Abstract

Background

According to current recommendations a multimodal approach is believed to be the gold standard for postoperative pain treatment in children. However, several surveys in the last few years demonstrated that postoperative pain in children is still a serious problem, mainly because opioids are avoided. One of the reasons for this is the fear of severe adverse events following opioid administration. Tramadol is a weak mu‐opioid agonist and inhibits reuptake of noradrenaline and serotonin (5HT). Because of a relatively wide therapeutic window and a ceiling effect with a lower risk for severe adverse events (for example respiratory depression) tramadol is a widely used opioid in children. However, the exact efficacy and occurrence of adverse events following tramadol (in comparison with placebo or other opioids) for postoperative pain treatment in children and adolescents are currently not clear.

Objectives

To assess the effectiveness and side effect profile of tramadol for postoperative pain relief in children and adolescents undergoing different surgical procedures.

Search methods

We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 6), MEDLINE via PubMed (January 1966 to July 2014) and EMBASE via Ovid (January 1947 to July 2014). There were no restrictions regarding language or date of publication. The reference lists of all included trials were checked for additional studies.

Selection criteria

All randomised controlled clinical trials investigating the perioperative administration of tramadol compared to placebo or other opioids for postoperative pain treatment in children and adolescents were included.

Data collection and analysis

Three review authors independently assessed the study eligibility, performed the data extraction and assessed the risk of bias of included trials.

Main results

Twenty randomised controlled trials involving 1170 patients were included in this systematic review. The overall risk of bias in included trials was assessed as unclear, because concealment of allocation processes and blinding of outcome assessors were poorly described. Due to inconsistent outcome reporting, data from 17 included trials could be pooled for some endpoints only. Eight trials compared tramadol administration with placebo and five trials found that the need for rescue analgesia in the postoperative care unit (PACU) was reduced in children receiving tramadol (RR 0.40; 95% CI 0.20 to 0.78; low quality evidence). Only one trial investigated the number of patients with moderate to severe pain, but a non‐validated pain scale was used (very low quality evidence). Four trials compared morphine with tramadol administration. There was no clear evidence of difference in the need for rescue analgesia in the PACU (RR 1.25; 95% CI 0.83 to 1.89; low quality evidence) with tramadol compared with morphine. No trials could be pooled for the outcome 'number of patients with moderate to severe pain'. Three trials were included for the comparison of tramadol with nalbuphine. There was no clear evidence for the need for rescue analgesia in the PACU (RR 0,63; 95% CI 0.16 to 2.45; low quality evidence). Only one trial reported the number of patients with moderate to severe pain, but used a non‐validated pain scale (very low quality evidence). Two out of six included trials, which compared pethidine with tramadol, reported the number of children with a need for rescue analgesia within the PACU and showed no clear evidence (RR 0.93; 95% CI 0.43 to 2.02; very low quality evidence). Two trials reported the number of patients with moderate to severe pain and showed a lower RR in patients treated with tramadol (RR 0.64; 95% CI 0.36 to 1.16; low quality evidence). Only one trial was included, which compared tramadol with fentanyl, reporting the number of patients with the need for rescue analgesia (very low quality evidence). Generally, adverse events were poorly reported. Most data could be pooled for the comparison with placebo focusing on the RR for postoperative nausea and vomiting (PONV) in the postoperative care unit and 24 h postoperation. Children treated with tramadol, compared to placebo, did not show clear evidence of benefit for PONV in the postoperative care unit (RR 0.84; 95% CI 0.28 to 2.52; moderate quality evidence) and 24 h postoperation (RR 0.78; 95% CI 0.54 to 1.12; moderate quality evidence).

Authors' conclusions

The overall evidence regarding tramadol for postoperative pain in children is currently low or very low and should be interpreted with caution due to small studies and methodological problems (different validated and non‐validated pain scales with different pain triggers, missing sample size calculations and missing intention‐to‐treat analysis). Nevertheless, we demonstrated that tramadol administration might provide appropriate analgesia when compared to placebo; this is based on results showing reduced rescue analgesia in children treated with tramadol compared to placebo. In contrast, the evidence regarding the comparison with other opioids (for example morphine) was uncertain. Adverse events were only poorly reported, so an accurate risk‐benefit analysis was not possible.

Author(s)

Alexander Schnabel, Sylvia U Reichl, Christine Meyer‐Frieβem, Peter K Zahn, Esther Pogatzki‐Zahn

Abstract

Plain language summary

Does the perioperative administration of tramadol provide effective and safe postoperative analgesia in children?

Children experience pain after surgery (‘postoperative pain’) and according to recently published trials the management of this pain is of major concern. A combination of drugs may be the best way to treat postoperative pain, for example drugs called ‘opioids’, like morphine and codeine. However, there are concerns about severe side effects (adverse events) when using opioids. Tramadol is a weak opioid that is used worldwide to treat children with moderate to severe acute or chronic pain. Tramadol can be given to children before surgery to help reduce pain afterwards. It is believed that tramadol administration might be associated with a lower risk for respiratory or haemodynamic depression and might therefore be the ideal analgesic drug for children in the perioperative period. Our systematic review assessed the efficacy and adverse events of tramadol administration compared to placebo or other opioids. In July 2014 we found 20 small randomised controlled trials involving 1170 patients. These small trials had limited data but tramadol may be better than placebo. In five trials, mostly preschool children undergoing minor surgery (for example tonsillectomy) were treated with tramadol or placebo before the start of surgery. 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.

Author(s)

Alexander Schnabel, Sylvia U Reichl, Christine Meyer‐Frieβem, Peter K Zahn, Esther Pogatzki‐Zahn

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

The overall quality of evidence regarding postoperative analgesia following tramadol use in children compared to placebo or other opioids is currently low or very low. Nevertheless, analysis of five included trials demonstrated that the prophylactic administration of tramadol (during induction of anaesthesia) might provide effective postoperative analgesia in children undergoing adeno‐tonsillectomy, compared to placebo. The ideal tramadol dose is currently unclear. The latter finding might be important because adeno‐tonsillectomies are one of the most painful surgical procedures during childhood (Groenewald 2012; Stanko 2013) and the use of other opioids (for example morphine) is feared due to an increased risk of postoperative respiratory problems (for example due to an underdiagnosed risk of sleep apnoea within this population) (Subramanyam 2014). One included trial specifically compared the risk of postoperative desaturation following tramadol or morphine administration in children with obstructive sleep apnoea who were undergoing adeno‐tonsillectomy. They reported 26% significantly fewer episodes of postoperative oxygen desaturation in the tramadol group (Hullett 2006). In contrast, a recently published case report revealed that a child with a ultrarapid CYP2D6 genotype and obstructive sleep apnoea syndrome suffered from severe postoperative respiratory depression following day‐case tonsillectomy (Orliaguet 2015). The latter finding highlights the possible influence of genetic variations on the efficacy (8% to 10% possibility of a cytochrome P450 enzyme deficiency causing an inability to metabolize the prodrug tramadol into the active component (M1)) and the adverse effects of tramadol administration, which are currently unknown. To conclude, although tramadol administration might be an interesting option, for example for post‐tonsillectomy pain, the current evidence is very limited and further research is urgently needed to further define a possible role of tramadol for postoperative pain treatment in children.

Implications for research 

The following implications for research could be defined based on the results of this review.

• Because the evidence for tramadol use in children is currently sparse, due to incomplete and insufficient outcome reporting (including adverse events), additional randomised controlled trials comparing tramadol with other commonly used opioids are needed in order to enable an appropriate risk‐benefit analysis. Postoperative pain should be assessed with validated pain scales and, accordingly, rescue analgesia should be given following clearly defined pain triggers (e.g. NRS > 3 based on a 0 to 10 point scale (Hirschfeld 2013)).
• Tramadol administration should be investigated in children undergoing different common paediatric surgical procedures in order to detect possible procedure specific differences.
• The possible influence of genetic variability on efficacy and adverse events should be assessed in children treated with tramadol for postoperative pain.
• Tramadol administration should be studied in patient groups with a high risk for opioid related adverse events (e.g. children with obstructive sleep apnoea undergoing adeno‐tonsillectomy).
• Finally, tramadol administration should be studied in different age groups and dosages to further evaluate the clinical consequences of the reported pharmacokinetic findings (e.g. ceiling effect, higher risk for specific adverse events in younger age groups (Allegaert 2011)).

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