To demonstrate the effect of opioid administration on postoperative pain scores, we assessed changes in CHIPPS ratings at each observational time point (minimum, 13 per patient), with and without Pi administration over 10-min intervals (equivalent to the lockout period). After the administration of Pi (n = 240), CHIPPS ratings were decreased by 3.2 ± 4.9, whereas CHIPPS ratings were only reduced by 0.2 ± 2.1 without the Pi administration (n = 560). There was a statistically significant difference among groups (P < 0.00001).
Blood samples for Ac plasma concentrations were taken from the indwelling venous cannulae; because of technical difficulties (e.g., venoconstriction), sampling from all patients was not possible. Fifty blood samples were collected for analysis (Table 2). There was no statistically significant difference in the time of blood sampling among groups. Ac 0 and 10 mg/kg produced only subtherapeutic plasma levels (<10 μg/mL). Maximum plasma concentrations of 13 and 21 μg/mL were achieved after 20 and 40 mg/kg, respectively. There were no statistically significant differences among groups. In addition, there was no correlation between Ac plasma concentrations achieved and postoperative opioid requirements (20 mg/kg Ac:r = −0.33; 40 mg/kg Ac:r = 0.45).
There was no incidence of bradycardia, respiratory depression ≤ 10 breaths/min, or oxygen desaturation ≤ 93% in the PACU. Furthermore, there was no incidence of vomiting or other adverse effects within the first 24 h after surgery.
The major findings of this study were that rectal Ac up to 40 mg/kg administered at anesthesia induction in infants and small children undergoing elective cleft palate repair (I) had no effect on early postoperative pain scores, (II) had no opioid-sparing effect in the early postoperative period, and (III) did not result in analgesic plasma concentrations, whereas (IV) carefully titrated IV opioid boluses produced rapid and reliable pain relief.
Postoperative Pain Scores and Opioid Requirements
Rectal Ac, given at anesthesia induction, is very popular in the treatment of mild-to-moderate postoperative pain in infants and small children. As an analgesic adjuvant, it reduces postoperative opioid requirements (3). The currently suggested rectal Ac dose recommendations for the treatment of postoperative pain in infants and children exceed the age-related manufacturer’s guidelines (Drugdex Drug Evaluations: Acetaminophen). Still, data about the efficacy of rectal Ac in the treatment of postoperative pain are conflicting. Rectal Ac 20 mg/kg (6) and 40 mg/kg (1) administered at anesthesia induction failed to adequately treat postoperative pain in up to 46%(1) and 90%(6) of the children undergoing adenotonsillectomies. Morton and O’Brien (5) demonstrated that 15–20 mg/kg rectal Ac had no significant morphine-sparing effect in children undergoing appendectomies. In contrast to these results, both 40 and 60 mg/kg rectal Ac significantly reduced pain and postoperative opioid requirements in children undergoing outpatient surgery in a dose-dependent way (3).
Our results differ from those of Korpela et al. (3), demonstrating that prophylactically-administered rectal Ac in the dose-range studied had no beneficial impact on postoperative pain scores and no opioid-sparing effect in infants or small children undergoing elective cleft palate repair. One possible reason for these conflicting results could be that the type of surgery performed has a significant effect on the analgesic efficacy of rectal Ac and on the additional postoperative opioid requirements. After the administration of rectal Ac, sufficient postoperative pain control was achieved after herniorrhaphies, whereas the analgesic demand was significantly increased after orchidopexies (17). In the study presented by Korpela et al. (3), depending on the group assignment, up to 80% of the patients underwent herniorrhaphies, possibly resulting in low postoperative pain intensities not requiring further opioid administration. Furthermore, patients’ demographics may significantly affect the postoperative pain intensity and opioid requirement. In contrast to investigations studying very heterogeneous age groups and mixed surgical procedures (1,3,10), the patients enrolled in the current study are very homogenous with respect to age, weight, sex, and surgical procedure. As a further standardization of the study design, in all patients, anesthesia, surgery, and postoperative pain assessment were performed by the same personnel.
Ac Plasma Concentrations
In this study, Ac plasma concentrations obtained after the rectal administration of 10, 20, and 40 mg/kg were mainly subtherapeutic (i.e., below the antipyretic range of 10–20 μg/mL) and did not exceed 21 μg/mL in any patient. Recently, Hansen et al. (8) determined Ac plasma concentrations in neonates and young infants. Similar to our results, after the rectal administration of 24 mg/kg Ac, mean peak plasma concentrations achieved were 11 μg/mL only (8). In children, mean peak plasma concentrations of 5.5, 8.8, and 14.2 μg/mL were obtained after rectal Ac doses of 10, 20, and 30 mg/kg at 107, 288, and 210 minutes, respectively (2). Even the administration of large-dose rectal Ac of 45 mg/kg yielded only peak plasma concentrations associated with antipyresis (9).
In 1999, a plasma concentration-analgesic effect relationship of rectal Ac in children was first established (10). Mean posttonsillectomy pain scores of <4 of 10 are achieved at an effect compartment concentration of 10 μg/mL. Using doses up to 40 mg/kg Ac, however, still results in pain scores more than 4 of 10 in the first 2 h postoperatively (10), whereas only pain scores of <4 of 10 are commonly considered satisfactory in children (7).
In addition to the Ac dosages used, the time and route of Ac administration are important. The bioavailability of rectal Ac is lower (18) and the time to peak plasma concentrations is longer than when compared with the same dose given orally (19). Thus, despite the current increase in recommended Ac dosage, the absorption after rectal administration remains erratic (9), and bioavailability is highly variable. Peak plasma concentration occurs in an average of 2 to 3 hours after insertion of rectal suppository (2,8–10). Therefore, after mean blood sampling times between 122 and 129 minutes in this study, analgesic Ac plasma concentrations should have been reached at anesthesia emergence.
The accuracy of the Ac plasma concentrations determined in our study may be limited because of technical difficulties (i.e., venoconstriction) and the study design (i.e., blood sampling from the indwelling cannulae). Only a limited number of blood samples were obtained. Furthermore, because blood samples were collected only once, we cannot exclude the possibility that we might have missed earlier peak Ac plasma concentrations.
Adverse Effects of Ac
In children, hepatotoxicity from Ac poisoning is an exceedingly rare event, with most of the reported cases resulting from chronic administration and not acute overdosage (11). However, Ac may be potentially hepatotoxic in doses twice those recommended by the manufacturer and close to those often prescribed for its antipyretic properties (12). As a precaution, especially in the outpatient surgical setting, parents should be advised about the potential liver damage from Ac in doses exceeding weight-based recommendations (11). Based on the recommendations of Birmingham et al. (2) and Anderson et al. (1,10) the maximum single dose of rectal Ac in this study was limited to 40 mg/kg leading to a safe maximum Ac plasma concentration of 21 μg/mL.
By using a pharmacokinetic dynamic simulation model, larger rectal Ac doses for satisfactory postoperative pain control than used in this study are effective (4). A loading dose of 70 mg/kg and a maintenance dose of 50 mg/kg every 8 hours is predicted to provide adequate postoperative analgesia in children. However, this model has not been used clinically. The potential hepatotoxic effect of Ac in daily doses above 150 mg/kg (4) and the maximum daily cumulative dose restriction of 90 mg/kg (20) should be adhered to. With respect to this safety margin, we feel that an increase in rectal Ac dosage is not advantageous for postoperative pain management in infants and small children, especially if equipotent (7) or even superior (5) clinical alternatives are available. Further investigations using different nonsteroidal antiinflammatory drugs are required to study their suitability and potential opioid-sparing effect in postoperative pain management after elective cleft palate repair.
Observational Scoring Systems for Postoperative Pain Assessment
Various observational scoring systems are available for postoperative pain assessment in preverbal infants and children (15,16,21,22). One of the shortcomings of these systems, however, is the potential inability to differentiate true pain from other forms of perioperative discomfort such as fear, hunger, and separation anxiety. The CHIPPS as a measure of postoperative pain especially in preverbal children is economic and suitable for most clinical settings, controlled data on the sensitivity, specificity, reliability, and validity of the CHIPPS have been presented (16). Explicitly, there was a significant interaction between repeated CHIPPS measurements and the supply of analgesics, whereas sedatives had no effect on CHIPPS scores. The CHIPPS ranges from no pain (0 of 10) to the worst imaginable pain (10 of 10). In our study, the effect of titrated opioid administration on CHIPPS ratings was determined, and a significant correlation between repeated pain assessments and the administration of analgesics was established. Pi significantly decreased CHIPPS ratings by 2.8, whereas no opioid administration reduced CHIPPS ratings by only 0.3, indicating that CHIPPS is actually assessing pain.
Postoperative IV opioid administration may be associated with the risk of respiratory depression and oversedation. Yet, these adverse effects constitute no rationale to deny infants and small children postoperative opioids if adequate monitoring is guaranteed and administration is titrated by need. In parts of Europe, the IV opioid Pi is the “gold standard” for postoperative pain management in adults (23). Its safe and efficient use in pediatric postoperative pain management has been described (24). Compared with morphine, the analgesic potency of Pi is 0.7, and it is associated with a decreased incidence of nausea and vomiting as well as less histamine liberation (23). When administered in equipotent doses, its respiratory depressant effect equals that of morphine (23). Compared with pethidine, it is characterized by remarkable cardiovascular stability (23). Compared with other opioids, Pi’s pharmacodynamic properties most closely matched those of the study design: After IV administration, it has a fast onset of action (2–5 minutes) with peak effect after 10 minutes. The mean duration of action is six hours (23).
Vomiting is a potential adverse effect of opioid administration; however, postoperative pain also seems to be a clear predictor of nausea and vomiting in children (25). In our study, there was no incidence of vomiting within the first 24 hours despite oral feeding via the nasogastric tube when fully awake. Furthermore, no other untoward effects from either Ac or Pi were observed.
Based on our results, we conclude that, in infants and small children undergoing elective cleft palate repair, rectally-administered Ac at anesthesia induction in the dose range studied lacks proof of its analgesic efficacy, has no opioid-sparing effect, and does not result in analgesic plasma concentrations in the early postoperative period, whereas carefully titrated IV opioid boluses produced rapid and reliable pain relief.
1. Anderson BJ, Kanagasundarum S, Woollard G. Analgesic efficacy of paracetamol in children using tonsillectomy as a pain model. Anaesth Intensive Care 1996; 24: 669–73.
2. Birmingham PK, Tobin MJ, Henthorn TK, et al. Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations. Anesthesiology 1997; 87: 244–52.
3. Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of acetaminophen in pediatric day-case surgery. Anesthesiology 1999; 91: 442–7.
4. Anderson BJ, Holford NHG. Rectal paracetamol dosing regimens: determination by computer simulation. Paediatr Anaesth 1997; 7: 451–5.
5. Morton NS, O’Brien K. Analgesic efficacy of paracetamol and diclofenac in children receiving PCA morphine. Br J Anaesth 1999; 82: 715–7.
6. Gaudreault P, Guay J, Nicol O, et al. Pharmacokinetics and clinical efficacy of intrarectal solution of acetaminophen. Can J Anaesth 1988; 35: 149–52.
7. 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.
8. Hansen TG, O’Brien K, Morton NS, et al. Plasma paracetamol concentrations and pharmacokinetics following rectal administration in neonates and young infants. Acta Anesthesiol Scand 1999; 43: 855–9.
9. Montgomery CJ, McCormack JP, Reichert CC, et al. Plasma concentrations after high-dose (45 mg/kg−1
) rectal acetaminophen in children. Can J Anaesth 1995; 42: 982–6.
10. Anderson BJ, Holford NHG, Woolard GA, et al. Perioperative pharmacodynamics of acetaminophen analgesia in children. Anesthesiology 1999; 90: 411–21.
11. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatoxicity after multiple doses in children. J Pediatr 1998; 132: 22–7.
12. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300–4.
13. Miles FK, Kamath R, Dorney SF, et al. Accidental paracetamol overdosing and fulminant hepatic failure in children. Med J Aust 1999; 171: 472–5.
14. Eguia L, Materson BJ. Acetaminophen-related acute renal failure without fulminant liver failure. Pharmacotherapy 1997; 17: 363–70.
15. Büttner W, Breitkopf L, Finke W, et al. Critical aspects of measuring postoperative pain in small children: a placebo-controlled, double-blind study of reliability and validity. Anaesthesist 1990; 39: 151–7.
16. Büttner W, Finke W. Analysis of behavioural and physiological parameters for the assessment of postoperative analgesic demand in newborns, infants and young children: a comprehensive report on seven consecutive studies. Paediatr Anaesth 2000; 10: 303–18.
17. Warth H, Astfalk W, Walz GU. Postoperative pain control with acetaminophen following inguinal herniorrhaphy or orchidopexy in childhood. Anästhesiol Intensivmed Notfallmed Schmerzther 1994; 29: 90–5.
18. Eandi M, Viano I, Ricci Gamalero S. Absolute bioavailability of paracetamol after oral and rectal administration in healthy volunteers. Drug Res 1984; 34: 903–7.
19. Albert KS, Sedman AJ, Wagner JG. Pharmacokinetics of orally administered acetaminophen in man. J Pharmacokinet Bio-pharm 1974; 2: 381–93.
20. Peters JWB, Vulto AG, Grobee R, et al. Postoperative pain management in children following (adeno)tonsillectomy: efficacy, pharmacokinetics and tolerability of paracetamol and diclofenac. Clin Drug Invest 1999; 17: 309–19.
21. McGrath PJ, Johnson G, Goodman JT, et al. CHEOPS: a behavioral scale for rating postoperative pain in children. Pain Res Ther 1985; 9: 395–402.
22. Tarbell SE, Cohen IT, Marsh JL. The Toddler-Preschooler Postoperative Pain Scale: an observational scale for measuring postoperative pain in children aged 1–5–preliminary report. Pain 1992; 50: 273–80.
23. Kumar N, Rowbotham DJ. Piritramide. Br J Anaesth 1999; 82: 3–5.
24. Petrat G, Klein U, Meiβner W. On-demand analgesia with piritramide in children: a study on dosage specification and safety. Eur J Pediatr Surg 1997; 7: 38–41.
© 2001 International Anesthesia Research Society
25. Kotiniemi LH, Ryhanen PT, Valanne J, et al. Postoperative symptoms at home following day-case surgery in children: a multicenter survey of 551 children. Anaesthesia 1997; 52: 963–9.