive group than in the control group. Patients in the pre-emptive group may have suffered less pain because of the pre-emptive therapy.

We found that tactile and pain sensitivities were suppressed by pre-emptive epidural sufentanil during the first 4 postoperative days after abdominal hysterectomy in patients with a Pfannenstiel incision, which supports a role for central sensitization in the generation of postoperative pain. Richmond and colleagues5 and Collis and colleagues16 studied the effect of pre-emptive i.v. morphine for hysterectomy and found that postoperative differential (i.e. forearm minus abdomen) pain detection thresholds to mechanical stimulation were lower in the pre-emptive group, suggesting less spinal sensitization. Tverskoy and colleagues17 and Wilder-Smith and colleagues18 also found that the pre-emptive administration of i.v. fentanyl (5 and 3 µg kg–1 respectively) decreased wound hyperalgesia after surgery.

Systemic endocrine–metabolic response is proportional to the severity of surgical stress; it can be influenced by the mode of anaesthesia and may be partially inhibited by efficient postoperative pain relief.19 Harukuni and colleagues20 showed that increases in plasma cortisol and ACTH are good indicators of surgical trauma and may be modulated by anaesthetic techniques. A few investigators have studied the pre-emptive effect of epidural opioids on neuroendocrine stress responses. Gottschalk and colleagues7 showed that pre-emptive epidural fentanyl 4 µg kg–1 in radical retropubic prostatectomy patients suppressed the cortisol response 2 h after incision compared with the control group. We found that cortisol and ACTH concentrations had increased in both groups 4 h after surgery, but the increase persisted to the next morning in the control group only. Despite the fact that the pre-emptive group tended to have slightly higher ACTH and cortisol baseline concentrations than the control group, the pre-emptive group patients had greater decreases in cortisol and ACTH concentrations from the baseline to the first postoperative day compared with the control group patients. Plasma ACTH and ß-endorphin originate from the same pituitary pro-opiomelanocortin (POMC) molecule and are released in equimolar amounts in response to various stressful stimuli, e.g. pain. All the current ß-endorphin antisera, including ours, also detect ß-lipoprotein, a third POMC-derived hormone, also released in equimolar quantities. As the half-lives of plasma ß-endorphin and ß-lipoprotein are considerably longer than that of ACTH, significant responses were to be expected in plasma ACTH but not in plasma ß-endorphin. It should be noted that plasma ß-endorphin increased significantly after the operation. For the reasons discussed above, however, no significant differences between the pre-emptive and control groups could be found. Our results support the presumption that pre-emptive epidural sufentanil is useful, because the acute responses of plasma ACTH and cortisol to surgery were significantly smaller in the pre-emptive group than in the control group.

We conclude that pre-emptive epidural sufentanil gives a short-term opioid-sparing effect and may reduce neuroendocrine responses, in addition to sensitization of touch and pain and improved patient satisfaction, compared with sufentanil given at the end of surgery. Our results support the theoretical importance of pre-emptive analgesia. Short-lasting clinical benefits have been documented.

Finally, our observations may be relevant to the concept of pre-emptive analgesia, because analgesic treatment for as long as surgical pain continues may be more important than short-lasting pre-emptive treatment. Therefore, pre-emptive analgesia should be combined with prolonged treatment.


    Acknowledgements
 
The authors are grateful for the help provided by Professor Juhani Leppäluoto, MD, Head of the Department of Physiology. The study was supported by research grants from the Elli Lehtinen fund, Oulu University and from the Eila and Veikko Takala foundation, North Finland Cancer Institution, Finland.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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16 Collis R, Brandner B, Bromley LM, et al. Is there any clinical advantage of increasing the pre-emptive dose of morphine or combining pre-incisional with postoperative morphine administration? Br J Anaesth 1995; 74: 396–9[Abstract/Free Full Text]

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20 Harukuni I, Yamaguchi H, Sato S, et al. The comparison of epidural fentanyl, epidural lidocaine, and intravenous fentanyl in patients undergoing gastrectomy. Anesth Analg 1995; 81: 1169–74[Abstract]