Comparison of intravenous and oral ketoprofen for postoperative pain after adenoidectomy in children

H. Tuomilehto1, H. Kokki2,* and K. Tuovinen3

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

Accepted for publication: March 2, 2000


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
One hundred children, aged 1–9 yr, undergoing adenoidectomy were randomized to receive ketoprofen 1 mg kg–1 either i.v. with an oral placebo (n=40) or ketoprofen 1 mg kg–1 orally with an i.v. placebo (n=40), or both oral and i.v. placebo (n=20). The study design was prospective and double blind with parallel groups. The pain was assessed at rest and during swallowing using the Maunuksela pain scale (0=no pain, 10=worst possible pain) after surgery for 3 h. Fentanyl 0.5 µg kg–1 i.v. was given for rescue analgesia. Children in the i.v. group needed significantly less doses (1, 1–3; median and 10th/90th percentiles) of rescue analgesic compared with the oral group (2, 1–3; P=0.024). Of those who needed rescue analgesic, three out of 30 children in the i.v. group required three or more doses of fentanyl compared with 10 out of 28 children in the oral group. There were no differences between the groups with respect to pain scores, operation times, perioperative bleeding or frequency of adverse events.

Br J Anaesth 2000; 85: 224–7

Keywords: pain, postoperative; analgesics, non-opioid, ketoprofen, i.v., oral; analgesia, paediatric; surgery, otolaryngological


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A low incidence of postoperative morbidity after day-case adenoidectomy in children is essential if we are to ensure parental and patient satisfaction.1 Children who need more opioids in hospital, experience more intense pain at home during the first week after surgery,2 and postoperative pain is related to behavioural problems.3 Thus, effective pain treatment in children is essential.

Non-steroidal anti-inflammatory drugs (NSAIDs) are highly effective analgesics for treatment of mild to moderate pain.1 4 In previous studies, we have shown the efficacy and safety of i.v. ketoprofen in small children following adenoidectomy.5 6 Furthermore, the results show that i.v. ketoprofen, administered during the operation, was associated with not only analgesia but also reduced opioid consumption and adverse effects, such as vomiting.7

Administration by different routes of ketoprofen and other NSAIDs has not been compared properly.8 If there is no difference in analgesic efficacy or adverse effects, the oral route is the most cost effective.

The aim of this study was to investigate whether the oral administration of ketoprofen is equivalent in analgesic efficacy to the i.v. route in the treatment of postoperative pain in small children following day-case adenoidectomy.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study was approved by our Ethics Committee, the National Agency for Medicines was notified of the use of ketoprofen in children <20 kg, and the study was conducted in accordance with the Declaration of Helsinki. Both parents and children of sufficient age received information regarding the study and written consent was obtained. We recruited 100 patients (1–9 yr, ASA 1 or 2) undergoing day-case adenoidectomy. Patients were excluded if they had known allergy to ketoprofen or other NSAIDs, asthma, haemorrhagic diathesis, kidney or liver dysfunction, or if they had any other contraindication for NSAIDs.

A randomized, prospective, double-blind, double-dummy, placebo-controlled, parallel groups study design was used. Children were allocated randomly to either one of two ketoprofen groups or a placebo group. The allocation was computer generated and a sealed envelope method was used to allow blinding. Forty children received ketoprofen orally, 40 children i.v., and 20 received placebo. In the oral group, children were given ketoprofen 1.0 mg kg–1 as a mixture (Orudis® 1 mg/ml mixture, Rhone-Poulenc Rorer, Cedex, France) 30 min before surgery, and placebo i.v. at induction (10 ml 0.9% normal saline) over 10 min. In the i.v. group, patients were given placebo mixture 30 min before surgery and ketoprofen 1.0 mg kg–1 in 10 ml 0.9% normal saline i.v. injected over 10 min at induction (Orudis® 50 mg/ml injection, Rhone-Poulenc Rorer, Helsinki, Finland). In the placebo group, children were given placebo mixture and normal saline injection. All study medications were prepared by a nurse not taking part in the study.

A standard anaesthetic technique was used. Each child was premedicated with diazepam 0.5 mg kg–1 orally (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 i.v. was given and anaesthesia 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 but no more opioids were allowed during the operation. 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. Haemostasis was controlled with temporary nasopharyngeal packs and electrocautery. Duration of surgery was recorded and at the end of the procedure the surgeon estimated the amount of bleeding using a five-point scale.5 After the operation, children were transferred to the post-anaesthesia care unit (PACU) for continuous monitoring of vital signs and assessment of pain by specially trained nurses. Postoperative pain was assessed using the Maunuksela scale.5 9 Pain expressed by the child at rest and during swallowing was assessed continuously and recorded every hour for up to 3 h. If the child was in pain with a pain score at rest of 3 or more, fentanyl 0.5 µg kg–1 i.v. was given. The dose was repeated at 5-min intervals until the pain had diminished to slight. No more than four doses were allowed in 1 h, and no other analgesic medication was permitted during the study. The last pain assessment and recording was made just before discharge, when the worst pain recorded during the PACU stay was noted. At discharge, sedation was assessed using a 100-mm visual analogue scale (VAS, 0=‘full alert’ and 100=‘not arousable’). All adverse events were recorded.

Patients were discharged when they were awake, able to walk unaided, had stable vital signs for at least 1 h, had no or mild pain, had not vomited for 1 h, were able to tolerate clear fluids, had passed urine, and had no bleeding. All children received ketoprofen 1 mg kg–1 i.v. just before discharge.

The sample size was based on detecting a difference of 35% or more in the need for rescue analgesia between the i.v. and oral groups at a 0.05 significance level with 80% power. In addition, a small placebo group was included to avoid study bias based on our previous studies in pain treatment following adenoidectomy.5 10 In a previous study, where a placebo group was not included, only 47% of the children who were given ketoprofen 2 mg kg–1 required rescue analgesia compared with 65% of the children in another previous study where children in the control group received placebo. This may be caused by observer bias, because it was known that in the study where placebo was not used, all the children had in fact received a previous analgesic. Therefore, a placebo group was included in this study and considered ethical.

Statistical analysis of continuous variables was performed using the Kruskal–Wallis test, and for post hoc analysis, the Mann–Whitney test with Bonferonni correction was used. For the categorical variables, the chi-squared test was used. P<0.05 was considered statistically significant. Results are presented as number of cases (%) or median (10th and 90th percentiles), as appropriate.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
There were no differences between study groups with respect to patient characteristics (Table 1). All except two children were ASA 1. There were no patient withdrawals from the study.


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Table 1 Patient characteristics. Data are as number of cases or median with 10th/90th percentiles. No significant differences
 
In the oral group, 28 out of 40 patients were given fentanyl for rescue analgesia, compared with 30 out of 40 patients in the i.v. group and 15 out of 20 patients in the placebo group.

There was a significant difference between the study groups in number of fentanyl doses given (P=0.019). Children in the i.v. group needed significantly fewer doses compared with the oral group (P=0.024). There was no difference between the oral and placebo group. In the i.v. group, three out of 30 children needed three or more doses of fentanyl, compared with 10 out of 28 children in the oral group and six out of 15 children in the placebo group (P=0.032). The median time to the first fentanyl dose was 36 (7–67) min in the i.v. group, 23 (8–50) min in the oral group, and 23 (7–62) min in the placebo group.

There was no significant difference between groups with respect to Maunuksela pain scores (Table 2).


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Table 2 Maunuksela pain scores. Score 0 = ‘no pain’, 1–3 = ‘slight pain’, 4–6 = ‘moderate pain’, 7–9 = ‘severe pain’, 10 = ‘worst possible pain’. Data are expressed as median with 10th/90th percentiles
 
There was no difference with respect to duration of surgery (20 (10–35) min in the i.v. group, 21 (10–42) min in the oral group, and 17 (8–37) min in the placebo group). There was no difference in the extent of surgeon-assessed bleeding. There was no incidence of postoperative bleeding requiring re-operation, delay of discharge, admission to hospital or any other interventions.

On discharge, sedation scores were 7 (0–21) in the i.v. group, 6 (0–22) in the oral group, and 6 (0–19) in the placebo group.

Adverse events noted in the PACU are shown in Table 3. In the oral group, six out of 40 children had at least one adverse event, compared with eight out of 40 children in the i.v. group, and eight out of 20 children in the placebo group. Nausea, retching and vomiting were the most common adverse events with a similar incidence in the study groups. Two children in the oral group were admitted overnight because of protracted vomiting. One child in the placebo group was discharged later in the same afternoon because of delayed urination.


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Table 3 Adverse events. Data are expressed as number of cases. No significant differences
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this study, ketoprofen 1 mg kg–1 given i.v. at the induction of anaesthesia provided better analgesic than a similar dose given orally 30 min before induction, as shown by reduced need for rescue analgesia in the i.v. group. Moreover, there was a tendency towards less requirement for rescue analgesia in the i.v. group compared to the oral group, although the difference was not significant. This was not expected, as ketoprofen syrup is absorbed rapidly (maximum plasma concentration occurs at 30 min, bioavailability >90%).11

The major mechanism of NSAID action is inhibition on prostaglandin synthesis,12 hence the onset of the analgesia is delayed.13 However, in addition to a peripheral action, i.v. ketoprofen also has a rapid central analgesic action.14 To support this, Debruyne and co-workers have shown that administration of i.v. ketoprofen suppresses pain within 5–30 min.15 Thus, we propose that the better analgesic action of the i.v. compared with the oral route in the present study is explained by a faster onset action.

Although the placebo group was included to avoid observational bias, it was interesting to notice that oral ketoprofen did not perform any better than placebo. This suggests that the dose used was inadequate or that drug absorption was incomplete or delayed, possibly relating to preoperative anxiety. On the other hand, this may also reflect delayed action of ketoprofen on prostaglandin synthesis. Kohler and co-workers showed a correlation between the analgesic effect of ketoprofen and drug plasma concentrations in adults. In their study, pain was at its lowest 2 h after oral administration of ketoprofen.16 The use of a larger or earlier administration requires further study.

NSAIDs prolong bleeding time by inhibiting cyclo-oxygenase.12 However, in the present study, no child receiving ketoprofen had postoperative bleeding requiring intervention or delayed discharge. In our earlier studies with ketoprofen, only one child out of 611 children experienced postoperative bleeding, but even he did not require further surgery.2

Pain assessment in small children is difficult because of their limited verbal abilities and understanding. Several other factors such as anxiety, excitement, fatigue and residual effects of anaesthetic agents can cause postoperative distress for children. This results in problems, not only for pain assessment, but also at home.4 17 Consequently, for small children, pain scale assessments based on multiple variables are recommended. The Maunuksela pain scale, used in the present study, is a multidimensional assessment based on physiological, behavioural and contextual indicators. It has been validated for use in children from 1 to 18 yr.9

In contrast to our previous studies where we used isoflurane for maintenance, sevoflurane was used in the present study. Sevoflurane increases agitation during early recovery, probably due to postoperative pain.18 Recently, Davis and co-workers have shown that intraoperatively administered NSAIDs reduced agitation in the immediate postoperative period.19 In the present study, most of the children experienced moderate or severe pain during early recovery, so a proactive approach for pain management is recommended.4 17


    Footnotes
 
* Corresponding author Back


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

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

4 Wolf AR. Tears at bedtime: a pitfall of extending paediatric day-case surgery without extending analgesia. Br J Anaesth 1999; 82: 319–20[Free Full Text]

5 Nikanne E, Kokki H, Tuovinen K. IV perioperative ketoprofen in small children during adenoidectomy. Br J Anaesth 1997; 78: 24–7[Abstract/Free Full Text]

6 Kokki H, Nikanne E, Tuovinen K. I.v. intraoperative ketoprofen in small children during adenoidectomy: a dose-finding study. Br J Anaesth 1998; 81: 870–4[Abstract/Free Full Text]

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

8 Tramer MR, Williams JE, Carroll D, Wiffen PJ, Moore RA, McQuay H. 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 Pharm Ther 1987; 42: 137–41[ISI][Medline]

10 Nikanne E, Kokki H, Tuovinen K. Comparison of perioperative ketoprofen 2.0 mg kg–1 with 0.5 mg kg–1 i.v. in small children during adenoidectomy. Br J Anaesth 1997; 79: 606–8[Abstract/Free Full Text]

11 Kokki H, Jekunen A, Le Liboux A, Montay G, Heikkinen M. Pharmacokinetics of ketoprofen syrup in small children. J Clin Pharmacol 2000; 40: 354–9[Abstract/Free Full Text]

12 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol 1971; 231: 232–5[ISI][Medline]

13 Maunuksela EL, Kokki H, Bullingham RES. Comparison of intravenous ketorolac with morphine for postoperative pain in children. Clin Pharm Ther 1992; 52: 436–43[ISI][Medline]

14 Willer JC, De Broucker 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]

15 Debruyne D, Hurault de Ligny B, Ryckelynck JP, Albessard F, Moulin M. Clinical pharmacokinetics of ketoprofen after single intravenous administration as a bolus or infusion. Clin Pharmacokinet 1987; 12: 214–21[ISI][Medline]

16 Kohler G, Primbs P, Morand J, Rubelt C. Correlation between ketoprofen plasma levels and analgesic effect in acute lumbar pain and radicular pain. Clin Rheumatol 1985; 4: 399–404[ISI][Medline]

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

18 Lerman J, Davis PJ, Welborn LG, et al. Induction, recovery, and safety characteristics of sevoflurane in children undergoing ambulatory surgery. A comparison with halothane. Anesthesiology 1996; 84: 1332–40[ISI][Medline]

19 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]