Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Schnabel (2015)

SR and meta-analysis of RCTs

Literature search up to; MEDLINE via PubMed (January 1966 to July 2014) and EMBASE via Ovid (January 1947 to July 2014).

A: Engelhardt, 2003;  Hullett 2006;  Ozalevli 2005;

Umuroglu 2004.

B Barsoum 1995: Moyao Garcia

 2009: Schäffer 1986: van den Berg 1999.

A: parallel RCT

B: parallel RCT

Inclusion criteria SR:

-Types of studies

 (included all randomised controlled trials (RCTs) investigating

 tramadol for postoperative pain in children), -Types of participants (included all children and adolescents (0 to 18 years old)

 irrespective of sex or type of surgery), -Types of interventions (included all RCTs investigating tramadol for postoperative pain in children and adolescents in comparison to placebo or any other opioid), -Types of outcome measures (included studies when they reported any of the following outcome measures: number of patients requiring rescue analgesia in PACU, 24 h postop), number of patients with moderate to severe pain, time to rescue analgesic, total required dose of rescue analgesic, number of rescue analgesic doses, number of participants with adverse events.

Exclusion criteria SR:

/

20 RCTs included

Important patient characteristics at baseline:

Number of patients; 1170 patients. The number of children and adolescents analysed in the 20 studies ranged from 24 to 152. Common paediatric surgical procedures were performed within the included trials: ear-nose-throat (ENT) surgery (such as adenotonsillectomy, tonsillectomy), lower abdominal surgery, and dental extraction.

characteristics important to the research question and/or for statistical adjustment (confounding in cohort studies); for example, age, sex, bmi, ...

Groups comparable at baseline? Yes

Describe intervention:

A: tramadol

B: tramadol

Describe control:

A: morphine

B: nalbuphine

End-point of follow-up:

A: 48 h post op

B: 48 h post op

For how many participants were no complete outcome data available?

(intervention/control)

All trials reported that all participants were included in the analysis. Therefore, in all included trials this item was assessed as being at

 low risk of bias.

A:

B:

A; tramadol vs morphine

B; tramadol vs nalbuphine

Outcome measure-1

Postoperative pain at PACU

Effect measure: RR, RD, mean difference [95% CI]:

A: not reported

B: not reported

Outcome measure-2

Postoperative opioid consumption

Effect measure: RR, RD, mean difference [95% CI]:

A:  not reported

B: not reported

Outcome measure-3

Complications

Nausea

A: not reported

B: not reported

Vomiting

A: not reported

B: not reported

Drowsiness/dozing

A: not reported

B: not reported

Constipation

A: not reported

B: not reported

Respiratory depression

Effect measure: RR [95% CI]:

A: RR 0.18 (95% CI 0.01 to 3.51) (Favors tramadol)

B: RR 0.0 (95% CI 0.0 to 0.0)

Pooling was not possible.

Risk of bias (high, some concerns or low):

Tool used by authors: risk of bias of included studies was assessed using the Cochrane Collaboration's tool for assessing risk of bias.

A: [high concerns]; lack of information about randomization or allocation of sequence.

B: [high concerns ; lack of blinding, no information about allocation of sequence, use of pain scale in 2-years old children which was not validated and therefore high risk of bias (Barsoum 1995)).

Conclusion:

Children needed less rescue medication in the postoperative care unit when given tramadol, indicating better analgesia with tramadol.

 Due to the low amount of usable data, the evidence focusing on the comparison of tramadol with other opioids (for example morphine, nalbuphine, pethidine, fentanyl) is currently unclear. Adverse events were generally only poorly reported in the trials so that the side effects as a result of tramadol administration were not clear.

The overall quality of the evidence is low and it should be interpreted with caution because all included trials used different validated and non-validated pain scales in children over a wide range of ages.

Schnabel (2015)

Parallel RCTs

A: Engelhardt, 2003; 

B: Hullett 2006;  C: Ozalevli 2005;

D: Umuroglu 2004.

Procedure and total patients included

A: Tonsillectomy or adeno‐tonsillectomy, n = 60, children

B: Adeno‐tonsillectomy, n = 60, children

C: Adeno‐tonsillectomy, n = 60

D: Adeno‐tonsillectomy, n = 60

Age (range) and specified per included arm in study

A: 2-14 years. Group 1: mean age 8.1 years (SD 4.2); Group 2: mean age 7.1 years (SD 3.6); Group 3: mean age 7 years (SD 4.2).

B: 1-8 years.  Group 1: median age 5.0 years (P25 to P75 4.5 to 7.0); Group 2: mean age 5.0 years (P25 to P75 3.0 to 7.0).

C: 6-12 years. Group 1: mean age 7 years (6 to 11); Group 2: mean age 6 years (6 to 12).

D: 5-12 years.

Intervention: mean age 6.06 (SD 2.51); Control: mean age 7.13 (SD 2.51)

Gender:

A: not reported

B: not reported

C: 37 males, 23 females

D: 32 males, 28 females

Describe intervention:

A:  Group 2: tramadol 1 mg/kg iv (n = 20)

Group 3: tramadol 2 mg/kg iv (n = 20)

Administration time: after induction of anaesthesia.

All patients received diclofenac (1 mg/kg) rectally prior to commencing surgery.

B: Group 2: tramadol 1 mg/kg iv (n = 32)

Administration time: at induction of anaesthesia

C: Group 1: tramadol iv (loading dose 1 mg/kg, bolus 0.2 mg/kg/10min) (n = 30).

Administration time: after surgery

D: Group 3: tramadol 1.5 mg/kg iv (n = 15). Administration time: during induction of anesthesia.

Describe control:

A: Group 1: morphine 0.1 mg/kg iv (n = 20). Administration time: after induction of anaesthesia.

All patients received diclofenac (1 mg/kg) rectally prior to commencing surgery.

B:  Group 1: morphine 0.1 mg/kg iv (n = 28). Administration time: at induction of anaesthesia

C: Group 2: morphine iv (loading dose 0.1 mg/kg, bolus 0.02 mg/kg/10min) (n = 30)

Administration time: after surgery

D: Group 2: morphine 0.1 mg/kg iv (n = 15). Administration time: during induction of anesthesia.

End-point of follow-up:

A: 48 h post op

B: 48 h post op

C: 48 h post op

D: 48 h post op

For how many participants were no complete outcome data available?

(intervention/control)

All trials reported that all participants were included in the analysis. Therefore, in all included trials this item was assessed as being at

 low risk of bias.

Outcome measure-1: Postoperative pain

Postoperative pain (0 hours)

A: not reported

B: Number and % of patients with pain score >= 6 using the pain assessment tool

I: 9 (28.1%)

C: 6 (21.4%)

C: postoperative pain 1 h after operation

I: score 3

C: score 3

D: postoperative pain 1 h after surgery,

using NRS Pain score:

I: 0.40

C: 0.25

Using CHEOPS Score

I: 6.2

C: 6.1

Postoperative pain (6 hours)

A: pain score at 4 h post operation (pain scores could vary between 1 and 5: in which a score of 1 = pain free, 5 = worst possible pain).

T1: 2

T2: 1

M: 2

B: not reported

C: pain score using CHEOPS scores (4 h post operation)

I: score 3

C: score 2

D: pain score 4 h post operative using the NRS Pain score

I: 0.6

C: 0.4

Pain score 6 h post operative using the NRS Pain score:

I: 0.15

C: 0.3

Postoperative pain (12 hours)

A: Pain score (range from 1-5)

T1 = 1

T2 = 1

M = 1

B: not reported

C: not reported

D: not reported

Postoperative pain (24 hours)

A: Pain score (range from 1-5)

T1 = 1

T2 = 1

M = 1

B: not reported

C: not reported

D: not reported

Risk of bias (high, some concerns, or low):

A: some concerns of bias

B: high risk of bias (selective outcome reporting, allocation concealment and blinding no information provided)

C: high risk (no blinding reported)

D: some concerns of bias

From SR: The overall quality of the evidence is low and it should be interpreted with caution because all included trials used different validated and non-validated pain scales in children over a wide range of ages.

Overall conclusion: Children needed less rescue medication in the postoperative care unit when given tramadol, indicating better analgesia with tramadol. Due to the low amount of usable data, the evidence focusing on the comparison of tramadol with other opioids (for example morphine, nalbuphine, pethidine, fentanyl) is currently unclear. Adverse events were generally only poorly reported in the trials so that the side effects as a result of tramadol administration were not clear.

Study characteristics are extracted from the SR and the results are obtained from the individual RCTs.

Pain Assessment Tool: scale range from 0-10 in which 0 indicates no pain and 10 indicates worst pain.

NRS: numeric rating scale: 0 = no pain, 1 = mild uncomforted, 2 = mild pain, 3 = intermediate pain, 4 = severe pain, 5 = very severe pain).

Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS scores): for pain assessment which ranges from 0 to 10 (0 = no pain, 10 = worst possible pain). Solely presented on a figure. Used in Ozalevli (2005).

 Schnabel (2015)

Parallel RCTs

A: Barsoum 1995

B: Moyao Garcia

 2009

C: Schäffer 1986

D: van den Berg 1999.

Procedure and total patients included

A: Lower abdominal surgery (appendectomy, hernia repair, testicular or urethral surgery), n = 75

B: Surgical procedures with expected moderate to severe postoperative pain (e.g. perineal fistula and bladder neck closure, bilateral oblique pelvic osteotomy, exploratory laparotomy, bilateral elongation of Achilles tendon, etc), n = 24

C: Herniotomy, orchidopexy, circumcision, hydrocelectomy, n = 60

D: Tonsillectomy with and without adenoidectomy; n = 152

Age (range)

A: children aged 2 to 12 years; Group 1: mean age 5.4 years (SD 2.6); Group 2: mean age 6.3 years (SD 1.9); Group 3: mean age 6.2 years (SD 2.8).

B: children aged 1 to 10 years; Group 1: mean age 6.2 years (2.5 to 10); Group 2: mean age 4.4 years (1.6 to 10)

C: Children aged 1 to 9 years; Group 1: mean age 4.5 years (SD 1.9); Group 2: mean age 4.87 years (SD 2.4)

D: children and young adults aged 8 to 21 years

Gender

A: 61 males, 14 females; Group 1: 22 males, 9 females; Group 2: 20 males, 5 females; Group 3: 19 males, 6 females.

B: 14 males, 10 females; Group 1: 7 males, 5 females; Group 2: 7 males, 5 females

C: Group 1: 25 males, 5 females; Group 2: 26 males, 4 females;

D: 99 males, 53 females;

Describe intervention

A: Group 2: 2 mg/kg tramadol im (n = 25). Administration time: after the end of surgery (first expression of pain) an additional injection of the half initial dose was administrated 30 and 60 min, if inadequate analgesia

B: Group 2: tramadol iv (bolus 1 mg/kg, 2.0 μg/kg/min for 72 h) (n = 12). Administration time: before the end of surgery.

C: Group 2: 0.75 to 1 mg/kg tramadol im. Administration time: after surgery (at the arrival in the recovery area).

D: Group 2: tramadol 3 mg/kg iv (n =38). Administration time: 30 sec before induction of anaesthesia.

Describe control

A: Group 1: 0.1 mg/kg nalbuphine im (n = 25). Administration time: after the end of surgery (first expression of pain) an additional injection of the half initial dose was administrated 30 and 60 min, if inadequate analgesia.

B: Group 1: nalbuphine iv (bolus 100 μg/kg, 0.2 μg/kg/min for 72 h) (n = 12). Administration time: before the end of surgery.

C: Group 1: 0.15 to 0.2 mg/kg nalbuphine im. Administration time: after surgery (at the arrival in the recovery area).

D: Group 4: nalbuphine 0.3 mg/kg iv (n = 39). Administration time: 30 sec before induction of anaesthesia.

End-point of follow-up:

A: 48 h post op

B: 72 h post op

C: 24 h post op

D: 48 h post op

For how many participants were no complete outcome data available?

(intervention/control)

All trials reported that all participants were included in the analysis. Therefore, in all included trials this item was assessed as being at

 low risk of bias.

Outcome measure-1: Postoperative pain

Postoperative pain (0 hours)

A:

1 h post operative, the percentage of patients indicating having pain:

Severe

I: 16 (64%)

C: 14 (56%)

Moderate

I: 9 (36%)

C: 11 (44%)

Slight

I: 0%

C: 0%

None

I: 0%

C: 0%

B: not reported

C:

1 h postoperative, percentage of patients indicating:

No pain

I: 70%

C: 70%

D: not reported

Postoperative pain (6 hours)

A:

None:

I: 96%

C: 81%

Slight:

I: 4%

C: 11%

Moderate

I: 0 %

C: 8%

Severe:

I: 0%

C: 0%

B: not reported

C: not reported

D: not reported

Postoperative pain (12 hours)

A:

None:

I: 100%

C: 85%

Slight:

I: 0%

C: 15%

moderate:

I: 0%

C: 0%

severe:

I: 0%

C: 0%

B: not reported

C: not reported

D: not reported

Postoperative pain (24 hours)

A:

None:

I: 100%

C: 96%

Slight:

I: 0%

C: 4%

Moderate:

I: 0%

C: 0%

Severe:

I: 0%

C: 0%

B: not reported

C: not reported

D: not reported

Complications: nausea/vomiting

Pooled effect (RR, 95% CI)

RR 1.00, 95% CI 0.50 to 2.01.

[high concerns risk of bias]; lack of information about randomization or allocation of sequence.

From SR: The overall quality of the evidence is low and it should be interpreted with caution because all included trials used different validated and non-validated pain scales in children over a wide range of ages.

Overall conclusion: Children needed less rescue medication in the postoperative care unit when given tramadol, indicating better analgesia with tramadol. Due to the low amount of usable data, the evidence focusing on the comparison of tramadol with other opioids (for example morphine, nalbuphine, pethidine, fentanyl) is currently unclear. Adverse events were generally only poorly reported in the trials so that the side effects as a result of tramadol administration were not clear.

Study characteristics are extracted from the SR and the results are obtained from the individual RCTs.

A: pain measured using the verbal rating scale (VRS) and was rated the percentage of patients indicating having none, slight, moderate or severe pain

B: The study outcomes (also pain) were not compared between groups due to low numbers and pain score was used as an indicator for pain dose.

C: pain measured using the visual analog scale

D: pain not reported

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Li 2023

Study design:

a prospective, randomized,

double-blinded, multiple-center clinical trial

Setting and Country:

Five university medical centers and three teaching hospitals in China.

Source of funding and conflicts of interest:

Funding:

This work is supported by National Natural Science Foundation of China (No.31000675), Key R & D projects of Shaanxi Province (2018SF-010), Henan Medical Science and Technology Project (2018020689, LHGJ20190956), and Projects of Xi’an International Medical Center Hospital (2022MS14).

Conflict:

The authors declare that they have no competing interests.

Inclusion criteria

-Patients aged between 3-month-old to 6-year-old

-Body Mass Index

(BMI) 18-29.5 kg/m2, -and American Society of Anesthe

siologists (ASA) I-III] undergoing major surgery including general, urinary, and orthopedic surgery under

general anesthesia were recruited.

Exclusion criteria:

Patients were excluded

if they met any following criteria: schizophrenia, epilepsy,

infantile autism, attention deficit hyperactivity disorder, myasthenia gravis, cerebral palsy, Down’s syndrome,

coma, and any other brain injury or neurosurgery; taking monoamine oxidase inhibitors within 2 weeks before

the surgery; children may ingested alcohol or narcotics for various reasons, including medication and family influence; diabetes; severe hepatic, renal, pulmonary

dysfunction; congenital heart disease or other congenital

malformation; prematurity; any other diseases potentially

interfering study results; surgery shorter than one hour;

incomplete case report form (CRF).

N total at baseline: 219

Intervention: 110

Control: 109

Important prognostic factors²:

For example

Mean age (year):

I: 2.40 (1.03, 4.00)

C: 2.50 (1.15, 4.00)

Gender

I:  29.4 %F

C: 39.3 %F

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

Tramadol (n=109);

Brief description:

Tramadol was administered with a loading dose at the end of surgery (1 or 0.1 mg.kg–1, respectively), then with a parent-controlled intravenous device with fixed bolus doses only (0.5 or 0.05 mg.kg–1, respectively), and a 10-min lockout time.

Patients were fasting from clear liquids for 4 h and solid

food for 6 h prior to undergoing anesthesia. No analgesic

or antiemetic drugs were administrated before the procedure. Thirty minutes before the procedure, patients

received an intramuscular administration of 0.01 mg.

 kg–1 atropine.

Upon completion of surgery, patients received intravenous

administration of tramadol

(1.0 mg.kg–1), followed by the administration of the

PCIA without background infusion.

The bolus dose was 0.5 mg.kg–1 for the tramadol group each time, with a lockout time of 10 min for all patients. Surgical time, consumption of sufentanil and remifentanil, incision length, and hemorrhage volume during surgery were recorded.

After surgery, all patients were transferred to the post anesthesia care unit.

Describe control (treatment/procedure/test):

Oxycodone (n=89);

Brief description:

Oxycodone was administered with a loading dose at the end of surgery (1 or 0.1 mg.kg–1, respectively), then with a parent-controlled intravenous device with fixed bolus doses only (0.5 or 0.05 mg.kg–1, respectively), and a 10-min lockout time.

Patients were fasting from clear liquids for 4 h and solid

food for 6 h prior to undergoing anaesthesia. No analgesic

or antiemetic drugs were administrated before the procedure. Thirty minutes before the procedure, patients

received an intramuscular administration of 0.01 mg.

 kg–1 atropine.

Upon completion of surgery, patients received intravenous

administration of oxycodone (0.1 mg.kg–1) followed by the administration of the

PCIA without background infusion.

The bolus dose was 0.05 mg.kg–1 for the oxycodone group each time, with a lockout time of 10 min for all patients. Surgical time, consumption of sufentanil and remifentanil, incision length, and hemorrhage volume during surgery were recorded.

After surgery, all patients were transferred to the post anesthesia care unit.

Length of follow-up:

Based on FLACC scores at different time points: until 30 minutes after extubation. Then patients were brought to the wards where follow-up measurements occurred. Adverse events were measured until 48 h after surgery.

Loss-to-follow-up:

Intervention:

N (%): 1

Reasons (describe)

Not reported

Control:

N (%): 20

Reasons (describe)

N=12 due to a drug supply problem; and n=3 had surgery cancellation.

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Various reasons

Control:

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Pstoperative pain relief after surgery in paediatric patients ^A.

(pain scores in PACU (FLACC scale)

FLACC score 10 min after extubation

I: 0 (0, 2.00)

C: 0 (0, 2.00)

FLACC score 20 min after extubation

I: 0 (0, 2.25)

C: 0 (0, 3.00)

FLACC score 30 min after extubatuin

I: 0 (0, 2.50)

C: 0 (0, 3.00)

FLACC scores in PACU

I: 4.49 +/- 1.74

C: 3.71 +/- 1.71

Complications in PACU (n, %)

Nausea

I: 2 (1.8)

C: 1 (1.1)

Vomiting

I: 0

C: 0

Drowsiness/dozing

I: not reported

C: not reported

Constipation

I: not reported

C: not reported

Respiratory depression

I: not reported

C: not reported

Comments:

-Clinical trial registered

Conclusion:

-Tramadol and oxycodone provided a similar level of adequate postoperative pain relief in PACU and in the wards. The main observed side effects in both groups were nausea and vomiting, with no difference between groups. However, patients in the oxycodone group showed less sedation

levels and had a shorter stay in the PACU, compared with the tramadol group.

^A= The definition of adequate postoperative

pain relief includes (1) the FLACC score< 4 in the PACU; and (2) patients do not need alternatively rescue analgesia. The FLACC evaluation was repeated

every 10 min until discharge from PACU.

(FLACC scores < 4; immediate postoperative pain relief after extubation in the PACU).

FLACC (Face, Legs, Activity, Cry and Consolability) score to measure pain intensity:

The FLACC scale contains 5 behaviors, including face, legs, activity, consolability, and cry, and each behavior is scored from 0 to 10, with 0 representing no pain.

^B= Bolus-administered amount of opioid in PACU (equal to morphine, mg.kg–1)

Parents’ satisfaction scores for pain relief: graded according to the 5-point scale: very dissatisfied (1 point), dissatisfied (2 points), neither satisfied nor dissatisfied (3 points), satisfied (4 points), and very satisfied (5 points).

Liaqat 2017

Type of study:

A randomized, controlled trial

Setting:Pediatric Surgery Unit of Services Hospital, Lahore, Pakistan, between January 2014 and December 2014.

Country: Lahore, Pakistan.

Funding and conflict of interests:

Both not reported.

Inclusion criteria:

Included all elective inguinal hernia and hydrocele patients (American Society of Anesthesiologists [ASA] class I and

II), -aged between 1 and 12 years.

Exclusion criteria:

Excluded patients who were already on analgesics, had an obstructed inguinal hernia, ASA

grade ≥ 3, or any sort of respiratory, cardiovascular, or neurological disorder. For measurement of pain, Wong-Baker Faces pain scale was used after getting permission from Wong-Baker

Faces foundation.

N total at baseline: 150

Intervention: 75

Control: 75

Important prognostic factors²:

For example

age (years):

I: 5.7 ± 2.8

C: 5.0 ± 3.2

Sex (absolute number)

I:  67  (89% M)

C:  63 (84% M)

Groups comparable at baseline? Yes

Describe  intervention (treatment/procedure/test):

Tramadol

Brief description;

Patients were given a single dose of tramadol (2 mg/kg) immediately after surgery.

All of the patients were drawn from the elective list of the pediatric surgical team of our hospital, and they were all administered standard anesthetics including midazolam (0.05 mg/kg),

ketorolac (0.5 mg/kg), and propofol (1.5–2.0 mg/kg) for induction.

Tramadol (2 mg/kg) was

given to patients just after arrival at the recovery room.

Describe control (treatment/procedure/test):

Nalbufine

Brief description;

Patients were given a single dose of nalbuphine (0.2 mg/kg) immediately after surgery.

All of the patients were drawn from the elective list of the pediatric surgical team of our hospital, and they were all administered standard anesthetics including midazolam (0.05 mg/kg),

ketorolac (0.5 mg/kg), and propofol (1.5–2.0 mg/kg) for induction.

Nalbuphine (0.2 mg/kg) was

given to patients just after arrival at the recovery room.

Length of follow-up:

Not specified; however mentioned ‘’ A limitation of our study was the fact that postoperative pain

was measured up to 8 h only’’. Length of FU presumably 8 h postop.

Loss-to-follow-up: not specified

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data: not specified

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Postoperative pain intensity using the Wong-Baker Faces Pain Scale at 0, 1, 2, 4, 6 and 8 h after surgery

Textually; ‘’There was a significant difference between groups in pain scores at 0 and 1

h (both P < 0.05), but not at 2, 4, or 8 h’’.

The study further solely presented figure with pain score per group (figure).

Pain score (mean ± SD)

At 0 hours

I: 0.5

C: 0.18

4 hours

I: 1.1

C:  1.2

12 hours

Not reported

24 hours

Not reported

Rescue analgesics

9 patients (12.0%) needed rescue analgesics in group A (nalbuphine) compared to 16 patients (21.3%) in group B (tramadol)

Complications

Vomiting

I: 10 (13.3)

C: 9 (12.0)

No other side effects were noted, solely stated textually ‘’Side effects were noted in both groups, of which the most common was vomiting (group A: n = 9, 12.0%; group B: n = 10, 13.3%). No other side effects were noted in either group.’’

Comments:

-conclusion:

 - A single dose of nalbuphine is sufficient, and superior to tramadol, for postoperative pain management in

children who have undergone daycare procedures.

Wong-Baker Faces Pain Scale:

-Funding, conflict of interest, and clinical trial number not reported

Xing 2019

Study design:

a randomized  controlled trial

Setting and Country:

Patients who underwent major

 craniotomy were screened for study participation between

 January 2016 and June 2018

Source of funding and conflicts of interest:

Funding:

This study was supported by the Beijing Municipal Science &Technology

 Commission, PR China (Grant No. Z151100004015027). The funding agent

 plays no role in study design, data collection, or data analyses.

Conflict:

The authors declare that they have no competing interests.

Inclusion criteria:

-Patients aged 1

12years, -with American Society of Anesthesiologists physical status grades I–III undergoing open craniotomy procedures. -Eligible subjects included patients undergoing

 surgery for brain tumors, craniofacial reconstruction and vascular malformations.

Exclusion criteria:

-Mental disorders; unsuitability for extubation; and development of

 hematomas or severe brain edema 3days after surgery, requiring a subsequent operation. -Additionally, we excluded patients with a history of allergy to opioids or other anesthetics, and those with a history of substance abuse.

Two age groups were composed:

-1-6 years old patients, and,

-7 to 12 years old patients

N total at baseline: 387

N total 1-6 years: 192

N total 7-12 years: 195

1-6 years old

Intervention: 40

Control: 40

7 to 12 years old

Intervention: 40

Control: 40

Age (Mean, SD)

(1-6 years old)

I: 3.70 ± 1.64

C: 4.05 ± 1.45

(7-12 years old)

I: 9.29 ± 1.60

C: 8.51 ± 2.69

Sex (male/female)

1-6 years old

I: 22/18

C: 24/16

7-12 years old

I: 24/16

C: 24/16

Groups comparable at baseline? yes

Important prognostic factors²:

For example

age ± SD:

I:

C:

Sex:

I: % M

C: % M

Groups comparable at baseline? Yes

Describe  intervention (treatment/procedure/test):

Children undergoing craniotomy.

Tramadol group was used with a background infusion of 100 400 μg/kg·h, bolus 100–200 μg/kg. After surgery, patients aged 1–6 years received a pump for nurse-controlled intravenous analgesia (NCIA), while those aged 7–12 received one for patient-controlled intravenous analgesia (PCIA). The regimens of PCIA or NCIA used the following formulas; (group T) was used with a loading dose of 500μg/kg, a single bolus dose of 100-200 μg/kg, and a background dose of 100–400μg/kg·h. The bolus locking time was 15min.

Describe control (treatment/procedure/test):

Children undergoing craniotomy. Morphine group was used with a background infusion of 10–20 μg/kg·h, bolus 10–20 μg/kg; After surgery, patients aged 1–6 years received a pump for nurse-controlled intravenous analgesia (NCIA), while those aged 7–12 received one for patient-controlled intravenous analgesia (PCIA). The regimens of PCIA or NCIA used the following formulas; Morphine was used with a loading dose of 50μg/kg, a single bolus dose of 10–20μg/kg, and a background dose of 10–20μg/kg·h. The bolus locking time was 15min.

Length of follow-up:

since pain intensity was measured up to 48 h after surgery, 48 h postop.

Loss-to-follow-up: not reported

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Postoperative pain scores (POPI) ^A

‘’lower pain scores were shown at 1 h and 8h after surgery in Morphine group versus Tramadol’’

1-6 years old patients

(median(interquartile range))

1 h after surgery

FLACC

I: 2 (2,4) (95% CI 0.000-0.019)

C: 2 (1.25; 2) (95% CI 0.000-0.019)

WBFS

I: 2 (2,4) (95% CI 0.000-0.019)

C: 2 (2;2) (95% CI 0.000-0.019)

4 h after surgery

FLACC

I: 2 (0.25; 2)

C: 1 (0;2)

WBFS

I: 2 (0.5;2)

C: 0 (0;2)

12 h after surgery

I: not reported

C: not reported

24 h after surgery

I: FLACC 2 (0, 2) and WBFS 2 (0, 2)

C: FLACC 2 (0,2) and WBFS 2 (0, 3.5)

7-12 years old patients

(median(interquartile range))

1 hours after surgery

WBFS

I: 2 (2;4)

C: 2 (2;4)

NRS:

I: 2 (2;4)

C: 2 (2;3)

4 hours after surgery

WBFS

I: 2 (2;4)

C: 0 (0;2) NRS

I: 2 (2;4)

C: 0 (0;2)

12 h post op

I: not reported

C: not reported

24 h after surgery

I: WBFS 2 (1,2); NRS 2 (1,2)

C: WBFS 2 (0,2) and NRS 2 (0,2)

WBFS <4

I: 63 (24%)

C: 75 (28.4%)

WBFS >4

I: 16 (28.3%)

C: 4 (7.5%)

Complications ^B

Anaesthesia recovery events in PACU

1-6 years old

Nausea

I: 5 (12.5%)

C: 12 (30%)

Vomiting

I: 0 (0)

C: 2 (5%)

7-12 years old

Nausea

I: 3 (7.5%)

C:3 (7.5%)

Vomiting

I: 2 (5%)

C: 1 (2.5%)

Comments:

Patients were  randomly  assigned to receive 4 different regimens of patient-controlled analgesia, solely studied the two arms whom study the intervention and control as defined in our PICO.

-conclusion: PCIA or NCIA with morphine could significantly de

crease postoperative pain scores without increasing the

 incidence of nausea, vomiting, respiratory depression

 and excessive sedation in pediatric patients after neuro

surgery.

^A= postoperative

 pain intensity (POPI):

Moderate POPI was defined as a median pain score ≥4  And <7 on the WBFS, FLACC or NRS scales. Severe pain was defined as a median pain score ≥7.

According to the particular characteristics of each patient, we adopted different evaluation methods for POPI. Patients aged 1–6years were  evaluated by the Faces, Legs, Activity, Cry and Consolability Scale (FLACC, 0–10 scores) and the Wong-Baker

 Faces Scale (WBFS). For patients aged 7–12years, both  the numeric rating scale (NRS) and the Wong-Baker Faces Scale (WBFS) were used.

The FLACC is a behavioral pain assessment tool that was developed to provide a simple and consistent evaluation method for these

 cases, while the WBFS is a self-reported pain assessment tool, currently considered the preferred alternative

 for pain assessment in children [16]. The WBFS is comprised of a series of facial images, in which the face that

 depicts the most pain indicates the “worst pain imaginable” and the happiest face indicates “no pain”.

The numeric rating scale (NRS) is a self-reported measure of

 pain intensity comprised of a line marked with numbers  0–10, in which 0 is “no pain” and 10 is the “worst pain  imaginable”.

^B= Nausea and

 vomiting were recorded if episodes of patient emesis were reported on nursing flow sheets, or if anti-emetic  therapy was required. Respiratory depression was operationalized as a clinically significant decline in respiratory rate which required intervention, with SpO2 < 92%.

^C= Expressed in average total medicines use in PCIA or NCIA pump (mcg/kg/d)

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Li (2023)

Probably yes

Reason:

A biostatistician who is unaware of treatments and patient follow-up, generates the random numbers using the SAS software (SAS Institute, USA) in a ratio of 1:1, named group A and group B. (the randomization sequence is stored online until the end of the study: https://pan.baidu.com). However, only biostatistician was aware of the randomization sequence. 

As new participants consented to join the study, the responsible anesthesiologist would

Contact the biostatistician, who would assign the participant to either group A or B based on the next unused

random number from the online sequence.

Probably no

Reason:

Not reported  

Definitely yes

Reason:

Double-blinded randomized controlled trial. With regards to randomization: only the biostatistician was aware of the randomization sequence and did not participate in the conduct of

the study or patient follow-up. Moreover, the responsible anesthesiologist was aware of the drugs being used, oxycodone or tramadol, but was not involved in patient assignment, follow-up, or data analysis.

The study drugs were prepared by the responsible

anesthesiologist, diluted to the same volume with normal

saline, and placed in similar PCIA devices without labeling. Throughout the study, all study personnel, patients, parents, and everyone except the responsible anesthesiologist, remained blind to the patients’ allocations.

Postoperative follow-up inwards was performed by research personnel or a healthcare member who was blinded to the allocation of the patient.

Parents’ satisfaction scores for the pain relief were graded by the blinded parents.

Outcome assessment was performed by researchers who

were kept blind to the patient’s group assignments.

Probably no

Reason:

During the study period, a total of twenty patients dropped out from the oxycodone (control) group and one

from the tramadol group (intervention) due to various reasons. Additionally, during follow-up in both intervention and control group patients dropped out. Not reported whehter statistical analyses adjusted for loss to follow-up.

Probably yes

Reason:

Study free of selective outcome reporting.

Probably yes

Reason:

No other comments.

Postoperative pain --> PACU / 0 hours, 6 and 24 hours: MIDDLE concerns of bias

Postoperative opioid consumption à morphine equivalent in PACU, at 24 hours and total: MIDDLE concerns of bias.

Complications  àrespiratory depression, nausea/vomiting, drowsiness/dozing, constipation: MIDDLE concerns of bias.

Liagat (2017)

Probably yes

Reason:

Randomization sequence: lottery method. 

Probably no

Reason:

Concealment of allocation not reported.

Probably no

Reason:

Postoperative pain was measured using the Wong-Baker Faces Pain Scale at 0, 1, 2, 4, 6 and 8 h after surgery, by an on-duty doctor who was unaware of the drugs given to patients.

Furthermore, not specified whether healthcare professionals providing control/intervention or data analysts were blinded.

Probably no

Reason:

Not reported, and cannot be seen from data since data comprises solely descriptive statistics and visual presentation of results (number of patients cannot be quantified).

Probably yes

Reason:

Study free of selective outcome reporting

Probably yes

Reason:

No other comments

Postoperative pain --> PACU / 0 hours, 6 and 24 hours: MIDDLE concerns of bias

Postoperative opioid consumption à morphine equivalent in PACU, at 24 hours and total: not reported  

Complications  àrespiratory depression, nausea/vomiting, drowsiness/dozing, constipation: MIDDLE concerns of bias.

Xing (2019)

Definitely yes

Reason:

Participants were randomly assigned 1:1:1:1 among four

 groups. The randomization schedule was generated by an

 independent investigator through a computerized random

number sequence.

Probably no

Reason

Not reported, solely stated that a specially selected nurse was informed

 of the group assignments.

Probably yes

Reason:

Unknown whether patients were aware or unaware about the allocated group, or data analysts.

Nurse whom prepared the postoperative

 analgesia pumps according to the patients’ weights was aware of the group assignments. Furthermore, anesthesiologists were blinded to grouping information.

Physicians responsible for postoperative follow-up were also blinded for the grouping.

Probably no

Reason:

Loss to follow-up was not reported.

Probably yes

Reason:

Study free of selective outcome reporting

Probably yes

Reason:

No other comments:

Postoperative pain --> PACU / 0 hours, 6 and 24 hours: MIDDLE concerns of bias

Postoperative opioid consumption à morphine equivalent in PACU, at 24 hours and total: MIDDLE concerns of bias.

Complications  àrespiratory depression, nausea/vomiting, drowsiness/dozing, constipation: MIDDLE concerns of bias.