Key messages
• We did not find enough good-quality evidence about the benefits and risks of opioids (a group of pain-relieving medicines) to manage pain after surgery in babies. We found only four studies and they had not enrolled enough babies to give reliable results.
• Larger, well-designed studies are needed to give better estimates of the benefits and potential harms of opioids, other medicines and non-medicine-based treatments.
Why are opioids given to manage pain after surgery in babies?
Babies (particularly in the first four weeks after birth) often have to have surgeries. Similar to adults, they need constant pain management after these operations and opioids are commonly used for post-surgery pain relief in babies.
What did we want to find out?
We wanted to find out the impact of giving opioids to babies having surgery, compared to:
1) no treatment or placebo (a 'dummy' treatment, or sham treatment, that does not contain any medicine but looks or tastes identical to the medicine being tested);
2) non-medicine-based treatments (such as sweet solutions);
3) other medicines; or
4) different types of opioids.
What did we do?
We searched for studies that compared opioids with the four treatments described above. We compared and summarized their results, and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We included four studies that involved 331 babies. The biggest study was in 171 babies and the smallest study was in 15 babies.
• Two studies compared opioids with placebo: it is unclear if opioids have an effect on mortality; no studies reported pain, long-term development, vision problems (retinopathy of prematurity) or bleeding to the brain (intraventricular hemorrhage).
• One study compared one type of opioid to another type of opioid: it is unclear if fentanyl has an effect on mortality compared to tramadol; no studies reported pain, long-term development, vision problems or bleeding to the brain.
• One study compared an opioid to a different type of pain-relieving medicine: it is unclear if the opioid morphine has an effect on pain compared with paracetamol; no studies reported long-term development, mortality, vision problems or bleeding to the brain.
What are the limitations of the evidence?
We are not confident in the evidence because there were not enough studies to be certain about the results of our outcomes. Also, it is possible that people in the studies were aware of what treatment they were given. Not all the studies provided data about everything that we were interested in.
How up-to-date is this review?
We searched for studies that were available up to May 2021.
Limited evidence is available on opioid administration for postoperative pain in newborn infants compared to either placebo, other opioids, or paracetamol.
We are uncertain whether tramadol reduces mortality compared to placebo; none of the studies reported pain scores, major neurodevelopmental disability, cognitive and educational outcomes in children older than five years old, retinopathy of prematurity, or intraventricular hemorrhage. We are uncertain whether fentanyl reduces mortality compared to tramadol; none of the studies reported pain scores, major neurodevelopmental disability, cognitive and educational outcomes in children older than five years old, retinopathy of prematurity, or intraventricular hemorrhage. We are uncertain whether morphine reduces pain compared to paracetamol; none of the studies reported major neurodevelopmental disability, cognitive and educational outcomes in children more than five years old, all-cause mortality during initial hospitalization, retinopathy of prematurity, or intraventricular hemorrhage. We identified no studies comparing opioids versus non-pharmacological interventions.
Neonates may undergo surgery because of malformations such as diaphragmatic hernia, gastroschisis, congenital heart disease, and hypertrophic pyloric stenosis, or complications of prematurity, such as necrotizing enterocolitis, spontaneous intestinal perforation, and retinopathy of prematurity that require surgical treatment. Options for treatment of postoperative pain include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. The assessment of the effects of opioids is of utmost importance, especially for neonates in substantial pain during the postoperative period.
To evaluate the benefits and harms of systemic opioid analgesics in neonates who underwent surgery on all-cause mortality, pain, and significant neurodevelopmental disability compared to no intervention, placebo, non-pharmacological interventions, different types of opioids, or other drugs.
We searched Cochrane CENTRAL, MEDLINE via PubMed and CINAHL in May 2021. We searched the WHO ICTRP, clinicaltrials.gov, and ICTRP trial registries. We searched conference proceedings, and the reference lists of retrieved articles for RCTs and quasi-RCTs.
We included randomized controlled trials (RCTs) conducted in preterm and term infants of a postmenstrual age up to 46 weeks and 0 days with postoperative pain where systemic opioids were compared to 1) placebo or no intervention; 2) non-pharmacological interventions; 3) different types of opioids; or 4) other drugs.
We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods, all-cause mortality during initial hospitalization, major neurodevelopmental disability, and cognitive and educational outcomes in children more than five years old. We used the fixed-effect model with risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) for continuous data. We used GRADE to assess the certainty of evidence for each outcome.
We included four RCTs enrolling 331 infants in four countries across different continents. Most studies considered patients undergoing large or medium surgical procedures (including major thoracic or abdominal surgery), who potentially required pain control through opioid administration after surgery. The randomized trials did not consider patients undergoing minor surgery (including inguinal hernia repair) and those individuals exposed to opioids before the beginning of the trial. Two RCTs compared opioids with placebo; one fentanyl with tramadol; and one morphine with paracetamol. No meta-analyses could be performed because the included RCTs reported no more than three outcomes within the prespecified comparisons. Certainty of the evidence was very low for all outcomes due to imprecision of the estimates (downgrade by two levels) and study limitations (downgrade by one level).
Comparison 1: opioids versus no treatment or placebo
Two trials were included in this comparison, comparing either tramadol or tapentadol with placebo. No data were reported on the following critical outcomes: pain; major neurodevelopmental disability; or cognitive and educational outcomes in children more than five years old. The evidence is very uncertain about the effect of tramadol compared with placebo on all-cause mortality during initial hospitalization (RR 0.32, 95% Confidence Interval (CI) 0.01 to 7.70; RD -0.03, 95% CI -0.10 to 0.05, 71 participants, 1 study; I² = not applicable). No data were reported on: retinopathy of prematurity; or intraventricular hemorrhage.
Comparison 2: opioids versus non-pharmacological interventions
No trials were included in this comparison.
Comparison 3: head-to-head comparisons of different opioids
One trial comparing fentanyl with tramadol was included in this comparison. No data were reported on the following critical outcomes: pain; major neurodevelopmental disability; or cognitive and educational outcomes in children more than five years old. The evidence is very uncertain about the effect of fentanyl compared with tramadol on all-cause mortality during initial hospitalization (RR 0.99, 95% CI 0.59 to 1.64; RD 0.00, 95% CI -0.13 to 0.13, 171 participants, 1 study; I² = not applicable). No data were reported on: retinopathy of prematurity; or intraventricular hemorrhage.
Comparison 4: opioids versus other analgesics and sedatives
One trial comparing morphine with paracetamol was included in this comparison. The evidence is very uncertain about the effect of morphine compared with paracetamol on COMFORT pain scores (MD 0.10, 95% CI -0.85 to 1.05; 71 participants, 1 study; I² = not applicable). No data were reported on the other critical outcomes, i.e. major neurodevelopmental disability; cognitive and educational outcomes in children more than five years old, all-cause mortality during initial hospitalization; retinopathy of prematurity; or intraventricular hemorrhage.