Pain management after adenoidectomy with ketoprofen: comparison of rectal and intravenous routes

H. Kokki1, H. Tuomilehto2 and K. Tuovinen3

1Department of Anaesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland. 2Department of Otorhinolaryngology, Kuopio University Hospital, Kuopio, Finland. 3Department of Pharmacy, Kuopio University Hospital, Kuopio, Finland*Corresponding author: Department of Anaesthesiology and Intensive Care, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland

Accepted for publication: July 10, 2000


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We compared the efficacy of rectally and intravenously administered ketoprofen for pain management after day-case adenoidectomy. Patients (123 children aged 1–9 yr) were allocated randomly to receive on induction of anaesthesia ketoprofen 25 mg rectally with an i.v. placebo, ketoprofen 25 mg i.v. with a rectal placebo, or placebo both i.v. and rectally. The method of anaesthesia and the operative technique were standardized. Postoperative pain was assessed at rest and during swallowing using the Maunuksela pain scale (0=no pain, 10=worst possible pain). Fentanyl 0.5 µg kg–1 was given as rescue analgesia. There was no significant difference between the two ketoprofen groups in their requirement for rescue analgesics. However, both the proportion of children needing rescue analgesics [55 of 84 children (65%) vs. 33 of 39 children (84%); difference 19%, 95% confidence interval 4–34%, P=0.029] and the number of rescue analgesic doses [mean 1.2 (SD 1.2) vs. 2.2 (1.4); mean difference 0.9, 95% confidence interval 0.4–1.4, P=0.001] were significantly lower among children receiving ketoprofen than in children receiving placebo. Adverse events, duration of operation, perioperative bleeding, pain scores and time of discharge were similar in the three groups.

Br J Anaesth 2000; 85: 836–40

Keywords: analgesia, paediatric; pain, postoperative; analgesics non-opioid, ketoprofen; surgery, otolaryngological


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Adenoidectomy is the most common day-case operation in children. Successful management provides a major challenge for the providers of health care and requires a multidisciplinary approach for the evaluation of quality. The criteria are minimal postoperative morbidity, low inpatient admission rate and high parental and child satisfaction.1

More than 50% of children undergoing day-case surgery experience clinically significant pain after discharge.2 3 Furthermore, the pain experienced by the child in hospital after adenoidectomy predicts the behavioural problems and pain at home.4 5 Non-opioid analgesics are effective in the treatment of mild and moderate pain in children.6 Non-steroidal anti-inflammatory drugs (NSAIDs) not only produce good analgesia but also reduce the consumption of opioids and the incidence of adverse events, such as nausea and vomiting.7 Ketoprofen is a derivative of propionic acid and is a commonly used NSAID in adults in many countries. The efficacy and safety of i.v. ketoprofen is also recognized in paediatric patients.4 7

During the perioperative period, oral analgesics may not be absorbed reliably, and therefore i.v. injection and rectal suppositories are used commonly. These routes of administration routes have not been compared adequately.8 Therefore, the aim of this study was to evaluate whether rectal ketoprofen is as effective an analgesic as i.v. ketoprofen for pain management in children after day-case adenoidectomy.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The study was approved by Ethics Committee of Kuopio University Hospital and was conducted in accordance with the Declaration of Helsinki. The National Agency for Medicines was notified of the use of ketoprofen in children weighing less than 20 kg. The parents and children who were old enough were informed about the study, and they provided written consent. Our study included 123 children (68 boys and 55 girls) aged 1–9 yr, ASA physical status I, who were undergoing day-case adenoidectomy during the autumn of 1999. Patients were excluded if they had known allergy to ketoprofen or other NSAIDs, asthma, haemorrhagic diathesis, kidney or liver dysfunction, or had any other known contraindication for NSAIDs.

A randomized, prospective, double-blind, double-dummy, placebo-controlled, parallel-group study design was used. Children were allocated randomly to either of the two ketoprofen groups or to a placebo group. The allocation was computer-generated and a sealed envelope method was used to ensure blinding. Forty-two children received ketoprofen rectally (suppository group), 42 children received ketoprofen i.v. (i.v. group), and 39 children received only placebo (placebo group).

In the suppository group, the children were given ketoprofen rectally 25 mg as a suppository (Ketorin® 25 mg supp., Orion, Espoo, Finland) after induction of anaesthesia but before surgery and placebo i.v. (0.9% normal saline 10 ml). In the i.v. group, the children were given a placebo suppository and ketoprofen 25 mg in 10 ml 0.9% normal saline i.v. injected over 5 min (Ketorin® 50 mg/ml injection, Orion). In the placebo group, the children were given a placebo suppository and an i.v. injection of normal saline. The buttocks were taped together after the insertion of the suppository to avoid displacement. After the operation we checked that the suppository had remained in the rectum. The injections were prepared by a nurse not taking part in the study, and the appearances of the ketoprofen and placebo suppositories were similar, thus ensuring blinding.

A standard anaesthetic technique was used. Each child was premedicated with diazepam 0.5 mg kg–1 orally up to a maximum of 10 mg 30 min before induction. EMLA® cream (Astra, Södertälje, Sweden) was used at the venous puncture site. Atropine 0.01 mg kg–1 was given i.v. and anaesthesia was induced with thiopental 5 mg kg–1 and fentanyl 1 µg kg–1 i.v. To facilitate tracheal intubation, cis-atracurium 0.1 mg kg–1 was given. Anaesthesia was maintained with 2–3% sevoflurane (inspired concentration) in 65% nitrous oxide in oxygen with intermittent positive-pressure ventilation. On completion of the procedure, muscle relaxation was reversed with neostigmine 50 µg kg–1 and glycopyrrolate 10 µg kg–1. All children received fentanyl 1 µg kg–1 at induction, and no more opioids were allowed during surgery. For intraoperative fluid maintenance, all children were given 0.9% saline 5–10 ml kg–1 h–1.

The adenoids were removed using a curettage technique under visual control. Haemostasis was by temporary nasopharyngeal packs and electrocautery. The operation time was recorded and, at the end of procedure, the surgeon estimated the amount of bleeding using a 5-point scale (0=no bleeding, 5=profuse bleeding).4

After surgery, the children were transferred to the postanaesthesia care unit (PACU), where vital signs were monitored and pain was assessed by specially trained nurses. Postoperative pain was assessed using the Maunuksela scale9 as modified by Nikanne and colleagues (0=no pain, 10=worst pain).4 Pain experienced by the child at rest and during swallowing was assessed continuously and recorded every hour up to 3 h. If the child was in pain with a pain score at rest >=3, fentanyl 0.5 µg kg–1 i.v. was given. The dose was repeated at 5 min intervals until the pain had diminished to a rating of ‘slight’. No more than four doses were allowed in any period of 1 h. No other analgesic medication was permitted during the study. The last pain assessment and recording was made just before discharge. At the same time, the worst pain during the patient’s stay in the PACU was noted. At discharge, sedation was assessed using a 100 mm visual analogue scale (VAS, left end=full alert, right end=not arousable). All adverse effects were recorded for each patient.

Patients were discharged when they were awake, were able to walk unaided, had had stable vital signs for at least 1 h, had no pain or only mild pain, had not vomited for 1 h, were able to tolerate clear fluid, and had no bleeding. All children received ketoprofen 1 mg kg–1 i.v. just before discharge. The discharge was defined as delayed if it was later than 5 h after surgery.

The sample size was based on detecting a difference of 35% or more in the need for rescue analgesic between the i.v. and suppository groups at a significance level of 0.05 with 80% power. Continuous variables were analysed with the Kruskal–Wallis test, and for post hoc analysis the Mann–Whitney test with Bonferonni correction was used. For the categorical variables, the {chi}2 test was used. P<0.05 was considered statistically significant. Results are presented as number of cases (%), median (10th and 90th percentiles), mean (SD) or mean difference [95% confidence interval (CI)] as appropriate.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The three groups were similar in age, weight and height. In the i.v. group there were more boys than in the two other groups (P=0.017, {chi}2 test) (Table 1). There were no protocol deviations or exclusions.


View this table:
[in this window]
[in a new window]
 
Table 1 Patient characteristics. Age, height and weight are given as median (10th and 90th percentiles). *P=0.017
 
The number of rescue analgesic doses needed in the study groups is presented in Fig 1. There was no difference between the two ketoprofen groups in the need for rescue analgesia; in the suppository group 27 out of 42 children (64%) and in the i.v. group 28 out of 42 children (67%) received rescue analgesia in the PACU. In the placebo group 33 out of 39 children (85%) needed rescue analgesia in the PACU; the difference with respect to the children receiving ketoprofen was significant (i.v./suppository groups vs placebo group: difference 19%, 95% CI 4–34%, P=0.029, {chi}2 test).



View larger version (18K):
[in this window]
[in a new window]
 
Fig 1 Use of rescue analgesics.

 
The number of rescue analgesic doses needed in the PACU was significantly smaller in children receiving ketoprofen than in children receiving placebo (P=0.004 compared with the suppository group, P=0.012 compared with the i.v. group; Mann–Whitney test with Bonferonni correction). There was no difference between the two ketoprofen groups.

For the 88 children who needed rescue analgesics in the PACU, ketoprofen significantly reduced the number of doses of rescue analgesia compared with the placebo group (P=0.038, Kruskal–Wallis test). There was no difference between the two ketoprofen groups.

Of the children who needed rescue analgesics in the PACU, seven out of 28 (25%) in the i.v. group needed three or more doses of rescue analgesics compared with nine out of 27 (33%) in the suppository group; the difference was not significant. In the placebo group, significantly more children [17 out of 33 (52%)] needed three or more doses of rescue analgesia compared with children receiving ketoprofen (i.v./suppository groups vs placebo group: difference 22%, 95% CI 2–45%, P=0.015, {chi}2 test).

Although the median time to the first fentanyl dose was 23 min (10th and 90th percentiles, 5 and 105 min) in the placebo group compared with 35 (10 and 100) min in the suppository group and 32 (5–90) min in the i.v. group, the differences were not significant.

There was no significant difference between the study groups in their Maunuksela pain scores during the PACU stay or at discharge. Sedation at discharge was also similar (Table 2). There were no differences between the study groups in the amount of intraoperative bleeding evaluated by the surgeon (Table 3). No children experienced postoperative bleeding that required further surgery, delay in discharge, admission to hospital or any other intervention. There were no differences between the study groups in the incidence of adverse events (Table 4). The most common adverse events were nausea, retching and vomiting [16 out of 123 children (13%)]. Anorectal adverse events did not occur.


View this table:
[in this window]
[in a new window]
 
Table 2 Maunuksela pain scores (0=no pain, 1–3=slight pain, 4–6=moderate pain, 7–9=severe pain, 10=worst possible pain). Data are medians (10th and 90th percentiles)
 

View this table:
[in this window]
[in a new window]
 
Table 3 Amount of intraoperative bleeding assessed by the surgeon. Data are numbers of cases
 

View this table:
[in this window]
[in a new window]
 
Table 4 Adverse events. Data are numbers of cases
 
Discharge was delayed in four out of 42 children (10%) in the i.v. group, three out of 42 children (7%) in the suppository group and one child (3%) in the placebo group, because of severe pain, protracted vomiting or excessive sedation. Seven children were discharged after 6 or 7 h. One child in the suppository group was admitted to hospital because of protracted vomiting. Her recovery was uneventful and she was discharged on the first postoperative morning.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this study, rectally administered ketoprofen was as effective as i.v. ketoprofen. There was no significant difference between the two ketoprofen groups in the number of children requiring rescue analgesia or in the number of rescue analgesic doses needed. However, compared with placebo, ketoprofen was significantly more effective. Overall, 65% of children needed rescue analgesia in the ketoprofen groups, whereas in the placebo group 85% of children needed rescue analgesia. This supports our earlier results, which showed that ketoprofen is a safe and effective non-opioid analgesic in children.4 7

A study in adults showed that 73–93% of ketoprofen is absorbed after administration of a rectal suppository.10 However, drug absorption after rectal administration in children may be delayed and erratic, as shown with paracetamol.11 We believe that one reason for unpredictable absorption could be evacuation of the suppository from the rectum as a result of the defaecation reflex caused by insertion of the suppository. In this study, the problem was avoided by taping the buttocks together after insertion of the suppository. When checked after surgery, none of the suppositories had come out.

Guidelines of the Royal Colleges of Surgeons of England suggest that day cases managed in a dedicated unit should have an inpatient admission rate of no higher than 2 or 3%. In this study, only one child was admitted and discharge was delayed in only eight children. One child had difficulty in passing urine, five children had protracted nausea and vomiting and two children in the placebo group had severe pain. Chung and Mezei evaluated factors predicting a prolonged stay after day-case surgery and found that excessive pain and protracted nausea and vomiting are the most significant factors.12 The overall rate of delayed discharge of 6% in this study was much higher than we have observed in our previous studies.4 7 Normally, day cases recover within a dedicated day-case recovery area but, because of maintenance work, children in this study recovered in the main inpatient recovery ward. We believe that this may explain our high rate of delayed discharge.

Volatile anaesthetics, for example sevoflurane, are common agents for the maintenance of anaesthesia. Sevoflurane allows easy control of the depth of anaesthesia and rapid recovery characteristics, but has been associated with recovery agitation.13 There is increasing evidence that sevoflurane must be combined with an analgesic. Katoh and colleagues showed recently that the use of fentanyl significantly reduced the requirement of sevoflurane.14 Moreover, Davis and colleagues showed that intraoperatively administered NSAID reduced agitation on emergence from anaesthesia.15 The effect of ketoprofen on the need for sevoflurane has not been determined. Since ketoprofen also has a central analgesic effect, it would be interesting to evaluate the interaction between sevoflurane and ketoprofen.16

Rectal administration is used in some countries but, in most cases, the principal reason for choosing the rectal route is based on tradition. In Finland, awake children dislike suppositories.17 Our results show that, during anaesthesia, rectally administrated ketoprofen is an effective alternative to i.v. administration.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 Brennan LJ. Modern day-case anaesthesia for children. Br J Anaesth 1999; 83; 91–103[Free Full Text]

2 Finley GA, McGrath PJ, Forward SP, McNeill G, Fitzgerald P. Parent’s management of children’s pain following ‘minor’ surgery. Pain 1996; 64; 83–7[ISI][Medline]

3 Kokki H, Ahonen R. Pain and activity disturbance after paediatric day case adenoidectomy. Paediatr Anaesth 1997; 7; 227–31[ISI][Medline]

4 Nikanne E, Kokki H, Tuovinen K. Postoperative pain after adenoidectomy in children. Br J Anaesth 1999; 82; 886–9[Abstract/Free Full Text]

5 Kotiniemi LH, Ryhanen PT, Moilanen IK. Behavioral changes in children following day-case surgery: a 4-week follow-up of 551 children. Anaesthesia 1997; 52; 970–6[ISI][Medline]

6 Morton NS. Prevention and control of pain in children. Br J Anaesth 1999; 83; 118–29[Free Full Text]

7 Kokki H, Homan E, Tuovinen K, Purhonen S. Peroperative treatment with i.v. ketoprofen reduces pain and vomiting in children after strabismus surgery. Acta Anaesthesiol Scand 1999; 43; 13–8[ISI][Medline]

8 Tramèr MR, Williams JE, Carroll D, Wiffen PJ, Moore RA, McQuay HJ. Comparing analgesic efficacy of non-steroidal anti-inflammatory drugs given by different routes in acute and chronic pain: a qualitative systematic review. Acta Anaesthesiol Scand 1998; 42; 71–9[ISI][Medline]

9 Maunuksela E-L, Olkkola KT, Korpela R. Measurement of pain in children with self-reporting and behavioral assessment. Clin Pharmacol Ther 1987; 42; 137–41[ISI][Medline]

10 Ishizaki T, Sasaki T, Suganuma T, Horai Y, Chiba K, Watanabe M, et al. Pharmacokinetics of ketoprofen following single oral, intramuscular and rectal doses and after repeated oral administration. Eur J Clin Pharmacol 1980; 18; 407–14[ISI][Medline]

11 Morton NS, O’Brien K. Analgesic efficacy of paracetamol and diclofenac in children receiving PCA morphine. Br J Anaesth 1999; 82; 715–7[Abstract/Free Full Text]

12 Chung F, Mezei G. Factors contributing to a prolonged stay after ambulatory surgery. Anesth Analg 1999; 89; 1352–9[Abstract/Free Full Text]

13 Fox AJ, Rowbotham DJ. Anaesthesia. Br Med J 1999; 28; 557–600

14 Katoh T, Kobayashi S, Suzuki A, Iwamoto T, Bito H, Sato S. Fentanyl augments block of sympathetic responses to skin incision during sevoflurane anaesthesia in children. Br J Anaesth 2000; 84; 63–6[Abstract]

15 Davis P, Greenberg J, Gendelman M, Fertal K. Recovery characteristics of sevoflurane and halothane in preschool-aged children undergoing bilateral myringotomy and pressure equalization tube insertion. Anesth Analg 1999; 88: 34–8[Abstract/Free Full Text]

16 Willer JC, De Broucher T, Bussel B, Roby-Brami A, Harrewyn JM. Central analgesic effect of ketoprofen in humans: electrophysiological evidence for a supraspinal mechanism in a double-blind and cross-over study. Pain 1989; 38: 1–7[ISI][Medline]

17 Sepponen K, Kokki H, Ahonen R. Training of medical staff positively influences postoperative pain management at home in children. Pharm World Sci 1999; 21: 168–72[ISI][Medline]