Schnabel Et Al. (2016), Nalbuphine For Postoperative Pain Treatment in Children (Review)

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Nalbuphine for postoperative pain treatment in children (Review)
Schnabel A, Reichl SU, Zahn PK, Pogatzki-Zahn E
Schnabel A, Reichl SU, Zahn PK, Pogatzki-Zahn E.

Nalbuphine for postoperative pain treatment in children.
Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD009583.
DOI: 10.1002/14651858.CD009583.pub2.
www.cochranelibrary.com

Nalbuphine for postoperative pain treatment in children (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Informed decisions.

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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 3
BACKGROUND.............................................................................................................................................................................................. 7
OBJECTIVES.................................................................................................................................................................................................. 7
METHODS..................................................................................................................................................................................................... 7
Figure 1.................................................................................................................................................................................................. 9
Figure 2.................................................................................................................................................................................................. 10
RESULTS........................................................................................................................................................................................................ 12
DISCUSSION.................................................................................................................................................................................................. 14
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 15
ACKNOWLEDGEMENTS................................................................................................................................................................................ 15
REFERENCES................................................................................................................................................................................................ 16
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 18
DATA AND ANALYSES.................................................................................................................................................................................... 28
Analysis 1.1. Comparison 1 Nalbuphine versus placebo, Outcome 1 Number of patients with moderate/severe pain (1h 29
postop)...................................................................................................................................................................................................
Analysis 1.2. Comparison 1 Nalbuphine versus placebo, Outcome 2 Number of patients with moderate/severe pain (2h 29
postop)...................................................................................................................................................................................................
Analysis 1.3. Comparison 1 Nalbuphine versus placebo, Outcome 3 Number of patients with the need for rescue analgesia (2h 30
postop)...................................................................................................................................................................................................
Analysis 1.4. Comparison 1 Nalbuphine versus placebo, Outcome 4 Number of patients with the need for rescue analgesia (12h 30
postop)...................................................................................................................................................................................................
Analysis 1.5. Comparison 1 Nalbuphine versus placebo, Outcome 5 Number of patients with PONV (PACU)................................ 30
Analysis 1.6. Comparison 1 Nalbuphine versus placebo, Outcome 6 Number of patients with PONV (postop 24h)....................... 31
Analysis 1.7. Comparison 1 Nalbuphine versus placebo, Outcome 7 Number of patient with vomiting (PACU)............................. 31
Analysis 1.8. Comparison 1 Nalbuphine versus placebo, Outcome 8 Number of patients with vomiting (postop 24h).................. 31
Analysis 1.9. Comparison 1 Nalbuphine versus placebo, Outcome 9 Number of patients with pruritus (postop 24h)................... 31
Analysis 1.10. Comparison 1 Nalbuphine versus placebo, Outcome 10 Number of patients with respiratory depression............. 32
Analysis 1.11. Comparison 1 Nalbuphine versus placebo, Outcome 11 Number of patients with urinary retention...................... 32
Analysis 1.12. Comparison 1 Nalbuphine versus placebo, Outcome 12 Number of patients with sedation (24h postop) )............ 32
Analysis 1.13. Comparison 1 Nalbuphine versus placebo, Outcome 13 Number with patients with bradycardia (PACU).............. 33
Analysis 2.1. Comparison 2 Nalbuphine versus morphine, Outcome 1 Number of patients with moderate/severe pain (1h 33
postop)...................................................................................................................................................................................................
Analysis 2.2. Comparison 2 Nalbuphine versus morphine, Outcome 2 Number of patients with moderate/severe pain (2h 34
postop)...................................................................................................................................................................................................
Analysis 2.3. Comparison 2 Nalbuphine versus morphine, Outcome 3 Number of patients with the need for rescue analgesia 34
(12h postop)..........................................................................................................................................................................................
Analysis 2.4. Comparison 2 Nalbuphine versus morphine, Outcome 4 Number of patients with PONV (PACU)............................. 34
Analysis 2.5. Comparison 2 Nalbuphine versus morphine, Outcome 5 Number of patients with PONV (24h postop).................... 35
Analysis 2.6. Comparison 2 Nalbuphine versus morphine, Outcome 6 Number of patient with respiratory depression................ 35
Analysis 2.7. Comparison 2 Nalbuphine versus morphine, Outcome 7 Number with patient with bradycardia (PACU)................. 35
Analysis 3.1. Comparison 3 Nalbuphine versus tramadol, Outcome 1 Number of patients with moderate/severe pain (1h 36
postop)...................................................................................................................................................................................................
Analysis 3.2. Comparison 3 Nalbuphine versus tramadol, Outcome 2 Number of patients with the need for rescue analgesia 36
(2h postop)............................................................................................................................................................................................
(12h postop)..........................................................................................................................................................................................
(24h postop)..........................................................................................................................................................................................
Analysis 3.5. Comparison 3 Nalbuphine versus tramadol, Outcome 5 Number of patients with PONV (24h postop)..................... 37
Analysis 3.6. Comparison 3 Nalbuphine versus tramadol, Outcome 6 Number of patients with vomiting (PACU)......................... 37
Nalbuphine for postoperative pain treatment in children (Review) i
Informed decisions.

Analysis 3.7. Comparison 3 Nalbuphine versus tramadol, Outcome 7 Number of patients with vomiting (24h postop)................ 38
Analysis 3.8. Comparison 3 Nalbuphine versus tramadol, Outcome 8 Number of patients with respiratory depression (PACU)..... 38
Analysis 3.9. Comparison 3 Nalbuphine versus tramadol, Outcome 9 Number of patients with sedation (24h postop)................ 38
Analysis 3.10. Comparison 3 Nalbuphine versus tramadol, Outcome 10 Number of patients with bradycardia (PACU)................ 39
Analysis 4.1. Comparison 4 Nalbuphine versus pethidine, Outcome 1 Number of patients with moderate/severe pain (1h 40
postop)...................................................................................................................................................................................................
Analysis 4.2. Comparison 4 Nalbuphine versus pethidine, Outcome 2 Number of patients with the need for rescue analgesia 40
(2h postop)............................................................................................................................................................................................
Analysis 4.3. Comparison 4 Nalbuphine versus pethidine, Outcome 3 Number of patients with the need for rescue analgesia 40
(24h postop)..........................................................................................................................................................................................
Analysis 4.4. Comparison 4 Nalbuphine versus pethidine, Outcome 4 Time to first rescue analgesic (h)....................................... 40
Analysis 4.5. Comparison 4 Nalbuphine versus pethidine, Outcome 5 Number of patients with vomiting (PACU)......................... 41
Analysis 4.6. Comparison 4 Nalbuphine versus pethidine, Outcome 6 Number of patients with vomiting (24h postop)............... 41
Analysis 4.7. Comparison 4 Nalbuphine versus pethidine, Outcome 7 Number of patients with respiratory depression (PACU)..... 41
Analysis 4.8. Comparison 4 Nalbuphine versus pethidine, Outcome 8 Number of patients with bradycardia (PACU).................... 42
Analysis 5.1. Comparison 5 Nalbuphine versus piritramid, Outcome 1 Number of patients with the need for rescue analgesia 42
(24h postop)..........................................................................................................................................................................................
Analysis 5.2. Comparison 5 Nalbuphine versus piritramid, Outcome 2 Number of patients with PONV (24h postop).................... 42
APPENDICES................................................................................................................................................................................................. 43
WHAT'S NEW................................................................................................................................................................................................. 43
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 43
DECLARATIONS OF INTEREST..................................................................................................................................................................... 44
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 44
NOTES........................................................................................................................................................................................................... 44
INDEX TERMS............................................................................................................................................................................................... 44
Nalbuphine for postoperative pain treatment in children (Review) ii

Informed decisions.

[Intervention Review]
Nalbuphine for postoperative pain treatment in children
Alexander Schnabel1, Sylvia U Reichl2, Peter K Zahn3, Esther Pogatzki-Zahn4
1Department of Anaesthesia and Critical Care, University of Würzburg, Würzburg, Germany. 2Department of Anesthesiology,
Perioperative and Intensive Care Medicine, Paracelsus Medical University, Salzburg, Austria. 3Department of Anaesthesiology, Intensive
Care Medicine, Palliative Care Medicine and Pain Management, Universitatsklinikum Bergmannsheil GmbH Bochum, Bochum, Germany.
4Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
Contact address: Alexander Schnabel, Department of Anaesthesia and Critical Care, University of Würzburg, Oberduerrbacher Str. 6,
Würzburg, Germany. alexander_schnabel@gmx.de.
Editorial group: Cochrane Pain, Palliative and Supportive Care Group.

Publication status and date: Stable (no update expected for reasons given in 'What's new'), published in Issue 5, 2016.
Citation: Schnabel A, Reichl SU, Zahn PK, Pogatzki-Zahn E. Nalbuphine for postoperative pain treatment in children. Cochrane Database
of Systematic Reviews 2014, Issue 7. Art. No.: CD009583. DOI: 10.1002/14651858.CD009583.pub2.
ABSTRACT
Background
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.
Objectives
To assess the efficacy and adverse events of nalbuphine for acute postoperative pain treatment in children undergoing surgery.
Search methods
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.
Selection criteria
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.
Main results
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
Nalbuphine for postoperative pain treatment in children (Review) 1
Informed decisions.

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).
Authors' conclusions
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.
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.

Informed decisions.

SUMMARY OF FINDINGS

Summary of findings for the main comparison. Nalbuphine compared with placebo
Nalbuphine compared with placebo for postoperative pain in children
Patient or population: children undergoing surgery
Settings: hospital
Intervention: 0.3 mg/kg nalbuphine intramuscular/intravenous
Comparison: placebo
Outcomes Relative effect No of Par- Quality of Com-

(95% CI) ticipants the evi- ments
(studies) dence
(GRADE)
Number of patients with moderate/severe pain (1 hour postop- RR 0.1 (0.01 to 0.71) 40 (1) ⊕⊕⊝⊝
eratively) low
Number of patients with moderate/severe pain (2 hours post- RR 0.14 (0.02 to 1.06) 40 (1) ⊕⊕⊝⊝
operatively) low
Number of patients with the need for rescue analgesia (2 hours RR 0.47 (0.27 to 0.84) 76 (1) ⊕⊕⊝⊝
postoperatively) low
Number of patients with the need for rescue analgesia (12 RR 0.06 (0.00 to 0.94) 16 (1) ⊕⊕⊝⊝
hours postoperatively) low
Number of patients with postoperative nausea and vomiting RR 1.00(0.16 to 6.42) 40 (1) ⊕⊕⊝⊝
(postoperative care unit) low
Number of patients with postoperative nausea and vomiting RR 0.59(0.12 to 2.83) 37 (1) ⊕⊕⊝⊝
(24 hours postoperatively) low
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk
(and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention
(and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change
the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to
change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2. Nalbuphine compared with morphine
Nalbuphine compared with morphine for postoperative pain in children
Settings: hospital

Informed decisions.

Intervention: 0.2/0.3 mg/kg nalbuphine intramuscularly
Comparison: 0.2 mg/kg morphine intramuscularly

(studies) dence
(GRADE)
Number of patients with moderate/severe pain (1 hour postop- RR 0.84 (0.12 to 5.74) 90 (2) ⊕⊕⊝⊝
eratively) low
Number of patients with moderate/severe pain (2 hours post- RR 1.09 (0.59 to 2.01) 90 (2) ⊕⊕⊝⊝
operatively) low
Number of patients with postoperative nausea and vomiting RR 1.33 (0.64 to 2.77)8 90 (2) ⊕⊕⊝⊝
(postoperative care unit) low
Number of patients with postoperative nausea and vomiting RR 1.20 (0.80 to 1.80) 50 (1) ⊕⊕⊝⊝
(and its 95% CI).

the estimate.

Summary of findings 3. Nalbuphine compared with tramadol
Nalbuphine compared with tramadol for postoperative pain in children
Settings: hospital
Intervention: 0.1/0.3 mg/kg nalbuphine intramuscularly/intravenously, 100 μg/kg nalbuphine bolus followed by 0.2 μg/kg/
min for 72 hours intravenously
Comparison: 0.75/1/2/3 mg/kg tramadol intramuscularly, 1000 μg/kg tramadol bolus followed by 2.0 μg/kg/min for 72 hours
intravenously

(studies) dence
(GRADE)

Informed decisions.

Number of patients with moderate/severe pain (1 hour postop- not estimable 50 (1) ⊕⊝⊝⊝
eratively) very low
Number of patients with the need for rescue analgesia (2 hours RR 0.75 (0.39 to 1.43) 76 (1) ⊕⊕⊝⊝
postoperatively) low
Number of patients with postoperative nausea and vomiting RR 0.50 (0.11 to 2.23) 24 (1) ⊕⊕⊝⊝
(and its 95% CI).

the estimate.

Summary of findings 4. Nalbuphine compared with pethidine
Nalbuphine compared with pethidine for postoperative pain in children
Settings: hospital
Intervention: 0.1/0.3 mg/kg nalbuphine intramuscularly/intravenously
Comparison: 1/1.5 mg/kg pethidine intramuscularly/intravenously
Outcomes Relative effect No of Par- Quality of the Com-

(95% CI) ticipants evidence ments
(studies) (GRADE)
Number of patients with moderate/severe pain (1 hour not estimable 50 (1) ⊕⊝⊝⊝
postoperatively) very low
Number of patients with the need for rescue analgesia RR 1.13 (0.52 to 2.44) 50 (1) ⊕⊝⊝⊝
(24 hours postoperatively) very low
(and its 95% CI).

Informed decisions.


the estimate.

Summary of findings 5. Nalbuphine compared with piritramid
Nalbuphine compared with piritramid for postoperative pain in children
Settings: hospital
Intervention: 0.1 mg/kg nalbuphine intravenously
Comparison: 0.1 mg/kg piritramid intravenously
Outcomes Relative effect No of Par- Quality of the Com-

(95% CI) ticipants evidence ments
(studies) (GRADE)
Number of patients with the need for rescue analgesia RR 8.17 (0.45 to 147.76) 37 (1) ⊕⊕⊝⊝
Number of patients with postoperative nausea and RR 0.59 (0.12 to 2.83) 37 (1) ⊕⊕⊝⊝
vomiting (24 hours postoperatively) low
(and its 95% CI).

the estimate.

Informed decisions.

BACKGROUND of nalbuphine is associated with sedation, dysphoria, and urinary

retention due to its kappa-agonist actions (Rushton 1997). In
Description of the condition adults, nalbuphine can be administrated either orally, parenterally
or intramuscularly; however, the bioavailability after an oral
Although postoperative paediatric pain management has become
administration is very low (20% to 25%) due to intense hepatic
a recognised topic in research during the last decade, establishing
first-pass metabolism (Errick 1983) and therefore not clinically
optimal pain treatment strategies in children continues to be
useful. Nevertheless, the systemic administration might be an
a problem (Cummings 1996; Segerdahl 2008; Taylor 2008).
option in the postoperative period.
Inappropriate pain treatment is often due to an underestimation
of pain, difficulties in pain assessment, inadequate prescriptions Why it is important to do this review
of analgesics and the restricted number of officially approved
analgesic drugs for paediatric care (Howard 2003; Karling 2002; Kart Although opioids are thought to be potent analgesics for
1996; Walker 2008). Furthermore, there is increasing evidence that postoperative pain management in children, they are still used
an ineffective treatment of postoperative pain is associated with reluctantly for pain treatment in children due to the fear of severe
delayed wound healing, a negative development of pain perception adverse effects such as respiratory depression or nausea and
and pain behaviour and chronic pain in the future (Anand 2000; vomiting (Karling 2002; Kart 1996). Nalbuphine may be a valuable
Weisman 1998). option for the treatment of moderate to severe postoperative
pain in children (Miller 1980). However, single studies assessing
Description of the intervention the efficacy of nalbuphine in children are inconclusive. Thus, this
systematic review about the efficacy and potential adverse effects
Regional analgesia seems to be the most effective way to treat
of nalbuphine for postoperative pain treatment in children is
postoperative pain early after surgery and regional analgesia
needed to assess it's viability in the treatment of these patients.
techniques are increasingly used in children after surgery (Ecoffey
2010). However, not all patients and procedures are suitable OBJECTIVES
for regional analgesia techniques. Multimodal analgesia using
a combination of nonopioid analgesics (e.g. non-steroidal anti- To assess the efficacy and adverse events of nalbuphine for acute
inflammatory drugs, Michelet 2012) and opioids are another postoperative pain treatment in children undergoing surgery.
perioperative pain management option in children. However, the
use of opioids (as a top up method on demand) is used very METHODS
infrequently, mainly due to fear of side effects. In fact, clinicians
are often concerned about their side effects, especially respiratory Criteria for considering studies for this review
depression. Nalbuphine is a commonly used kappa-receptor
Types of studies
agonist and µ-receptor antagonist. Nalbuphine and morphine
are considered to be equianalgesic, but due to nalbuphine's We included all RCTs investigating nalbuphine for postoperative
own pharmacodynamics, there seems to be a lower risk for pain in children.
opioid-induced respiratory depression at higher doses, itching,
psychological effects (euphoria) and haemodynamic depression Types of participants
(Beaver 1978; Hoskin 1991). Due to the lack of pharmacodynamic We included children (0 to 18 years old) irrespective of their
data in the paediatric population, the majority of information sex, type of surgery or specific comorbidities (e.g. neuromuscular
available to date has been reported in adults. Nalbuphine is a world disorders).
wide available opioid, but it is more frequently used in French
speaking countries. There are currently no data available about Types of interventions
average treatment costs of nalbuphine in children, but from adult
data it is known that it might be more expensive than morphine or We included all RCTs investigating nalbuphine for postoperative
pethidine (Rhodes 1986). pain in children in comparison with placebo or any other opoid.
Types of outcome measures

How the intervention might work
We included studies, when they reported any of the following
Nalbuphine is a synthetic agonist-antagonist analgesic offering a
outcome measures.
duration of analgesia of four to five hours (Chen 1993). Recently
published pharmacokinetic data in children showed that the total Primary outcomes
clearance of nalbuphine - mainly via liver enzymes cytochrome P450
3A4 and 2C19 (Stringer 2009) - decreased, while the elimination 1. Postoperative pain scores (assessed by validated pain scores
half-life increased significantly with increasing age (Bressolle based on a 0 to 10 scale) (1 hour, 2 hours, 12 hours, 24 hours
2011). Furthermore, another trial in neonates (Jacqz-Aigrain 2003) postop).
revealed that birth weight influences the disposition to nalbuphine. 2. Number of patients with moderate/severe pain (assessed by
In adults, its analgesic potency is about equal to that of morphine using pain score tools) (1 hour, 2 hours, 12 hours, 24 hours
while the antagonist potency is about 1/25 of naloxone (Beaver postop).
1978). The dual action as agonist and antagonist could improve 3. Number of patients with the need for rescue analgesia (1 hour, 2
common side effects of opioids (addiction, respiratory depression) hours, 12 hours, 24 hours postop).
(Miller 1980). The µ-antagonist effects of nalbuphine in higher doses
antagonise the respiratory depression of opioid agonists, while
still maintaining effective analgesia. However, the administration

Informed decisions.

Secondary outcomes Selection of studies

1. Number of rescue analgesic doses (postoperative care unit Two review authors (AS, SR) independently performed the study
(PACU), 24 hours postop). quality assessment using the 'Risk of bias' tool provided by
2. Total required dose of rescue analgesia (PACU, 24 hours postop). The Cochrane Collaboration (Higgins 2011). All differences were
3. Time to first rescue analgesic (hours). resolved by discussion among the review authors.
4. Number of patients with adverse events (postoperative nausea Data extraction and management
and vomiting (PONV), pruritus, respiratory depression, urinary
retention, sedation, bradycardia, hypotension) (PACU, 24 hours Two review authors (AS, SR) independently extracted the data
postop). using standardised data extraction forms developed by the review
authors. The number of participants with moderate/severe pain
Search methods for identification of studies was defined as participants with a pain score of > 3 (Hirschfeld
2013). If different pain scales (Visual Analog Scale (VAS), Numerical
The general principle of the systematic search consisted of a Rating Scale (NRS), Faces pain scale revised) were used in the
combination of indexed and free text terms to reflect the concepts included studies, all pain scales were estimated to be equivalent,
of 'nalbuphine', 'postoperative pain' and 'children'. The search as long as they were based on 0 to 10 scale (Standing 2009).
terms were modified according to the constraints of each database Additionally, if the pain degree was assessed with nonvalidated
(Please see Appendix 1 for the MEDLINE search strategy). scales (e.g. three point scales (low/moderate/severe pain), we also
used these results, but reported this specifically in the text. If
Electronic searches
there were multi-arm trials, we extracted the data exclusively for
The following data sources were searched. each comparison (e.g. nalbuphine versus tramadol). If necessary,
we retrieved additional missing data in published studies by
1. The Cochrane Central Register of Controlled Trials (CENTRAL) contacting the study authors of the relevant articles. We resolved
(The Cochrane Library 2013, Issue 7) all differences by discussion among the review authors at each step
2. MEDLINE (Pubmed) (January 1966 to July 2013). of the data extraction.
3. EMBASE (Ovid) (January 1947 to July 2013).
Assessment of risk of bias in included studies
Searching other resources We assessed the risk of bias of included studies using The
In addition, we searched reference lists of included and excluded Cochrane Collaboration's tool for assessing risk of bias (Higgins
studies. 2011). The standard components in the specific domains included
adequacy of allocation generation, allocation concealment,
Data collection and analysis blinding, completeness of outcome data, possible selected
outcome reporting and any other potential sources of bias. We
Two review authors (AS, SR) independently scanned the titles
judged each component as 'low risk' of bias, 'high risk' of bias
retrieved by the initial search to exclude irrelevant studies. The
or 'unclear'. We included 'Risk of bias' tables as part of the
systematic search was not limited to any specific language. Two
Characteristics of included studies tables and risk of bias summary
review authors (AS, SR) identified studies that were included in
figures (Figure 1 and Figure 2), which detail all of the judgements
this review using a standardised study eligibility form developed by
made for all included studies in the review. Two review authors (AS,
the review authors. If there were any differences or disagreements
SR) independently carried out an assessment of the risk of bias.
among the authors, these conflicts were reviewed by a third review
We resolved any disagreements by discussion between the review
author (EPZ).
authors, with a further review author acting as arbiter (PK).


Informed decisions.

Figure 1. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.


Informed decisions.

Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Informed decisions.

1. Allocation of intervention Assessment of heterogeneity

We considered allocation of intervention as adequate if it was We assessed clinical and methodological differences of included
generated by a random system (e.g. computer, random number studies in order to decide if studies were sufficiently homogeneous
table algorithm, tossing of a coin). We considered allocation to be combined. We analysed statistical heterogeneity using the I2
inadequate if a nonrandom system was used (e.g. names, dates). statistic. We used this test to calculate each of the outcomes listed
above for the comparison with sham interventions. We assumed
2. Concealment of allocation there was heterogeneity, if the I2 was ≧ 30%.
We considered concealment adequate if an acceptable method,
such as a central allocation system, sequentially-numbered sealed Data synthesis
opaque envelopes or an on-site locked computer was used, We used either an inverse variance fixed-effect or random-effects
ensuring that the group assignment was not revealed to participant model to analyse the data in Review Manager 5.2 (Review Manager
recruiters, investigators or participants prior to the final allocation 2012). If the test for heterogeneity (I2 statistic ≧ 30%) was positive,
into the respective group. We considered concealment inadequate we undertook the analysis using a random-effects model. However,
if it allowed the participant recruiters, investigators or participants taking into account that random-effects models sometimes do not
to know the treatment allocation in advance or if the concealment deliver more conservative results, especially in the presence of a
procedure was not reported. small-study effect, we reported the obtained summary statistics
in conjunction with a sensitivity analysis (results obtained with a
3. Blinding of participants and personnel
fixed-effect model). If the random-effects estimate demonstrated
We considered blinding adequate if participants, persons a larger effect size, we discussed whether it was reasonable to
responsible for participants' care (e.g. nurses) were all blinded to conclude that the intervention was more effective in smaller
the intervention. We considered blinding inadequate if participants studies. We reported summary RRs and MDs with 95% CIs. We
or persons responsible for participants' care were not blinded to the considered RRs with the range of the lower and upper bounds
intervention. of the 95% CI not crossing one, and MDs with the range of the
lower and upper bounds of the 95% CI not crossing zero, as
4. Blinding of outcome assessment statistically significant. To determine if studies were of different
We considered blinding adequate if the outcome assessors were methodological quality, we performed sensitivity analyses (high
blinded to the intervention. We considered blinding inadequate if quality studies versus low quality studies).
outcome assessors were not blinded to the intervention.
Subgroup analysis and investigation of heterogeneity
5. Incomplete outcome data reporting Consideration was given to the magnitude of clinical and
We considered outcome data reporting adequate if all withdrawals methodological heterogeneity. To evaluate the effects of clinical
and drop-outs were described. We considered outcome data heterogeneity, we planed to perform subgroup analyses calculating
reporting inadequate if the number of drop-outs and withdrawals the RR or MD in conjunction with the corresponding CI for each
were lacking or if the reason for them was not given. subgroup. We used a fixed-effect heterogeneity Chi2 statistic to
compare subgroups. Additionally, we considered nonoverlapping
6. Selective reporting subgroup CIs as consistent with a statistically significant difference.
We considered data reporting as adequate, if all relevant pain We planned to analyse the following subgroups.
outcomes (at least validated pain scores) were reported. We
considered outcome data reporting as inadequate if only selected 1. Type of surgery (head and neck, thoracic, abdominal, extremity).
pain outcomes or not validated measurements were used. 2. Different drug doses and application types (orally, intravenous)
of nalbuphine.
Measures of treatment effect
3. Different age groups of the included children.
For binary data (dichotomous outcomes), we calculate the risk ratio
(RR) with 95% confidence interval (CI), while for continuous data, However, if the overall number of included trials was low no
we estimated the mean difference (MD) with 95% CI. To estimate the subgroup analyses were performed. (Differences between protocol
statistical significance of the results, we calculated the 95% CI for and review)
each item. Furthermore, we calculated the number needed to treat
to benefit (NNT) for the efficacy outcome, and the number needed Summary of findings tables
to treat to harm (NNH) for adverse events. We used the principles of the GRADE system (Schunemann 2008) to
assess the quality of the body of evidence associated with specific
Dealing with missing data outcomes (number of patients with moderate/severe pain, number
If there were doubts about missing data (patient drop-outs, of participants requiring rescue) in our review and constructed
selective outcome reporting, etc.), we contacted the relevant 'Summary of findings’ (SoF) tables (Summary of findings for the
authors to obtain further information. If full information could be main comparison, Summary of findings 2, Summary of findings 3,
obtained, we intended to perform intention-to-treat (ITT) analyses. Summary of findings 4, Summary of findings 5) using the GRADE
If full information could not be obtained, we performed complete- software. The GRADE approach appraises the quality of a body of
case analyses. We planed to perform sensitivity analyses by evidence based on the extent to which one could be confident
imputing missing data (best case/worst case) in order to test the that an estimate of effect or association reflected the item being
robustness of retrieved results. assessed.

Informed decisions.

RESULTS surgery or teeth extraction (Habre 1997; Krishnan 1987; Littlejohn

1996; van den Berg 1999) and lower abdominal surgery (Barsoum
Description of studies 1995; Büttner 1990; Schäffer 1986; Wandless 1987). The surgical
procedures were not explicitly described in two studies (Galy 1991;
See: Characteristics of included studies and Characteristics of
Moyado-Garcia 2009).
excluded studies.
Interventions
Results of the search
Six trials were multi-arm trials (Barsoum 1995; Büttner 1990; Galy
From the systematic literature search we identified 24 potentially
1991; Littlejohn 1996; van den Berg 1999; Littlejohn 1996). Five
relevant publications. After further review of title and abstract, we
included trials investigated postoperative analgesic efficacy of
identified eleven studies as being potentially eligible for inclusion
nalbuphine versus placebo treatment (Büttner 1990; Galy 1991;
in the study. Finally, we included ten RCTs in the present meta-
Krishnan 1987; Littlejohn 1996; van den Berg 1999). Eight studies
analysis after reading the full-text. There were no significant
compared patients receiving nalbuphine or other different opioid
disagreements between review authors during the extraction
treatments: morphine (Krishnan 1987; Wandless 1987), pethidine
process.
(Barsoum 1995; Habre 1997; van den Berg 1999), tramadol
Included studies (Barsoum 1995; Moyado-Garcia 2009; Schäffer 1986; van den Berg
1999) or piritramid (Büttner 1990).
Summary details of the ten included studies are given in the
Characteristics of included studies tables. Outcomes
Design As described in the methods section we tried to contact the authors

for further relevant data, but we did not receive any response.
All ten included studies were parallel group RCTs and so Therefore, a ITT analysis was not possible. All trials investigated
met the inclusion criteria of this review. No trial was funded the efficacy and adverse effects following perioperative (before or
by any drug company. Nalbuphine was administrated either after anaesthesia induction, before or after the end of surgery)
intramuscularly (Barsoum 1995; Krishnan 1987; Schäffer 1986; administration of nalbuphine in comparison with placebo or other
Wandless 1987) or intravenously (Büttner 1990; Galy 1991; Habre opioid treatments (morphine, pethidine, tramadol or piritramid).
1997; Littlejohn 1996; Moyado-Garcia 2009; van den Berg 1999). Three studies reported the number of patients with moderate/
In one study nalbuphine was administered before induction severe pain (assessed by using three/four point postoperative pain
of general anaesthesia (Galy 1991). Four authors noted that severity scales (low/moderate/severe pain) (1 hour, 2 hours, 12
nalbuphine was given directly after induction (Habre 1997; hours, 24 hours postop) (Barsoum 1995; Krishnan 1987; Wandless
Littlejohn 1996; van den Berg 1999; Wandless 1987), whereas five 1987). The number of patients requiring rescue analgesia was
studies administered nalbuphine before or after the end of surgery recorded in six studies (Barsoum 1995; Büttner 1990; Galy 1991;
(Barsoum 1995; Büttner 1990; Krishnan 1987; Moyado-Garcia 2009; Moyado-Garcia 2009; van den Berg 1999; Wandless 1987). Outcome
Schäffer 1986). Only one trial used a combination of intravenous variables were either ordinal (e.g. severity of pain) or nominal
nalbuphine bolus with subsequent continuous infusion (Moyado- in nature (e.g. presence of postoperative nausea and vomiting
Garcia 2009). (PONV)).
Sample sizes Excluded studies
The number of children analysed in the ten studies ranged from 24 Reasons for exclusions of the six studies are given in the
to 152 (658 in total). Sample size calculations and ITT analysis were Characteristics of excluded studies table. One trial was excluded,
not reported in any of the included studies. because it analysed retrospective data (Nascimento 2002), while
two trials were not included, because they were only published
Setting as abstracts (Quaki 2007; Velegrakis 1998). Another trial included
Four studies were carried out in the UK (Habre 1997; Krishnan 1987; also data from adults (van den Berg 1994), whereas in two trials
Littlejohn 1996; Wandless 1987), two in Germany (Büttner 1990; nalbuphine was administered either only as rescue medication
Schäffer 1986), one in France (Galy 1991), one in the United Arab (Bazin 2010) or patient controlled IV analgesia (Dongmin 2001).
emirates (Barsoum 1995), one in Saudia Arabia (van den Berg 1999)
and one in Canada (Moyado-Garcia 2009). Risk of bias in included studies
We assessed the methodological quality of included trials by using
Participants
The Cochrane Collaboration's tool for assessing risk of bias (Higgins
Studies involved children aged from 11 months to 21 years of 2011), which can be seen within Figure 1 and Figure 2.
age mainly without any relevant comorbidities (only one trial
specifically investigated children with obstructive sleeping disorder Allocation
(Habre 1997)), with each study having a different age range. In All included trials (not Barsoum 1995) reported that they used a
one trial, young adults (up to 21 years) were included; however, randomised study design and were rated as being at low risk of
a specific analysis of the demographic data of the different study selection bias. In contrast only two studies described explicitly
groups showed that the mean age in all study groups was below the concealment of allocation and were rated as being at low
18 years (van den Berg 1999). Therefore, the reviewers decided risk of bias (Moyado-Garcia 2009; Schäffer 1986). The method of
to include the data of this RCT. Common paediatric surgical allocation concealment was not reported in the remaining studies
procedures were performed in all trials: Ear-nose-throat (ENT) and therefore they were assessed as being at unclear risk of bias,

Informed decisions.

whereas one study was an open label trial and was rated at high risk 12 hours postop (Analysis 1.4; Galy 1991); the RRs for the need
of bias (Barsoum 1995). for rescue analgesia was significantly lower in children receiving
0.3 mg/kg nalbuphine compared to placebo in the beginning
Blinding of surgery. There were no data available focusing on secondary
Nine trials were performed as double-blinded studies, in which the postoperative pain outcomes.
participant and provider of investigation were blinded to therapy
Adverse events
(Barsoum 1995; Büttner 1990; Habre 1997; Krishnan 1987; Littlejohn
1996; Moyado-Garcia 2009; Schäffer 1986; van den Berg 1999; All included trials reported data on adverse events following
Wandless 1987). These trials were rated at low risk of performance nalbuphine administration compared to placebo. The RRs for
bias. Only one trial did not state explicitly that a double-blind PONV in the postoperative care unit (PACU) or 24 hours postop
design was used and was rated as being at unclear risk (Galy 1991). were not significantly different (RR PACU 1.00; 95% CI 0.16 to
In contrast only two trials were assessed as being at low risk for 6.42; Analysis 1.5; Krishnan 1987) or lower (RR 24 hours postop
detection bias, because they reported that the outcome assessors 0.59; 95% CI 0.12 to 2.83; Analysis 1.6; Büttner 1990) between
were blinded (Barsoum 1995; Littlejohn 1996). All other studies children receiving intraoperative nalbuphine or placebo at the end
were assessed as being at unclear risk of bias. of surgery. Comparable results were seen for the more specific
outcome 'number of patients with vomiting': van den Berg 1999
Incomplete outcome data reported a nonsignificantly lower RR for postoperative vomiting in
All trials explicitly stated that all patients were included and there the PACU in children treated with nalbuphine at the beginning of
were no drop-outs; therefore all trials were assessed as being at low surgery (RR 0.24; 95% CI 0.03 to 2.03; Analysis 1.7). At 24 hours
risk of attrition bias. postop the RR for vomiting in children treated with nalbuphine
was nonsignificantly higher (RR 5.6; 95% CI 0.34 to 93.35; Analysis
Selective reporting 1.8; Galy 1991). The RR for pruritus 24 hours postop was similar
in children receiving nalbuphine compared to placebo (RR 0.78;
In contrast to the latter finding, all included trials reported only a 95% CI 0.06 to 10.37; Analysis 1.9). One trial reported that children
low number of relevant outcomes and were therefore rated as being treated with 0.3 mg/kg nalbuphine in the beginning of surgery were
at high risk for reporting bias. more sedated in the first 24 hours postop (Analysis 1.12; Galy 1991).
Other potential sources of bias No children suffered from respiratory depression (Analysis 1.10),
urinary retention (Analysis 1.11) or bradycardia (Analysis 1.13) in
There were no other potential sources of bias within the included four trials assessing these side effects (Galy 1991; Krishnan 1987;
trials. Littlejohn 1996; van den Berg 1999).
Effects of interventions Nalbuphine versus Morphine (Comparison 2)

See: Summary of findings for the main comparison Nalbuphine The comparison 'nalbuphine versus morphine' was investigated in
compared with placebo; Summary of findings 2 Nalbuphine two included trials (Krishnan 1987; Wandless 1987) (Summary of
compared with morphine; Summary of findings 3 Nalbuphine findings 2).
compared with tramadol; Summary of findings 4 Nalbuphine
compared with pethidine; Summary of findings 5 Nalbuphine Postoperative pain outcomes
compared with piritramid Two included trials (Krishnan 1987; Wandless 1987) investigated
the number of patients with moderate/severe postoperative pain
In general, due to different outcome data reporting, the overall
following tonsillectomy (assessed on a four point numeric scale
number of pooled outcomes was very low.
(no pain, mild, moderate, severe pain)) (Krishnan 1987) and minor
Nalbuphine versus Placebo (Comparison 1) abdominal surgery (assessed on a three point scale (no pain,
moderate, severe pain)) (Wandless 1987). The RR for moderate/
Five included trials reported data for the comparison 'nalbuphine severe pain in children treated with 0.2/0.3 mg/kg nalbuphine
versus placebo' (Büttner 1990; Galy 1991; Krishnan 1987; Littlejohn was not significantly lower at 1 hour (RR 0.84; 95% CI 0.12 to
1996; van den Berg 1999)(Summary of findings for the main 5.74; I2= 66%; Analysis 2.1) and 2 hours postop (RR 1.09; 95% CI
comparison). 0.59 to 2.01; I2= 0%; Analysis 2.2) following nalbuphine compared
to morphine. The observed heterogeneity might be related to
Postoperative pain outcomes
the different application times of the study drugs in both trials
Only one trial including 40 children (Krishnan 1987) investigated (postop (Krishnan 1987) versus after induction of anaesthesia
the number of children with moderate/severe postoperative pain (Wandless 1987)). Additionally, in one trial (Wandless 1987), the RR
following tonsillectomy; postoperative pain was assessed with a for the need for rescue analgesia was not significantly reduced (RR
four point numeric scale (no pain, mild, moderate, severe pain) 0.61; 95% CI 0.37 to 1.01; Analysis 2.3), when the children were
1 hour and 2 hours postop. The RR for moderate/severe pain in treated with 0.2 mg/kg nalbuphine instead of 0.2 mg/kg morphine
children treated with 0.3 mg/kg nalbuphine at the end of surgery intraoperatively.
following tonsillectomy was lower compared to those receiving
only placebo (RR 1 hour postop 0.10; 95% CI 0.01 to 0.71 (Analysis Adverse events
1.1); RR 2 hours postop 0.14; 95% CI 0.02 to 1.06 (Analysis 1.2)). Data were only available for a low number of adverse events. The
Furthermore, two included trials (Galy 1991; van den Berg 1999) RR for PONV in the PACU was similar in the group of children treated
investigated the outcome 'number of patients requiring rescue with nalbuphine compared to those receiving morphine (RR 1.33;
analgesia': 2 hours postop (Analysis 1.3; van den Berg 1999) and
Informed decisions.

95% CI 0.64 to 2.77; I2= 0%; Analysis 2.4; Krishnan 1987; Wandless kg nalbuphine compared to 1 mg/kg tramadol administered after
1987). The same holds true for PONV 24 hours postop (RR 1.2; 95% induction in children undergoing tonsillectomy (Analysis 4.4; Habre
CI 0.8 to 1.8; Analysis 2.5; Wandless 1987). The number of patients 1997).
with respiratory depression (Analysis 2.6) or bradycardia (Analysis
2.7) in the PACU was low in both groups - only one child receiving 0.2 Adverse events
mg/kg morphine after induction suffered respiratory depression in All three trials reported data on adverse events. In the PACU the
the PACU (Wandless 1987). RR for vomiting was not significantly lower in the nalbuphine
group mentioned in one trial comparing 0.3 mg/kg nalbuphine
Nalbuphine versus Tramadol (Comparison 3)
with 3.0 mg/kg tramadol administered after induction (RR 0.32;
Four trials were available for the comparison 'nalbuphine versus 95% CI 0.04 to 2.99; Analysis 4.5). However, 24 hours postop
tramadol' (Barsoum 1995; Moyado-Garcia 2009; Schäffer 1986; van the RR for vomiting was comparable (RR 1.00; 95% CI 0.7 to
den Berg 1999) (Summary of findings 3). 1.42; Analysis 4.6). Furthermore, the RR for respiratory depression
was not significantly lower in children treated with nalbuphine
Postoperative pain outcomes compared to pethidine (RR 0.3; 95% CI 0.01 to 7.74; Analysis 4.7;
Only one included trial reported data on the outcome number of Habre 1997; van den Berg 1999). No children suffered bradycardia in
patients with moderate/severe pain (1 hour postop) (assessed on a the PACU in either group (Analysis 4.8; Barsoum 1995; Habre 1997).
four point verbal scale (no pain, mild, moderate, severe pain) after Nalbuphine versus Piritramid (Comparison 5)
lower abdominal surgery (Barsoum 1995); however, there were no
children in either group complaining about moderate/severe pain Only one trial investigated 'nalbuphine versus piritramid' in 54
following 0.1 mg/kg nalbuphine or 2 mg/kg tramadol (Analysis 3.1). children (Büttner 1990) (Summary of findings 5).
The number of patients with the need for rescue analgesia was
assessed in all four included trials. At 2 hours and 12 hours postop Postoperative pain outcomes
the RR for the need for rescue analgesia was nonsignificantly lower Only the number of patients requiring rescue analgesia was
in children treated with nalbuphine 0.1 to 0.3 mg/kg (RR 2 hours assessed in the study. The RR for the need for rescue analgesia
postop 0.75; 95% CI 0.39 to 1.43; Analysis 3.2; van den Berg 1999); was not significantly higher in children treated with 0.1 mg/kg
RR 12 hours postop 0.33; 95% CI 0.04 to 2.77; Analysis 3.3; Moyado- nalbuphine compared to children treated with 0.1 mg/kg piritramid
Garcia 2009). However, 24 hours postop the RR was nonsignificantly 24 hours postop (RR 8.17; 95% CI 0.45 to 147.76; Analysis 5.1).
higher in the nalbuphine group (RR 1.45; 95% CI 0.50 to 4.16; I2=
34%; Analysis 3.4; Barsoum 1995; Schäffer 1986). Adverse events
Adverse events The RR for PONV 24 hours postop was nonsignificantly lower in the
nalbuphine group (RR 0.59; 95% CI 0.12 to 2.83; Analysis 5.2).
Adverse events were reported in all included trials. The number of
patients with PONV 24 hours postop was nonsignificantly lower in DISCUSSION
the nalbuphine group compared to the tramadol group (Analysis
3.5; Moyado-Garcia 2009). The same holds true for the more specific Summary of main results
outcome 'vomiting' 24 hours postop (RR 0.33; 95% CI 0.01 to
This quantitative systematic review included ten RCTs with
7.81; Analysis 3.7; Barsoum 1995), while in the PACU the RR was
658 paediatric patients focusing on the analgesic efficacy and
completely comparable (RR 1.0; 95% CI 0.50 to 2.0; Analysis 3.6;
safety of nalbuphine compared to placebo and other opioids
Schäffer 1986; van den Berg 1999). The RR for sedation was not
for postoperative pain treatment. However, the overall evidence
significantly higher in the group of children treated with 0.1 mg/
was only of low quality so we could not definitively show a
kg nalbuphine compared to those receiving 1 mg/kg tramadol for
superior analgesic efficacy of nalbuphine compared to placebo
postoperative pain (RR 2.0; 95% CI 0.21 to 19.23; Analysis 3.9;
or other opioids. The currently existing data suggested that
Moyado-Garcia 2009). No patients with bradycardia (Analysis 3.10)
patients treated with nalbuphine in comparison with placebo may
or with respiratory depression (Analysis 3.8) were mentioned in two
have a lower RR for moderate/severe postoperative pain in the
included trials (Barsoum 1995; van den Berg 1999).
PACU and consecutively a lower RR for the need for additional
Nalbuphine versus Pethidine (Comparison 4) rescue analgesics. The evidence regarding adverse events following
nalbuphine compared to placebo or other opioids is also very
Three RCTs investigated 'nalbuphine versus pethidine' for limited. Generally, the results should be interpreted with great
postoperative pain (Barsoum 1995; Habre 1997; van den Berg 1999) caution due to the small number of usable data, heterogeneous
(Summary of findings 4). studies (procedures, time of administration and drug doses used)
and a high risk of reporting bias.
Postoperative pain outcomes
Barsoum and colleagues noted that no children complained Overall completeness and applicability of evidence
about moderate/severe pain 1 hour postop following 0.1 mg/kg Several surveys in recent years demonstrated that postoperative
nalbuphine or 1 mg/kg pethidine (Analysis 4.1; Barsoum 1995). pain in children is still a relevant problem (Groenewald 2012;
Furthermore, the RR for the need for rescue analgesia (Barsoum Segerdahl 2008). Furthermore, despite the increasing use of
1995; van den Berg 1999) was almost comparable between both regional anaesthetic techniques (Ecoffey 2010; Rabbitts 2010), a
groups (RR 2 hours postop 1.07; 95% CI 0.52 to 2.23; Analysis 4.2; recently published database analysis showed that despite effective
RR 24 hours 1.12; 95% CI 0.52 to 2.44; Analysis 4.3). The time to first regional analgesia, 60% of children required an opioid as rescue
rescue analgesic was around 1.02 hours longer following 0.1 mg/ medication at least once (Dadure 2009). This finding highlights
Informed decisions.

the important role of opioids as possible rescue analgesics for an this quantitative review could not definitively demonstrate that
effective multimodal postoperative pain treatment. 0.1 to 0.3 mg/kg nalbuphine compared to placebo might be an
effective postoperative analgesic. The same holds true for the
Our review could not definitively show that nalbuphine compared comparison with other opioids. Due to limited data we could not
to placebo might improve analgesic efficacy in children, because perform a subgroup analysis focusing on the influence of age, which
only data from a low number of included trials could be pooled might be an influencing factor, because the elimination half-life
for this comparison. The comparison of nalbuphine with opioids of nalbuphine is significantly shorter in young children compared
was also influenced by the small amount of usable data. Only to young adults (Jaillon 1989). Thus, younger infants might need
nonsignificant results were retrieved so that the evidence is earlier additional drug doses than older children for effective pain
currently not clear. The same holds true for analysis of adverse treatment. Finally, again due to limited data, we were not able to
events following nalbuphine versus placebo or other opioids, show a benefit, by a lower number of adverse events following
so that the overall evidence regarding efficacy and adverse nalbuphine administration compared to placebo or other opioids.
events following nalbuphine administration in children is currently However, the number of studied patients does not allow a definite
unclear. conclusion yet.
Quality of the evidence Implications for research
Although the overall number of included trials (10) and patients Based on the findings of this review we determined the following
(658 paediatric patients) was reasonable, only a low number of implications for research.
relevant outcomes and heterogenous assessments were reported.
Therefore, the presented results might be influenced by the high • Due to the low amount of available data, further RCTs comparing
risk of selective reporting. Additionally, the included studies were nalbuphine with other postoperative opioids (tramadol,
only small so that the observed CIs were wide (imprecision of morphine, and piritramid in Germany) are needed. This would
results). Apart from that, there was large clinical heterogeneity enable an appropriate risk benefit analysis. Trials should use a
(pain scores, drug administration) in the study design, which might clearly defined age group of children, comparable procedures
limit the results. As in other reviews focusing on postoperative and specific validated observational and self reported pain
pain therapy in children, different pain assessments with various assessment scales in order to get validated and comparable
observational or self reporting postoperative pain scales were a results.
specific problem and might have influenced the retrieved results; • Nalbuphine administration in children should be studied
more specifically the trials included in our review did not use following different surgical procedures in order to detect
validated pain scoring systems, which might have influenced possible procedure-specific efficacy and dosing.
the outcome 'number of patients with moderate/severe pain'. • Additionally, nalbuphine administration should be studied in
Furthermore, the study design was limited, because we observed children with specific comorbidities, like obstructive sleep
a large heterogeneity concerning the application times (before apnoea, who are at higher risk for opioid-related adverse events.
surgery versus at the end of surgery), types of administration Nalbuphine might be a useful drug, because it might offer
(intravenous versus intramuscular) and administered drug doses. analgesia without causing respiratory depression.
Additionally, due to the low number of reported outcomes,
subgroup and sensitivity analyses (especially focusing on the ACKNOWLEDGEMENTS
influence of surgery) were not possible. So we could not adequately
analyse heterogeneity. Finally, the overall methodological quality We would like to thank the peer reviewers for their valuable
of included trials was only rated as moderate, because only comments and the editorial office of the Cochrane Pain, Palliative
selected outcomes were reported, allocation concealment was only and Supportive Care Group for their support. This review was not
seldom described in detail and a blinding of outcome assessment registered in any kind of database.
was not performed. To conclude, according to the GRADE approach
(Schunemann 2008), we double-downgraded almost all RCTs and CRG Funding Acknowledgement: The National Institute for Health
we triple-downgraded one RCT because it was an open label trial Research (NIHR) is the largest single funder of the Cochrane PaPaS
(Barsoum 1995). Therefore, we rated the overall evidence as low Group. Disclaimer: The views and opinions expressed therein are
quality. those of the authors and do not necessarily reflect those of the
NIHR, NHS or the Department of Health.
AUTHORS' CONCLUSIONS
Implications for practice

Because the overall evidence was limited, mainly by selective
outcome reporting and imprecision of results due to lack of data,

Informed decisions.

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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Barsoum 1995
Methods Open trial
Parallel design
Participants Mainly lower abdominal surgery (appendectomy, hernia repair, testicular or urethral surgery), n = 75
(61 males, 14 females), children aged 2 to 12 years
Group 1: 22 males, 9 females; mean age 5.4 years (standard deviation (SD) 2.6)
Group 2: 20 males, 5 females; mean age 6.3 years (SD 1.9)
Interventions Group 1: 0.1 mg/kg Nalbuphine intramuscularly (IM), (n = 25)
Group 2: 2 mg/kg Tramadol IM, (n = 25)
Group 3: 1 mg/kg Pethidine IM, (n = 25)
Administration time: after the end of surgery (first expression of pain)
An additional injection of half the initial dose was administrated 30 and 60 min if inadequate analgesia
Outcomes - Postoperative pain scales (VRS) (0.5, 1, 3, 6, 12, 24 hours postoperatively)
- Number of patiens with no/slight pain 1 hour postoperatively
- Total analgesic consumption 24 hours postoperatively
- Frequency of administration 24 hours postoperatively
- Investigators assessment of overall pain relief (excellent, very good, good, satisfactory, poor) at 24
hours postoperatively
- Number, nature, time of onset of adverse events (vomiting, haemodynamic, respiratory parameters)
- Overall assessment of tolerability 24 hours postoperatively
Notes

Informed decisions.

Barsoum 1995 (Continued)
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Unclear risk Not described

tion (selection bias)
Allocation concealment High risk Open label trial

(selection bias)
Blinding of participants Low risk "The study was intended to be a double-blind (observer blinded),.."
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Low risk "The study was intended to be a double-blind (observer blinded),.."
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk All patients evaluated

(attrition bias)
All outcomes
Selective reporting (re- High risk Only selective outcome reporting

porting bias)

Büttner 1990
Methods Randomised controlled trial
Parallel design
Participants Small urological surgery (herniotomy, circumcision, orchidopexy), n = 54
Children aged 1 to 4 years
Interventions Group 1: 0.1 mg/kg Nalbuphine intravenously (IV) (n = 20),
Group 2: 0.1 mg/kg Piritramid IV (n = 17)
Group 3: Placebo IV (n = 17)
Administration time: after the end of surgery
Outcomes - Observational pain scale (0 to 15 points)
- Number of patients with pain
- Number of patients with need for additional analgesics
- Number of adverse events (vomiting)
Notes
Risk of bias

Informed decisions.

Büttner 1990 (Continued)
Random sequence genera- Low risk "... was tested in a randomized double-blind trial..."
Allocation concealment Unclear risk Not described

(selection bias)
Blinding of participants Low risk "... was tested in a randomized double-blind trial..."
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Not described

All outcomes

(attrition bias)
All outcomes

porting bias)

Galy 1991
Parallel design
Participants Small surgeries, n = 33, children aged 11 months to 9 years
Interventions Group 1: 0.3 mg/kg Nalbuphine intravenously (IV) + caudal anaesthesia (with lidocaine) (n = 9)
Group 2: Placebo IV + caudal anaesthesia (with lidocaine) (n = 7)
Group 3: 0.3 mg/kg Nalbuphine supp + caudal anaesthesia (with lidocaine) (n = 10)
Group 4: Placebo + caudal anaesthesia (with lidocaine) (n = 7)
Administration time: premedication
Outcomes - Postoperative pain (0, 0.5, 1, 2, 3, 4, 5, 6 hours after surgery)
- Duration of analgesia
- Number of adverse events (vomiting, pruritus)
Notes
Risk of bias
Random sequence genera- Low risk " randomized allocation" (in the French original: "...sont tirès au sort pour re-
tion (selection bias) cevoir...")

Informed decisions.

Galy 1991 (Continued)
(selection bias)
Blinding of participants Unclear risk Not described

mance bias)
All outcomes

All outcomes

(attrition bias)
All outcomes

porting bias)

Habre 1997
Parallel design
Participants Adenotonsillectomy, n = 90, children aged 2 to 12years
Group 1: 26 males, 19 females; mean age 67 months (standard deviation (SD) 26)
Group 2: 18 males, 27 females; mean age 76 months (SD 29)
Interventions Group 1: 0.1 mg/kg Nalbuphine intravenously (IV) (n = 45)
Group 2: 1 mg/kg Pethidine IV (n = 45)
Administration time: after induction
All children were given 15 mg/kg paracetamol orally 1 hour before surgery.
Outcomes - Observational pain score (facial expression, position in bed, vocalisation, nurse assessment; 0 to 8
points) at different time points
- Number of analgesic doses in the recovery area
- Number of patients with more than 3 doses of opioids
- Time to first analgesic
- Sedation score
Notes
Risk of bias

Informed decisions.

Habre 1997 (Continued)
Random sequence genera- Low risk "Children were then randomly assigned to receive on induction .."

(selection bias)
Blinding of participants Low risk "Recovery nursing staff were therefore blinded to the choice of opioid"
mance bias)
All outcomes

All outcomes

(attrition bias)
All outcomes

porting bias)

Krishnan 1987
Parallel design
Participants Tonsillectomy, n = 60, children aged 4 to 12 years
Group 1: males 11, females 9, mean age 6.579 years (standard error of mean (SEM) 0.528)
Group 2: males 10, females 10, mean age 6.469 years (SEM 0.629)
Group 3: males 8, females 12, mean age 7.016 years (SEM 0.488)
Interventions Group 1: 0.3 mg/kg Nalbuphine intramuscularly (IM) (n = 20)
Group 2: 0.2 mg/kg Morphin IM (n = 20)
Group 3: Placebo IM (n = 20)
Administration time: 5 minutes before the end of surgery
Outcomes - Observational pain and restlessness scale (none, mild, moderate, severe)
- Number of adverse events (vomiting, cardiovascular, respiratory effects)
Notes
Risk of bias

Informed decisions.

Krishnan 1987 (Continued)
Random sequence genera- Low risk
Blinding of participants Low risk

mance bias)
All outcomes
Incomplete outcome data Low risk

(attrition bias)
All outcomes
Selective reporting (re- High risk

porting bias)

Littlejohn 1996
Parallel design
Participants Teeth extraction, n = 60, children aged 3 to 7 years
Interventions Group 1: 0.3 mg/kg Nalbuphine intravenously (IV) (n = 21)
Group 2: 1 to 2 mg/kg Diclofenac rectally (n =19)
Group 3: control (no analgesic) (n = 20)
Administration time: after induction
Outcomes - Hannallah observational pain scale (0 to 10 points)
Notes
Risk of bias
Random sequence genera- Low risk "In a randomized, double-blind study ..."

(selection bias)

Informed decisions.

Littlejohn 1996 (Continued)
Blinding of participants Low risk "In a randomized, double-blind study ..."
mance bias)
All outcomes
Blinding of outcome as- Low risk "Pain related behaviour was evaluated in all patients by the same blinded ob-
sessment (detection bias) server..."
All outcomes

(attrition bias)
All outcomes

porting bias)

Moyado-Garcia 2009
Parallel design
Participants Various surgical procedures with expected moderate to severe postoperative pain, n = 24, children
aged 1 to 10 years
Group 1: 7 males, 5 females; mean age 6.2 years (range 2.5 to 10.0)
Group 2: 7 males, 5 females; mean age 4.4 years (range 1.6 to 10.0)
Interventions Group 1: Nalbuphine (bolus 100 μg/kg, 0.2 μg/kg/min for 72 hours) intravenously (IV) (n = 12)
Group 2: Tramadol (bolus 1,000 μg/kg, 2.0 μg/kg/min for 72 hours) IV (n = 12)
Administration time: immediately before the closure of the surgical incision
Outcomes - Children's Hospital of Eastern Ontario Pain Scale (CHEOPS), facial pain intensity scale (0 to 5 points),
Visual Analogue Scale (VAS) (every hour until 24 hours postoperatively)
- Sedation score (1 to 5 points)
- Number of adverse events (vomiting, cardiovascular, respiratory effects)
Notes
Risk of bias
Random sequence genera- Low risk "... a scheduled surgical procedure were randomly
tion (selection bias) allocated to receive either ..."
Allocation concealment Low risk "By means of a pre designed table of random numbers,
(selection bias) children were allocated to receive either ..."

Informed decisions.

Moyado-Garcia 2009 (Continued)
Blinding of participants Low risk "In a double blind design ..."
mance bias)
All outcomes

All outcomes

(attrition bias)
All outcomes

porting bias)

Schäffer 1986
Parallel design
Participants Herniotomy, orchidopexy, circumcision, hydrocelectomy, n = 60, children aged 1 to 9 years
Interventions Group 1: 0.15 to 0.2 mg/kg Nalbuphine intramuscularly (IM)
Group 2: 0.75 to 1 mg/kg Tramadol IM
Administration time: after surgery (at the arrival in the recovery area)
Outcomes - Visual Analogue Scale (VAS) (1, 2, 3, 4, 6, 8, 24 hours postoperatively)
- Number of adverse events (vomiting, headache, singultus, hallucination, dry mouth)
Notes
Risk of bias
Random sequence genera- Low risk "...each group received in a randomized and double-blind manner ..."
Allocation concealment Low risk "... received according to the plan of randomisation..."
(selection bias)
Blinding of participants Low risk "...each group received in a randomized and double-blind manner ..."
mance bias)
All outcomes


Informed decisions.

Schäffer 1986 (Continued)
All outcomes

(attrition bias)
All outcomes

porting bias)

van den Berg 1999
Parallel design
Participants Adenotonsillectomy, n = 152, children aged 8 to 21 years
Group 1: 23 males, 16 females; mean age 15 years (standard deviation (SD) 14)
Group 2: 25 males, 13 females; mean age 14 years (SD 15)
Interventions Group 1: 0.3 mg/kg Nalbuphine intravenously (n = 39)
Group 2: 3.0 mg/kg Tramadol IV (n = 38)
Group 3: 1.5 mg/kg Pethidine IV (n = 38)
Group 4: Placebo IV (n = 37)
Administration time: at induction
All children received 1 mg/kg diclofenac rectally/intramuscularly 1 to 2 hours before surgery.
Outcomes - Observational restlessness-pain score (0 to 3 points)
- Sedation score (1 to 4 points)
- Recovery time (minutes)
- Awakening time (minutes)
Notes
Risk of bias
Random sequence genera- Low risk "Each patient was block randomized on arrival ..."

Informed decisions.

van den Berg 1999 (Continued)

(selection bias)
Blinding of participants Low risk "A prospective, double-blind, randomized, controlled study .. "
mance bias)
All outcomes

All outcomes

(attrition bias)
All outcomes

porting bias)

Wandless 1987
Parallel design
Participants Orchidopexy, n = 50, children aged < 11 years
Group 1: 25 males; mean age 6.1 years (standard deviation (SD) 2.7)
Group 2: 25 males; mean age 4.1 years (SD 2.2)
Interventions Group 1: 0.2 mg/kg Nalbuphine intramuscularly (IM) (n = 25)
Group 2: 0.2 mg/kg Morphine IM (n = 25)
Administration time: immediately after induction
Outcomes - Observational postoperative pain scale (none, moderate, severe) (1, 2, 4, 24 hours postoperatively)
- Number of patients with moderate/severe pain
- Number of adverse events (vomiting, sweating, respiratory depression)
Notes
Risk of bias
Random sequence genera- Low risk "Fifty boys under 11 years of age were allocated randomly to receive ..."

(selection bias)

Informed decisions.

Wandless 1987 (Continued)
Blinding of participants Low risk "A double-blind investigation was conducted..."
mance bias)
All outcomes

All outcomes

(attrition bias)
All outcomes

porting bias)

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Bazin 2010 Nalbuphine as rescue medication
Dongmin 2001 Intravenous patient-controlled-analgesia
Nascimento 2002 Retrospective study
Quaki 2007 Only published as abstract
van den Berg 1994 Adult patients (> 18 years)
Velegrakis 1998 Only published as abstract

DATA AND ANALYSES

Comparison 1. Nalbuphine versus placebo
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1 Number of patients with moderate/severe 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.1 [0.01, 0.71]
pain (1h postop)
pain (2h postop)
3 Number of patients with the need for rescue 1 76 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.27, 0.84]
analgesia (2h postop)

Informed decisions.


studies partici-
pants
5 Number of patients with PONV (PACU) 1 40 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.16, 6.42]
6 Number of patients with PONV (postop 24h) 1 37 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.12, 2.83]
7 Number of patient with vomiting (PACU) 1 76 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.03, 2.03]
8 Number of patients with vomiting (postop 1 16 Risk Ratio (M-H, Fixed, 95% CI) 5.6 [0.34, 93.35]
24h)
9 Number of patients with pruritus (postop 1 16 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.06, 10.37]
24h)
10 Number of patients with respiratory depres- 3 157 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
sion
11 Number of patients with urinary retention 1 16 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
12 Number of patients with sedation (24h 1 16 Risk Ratio (M-H, Fixed, 95% CI) 15.2 [1.03,
postop) ) 223.37]
13 Number with patients with bradycardia 2 81 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
(PACU)

Analysis 1.1. Comparison 1 Nalbuphine versus placebo, Outcome
1 Number of patients with moderate/severe pain (1h postop).
Study or subgroup Nalbuphine Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Krishnan 1987 1/20 10/20 100% 0.1[0.01,0.71]

Total (95% CI) 20 20 100% 0.1[0.01,0.71]
Total events: 1 (Nalbuphine), 10 (Placebo)
Heterogeneity: Not applicable
Test for overall effect: Z=2.3(P=0.02)
Favours nalbuphine 0.01 0.1 1 10 100 Favours placebo

Analysis 1.2. Comparison 1 Nalbuphine versus placebo, Outcome
Krishnan 1987 1/20 7/20 100% 0.14[0.02,1.06]


Informed decisions.


Total (95% CI) 20 20 100% 0.14[0.02,1.06]

Analysis 1.3. Comparison 1 Nalbuphine versus placebo, Outcome 3
Number of patients with the need for rescue analgesia (2h postop).
van den Berg 1999 11/39 22/37 100% 0.47[0.27,0.84]

Total (95% CI) 39 37 100% 0.47[0.27,0.84]

Analysis 1.4. Comparison 1 Nalbuphine versus placebo, Outcome 4
Galy 1991 0/9 6/7 100% 0.06[0,0.94]

Total (95% CI) 9 7 100% 0.06[0,0.94]

Analysis 1.5. Comparison 1 Nalbuphine versus placebo, Outcome 5 Number of patients with PONV (PACU).
Krishnan 1987 2/20 2/20 100% 1[0.16,6.42]

Total (95% CI) 20 20 100% 1[0.16,6.42]
Test for overall effect: Not applicable

Informed decisions.


Analysis 1.6. Comparison 1 Nalbuphine versus placebo, Outcome 6 Number of patients with PONV (postop 24h).
Büttner 1990 2/17 4/20 100% 0.59[0.12,2.83]

Total (95% CI) 17 20 100% 0.59[0.12,2.83]

Analysis 1.7. Comparison 1 Nalbuphine versus placebo, Outcome 7 Number of patient with vomiting (PACU).
van den Berg 1999 1/39 4/37 100% 0.24[0.03,2.03]

Total (95% CI) 39 37 100% 0.24[0.03,2.03]

Analysis 1.8. Comparison 1 Nalbuphine versus placebo, Outcome 8 Number of patients with vomiting (postop 24h).
Galy 1991 3/9 0/7 100% 5.6[0.34,93.35]

Total (95% CI) 9 7 100% 5.6[0.34,93.35]

Analysis 1.9. Comparison 1 Nalbuphine versus placebo, Outcome 9 Number of patients with pruritus (postop 24h).
Galy 1991 1/9 1/7 100% 0.78[0.06,10.37]

Total (95% CI) 9 7 100% 0.78[0.06,10.37]

Informed decisions.


Analysis 1.10. Comparison 1 Nalbuphine versus placebo,
Outcome 10 Number of patients with respiratory depression.
Krishnan 1987 0/20 0/20 Not estimable
Littlejohn 1996 0/21 0/20 Not estimable
van den Berg 1999 0/39 0/37 Not estimable

Total (95% CI) 80 77 Not estimable

Analysis 1.11. Comparison 1 Nalbuphine versus placebo, Outcome 11 Number of patients with urinary retention.
Galy 1991 0/9 0/7 Not estimable


Outcome 12 Number of patients with sedation (24h postop) ).
Galy 1991 9/9 0/7 100% 15.2[1.03,223.37]

Total (95% CI) 9 7 100% 15.2[1.03,223.37]


Informed decisions.


Outcome 13 Number with patients with bradycardia (PACU).
Littlejohn 1996 0/21 0/20 Not estimable


Comparison 2. Nalbuphine versus morphine

studies partici-
pants
1 Number of patients with moderate/severe 2 90 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.12, 5.74]
pain (1h postop)
pain (2h postop)
4 Number of patients with PONV (PACU) 2 90 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.64, 2.77]
5 Number of patients with PONV (24h postop) 1 50 Risk Ratio (M-H, Fixed, 95% CI) 1.2 [0.80, 1.80]
6 Number of patient with respiratory depres- 2 90 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.81]
sion
7 Number with patient with bradycardia 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
(PACU)

Analysis 2.1. Comparison 2 Nalbuphine versus morphine, Outcome
Study or subgroup Nalbuphine Morphine Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Krishnan 1987 1/20 4/20 38.69% 0.25[0.03,2.05]
Wandless 1987 9/25 5/25 61.31% 1.8[0.7,4.62]

Total (95% CI) 45 45 100% 0.84[0.12,5.74]
Total events: 10 (Nalbuphine), 9 (Morphine)
Heterogeneity: Tau2=1.34; Chi2=2.94, df=1(P=0.09); I2=66.01%
Favours nalbuphine 0.01 0.1 1 10 100 Favours morphine

Informed decisions.



Analysis 2.2. Comparison 2 Nalbuphine versus morphine, Outcome
Krishnan 1987 1/20 0/20 4.35% 3[0.13,69.52]
Wandless 1987 11/25 11/25 95.65% 1[0.54,1.87]

Total (95% CI) 45 45 100% 1.09[0.59,2.01]
Heterogeneity: Tau2=0; Chi2=0.47, df=1(P=0.49); I2=0%

Analysis 2.3. Comparison 2 Nalbuphine versus morphine, Outcome 3
Wandless 1987 11/25 18/25 100% 0.61[0.37,1.01]

Total (95% CI) 25 25 100% 0.61[0.37,1.01]

Analysis 2.4. Comparison 2 Nalbuphine versus morphine, Outcome 4 Number of patients with PONV (PACU).
Krishnan 1987 2/20 2/20 22.22% 1[0.16,6.42]
Wandless 1987 10/25 7/25 77.78% 1.43[0.65,3.15]

Total (95% CI) 45 45 100% 1.33[0.64,2.77]
Heterogeneity: Tau2=0; Chi2=0.12, df=1(P=0.73); I2=0%


Informed decisions.

Analysis 2.5. Comparison 2 Nalbuphine versus morphine, Outcome 5 Number of patients with PONV (24h postop).
Wandless 1987 18/25 15/25 100% 1.2[0.8,1.8]

Total (95% CI) 25 25 100% 1.2[0.8,1.8]

Analysis 2.6. Comparison 2 Nalbuphine versus morphine,
Outcome 6 Number of patient with respiratory depression.
Wandless 1987 0/25 1/25 100% 0.33[0.01,7.81]

Total (95% CI) 45 45 100% 0.33[0.01,7.81]

Analysis 2.7. Comparison 2 Nalbuphine versus morphine, Outcome 7 Number with patient with bradycardia (PACU).


Comparison 3. Nalbuphine versus tramadol

studies partici-
pants
1 Number of patients with moderate/severe pain 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
(1h postop)

Informed decisions.


studies partici-
pants
4 Number of patients with the need for rescue 2 110 Risk Ratio (M-H, Random, 95% CI) 1.45 [0.50, 4.16]
6 Number of patients with vomiting (PACU) 2 137 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.50, 2.00]
7 Number of patients with vomiting (24h postop) 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.81]
8 Number of patients with respiratory depression 2 127 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
(PACU)
9 Number of patients with sedation (24h postop) 1 24 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [0.21, 19.23]
10 Number of patients with bradycardia (PACU) 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Analysis 3.1. Comparison 3 Nalbuphine versus tramadol, Outcome
Study or subgroup Nalbuphine Tramadol Risk Ratio Weight Risk Ratio
Barsoum 1995 0/25 0/25 Not estimable

Total events: 0 (Nalbuphine), 0 (Tramadol)
Favours nalbuphine 0.01 0.1 1 10 100 Favours tramadol

2 Number of patients with the need for rescue analgesia (2h postop).
van den Berg 1999 11/39 14/37 100% 0.75[0.39,1.43]

Total (95% CI) 39 37 100% 0.75[0.39,1.43]

Informed decisions.


Analysis 3.3. Comparison 3 Nalbuphine versus tramadol, Outcome 3
Moyado-Garcia 2009 1/12 3/12 100% 0.33[0.04,2.77]

Total (95% CI) 12 12 100% 0.33[0.04,2.77]

Analysis 3.4. Comparison 3 Nalbuphine versus tramadol, Outcome 4
Barsoum 1995 9/25 4/25 59.75% 2.25[0.8,6.36]
Schäffer 1986 3/30 4/30 40.25% 0.75[0.18,3.07]

Total (95% CI) 55 55 100% 1.45[0.5,4.16]
Heterogeneity: Tau2=0.21; Chi2=1.51, df=1(P=0.22); I2=33.98%

Analysis 3.5. Comparison 3 Nalbuphine versus tramadol, Outcome 5 Number of patients with PONV (24h postop).
Moyado-Garcia 2009 2/12 4/12 100% 0.5[0.11,2.23]

Total (95% CI) 12 12 100% 0.5[0.11,2.23]

Analysis 3.6. Comparison 3 Nalbuphine versus tramadol, Outcome 6 Number of patients with vomiting (PACU).
Schäffer 1986 10/30 10/30 90.8% 1[0.49,2.05]
van den Berg 1999 1/39 1/38 9.2% 0.97[0.06,15.02]
Favours nalbupine 0.01 0.1 1 10 100 Favours tramadol

Informed decisions.



Total (95% CI) 69 68 100% 1[0.5,2]
Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.99); I2=0%
Favours nalbupine 0.01 0.1 1 10 100 Favours tramadol

Analysis 3.7. Comparison 3 Nalbuphine versus tramadol,
Outcome 7 Number of patients with vomiting (24h postop).
Barsoum 1995 0/25 1/25 100% 0.33[0.01,7.81]

Total (95% CI) 25 25 100% 0.33[0.01,7.81]

8 Number of patients with respiratory depression (PACU).
van den Berg 1999 0/39 0/38 Not estimable


Outcome 9 Number of patients with sedation (24h postop).
Moyado-Garcia 2009 2/12 1/12 100% 2[0.21,19.23]

Total (95% CI) 12 12 100% 2[0.21,19.23]

Informed decisions.



Outcome 10 Number of patients with bradycardia (PACU).


Comparison 4. Nalbuphine versus pethidine

studies partici-
pants
pain (1h postop)
4 Time to first rescue analgesic (h) 1 90 Mean Difference (IV, Fixed, 95% CI) 1.02 [-0.20, 2.24]
5 Number of patients with vomiting (PACU) 1 77 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.04, 2.99]
6 Number of patients with vomiting (24h 2 140 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.70, 1.42]
postop)
7 Number of patients with respiratory depres- 2 167 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.74]
sion (PACU)
8 Number of patients with bradycardia (PACU) 2 140 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]


Informed decisions.

Analysis 4.1. Comparison 4 Nalbuphine versus pethidine, Outcome

Study or subgroup Nalbuphine Pethidine Risk Ratio Weight Risk Ratio

Total events: 0 (Nalbuphine), 0 (Pethidine)
Favours nalbuphine 0.01 0.1 1 10 100 Favours pethidine

Analysis 4.2. Comparison 4 Nalbuphine versus pethidine, Outcome
2 Number of patients with the need for rescue analgesia (2h postop).
van den Berg 1999 11/39 10/38 100% 1.07[0.52,2.23]

Total (95% CI) 39 38 100% 1.07[0.52,2.23]

Analysis 4.3. Comparison 4 Nalbuphine versus pethidine, Outcome 3
Barsoum 1995 9/25 8/25 100% 1.13[0.52,2.44]

Total (95% CI) 25 25 100% 1.13[0.52,2.44]

Analysis 4.4. Comparison 4 Nalbuphine versus pethidine, Outcome 4 Time to first rescue analgesic (h).
Study or subgroup Nalbuphine Pethidine Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
Habre 1997 45 4.1 (2.7) 45 3.1 (3.2) 100% 1.02[-0.2,2.24]

Total *** 45 45 100% 1.02[-0.2,2.24]
Favours pethidine -2 -1 0 1 2 Favours nalbuphine

Informed decisions.

Study or subgroup Nalbuphine Pethidine Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
Favours pethidine -2 -1 0 1 2 Favours nalbuphine

Analysis 4.5. Comparison 4 Nalbuphine versus pethidine, Outcome 5 Number of patients with vomiting (PACU).
van den Berg 1999 1/39 3/38 100% 0.32[0.04,2.99]

Total (95% CI) 39 38 100% 0.32[0.04,2.99]

Analysis 4.6. Comparison 4 Nalbuphine versus pethidine,
Outcome 6 Number of patients with vomiting (24h postop).
Habre 1997 26/45 26/45 100% 1[0.7,1.42]

Total (95% CI) 70 70 100% 1[0.7,1.42]

Analysis 4.7. Comparison 4 Nalbuphine versus pethidine,
Outcome 7 Number of patients with respiratory depression (PACU).
Habre 1997 0/45 0/45 Not estimable
van den Berg 1999 0/39 1/38 100% 0.33[0.01,7.74]

Total (95% CI) 84 83 100% 0.33[0.01,7.74]


Informed decisions.

Analysis 4.8. Comparison 4 Nalbuphine versus pethidine, Outcome 8 Number of patients with bradycardia (PACU).
Habre 1997 0/45 0/45 Not estimable


Comparison 5. Nalbuphine versus piritramid

studies partici-
pants
1 Number of patients with the need for rescue 1 37 Risk Ratio (M-H, Fixed, 95% CI) 8.17 [0.45,
analgesia (24h postop) 147.76]

Analysis 5.1. Comparison 5 Nalbuphine versus piritramid, Outcome 1
Study or subgroup Nalbuphine Piritramid Risk Ratio Weight Risk Ratio
Büttner 1990 3/17 0/20 100% 8.17[0.45,147.76]

Total (95% CI) 17 20 100% 8.17[0.45,147.76]
Total events: 3 (Nalbuphine), 0 (Piritramid)
Favours nalbuphine 0.01 0.1 1 10 100 Favours piritramid

Analysis 5.2. Comparison 5 Nalbuphine versus piritramid, Outcome 2 Number of patients with PONV (24h postop).
Study or subgroup Nalbuphine Piritramid Risk Ratio Weight Risk Ratio
Büttner 1990 2/17 4/20 100% 0.59[0.12,2.83]

Total (95% CI) 17 20 100% 0.59[0.12,2.83]
Total events: 2 (Nalbuphine), 4 (Piritramid)
Favours nalbuphine 0.01 0.1 1 10 100 Favours piritramid

Informed decisions.


APPENDICES
Appendix 1. MEDLINE search strategy

1. Nalbuphine/
2. nalbuphine.mp.
3. (en2234a or en 2234a or nubain).mp.
4. 1 or 2 or 3
5. Pain, Postoperative/
6. (pain* and (postoperative or post operative or surg*)).mp.
7. 5 or 6
8. exp Infant/
9. exp Child/
10.Adolescent/
11.(infant* or child* or adolesc*).mp.
12.8 or 9 or 10 or 11
13.randomized controlled trial.pt.
14.controlled clinical trial.pt.
15.randomized.ab.
16.placebo.ab.
17.drug therapy.fs.
18.randomly.ab.
19.trial.ab.
20.groups.ab.
21.13 or 14 or 15 or 16 or 17 or 18 or 19 or 20
22.4 and 7 and 12 and 21
key:
mp=title, original title, abstract, name of substance word, subject heading word, unique identifier
pt=publication type
ab=abstract
fs=floating subheading
WHAT'S NEW

Date Event Description
25 May 2016 Review declared as stable See Published notes.

CONTRIBUTIONS OF AUTHORS

Drafted the protocol AS
Developed a search strategy AS
Searched for studies (usually 2 authors) AS, SR

Informed decisions.

Obtained copies of studies AS, SR
Selected which studies to include (2 + 1 arbiter) AS, SR, PZ
Extracted data from studies (2 authors) AS, SR
Entered data into RevMan AS, SR
Carried out the analysis AS, SR
Interpreted the analysis AS, PZ
Drafted the final write-up of the review AS, SR, PZ, EPZ
Update the review AS, SR
Content expert name AS, PZ
Methodologist name AS

DECLARATIONS OF INTEREST
Alexander Schnabel: No conflicts of interest.
Sylvia Reichl: No conflicts of interest.
Peter Zahn: No conflicts of interest.
Esther Pogatzki-Zahn: No conflicts of interest.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
Due to inconsistent outcome data reporting with regard to pain scores, we could not extract data for the primary outcome postoperative
pain scores. Therefore, the authors decided to assess the outcome 'number of patients with the need for rescue analgesia' as the primary
outcome. Additionally, the planned subgroup analysis focusing on different durations of postoperative care (PACU/24 hours/48 hours) was
deleted, because we primarily analysed the outcomes at different times (primary outcomes at 1 hour, 2 hours, 12 hours, 24 hours postop;
adverse events within the PACU and 24 hours postop).
NOTES
A restricted search in May 2016 did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review has
now been stabilised following discussion with the authors and editors. If appropriate, we will update the review if new evidence likely to
change the conclusions is published, or if standards change substantially which necessitate major revisions.
INDEX TERMS
Medical Subject Headings (MeSH)

Analgesics, Opioid [adverse effects] [*therapeutic use]; Meperidine [adverse effects] [therapeutic use]; Morphine [adverse effects]
[therapeutic use]; Nalbuphine [adverse effects] [*therapeutic use]; Pain, Postoperative [*drug therapy]; Randomized Controlled Trials
as Topic; Tramadol [adverse effects] [therapeutic use]
MeSH check words

Adolescent; Child; Child, Preschool; Humans; Young Adult


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Schnabel A, Reichl SU, Zahn PK, Pogatzki-Zahn E

Schnabel A, Reichl SU, Zahn PK, Pogatzki-Zahn E.

Nalbuphine for postoperative pain treatment in children (Review) ii

Nalbuphine for postoperative pain treatment in children

Alexander Schnabel1, Sylvia U Reichl2, Peter K Zahn3, Esther Pogatzki-Zahn4

Editorial group: Cochrane Pain, Palliative and Supportive Care Group.

Data collection and analysis

Nalbuphine for postoperative pain treatment in children (Review) 2

Nalbuphine compared with placebo for postoperative pain in children

Patient or population: children undergoing surgery

Intervention: 0.3 mg/kg nalbuphine intramuscular/intravenous

Outcomes Relative effect No of Par- Quality of Com-

GRADE Working Group grades of evidence

Nalbuphine compared with morphine for postoperative pain in children

Patient or population: children undergoing surgery

Nalbuphine for postoperative pain treatment in children (Review) 3

Intervention: 0.2/0.3 mg/kg nalbuphine intramuscularly

Comparison: 0.2 mg/kg morphine intramuscularly

Outcomes Relative effect No of Par- Quality of Com-

GRADE Working Group grades of evidence

Nalbuphine compared with tramadol for postoperative pain in children

Patient or population: children undergoing surgery

Outcomes Relative effect No of Par- Quality of Com-

Nalbuphine for postoperative pain treatment in children (Review) 4

GRADE Working Group grades of evidence

Nalbuphine compared with pethidine for postoperative pain in children

Patient or population: children undergoing surgery

Intervention: 0.1/0.3 mg/kg nalbuphine intramuscularly/intravenously

Comparison: 1/1.5 mg/kg pethidine intramuscularly/intravenously

Outcomes Relative effect No of Par- Quality of the Com-

Nalbuphine for postoperative pain treatment in children (Review) 5

GRADE Working Group grades of evidence

Nalbuphine compared with piritramid for postoperative pain in children

Patient or population: children undergoing surgery

Intervention: 0.1 mg/kg nalbuphine intravenously

Comparison: 0.1 mg/kg piritramid intravenously

Outcomes Relative effect No of Par- Quality of the Com-

GRADE Working Group grades of evidence

Nalbuphine for postoperative pain treatment in children (Review) 6

BACKGROUND of nalbuphine is associated with sedation, dysphoria, and urinary

Types of outcome measures

Nalbuphine for postoperative pain treatment in children (Review) 7

Secondary outcomes Selection of studies

Nalbuphine for postoperative pain treatment in children (Review) 8

Nalbuphine for postoperative pain treatment in children (Review) 9

Nalbuphine for postoperative pain treatment in children (Review) 10

1. Allocation of intervention Assessment of heterogeneity

Nalbuphine for postoperative pain treatment in children (Review) 11

RESULTS surgery or teeth extraction (Habre 1997; Krishnan 1987; Littlejohn

Design As described in the methods section we tried to contact the authors

Nalbuphine for postoperative pain treatment in children (Review) 12

Effects of interventions Nalbuphine versus Morphine (Comparison 2)

Implications for practice

Nalbuphine for postoperative pain treatment in children (Review) 15

Nalbuphine for postoperative pain treatment in children (Review) 16

Chen 1993 Jaillon 1989

Higgins 2011 Review Manager 2012 [Computer program]

Hirschfeld 2013 Rhodes 1986

Jacqz-Aigrain 2003 Segerdahl 2008

Anaesthesiologica Scandinavica 2008;52(6):821-8. [PUBMED: Taylor 2008

Characteristics of included studies [ordered by study ID]

Group 2: 20 males, 5 females; mean age 6.3 years (SD 1.9)

Group 3: 19 males, 6 females; mean age 6.2 years (SD 2.8)