Nalbuphine for postoperative pain treatment in children
Several surveys over the past few years have demonstrated that postoperative pain in children is not treated appropriately. One pharmacological treatment option in a multimodal approach for postoperative pain treatment is the systemic administration of opioids. However, opioids are rarely used for postoperative pain treatment in children due to fear of adverse events. One long‐standing opioid for systemic use is nalbuphine, a kappa‐receptor agonist and µ‐receptor antagonist. The efficacy of nalbuphine is believed to be similar to morphine. Increased dosing might result in a ceiling effect, and thus less analgesia than expected. In addition, there might be a lower risk for opioid‐induced side effects (nausea, vomiting) and severe adverse events (respiratory depression) due to the antagonistic effect of the µ‐receptor. Nalbuphine may be an useful opioid for postoperative use in children, but exact efficacy (e.g. compared to other commonly used opioids) has not been determined yet.
To assess the efficacy and adverse events of nalbuphine for acute postoperative pain treatment in children undergoing surgery.
We systematically searched the following databases: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 7), MEDLINE via Pubmed (January 1966 to July 2013) and EMBASE via Ovid (January 1947 to July 2013). We did not impose any restrictions regarding language or publication date. We checked all reference lists of retrieved articles for additional references.
All randomised controlled trials (RCTs) investigating nalbuphine compared with placebo or other opioids were included.
Data collection and analysis
Two review authors independently scanned the retrieved articles and made a decision regarding inclusion or exclusion of studies for this review. The same authors also performed the data extraction and the assessment of risk of bias.
Ten RCTs including 658 patients were finally included in this systematic review. Five trials compared nalbuphine with placebo. Data from one out of five studies for the outcome moderate/severe pain following nalbuphine compared to placebo gave a risk ratio (RR) 1 hour postoperatively (postop) of 0.1 (95% confidence interval (CI) 0.01 to 0.71; low quality evidence) and a RR 2 hours postop of 0.14 (95% CI 0.02 to 1.06; low quality evidence). The estimated RR based on data from a single study indicated that nalbuphine reduced the requirement for analgesia two hours postop (RR 0.47; 95% CI 0.27 to 0.84; low quality evidence). Two included trials compared nalbuphine with morphine and showed a nonsignificant lower or comparable RR for moderate/severe pain at 1 hour postop (RR 0.84; 95% CI 0.12 to 5.74; low quality evidence), and 2 hours postop (RR 1.09; 95% CI 0.59 to 2.01; low quality evidence) for nalbuphine versus morphine. Four trials compared nalbuphine with tramadol for postoperative pain; data from one trial (per outcome) revealed a lower but nonsignificant RR for the need of additional rescue analgesics in children receiving nalbuphine (RR 2 hours postop 0.75; 95% CI 0.39 to 1.43; low quality evidence) (RR 12 hours postop 0.33; 95% CI 0.04 to 2.77; low quality evidence). One out of three trials comparing nalbuphine with pethidine demonstrated that the RR was not significantly lower following nalbuphine administration compared to pethidine (RR 2 hours postop 1.07; 95% CI 0.52 to 2.23; low quality evidence) (RR 24 hours postop 1.13; 95% CI 0.52 to 2.44; very low quality evidence). The most common adverse event was postoperative nausea and vomiting (PONV). Only one included trial reported that the RR for PONV in the postoperative care unit (PACU) was not significantly higher following nalbuphine compared to placebo (RR 1.00; 95% CI 0.16 to 6.42; low quality evidence) nor to morphine (RR 1.33; 95% CI 0.64 to 2.77; low quality evidence).
Because the overall quality of available evidence was low, this systematic review could not definitively show that the analgesic efficacy of nalbuphine is superior compared to placebo. Furthermore, due to the lack of significant results the comparison with other common opioids is also unclear. The same holds true for the evidence focusing on adverse events following nalbuphine compared to placebo or other opioid administration. The evidence is limited, because studies did not report conclusively all important postoperative pain outcomes (e.g. number of patients with the need for rescue analgesia, postoperative pain scores). Thus, a quantitative analysis was not possible for many major aspects (e.g. rescue analgesia, pain scores) and heterogeneity could not be further explored.
Alexander Schnabel, Sylvia U Reichl, Peter K Zahn, Esther Pogatzki‐Zahn
Plain language summary
Does the administration of nalbuphine provide effective and safe postoperative pain treatment in children?
Postoperative pain is still a major problem following surgery in children. There is currently clear evidence that multimodal postoperative pain treatment is the best choice. This approach may involve using nonsteroidal anti‐inflammatory drugs (NSAIDs) and opioids. However, due to the fear of side effects such as respiratory depression (where the lungs cannot provide enough oxygen), opioids are not frequently used for postoperative pain treatment in children. Nalbuphine may provide effective pain relief without causing respiratory depression. In this review, we investigated how well nalbuphine worked, compared to placebo and other opioids, in children with postoperative pain. We also looked at the side effects. We performed a systematic literature search in July 2013. Ten randomised controlled trials with 658 patients were included. The patients were children aged from 0 ‐ 18 years and most did not have any other relevant medical conditions. The overall quality of evidence was low, so this review could not definitively show that nalbuphine is better than placebo. The same holds true for the comparison with other opioids (morphine, tramadol, pethidine, piritramid). We were not able to comment on side effects due to the small numbers of participants in the trials. Future studies need to address these issues, including more robust data for effectiveness and side effects.
Alexander Schnabel, Sylvia U Reichl, Peter K Zahn, Esther Pogatzki‐Zahn
Implications for practice
Because the overall evidence was limited, mainly by selective outcome reporting and imprecision of results due to lack of data, this quantitative review could not definitively demonstrate that 0.1 to 0.3 mg/kg nalbuphine compared to placebo might be an effective postoperative analgesic. The same holds true for the comparison with other opioids. Due to limited data we could not perform a subgroup analysis focusing on the influence of age, which might be an influencing factor, because the elimination half‐life of nalbuphine is significantly shorter in young children compared to young adults (Jaillon 1989). Thus, younger infants might need earlier additional drug doses than older children for effective pain treatment. Finally, again due to limited data, we were not able to show a benefit, by a lower number of adverse events following nalbuphine administration compared to placebo or other opioids. However, the number of studied patients does not allow a definite conclusion yet.
Implications for research
Based on the findings of this review we determined the following implications for research.
- Due to the low amount of available data, further RCTs comparing nalbuphine with other postoperative opioids (tramadol, morphine, and piritramid in Germany) are needed. This would enable an appropriate risk benefit analysis. Trials should use a clearly defined age group of children, comparable procedures and specific validated observational and self reported pain assessment scales in order to get validated and comparable results.
- Nalbuphine administration in children should be studied following different surgical procedures in order to detect possible procedure‐specific efficacy and dosing.
- Additionally, nalbuphine administration should be studied in children with specific comorbidities, like obstructive sleep apnoea, who are at higher risk for opioid‐related adverse events. Nalbuphine might be a useful drug, because it might offer analgesia without causing respiratory depression.