Initially, 4,596 article citations were identified, with 2,252 duplicates removed. Following screening, 2,316 records were excluded based on title and abstract, leaving 29 references. One reference could not be retrieved,25 and after a full-text assessment of 28 reports, 17 were excluded primarily because of incorrect comparisons. Three additional RCTs were found through a Google Scholar search and included in the review. Ultimately, 14 RCTs involving 829 patients met the inclusion criteria.8,24,25,26,27,28,29,30,31,32,33,34,35,36,37 Additional details about the selection process are outlined in the PRISMA flowchart (Fig. 1).

Study flow diagram summarizing the retrieved, included, and excluded trials

Of the 14 RCTs included, eight administered the intervention in the intraoperative period,8,26,28,29,30,31,35,36 two in the preoperative period,34,37 one in the postoperative period,33 and three in a combination of the preoperative and intraoperative period because of the need for intravenous access.24,27,32 Three RCTs compared intravenous and oral routes.24,32,37 Six studies compared intravenous and rectal routes,28,29,30,31,33,35 and five studies compared oral and rectal routes.8,26,27,34,36 In addition, one trial, by Aslani et al.,24 was available only as a poster meeting from which we extracted the relevant data. Only two trials, by Khalili et al. and Nour et al., included placebo as a control group.31,32 Finally, Kumar et al.35 reported pain scores with unexplained low variability.

Included RCTs recruited children between three months and 15 yr of age undergoing general anesthesia with orotracheal intubation as the main anesthetic technique. One study included patients undergoing primary cleft repair,32 one included patients for surgical repair of a unilateral inguinal hernia,31 two included patients undergoing surgical correction of major craniofacial malformations,8,33 and ten included patients undergoing tonsillectomy with or without adenoidectomy.24,26,27,28,29,30,34,35,36,37 Four RCTs were conducted in the USA,24,32,34,37 two in Iran,26,31 two in the Netherlands,8,32 two in India,28,29 and one each in Australia, Italy, Pakistan, and Denmark.27,30,35,36 Trials testing the rectal route used acetaminophen doses ranging from 15 mg·kg−1 to 90 mg·kg−1, those testing the oral route used doses ranging from 15 mg·kg−1 to 60 mg·kg−1, and those investigating the intravenous route used doses ranging from 10 mg·kg−1 to 40 mg·kg−1. Characteristics of the included trials are detailed in Table 1 and ESM eTables 2 and 3, the risk of bias assessment is shown in Fig. 2, and the summary of the risk of bias is presented in ESM eFig. 1. Of the 14 RCTs included, eight did not declare their source of funding,8,24,28,31,33,34,35,36 five declared funding by universities or no external sources,26,29,30,32,37 and one declared funding by a pharmaceutical company27 (for the analyses of plasma concentrations) (ESM eTable 4).

Risk of bias assessment of included trials using the Cochrane Risk of Bias 1.0 tool

? = unclear risk of bias; − = high risk of bias; + = low risk of bias

Among the 14 RCTs included in our analysis, seven provided sufficient detail regarding the randomization process,8,26,27,30,32,35,37 and seven provided insufficient information.24,28,29,31,33,34,36 Seven RCTs described the methods for allocation concealment,8,26,27,30,32,33,37 one RCT allowed patients to choose their intervention route,