Design

All 20 included studies were parallel group RCTs. Tramadol was administrated intravenously (Ali 2008; Antila 2006; Bösenberg 1998; Chiaretti 2000; Cocelli 2012; Ekemen 2008; Engelhardt 2003; Hullett 2006; Moyado Garcia 2009; Ozalevli 2005; Ozer 2003; Ozköse 2000; Umuroglu 2004; van den Berg 1999; Viitanen 2001), orally (Payne 1999; Roelofse 1999) or by intramuscular injection (Barsoum 1995; Ertugrul 2006; Schäffer 1986). In four studies tramadol was applied before induction of general anaesthesia (Ali 2008; Chiaretti 2000; Payne 1999; Roelofse 1999), while in 12 trials tramadol was administered directly after induction (Antila 2006; Bösenberg 1998; Cocelli 2012; Ekemen 2008; Engelhardt 2003; Ertugrul 2006; Hullett 2006; Ozer 2003; Ozköse 2000; Umuroglu 2004; van den Berg 1999; Viitanen 2001). Four trials specifically mentioned that tramadol was given before (Moyado Garcia 2009) or after the end of surgery (Barsoum 1995; Ozalevli 2005; Schäffer 1986). Apart from two trials (Barsoum 1995; Ozalevli 2005) that applied tramadol specifically for postoperative pain treatment, in the other 18 trials tramadol was always applied as a prophylactic analgesic drug. Four trials applied tramadol as a bolus followed by a continuous infusion (Chiaretti 2000; Moyado Garcia 2009; Ozalevli 2005), while the remaining trials applied a bolus injection alone.

Sample sizes

The number of children and adolescents analysed in the 20 studies ranged from 24 to 152 (1170 in total). Sample size calculation and intention‐to‐treat analysis were not reported in any of the included studies.

Participants

Studies involved children aged from 1 to 18 years of age, with each study having a different age range. One trial reported that young adults ( to 21 years) were also included; but a specific analysis of the demographic data of the different study groups showed that the mean age in all study groups was below 18 years (van den Berg 1999). Therefore, the review authors decided to include the data of this RCT. Another trial investigated the administration of tramadol only in neonates (up to 28 days old) that were undergoing surgery, as a postoperative continuous infusion (Alencar 2012). Due to this specific age, the authors decided to exclude this study because only this trial focused explicitly on neonates.

Common paediatric surgical procedures were performed within the included trials: ear‐nose‐throat (ENT) surgery (for example adeno‐tonsillectomy, tonsillectomy) (Ali 2008; Antila 2006; Cocelli 2012; Engelhardt 2003; Ertugrul 2006; Hullett 2006; Ozalevli 2005; Ozer 2003; Ozköse 2000; Umuroglu 2004; van den Berg 1999; Viitanen 2001), lower abdominal surgery (Barsoum 1995; Bösenberg 1998; Ekemen 2008; Schäffer 1986) and dental extraction (Payne 1999; Roelofse 1999). In one study children underwent neurosurgical interventions for various disorders (Chiaretti 2000), while in another trial the surgical procedures were not explicitly described (Moyado Garcia 2009).

Interventions

Eleven trials were performed as multi‐arm trials. The following interventions were compared in the included studies.

1. Tramadol versus placebo (Ali 2008; Antila 2006; Bösenberg 1998; Cocelli 2012; Ozköse 2000; Payne 1999; Roelofse 1999; Umuroglu 2004; van den Berg 1999; Viitanen 2001).

2. Tramadol versus morphine (Engelhardt 2003; Hullett 2006; Ozalevli 2005; Umuroglu 2004).

3. Tramadol versus nalbuphine (Barsoum 1995; Moyado Garcia 2009; Schäffer 1986; van den Berg 1999).

4. Tramdadol versus pethidine (Barsoum 1995; Bösenberg 1998; Ekemen 2008; Ertugrul 2006; Ozer 2003; van den Berg 1999).

5. Tramadol versus fentanyl (Chiaretti 2000).

Outcomes

All trials investigated the efficacy and adverse effects following perioperative (before or after anaesthesia induction, before or after the end of surgery) administration of tramadol in comparison with placebo or other opioids (morphine, nalbuphine, pethidine, fentanyl). A validated pain scale (Visual Analogue Scale (VAS), Numeric Rating Scale (NRS), Faces Pain Scale (FPS), Toddler‐Preschooler Postoperative Pain Scale (TPPPS), Children's Hospital of Eastern Ontario Pain Scale (CHEOPS)) was used in nine studies (Ali 2008; Chiaretti 2000; Ertugrul 2006; Moyado Garcia 2009; Ozalevli 2005; Ozköse 2000; Payne 1999; Schäffer 1986; Umuroglu 2004); however, the pain‐trigger used for rescue analgesia differed significantly between the trials. The number of patients requiring rescue analgesia was recorded in 13 studies (Ali 2008; Barsoum 1995; Bösenberg 1998; Chiaretti 2000; Engelhardt 2003; Hullett 2006; Moyado Garcia 2009; Ozalevli 2005; Ozköse 2000; Schäffer 1986; Umuroglu 2004; van den Berg 1999; Viitanen 2001), while only three studies reported the time to rescue analgesic (Bösenberg 1998; Umuroglu 2004; Viitanen 2001). Outcome variables were either ordinal (for example severity of pain) or nominal in nature (for example presence of PONV). Methods used for statistical analysis included both nonparametric and parametric tests.

Sequence generation

Eight trials were rated as being at low risk of bias because a computer‐generated random sequence (Antila 2006; Bösenberg 1998; Cocelli 2012; Engelhardt 2003; Viitanen 2001) or a predesigned table of random numbers (Moyado Garcia 2009; Ozköse 2000; van den Berg 1999) was used. The other included studies did not give clear information on how the randomisation sequence was generated; they were assessed as being at unclear risk of bias.

Concealment of allocation

In contrast, only three trials explicitly described the method of allocation concealment and were rated as being at low risk of bias (Ali 2008; Engelhardt 2003; Umuroglu 2004). The majority of included studies did not describe allocation concealment and thus were assessed as being at unclear risk of bias.

Performance bias

Eight trials were performed as double‐blinded studies, with the participant and provider of the intervention blinded to therapy (Bösenberg 1998; Ekemen 2008; Ertugrul 2006; Moyado Garcia 2009; Ozalevli 2005; Ozköse 2000; Roelofse 1999; Viitanen 2001). In three studies the participants and observers were blinded (Barsoum 1995; Ozer 2003; van den Berg 1999); the participants and investigators were blinded in six studies (Ali 2008; Antila 2006; Engelhardt 2003; Payne 1999; Schäffer 1986; Umuroglu 2004). Three studies were assessed as being at unclear risk of bias because the blinding was unclear (Chiaretti 2000; Cocelli 2012; Hullett 2006).

Detection bias

Only three studies explicitly noted that the observers were blinded to the investigation (Barsoum 1995; Ozer 2003; van den Berg 1999). One trial was rated as being at high risk for detection bias because the triallists stated that the drug doses were noted within the patients´records (Barsoum 1995). All other trials did not describe the blinding of outcome assessment and were rated as being at unclear risk of bias.

Primary outcomes

Five studies including 289 patients investigated the number of children requiring rescue analgesia in the PACU (Ali 2008; Bösenberg 1998; Ozköse 2000; van den Berg 1999; Viitanen 2001). All the included trials for this outcome used different pain scales with different pain triggers. The RR for the need for rescue analgesia was significantly reduced in children treated with 1 to 3 mg/kg tramadol (administered during induction for adeno‐tonsillectomy) compared to placebo (RR 0.40; 95% CI 0.20 to 0.78; I² = 87%; Analysis 1.1). We explored the observed heterogeneity in subgroup analyses. The study quality was comparable and was therefore not further explored. There was only one trial which applied tramadol in children undergoing abdominal surgery (Bösenberg 1998), while the other trials investigated children undergoing ENT surgery (Ali 2008; Ozköse 2000; van den Berg 1999; Viitanen 2001). The subgroup analysis focusing on the influence of surgery revealed that following ENT surgery the RR for the need for rescue analgesia was lower (RR 0.39; 95% CI 0.3 to 0.52; Analysis 1.2) compared to abdominal surgery (RR 0.60; 95% CI 0.34 to 1.07; Analysis 1.2), but this result was influenced by heterogeneity (I² = 38.8%) and the 95% CIs overlapped, which assumed a non‐significant influence of surgery. The subgroup analysis (Analysis 1.3) focusing on the influence of tramadol dose revealed that the RR for the need for rescue analgesia was lower in children undergoing ENT surgery following 1 mg/kg tramadol (RR 0.07; 95% CI 0.02 to 0.21) (Ali 2008; Ozköse 2000) compared to 2 mg/kg (RR 0.63; 95% CI 0.48 to 0.83) (Bösenberg 1998; Viitanen 2001) or 3 mg/kg tramadol (RR 0.62; 95% CI 0.38 to 1.02) (van den Berg 1999). However, this subgroup analysis was influenced by heterogeneity (I² = 86.2%) and the 95% CIsoverlapped, which indicated a non‐significant influence of tramadol dose on this outcome. In contrast, the number of patients with moderate to severe pain was only reported in one trial, which used a non‐validated five point verbal pain scale (none, mild, moderate, severe, very severe) (Bösenberg 1998). Fewer children undergoing adeno‐tonsillectomy (9 out of 22) who received 2 mg/kg tramadol during induction, compared to placebo (15 out of 22), complained about moderate to severe pain in the PACU (P > 0.05).

Secondary outcomes

Three included trials (Bösenberg 1998; Umuroglu 2004; Viitanen 2001) investigated the outcome time to first rescue analgesic'. Children treated with 1.5 (Umuroglu 2004) to 2 mg/kg tramadol (Bösenberg 1998; Viitanen 2001) for adeno‐tonsillectomy did not show a significantly longer time to first rescue analgesic compared to placebo (MD 44.66; 95% CI ‐24.26 to 113.58; I² = 71%; Analysis 1.4). Two included trials investigated the cumulative postoperative analgesic consumption of pethidine (relative potency compared to morphine 0.1) (Viitanen 2001) or fentanyl (relative potency compared to morphine 100) (Antila 2006) following administration of 1 to 2 mg/kg tramadol (during induction) or placebo in children undergoing adenoid‐tonsillectomy. In the PACU, children treated with 2 mg/kg tramadol showed a significantly lower opioid consumption (calculated as morphine equivalents) (tramadol 0.4 mg/kg ± 0.5 versus placebo 0.7 mg/kg ± 0.39) (Viitanen 2001); however, 24 h postoperation, this difference was not confirmed in another trial following 1 mg/kg tramadol (tramadol 1.52 mg/kg ± 0.84 versus placebo 1.39 mg/kg ± 0.79) (Antila 2006). Adverse events were poorly reported. Six included trials reported data regarding the RR for PONV (Ali 2008; Antila 2006; Cocelli 2012; Ozköse 2000; Umuroglu 2004; van den Berg 1999). The pooled data analysis demonstrated that following tramadol administration the RR for PONV was not significantly higher in the PACU (RR 0.84; 95% CI 0.28 to 2.52; I² = 15%; Analysis 1.5) or 24 h postoperation (RR 0.78; 95% CI 0.54 to 1.12; I² = 0%; Analysis 1.6). In three included trials no children suffering from respiratory depression were noted following tramadol administration (Ali 2008; Umuroglu 2004; van den Berg 1999) (Analysis 1.7). Other adverse events were not reported.

Primary outcomes

All trials reported data focusing on the outcome number of patients requiring rescue analgesia (Engelhardt 2003; Hullett 2006; Ozalevli 2005; Umuroglu 2004). All included trials used different pain scales with different pain triggers for this outcome. In the PACU and 24 h postoperation, children undergoing adeno‐tonsillectomy who were treated with intraoperative tramadol 1 mg/kg to 2 mg/kg showed a non‐significantly higher RR for the need for rescue analgesia compared to children treated with morphine 0.1 mg/kg (RR (PACU) 1.25; 95% CI 0.83 to 1.89; I² = 0%; Analysis 2.1 (Engelhardt 2003; Hullett 2006; Umuroglu 2004); RR (2 4h postoperation) 1.62; 95% CI 0.65 to 4.04; I² = 0%; Analysis 2.2 (Engelhardt 2003; Hullett 2006; Ozalevli 2005)). Three trials applied tramadol during induction (Engelhardt 2003; Hullett 2006; Umuroglu 2004) while only one specifically mentioned that tramadol was applied postoperation (Ozalevli 2005;). Due to a lack of data the outcome number of patients with moderate to severe pain could not be assessed.

Secondary outcomes

Only one trial investigated the outcome time to first rescue analgesic and reported that 15 children undergoing adeno‐tonsillectomy and treated with 1.5 mg/kg tramadol during induction (155.6 min ± 172.7) required the first rescue analgesic 112.4 min earlier than 15 children receiving 0.1 mg/kg morphine during induction (268 min ± 157.9) (Umuroglu 2004). All trials reported data on adverse events. Two trials investigated children with PONV in the PACU (Umuroglu 2004) and 24 h postoperation (Ozalevli 2005). In the PACU 3 out of 15 patients in each group complained about PONV following 1.5 mg tramadol compared to 0.1 mg/kg morphine during induction (Umuroglu 2004). In contrast, another study comparing 1 mg/kg tramadol versus 0.1 mg/kg morphine after surgery in children undergoing adeno‐tonsillectomy reported that less children suffered from PONV following tramadol administration 24 h postoperation (3 out of 30 versus 11 out of 30) (Ozalevli 2005). Four trials reported the number of children with respiratory depression (Engelhardt 2003; Hullett 2006; Ozalevli 2005; Umuroglu 2004) but only one trial mentioned two children suffering from respiratory problems following 0.1 mg/kg morphine (Hullett 2006) (Analysis 2.3). Only one trial assessed the outcomes bradycardia, hypotension, pruritus and urinary retention following tramadol or morphine administration postoperation. Generally, either no children (in both groups) suffered from these adverse events (bradycardia, hypotension) or the results (pruritus: 0 in tramadol group versus 1 in morphine group, and urinary retention: 1 patient in each group) were comparably low (Ozalevli 2005).

Primary outcomes

The number of patients with a need for rescue analgesia was assessed in three included trials. All trials used different pain scales with different pain triggers. One trial reported that a higher number of patients treated with tramadol (3 mg/kg) compared to nalbuphine (0.3 mg/kg) required rescue analgesia in the PACU (14 out of 38 versus 11 out of 34) (van den Berg 1999); however, 24 h postoperation the latter result was not confirmed (RR 0.63; 95% CI 0.16 to 2.45; I² = 54%; Analysis 3.1) (Barsoum 1995; Schäffer 1986). Only one included trial, which investigated drug administration for postoperative pain treatment following surgery, reported data on the outcome number of patients with moderate to severe pain (PACU) assessed on a four point verbal scale (no pain, mild, moderate, severe pain) following drug administration (Barsoum 1995); there was only one child in the nalbuphine group (0.1 mg/kg) that complained about moderate to severe pain 0.5 h after drug administration.

Secondary outcomes

In the PACU the RR for PONV was not significantly different in both groups (RR (PACU) 1.00; 95% CI 0.50 to 2.01; Analysis 3.2) (Schäffer 1986; van den Berg 1999). Only one trial reported that at 24 h postoperation 1 child out of 25 children treated with tramadol suffered from PONV compared to no child treated with nalbuphine (Barsoum 1995). No patient with bradycardia (Analysis 3.4) or with respiratory depression (Analysis 3.3) was mentioned in two included trials (Barsoum 1995; Moyado Garcia 2009). Only one trial reported patients with sedation or hypotension following 1 mg/kg tramadol compared to 0.1 mg/kg nalbuphine given at the end of surgery (Moyado Garcia 2009); whereas no patient suffered from hypotension, one patient in the tramadol group and two patients in the nalbuphine group complained about sedation postoperatively.

Primary outcomes

Only two trials reported the number of patients requiring rescue analgesia and demonstrated that children treated with 2 to 3 mg/kg tramadol versus 1 to 1.5 mg/kg pethidine during induction showed a lower but non‐significant RR for the need for rescue analgesia (RR 0.93; 95% CI 0.43 to 2.02; I² = 66%; Analysis 4.1) (Bösenberg 1998; van den Berg 1999). All included trials used different pain scales and pain triggers. At 24 h postoperation only one included trial reported that 3 out of 25 patients treated with tramadol required rescue analgesia compared to 8 out of 25 patients receiving pethidine; this trial compared the application of tramadol versus pethidine postoperation (Barsoum 1995). A similar result was seen in two trials regarding the number of patients with moderate to severe pain (RR 0.64; 95% CI 0.36 to 1.16; Analysis 4.2) (Barsoum 1995; Bösenberg 1998).

Secondary outcomes

Only one trial investigated the time to first rescue analgesic and reported that 22 children treated with tramadol (251 min ±143) instead of pethidine (223 min ± 123) during induction required their first rescue analgesic 28 minutes later (Bösenberg 1998). Adverse events were poorly reported. The most commonly reported outcome was PONV in the PACU. The results of three included trials could be pooled (Ertugrul 2006; Ozer 2003; van den Berg 1999) and revealed that the RR for PONV in the PACU was lower in children treated with tramadol compared to pethidine, but this result failed to reach significance (RR 0.75; 95% CI 0.28 to 2.02; I² = 0%; Analysis 4.3). In one trial (van den Berg 1999) out of three included trials, two children treated with 1.5 mg/kg pethidine suffered from respiratory depression after surgery (RR 0.20; 95% CI 0.01 to 4.03; Analysis 4.4) (Barsoum 1995; Ekemen 2008; van den Berg 1999). Furthermore, no child with bradycardia (Analysis 4.5) (Barsoum 1995; Ekemen 2008) or hypotension (Ekemen 2008) was noted in the included trials.

Primary outcomes

The included trial reported data on the postoperative pain outcome in children treated with tramadol (bolus during induction followed by continuous infusion during surgery) or fentanyl (same regimen as in the tramadol group) for neurosurgical procedures (Chiaretti 2000). During the observation period (around 18 h) only 2 out of 14 children in the tramadol group compared to 0 out of 14 children in the fentanyl group required additional rescue analgesia.

Secondary outcomes

No other postoperative pain outcomes were reported. Adverse events were also poorly reported. More patients in the fentanyl group complained about PONV (6 out of 14 compared to 0 out of 14 in the tramadol group). No child suffering from respiratory depression or bradycardia was reported.