British Journal of Anaesthesia 82 (1): 56 60 (1999) Ketoprofen, diclofenac or ketorolac for pain after tonsillectomy in adults? P. Tarkkila* and L. Saarnivaara Department of Anaesthesia, Otolaryngological Hospital, Helsinki University Central Hospital, Haartmaninkatu 4 E, FIN-00290 Helsinki, Finland *To whom correspondence should be addressed We have compared the analgesic and opioid sparing effect of three i.v. non-steroidal antiinflammatory drugs with placebo in a randomized, double-blind, placebo-controlled study in 80 adult patients after elective tonsillectomy. A standard anaesthetic was used. After induction of anaesthesia, patients received ketoprofen 100 mg, diclofenac 75 mg or ketorolac 30 mg by i.v. infusion over 30 min. Patients in the placebo group received saline. Ketoprofen and diclofenac infusions were repeated after 12 h and ketorolac infusion at 6 h and 12 h. Oxycodone was used as rescue analgesic. Patients in the ketoprofen group requested 32% less opioid and patients in the diclofenac and ketorolac groups 42% less opioid than those in the placebo group (P 0.05). There were one, two and six patients in the placebo, diclofenac and ketorolac groups, respectively, but none in the ketoprofen group, who did not request opioid analgesia during the study (P 0.05, ketorolac vs placebo and ketoprofen). Visual analogue pain scores were similar in all groups. Visual analogue satisfaction scores were significantly higher in the diclofenac group compared with the placebo group. The incidence of nausea was 44 54%. There were no differences in the incidence of other adverse reactions. We conclude that all three non-steroidal anti-inflammatory drugs were superior to placebo after tonsillectomy. Br J Anaesth 1999; 82: 56 60 Keywords: pain, postoperative; non-steroidal anti-inflammatory drugs; analgesics non-opioid, ketoprofen; analgesics non-opioid, diclofenac; analgesics non-opioid, ketorolac; surgery, otolaryngological Accepted for publication: April 17, 1998 Various studies have shown that non-steroidal antiinflammatory drugs (NSAID) are effective in reducing pain after different types of surgery. 12 They decrease the need for opioids, thus reducing the risk of opioid related side effects. Although the mechanism of analgesic action (i.e. inhibition of prostaglandin synthesis) is the same for all presently used NSAID, analgesic efficacy relative to side effects may vary from agent to agent. 2 4 NSAID have potential side effects because of derangement of haemostasis caused by decreased platelet function. The effect of some NSAID on platelets is reversible and they inhibit platelet aggregation for a few hours only. 5 Recently, there have been several studies reporting increased per- and postoperative bleeding associated with ketorolac and tonsillectomy. 6 9 Comparative studies of the analgesic potency of various NSAID are rare. As the type of surgery may influence the efficacy of individual NSAID on postoperative pain and side effects, 10 we have compared ketoprofen, diclofenac and ketorolac with placebo after elective tonsillectomy in adults. Patients and methods This randomized, double-blind, placebo-controlled study was approved by the Ethics Committee of the hospital. After obtaining written, informed consent, we studied 80 ASA I II patients, aged 16 50 yr, undergoing elective tonsillectomy, allocated randomly to one of four groups of equal size. Patients with a history of allergic reactions to NSAID, bronchial asthma, gastrointestinal ulceration or bleeding disorders were excluded. All operations were performed between 08:00 and 14:00. All patients were premedicated with atropine 0.01 mg kg 1 i.m. approximately 45 min before induction of anaesthesia. After alfentanil 30 gkg 1, anaesthesia was induced with a sleep dose of propofol 2 3 mg kg 1 and maintained with sevoflurane in 70% nitrous oxide in oxygen. Tracheal intubation was facilitated with succinylcholine (suxamethonium) 1.5 mg kg 1 and neuromuscular block was achieved with rocuronium. If systolic arterial pressure increased by 20% from preoperative values, alfentanil 10 gkg 1 was given. British Journal of Anaesthesia
Which NSAID after tonsillectomy? Table 1 Patient and operation characteristics (mean (SD or range) or number of patients). No significant differences between groups Placebo Ketoprofen Diclofenac Ketorolac Sex (M/F) 6/14 8/12 7/13 9/11 Age (yr) 27 (8) 33 (4) 30 (10) 31 (8) Height (cm) 170 (10) 168 (9) 168 (9) 172 (7) Weight (kg) 66 (11) 67 (16) 65 (11) 66 (9) Duration of surgery (min) 24 (6) 31 (15) 27 (8) 26 (11) Alfentanil (mg) 2.5 (0.8) 2.6 (0.9) 2.3 (0.7) 2.4 (0.7) Blood loss (ml) 71 (5 250) 80 (10 200) 97 (10 300) 86 (10 200) Fig 1 Number of oxycodone doses during the study in each group. Residual neuromuscular block was antagonized with atropine 0.3 mg and edrophonium 10 mg. The ECG, Sp O2, PE CO2, noninvasive arterial pressure (oscillotonometry) and heart rate were monitored during anaesthesia. After induction of anaesthesia, before surgical incision, patients received ketoprofen (Ketorin, Orion, Finland) 100 mg, diclofenac (Voltaren, Ciba Geigy, Switzerland) 75 mg, ketorolac (Toradol, Syntex, Sweden) 30 mg or placebo (saline) as an i.v. infusion. These doses were chosen on the basis of manufactures recommendations. All drugs were mixed with 100 ml of saline and given over 30 min. In the ketorolac group, the same i.v. dose was repeated twice at 6-h intervals. In the diclofenac and ketoprofen groups, patients received placebo (saline) after 6 h and active drug (the initial dose) after 12 h. In the placebo group, patients received saline twice at 6-h intervals after operation. No other NSAID medication was allowed during the study. The drugs were mixed by a nurse not participating in the study. Rescue analgesic medication consisting of oxycodone 0.05 mg kg 1 i.v. during the first 2 h after operation (in the recovery room) and thereafter 1.0 mg kg 1 i.m. (on the ward) was administered on patient request. Patients were advised to demand analgesia in order to become pain free. The number of oxycodone doses and exact time of administration were recorded. The intensity of pain after tonsillectomy was assessed at rest and on swallowing. Pain was assessed using a verbal rating scale (VRS) where 0 no pain, 1 slight pain, 2 moderate pain and 3 severe pain. A visual analogue scale (VAS) for assessment of pain, nausea and satisfaction was also used. Each VAS comprised a 50-cm long, 10-cm high Fig 2 Verbal rating scores (no pain, slight, moderate or severe pain) at rest (A) and on swallowing (B) during the study in the placebo (P), ketoprofen (Kp), diclofenac (D) and ketorolac (Kl) groups. unmarked red triangle, 11 the ends of which denoted extremes of the variables in question, that is no pain worst imaginable pain; no nausea extreme nausea; very unhappy delighted with everything. These measurements were made at recovery from anaesthesia and thereafter every 30 min for 2 h after operation. On the ward, measurements were repeated at 21:00 and 06:00. Adverse reactions, recorded at predetermined intervals (i.e. during stay in the recovery 57
Tarkkila and Saarnivaara room, at 0.5 and 2 h after operation, on the ward at 21:00 and 06:00) were sought by active questioning. Reducing opioid requirements was the primary determinant of the sample size. With 0.05 and 0.2, 20 patients were required in each treatment group to detect a 30% decrease in opioid requirements. Differences between groups were evaluated using the Mann Whitney U test, chi-square and Fisher s exact test, in addition to the Student s t test, as appropriate. Area under the VAS scores was calculated using the linear trapezoidal rule and thereafter differences between groups were analysed using the Kruskal Wallis and Mann Whitney U tests. P 0.05 was considered statistically significant. Fig 3 Visual analogue scores (VAS) for pain at rest (A) and on swallowing (B) during the study in the placebo, ketoprofen, diclofenac and ketorolac groups (mean (SEM)). Fig 4 Visual analogue scores (VAS) for satisfaction during the study in the placebo, ketoprofen, diclofenac and ketorolac groups. P 0.05, diclofenac vs placebo. Results The groups were comparable in patient characteristics and duration of anaesthesia and operation (Table 1). Three patients (two in the placebo group, one in the ketorolac group) were withdrawn because of postoperative bleeding requiring reoperation. Patients in the placebo group requested, on average, 5.0 doses of oxycodone during the study. Total consumption of oxycodone was significantly lower in all NSAID groups compared with the placebo group (Fig. 1). Patients in the ketoprofen group requested, on average, 3.4 doses of oxycodone (P 0.05 compared with placebo). The corresponding value in the diclofenac and ketorolac groups was 2.9 (P 0.05). In the ketorolac group, there were significantly more patients who did not request oxycodone during the study compared with the placebo and ketoprofen groups (six patients vs one and none, respectively; P 0.05). VRS scores were similar in all groups (Fig. 2). There were no significant differences in VAS scores for pain at rest or during swallowing between groups (Fig. 3). Patients in the diclofenac group had better VAS values for satisfaction during the study compared with placebo (P 0.05). Otherwise there were no significant differences between groups (Fig. 4). There were no serious side effects during the study. Nausea VAS scores were comparable in all groups. The greatest nausea VAS scores during the study were mean 7.7 (SD 14.4), 7.4 (11.8), 6.8 (9.4) and 10.7 (14.0) in the placebo, ketoprofen, diclofenac and ketorolac groups, Table 2 Adverse reactions during the study (number of patients (%)). Three patients (two in the placebo group and one in the ketorolac group) were excluded because of postoperative bleeding. No significant differences between groups Placebo Ketoprofen Diclofenac Ketorolac Nausea 8 (44) 10 (50) 11 (55) 9 (47) Vomiting 5 (28) 6 (30) 5 (25) 5 (26) Itching 4 (22) 4 (20) 1 (5) 4 (21) Pain at the injection site 9 (50) 12 (60) 7 (35) 9 (47) Urinary problems 3 (17) 1 (5) 3 (16) Skin rash 1 (6) 1 (5) Headache 8 (44) 7 (35) 5 (25) 6 (32) Earache 7 (39) 8 (40) 7 (35) 7 (37) Stomach ache 2 (11) 3 (15) 4 (20) 2 (11) 58
Which NSAID after tonsillectomy? respectively. In all groups, two or three patients requested medication for nausea. There were no differences in the incidence of other minor adverse events (Table 2). Discussion In this study, consumption of oxycodone was significantly smaller in each NSAID group compared with placebo. NSAID use was associated with different profiles. Ketoprofen reduced opioid request (mean 32%), but did not provide complete analgesia, as all ketoprofen patients required oxycodone supplementation during the postoperative period. In the ketoprofen group, there were also five patients (25%) whose need for oxycodone was great (more than five doses). Diclofenac reduced opioid requirements by 42%, and in two patients (10%) diclofenac provided complete analgesia without the need for oxycodone. None of the patients in the diclofenac group needed more than five doses of rescue opioid. In the ketorolac group, 32% (six) of patients did not request extra opioids during the study. In contrast, there were five (26%) patients in the ketorolac group who needed more than five oxycodone doses during the study. The opioid sparing effect of 32 42% agrees with previous studies after orthopaedic surgery. 12 13 Pain scores are usually used to measure efficacy compared with placebo. However, if all patients are given sufficient rescue analgesia, one would not expect differences in pain scores. Before operation, we advised our patients to request enough rescue analgesia in order to be pain free. As both VRS and VAS scores were similar in all groups, we can assume that the number of rescue opioid demands gives an objective estimation of the efficacy of the different NSAID for postoperative pain. In our study, infusion of drugs was commenced before operation because NSAID do not have immediate analgesic effects. 14 The dosing interval and doses of NSAID were chosen on the basis of current recommendations. Although the elimination half-life of diclofenac is only 1.1 h, 15 it has a long therapeutic effect, probably because of active metabolites 16 and because of accumulation in inflamed tissue. 17 The elimination half-life of ketorolac (5.1 h) 15 warrants the use of repeated doses at 6-h intervals. The half-life of ketoprofen has been estimated as 2 4 h. 18 All NSAID have antiplatelet effects that are reversible and limited to the time the drug is present in the body. As the half-life of ketorolac is 5 6 h, platelet function returns to normal within 24 h of a single dose of ketorolac. 19 With our 30-min infusion regimen repeated at fixed intervals, no adverse effect on peroperative bleeding during operation or in the first 24 h was seen. Ketorolac has been associated with postoperative bleeding after tonsillectomy in adults and children. 7 9 However, the study of Judkins, Todd and Hubbell 6 was retrospective and the dose regimen of ketorolac was not given. In paediatric studies, 7 9 the loading dose of ketorolac was greater (1 mg kg 1 ) than in our study (mean 0.5 mg kg 1 ). The reason for differences between our results and those of others may be that we studied adult patients undergoing elective surgery. The dose relative to patient weight was lower than that in the paediatric studies and our infusion rate was low. We conclude that i.v. ketoprofen, diclofenac and ketorolac, in the doses used, were superior to placebo after elective tonsillectomy. In the majority of patients, additional opioid was also necessary. There were no marked differences between the drugs with respect to analgesia, opioid sparing effects or side effects. None of the NSAID in our study increased bleeding during operation or the incidence of haemorrhage on the first day after operation. Acknowledgements We thank the nurses in the recovery room and in the wards for their skilful assistance during the study. References 1 Souter AJ, Fredman B, White PF. Controversies in the perioperative use of nonsteroidal antiinflammatory drugs. Anesth Analg 1994; 79: 1178 90 2 Saarnivaara L, Metsä-Ketelä T, Männistö P, Vapaatalo H. Pain relief and sputum prostaglandins in adults treated with pethidine, tilidine and indomethacin. A double-blind study. Acta Anaesthesiol Scand 1980; 24: 79 85 3 Moote C. Efficacy of nonsteroidal anti-inflammatory drugs in the management of postoperative pain. Drugs 1992; 44 (Suppl. 5): 14 30 4 Niemi L, Tuominen M, Pitkänen M, Rosenberg PH. Comparison of parenteral diclofenac and ketoprofen for postoperative pain relief after maxillofacial surgery. Acta Anaesthesiol Scand 1995; 39: 96 9 5 O Brien WM. Adverse reactions to nonsteroidal anti-inflammatory drugs. Diclofenac compared with other nonsteroidal antiinflammatory drugs. Am J Med 1986; 80 (Suppl. 4B): 70 80 6 Judkins JH, Todd GD, Hubbell RN. Intraoperative ketorolac and post-tonsillectomy bleeding. Arch Otolaryngol Head Neck Surg 1996; 122: 937 40 7 Gunter JB, Varugese AM, Harrington JF, et al. Recovery and complications after tonsillectomy in children: A comparison of ketorolac and morphine. Anesth Analg 1995; 81: 1136 41 8 Rusy LM, Houck CS, Sullivan LJ, et al. A double-blind evaluation of ketorolac tromethamine versus acetaminophen in pediatric tonsillectomy: Analgesia and bleeding. Anesth Analg 1995; 80: 226 9 9 Splinter WM, Rhine EJ, Roberts DW, Reid CW, MacNeill HB. Preoperative ketorolac increases bleeding after tonsillectomy in children. Can J Anaesth 1995; 43: 560 3 10 Yee JP, Koshiver JE, Allbon C, Brown CR. Comparison of intramuscular ketorolac tromethamine and morphine sulfate for analgesia of pain after main surgery. Pharmacotherapy 1986; 6: 253 61 11 Tigerstedt I, Tammisto T. A modified visual analogue scale (VAS) for evaluation of pain intensity during immediate postoperative recovery. Schmerz Pain Douleur 1988; 9: 27 31 12 Kostamovaara PA, Laitinen JO, Nuutinen LS, Koivuranta MK. Intravenous ketoprofen for pain relief after total hip or knee replacement. Acta Anaesthesiol Scand 1996; 40: 697 703 13 Laitinen J, Nuutinen L. Intravenous diclofenac coupled with PCA fentanyl for pain relief after total hip replacement. Anesthesiology 1992; 76: 194 8 59
Tarkkila and Saarnivaara 14 Rømsing J, Walther-Larsen S. Peri-operative use of non-steroidal anti-inflammatory drugs in children: analgesic efficacy and bleeding. Anaesthesia 1997; 52: 673 83 15 Mather LE. Do the pharmacodynamics of the nonsteroidal antiinflammatory drugs suggest a role in the management of postoperative pain? Drugs 1992; 44 (Suppl. 5): 1 13 16 Menassé R, Hedwall PR, Kraetz J, et al. Pharmacological properties of diclofenac sodium and its metabolites. Scand J Rheumatol 1978; 22 (Suppl. ): 5 16 17 Fowler PD, Shadforth MF, Crook PR, John VA. Plasma and synovial fluid concentrations: diclofenac sodium and its major hydroxylated metabolites during long-term treatment of rheumatoid arthritis. Eur J Clin Pharmacol 1983; 25: 389 94 18 Olkkola KT, Maunuksela EL. The pharmacokinetics of postoperative intravenous ketorolac tromethamine in children. Br J Clin Pharmacol 1991: 31: 182 4 19 Williams RL, Upton RA. The clinical pharmacology of ketoprofen. J Clin Pharmacol 1988; 28: S13 22 60