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Alexandria Journal of Anaesthesia and Intensive Care 49

Propacetamol Versus Placebo for Management of Acute Postoperative Pain After Elective Tonsillectomy in Children.

Mahmoud A Nassef, MD*. Ashraf M Moustafa, MD**. Ashraf A Moussa, MD***. *Department of Anesthesia, Beni-Suef Faculty of Medicine, Cairo University **Department of Anesthesia, Menoufiya University ***Department of Anesthesia,Menoufiya Liver Institute, Menoufiya University

ABSTRACT The efficacy and safety of propacetamol, an injectable of acetaminophen, was assessed versus placebo after elective tonsillectomy operation in children. Using a double-blind, randomized parallel group design, 70 children aged 6-12 years were included to evaluate the effect of a single iv infusion of 40 mg/kg propacetamol versus a single infusion of 100 ml normal saline ( placebo ) given at the recovery room. Analgesic efficacy was assessed on pain scores rated on a four-points verbal scale, a five-points visual scale ( faces ) and a four-points pain relief verbal scale; before administration ( T0 ) and 0.25, 0.5, 1, 2, 3, 4, 5 and 6 hours after the infusion. The global efficacy was rated on a five-point scale at the end of the study. Rescue medication was allowed freely and the time for re-medication as well as the occurrence of any side effects was recorded. Propacetamol was statistically superior to placebo on all assessment criteria. The global final efficacy evaluation demonstrated 12 patients in the propacetamol group with good and very good scores compared to only one patient in the placebo group. Rescue medication was used in 40% of patients in the propacetamol group versus 83% in the placebo group. No serious side effects were recorded in both groups and pain at the infusion arm was noticed in 4 patients with propacetamol and 2 patients in the placebo group (P> 0.05). We concluded that, although propacetamol 40 mg/kg infusion may provide greater pain relief than placebo in children after tonsillectomy operation without any significant adverse effects, it is better to be used as a complementary drug to other in the treatment of moderate to severe postoperative pain. Key words: propacetamol, postoperative pain, acetaminophen, tonsillectomy.

Introduction The use of in the post- operative period was limited because of the Tonsillectomy is a common procedure temporary contraindication to the oral route (especially in children) in ear-nose-throat and the irregular or slow bioavailability of the (ENT) surgery, causing considerable post- rectal route (5). operative pain. Analgesia with non- is often insufficient while the use of opioids is Propacetamol, N-acetylparaminophenol di- associated with side effects such as nausea, ethyl amino acetic ester, is the first form of sedation and respiratory depression (1, 2). paracetamol that can be injected parentraly. It is a water–soluble prodrug which is rapidly Paracetamol is an effective analgesic in metabolized to acetaminophen ( paracetamol) children (3, 4), it lacks adverse bleeding effects and diethylglycine in a 1: 1 ratio by non- and remains the most commonly used non- specific plasma esterases ; as a result an narcotic analgesic drug. In recent studies, it intravenous administration of one gram has been claimed to be as efficacious as propacetamol yields only 0.5 gram of paracetamol ( 6,7 ). in post- tonsillectomy pain relief but it is associated with a lower incidence of The present study was designed to adverse effects like bleeding, adverse renal evaluate the analgesic efficacy as well as the effects and acute bronchospasm. safety of propacetamol versus placebo after elective tonsillectomy operation in children.

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METHODS = weak, 2 = moderate, 3 = good and 4 = very good). The occurrence of any side – effects Seventy children aged 6-12 years, ASA was recorded. class 1 and 2 scheduled for elective tonsille- Withdrawal of the children from the study ctomy were included in this study after for insufficient pain relief on evaluation of the obtaining an informed parental written consent. observer was allowed from the beginning of Children with a history of paracetamol allergy the study, but considered valid for the study were excluded. All patients were premedicated only if it occurred at least 30 minutes after the with midazolam 0.3 mg/kg orally one hour beginning of the treatment. The physician was before surgery. Anesthesia was induced with free to choose whether additional medication thiopentone sodium 5mg/kg IV and 1.5 should be given and the time for re-medication μg/kg IV, endotracheal intubation was was recorded facilitated with the use of atracurium 0.5 mg/kg IV. Children were mechanically ventilated and For the primary analgesic efficacy data, the anesthesia was maintained with 50% N2O in following variables were derived or computed O2 plus isoflurane 1-2%. Bolus doses of to assess the analgesic efficacy of the study fentanyl and/or atracurium were injected drug: accordingly. At the end of surgery the 1. Pain Intensity Difference (PID): for both neuromuscular block was reversed with visual and verbal scores, PID was calculated neostigmine 0.025 mg/kg and atropine 0.015 as the difference between the base line pain mg/kg IV. ECG, end tidal CO2, pulse oximetery intensity and the pain intensity at each and blood pressure were monitored during evaluation time point. anesthesia. 2. Sum of Pain intensity Difference (SPID): In the recovery room, the children were calculated by adding the PID score over the rated on a five-point visual scale (8) (sequence 6 hours of the study. of faces – Figure 1) as well as a four-point 3. Total Pain Relief (TOTPAR): calculated as verbal scale (0 = none, 1 = mild, 2 = moderate the sum of PID and the pain relief score over and 3 = severe) by an observer who is blind for the 6 hours period. the treatment group. Children with a score of 3- To allow calculation of SPID and TOTPAR, 5 on the visual scale and/or 2-3 on the verbal missing data were replaced by the assessment scale were included in this study (i.e. moderate at the time of withdrawn when patient was to severe pain). Children included in the study withdrawn for insufficient analgesia and by the were randomly allocated into 2 main groups: previous assessment when the patient was Group I {propacetamol group}, received 40 asleep. mg/kg propacetamol (mixed in 100 ml of All data were represented as means ± normal saline) as an IV infusion; and Group II standard deviation, or number of patient {placebo group}, received an IV infusion of 100 Statistical analysis was performed with SPSS ml of normal saline. Infusion was done over 15 version 10.0 Program. For SPID, TOTPAR and minutes in both groups. global efficacy, the tow groups were compared Pain intensity was re-assessed by the using one- sided non- parametric Wilcoxon same observer at 0.25, 0.5, 1, 2, 3, 4, 5 and 6 sign rank tests. Parametric Data and difference hours after the infusion. At the same times, between both groups were analyzed with one- pain relief was measured using a 4 point- way analysis of variance (ANNOVA) and verbal rating scale (0 = complete pain relief, 1 Student’s t-test. The Chi-square test and = good, 2 = slight and 3 = none). At the end of Fisher’s exact test were applied to non- the 6 hours study period, a global rating of the parametric data when appropriate. P value of treatment efficacy was made by both a less than 0.05 was considered statistically physician observer as well as by a nurse significant. observer using the following scale (0 = none, 1

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Figure 1: Visual analogue Scale The final global efficacy evaluation (Sequence of Faces) (8) recorded 10 patients with good result and 2 patients with very good result in the propacetamol group compared to only one patient in the placebo group with good result (Figure 5). Fourteen patients in the propa- cetamol group were withdrawn from the study for insufficient analgesia, versus 29 5 4 3 2 1 patients in the placebo group. Also the mean time for re-medication was significantly RESULTS longer in the propacetamol group ( 163 ± 88 min Vs 116 ± 79 min ) [ p< 0.05] ( Table 3 ). There was no significant difference There were no serious adverse effects between the two groups as regards age, sex, recorded in both groups during the study weight, and duration of surgery as well as hours. Four patients in the propacetamol the amount of intraoperative fentanyl group complained a burning sensation at the requirements (Table 1). infusion arm and 3 patients experienced Pain scores (visual and verbal scales) were postoperative vomiting, while in the placebo almost similar in both groups before starting group burning sensation was recorded only the infusion and during the first 30 min after in 2 patients while 4 patients had post- the infusion, no significant difference was operative vomiting (P > 0.05). detected (P > 0.05). After 30min and till the end of the 6th hour, pain scores were DISCUSSION significantly lower in the propacetamol group than in the placebo group (Figure 2 – 3). A The recommended oral dose of similar significant difference was detected paracetamol for effective analgesia is 15-20 with the pain relief score (Figure 4). For mg/kg every 6 hours (9, 10). In the present derived variables: SPID was significantly study a dose of 40 mg/kg of propacetamol, higher in the propacetamol group than in the which is equivalent to an oral dose of placebo group ( 452.6 ± 68.5 Vs 295.3 ± 20mg/kg was used. Such dose was clearly 76.1 for visual scale and 289.8 ± 51.2 Vs demonstrated to be more efficient than 183.7 ± 63.2 for verbal scale) [P< 0.05], and placebo on every assessment criterion, with TOTPAR was significantly lower (indicating statistically significant difference recorded at better analgesia) in the propacetamol group 30min after infusion and continued till the than the placebo group (593.2 ± 81.1 Vs end of the 6hours of the study. 811.2 ± 63.3 ) [ P< 0.05] (Table 2).

Table 1: Patient’s demographics in both groups

Propacetamol Group Placebo Group Age (years) 8.7 ± 1.1 ( 6 – 12 ) 8.4 ± 0.96 ( 6 – 11 ) Sex Male 19 18 Female 16 17 Weight (Kg) 32.3 ± 1.2 ( 21 – 53 ) 33.3 ± 1.2 ( 19.5 – 61 ) Duration of Surgery (Min) 38.2 ± 8.1 ( 25 – 48 ) 36.1 ± 9.2 ( 24 – 51 ) Intraoperative Fentanyl (μg) 55 ± 8 53 ± 9

No significant difference between both groups (P>0. 05) Data are presented as number of the patients or [Mean ± SD (Range)].

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Figure 2: Pain Score on Visual Scale for Both Groups

4.5 *** 4 * * * * 3.5 3 2.5 2 T0 T15min T30min T1h T2h T3h T4h T5h T6h

Propacetamol Placebo

Mean ± SD Pain score (visual scale) for both groups ( * ) Significant differences at all assessment times after 30 min. (P≤ 0.05) SPID = 452.6± 68.5 for propacetamol group Vs 295.3± 76.1 for placebo (P<0.05)

Figure 3: Pain Scores on Verbal Scale for Both Groups

3 * * * 2.5 * * * * 2

1.5

1 T0 T15min T30min T1h T2h T3h T4h T5h T6h

Propacetamol Placebo

Mean ± SD Pain Scores in Both groups on Verbal Scale ( * ) Significant differences between both groups at all assessment times after 30 min. (P≤ 0.05) SPID = 289.6± 51.2 for Propacetamol Group Vs 183.1± 63.2 for Placebo Group (P < 0.05)

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Figure 4: Pain Relief Score in Both Groups

3 * * * * * 2.5 * *

2 1.5

1 T15min T30min T1h T2h T3h T4h T5h T6h

Propacetamol Placebo

Mean ± SD of Pain relief Score (Verbal Scale) in Both Groups ( * ) Significant differences at all assessment times after 30 min. P≤ 0.05 TOTPAR = 593.2± 81.3 for Propacetamol Group Vs 811.2± 63.1 for Placebo Group (P< 0.05)

Figure 5: Final efficacy Evaluation for Both Groups (Number of Patients)

20 18 14 16 11 12 14 11 10 12 8 10 8 6 2 1 1 4 0 2 0 None Weak Moderate Good Very good

Propacetamol Placebo

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The number of patients withdrawn from analgesic efficacy of rectal and parentral this study for insufficient analgesia was paracetamol and they concluded that the significantly less in the propacetamol group concurrent use of paracetamol and NSAIDs than in the placebo group [14 Vs 29, is superior to paracetamol alone but not to equivalent for 40% Vs 83%]. Also the time of NSAIDs alone for postoperative analgesia. occurrence of treatment failure, withdrawal, Regarding the incidence of side effects, was significantly different between both we did not detect any significant difference groups. Both observations indicate a better between both groups. Burning sensation at survival curve in the propacetamol group. the infusion arm was the main complaint but But still, the overall final efficacy evaluation no significant difference between both demonstrated 10 patients with good and 2 groups was recorded. Burning sensation at patients with very good scores in the the infusion arm during propacetamol propacetamol group (a total of 35%), versus infusion was also reported in several only one patient with good assessment in the previous studies(11-14). Hiller et al(13) recomm- placebo group (3%). ended the 2 gram adult dose of propa- Several studies had evaluated the use of cetamol to be mixed with 250 ml of normal paracetamol by the rectal route and/or saline, instead of the 100 ml recommended parentraly for postoperative pain relief in by the manufacturer, and to increase the three different ways: 1) alone for moderate infusion time from 15 minutes to 30 – 40 pain relief, 2) with opioids analgesics to minutes to reduce the incidence of burning reduce the total consumption and 3) in sensation. Our impression is that such combination with non-steroidal anti- manipulation is not necessary as this burning inflammatory drugs (5,9,10-16). sensation was also noted with the use of Grany et al (5) concluded that propa- placebo without any significant difference cetamol, 30mg/kg, provides significantly between both groups. greater pain relief than placebo after limb In conclusion, although the infusion of orthopedic surgery in children. Hiller et al (13) propacetamol 40mg/kg may provide a demonstrated that the combined therapy significantly greater pain relief than placebo with propacetamol and diclofenac offers no following elective tonsillectomy in children clinical advantage over monotherapy with without any significant adverse effects, it is propacetamol or diclofenac with respect to better to be used as a complementary drug postoperative analgesia following elective to other analgesics for the treatment of tonsillectomy in adults. Also, Tian Zhou et al moderate to severe postoperative pain. (14) concluded that propacetamol was more effective than saline and not different from REFERENCES with respect to the main analgesic variance when administered on the first day 1. Schmidt A, Bjorkman S, Akeson J. Pre- after a total hip or knee replacement surgery, operative rectal diclofenac versus placebo but both drugs reduced the total opioids for tonsillectomy: effects on pain and blood consumption. loss. Acta Anesthesiol Scand 2001; 45: 48- 52. On contrary, Fletcher et al(11) demon- 2. Romsing J, Osterguard D, Dorzdziewicz D, strated that the combination of propa- et al. Diclofenac or acetaminophen for cetamol and though it reduces analgesia in pediatric tonsillectomy the pain scores after disc surgery, it did not outpatients. Acta Anesthesiol Scand 2000; reduce the total consumption or 44: 291- 5. the incidence of side effects. Pasi lahtinem 3. Rumack BH. versus acetamino- (15) et al concluded that the use of propa- phen: a comparative view. Pediaterics cetamol after cardiac surgery did not en- 1978; 62: 943-6. hance analgesia or decrease the cumulative 4. Schannon M, Berde CB. Acute pain in opioid consumption. Also, Romsing et al(16) children. Pharmacologic management of had reviewed several studies about the

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