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Review
. 2023 Apr 5;4(4):CD015056.
doi: 10.1002/14651858.CD015056.pub2.

Opioids for procedural pain in neonates

Mari Kinoshita  1 , Emma Olsson  2 , Franciszek Borys  3 , Matteo Bruschettini  4   5
Affiliations
Review

Opioids for procedural pain in neonates

Mari Kinoshita et al. Cochrane Database Syst Rev. .

Update in

  • Opioids for procedural pain in neonates.
    Kinoshita M, Olsson E, Borys F, Bruschettini M. Kinoshita M, et al. Cochrane Database Syst Rev. 2023 Jun 23;6(6):CD015056. doi: 10.1002/14651858.CD015056.pub3. Cochrane Database Syst Rev. 2023. PMID: 37350685 Free PMC article. Review.

Abstract

Background: Neonates might be exposed to numerous painful procedures due to diagnostic reasons, therapeutic interventions, or surgical procedures. Options for pain management 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.

Objectives: To evaluate the benefits and harms of opioids in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non-pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route.

Search methods: We used standard, extensive Cochrane search methods. The latest search date was December 2021.

Selection criteria: We included randomized controlled trials conducted in preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days exposed to procedural pain where opioids were compared to 1) placebo or no drug; 2) non-pharmacological intervention; 3) other analgesics or sedatives; 4) other opioids; or 5) the same opioid administered by a different route.

Data collection and analysis: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods and any harms. We used a fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and their confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome.

Main results: We included 13 independent studies (enrolling 823 newborn infants): seven studies compared opioids to no treatment or placebo (the main comparison in this review), two studies to oral sweet solution or non-pharmacological intervention, and five studies (of which two were part of the same study) to other analgesics and sedatives. All studies were performed in a hospital setting. Opioids compared to placebo or no drug Compared to placebo, opioids probably reduce pain score assessed with the Premature Infant Pain Profile (PIPP)/PIPP-Revised (PIPP-R) scale during the procedure (MD -2.58, 95% CI -3.12 to -2.03; 199 participants, 3 studies; moderate-certainty evidence); may reduce Neonatal Infant Pain Scale (NIPS) during the procedure (MD -1.97, 95% CI -2.46 to -1.48; 102 participants, 2 studies; low-certainty evidence); and may result in little to no difference in pain score assessed with the Douleur Aiguë du Nouveau-né (DAN) scale one to two hours after the procedure (MD -0.20, 95% CI -2.21 to 1.81; 42 participants, 1 study; low-certainty evidence). The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R scale up to 30 minutes after the procedure (MD 0.14, 95% CI -0.17 to 0.45; 123 participants, 2 studies; very low-certainty evidence) or one to two hours after the procedure (MD -0.83, 95% CI -2.42 to 0.75; 54 participants, 2 studies; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of bradycardia (RR 3.19, 95% CI 0.14 to 72.69; 172 participants, 3 studies; very low-certainty evidence). Opioids may result in an increase in episodes of apnea compared to placebo (RR 3.15, 95% CI 1.08 to 9.16; 199 participants, 3 studies; low-certainty evidence). The evidence is very uncertain about the effect of opioids on episodes of hypotension (RR not estimable, risk difference 0.00, 95% CI -0.06 to 0.06; 88 participants, 2 studies; very low-certainty evidence). No studies reported parent satisfaction with care provided in the neonatal intensive care unit (NICU). Opioids compared to non-pharmacological intervention The evidence is very uncertain about the effect of opioids on pain score assessed with the Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) scale during the procedure when compared to facilitated tucking (MD -4.62, 95% CI -6.38 to -2.86; 100 participants, 1 study; very low-certainty evidence) or sensorial stimulation (MD 0.32, 95% CI -1.13 to 1.77; 100 participants, 1 study; very low-certainty evidence). The other main outcomes were not reported. Opioids compared to other analgesics or sedatives The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R during the procedure (MD -0.29, 95% CI -1.58 to 1.01; 124 participants, 2 studies; very low-certainty evidence); up to 30 minutes after the procedure (MD -1.10, 95% CI -2.82 to 0.62; 12 participants, 1 study; very low-certainty evidence); and one to two hours after the procedure (MD -0.17, 95% CI -2.22 to 1.88; 12 participants, 1 study; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of apnea during (RR 3.27, 95% CI 0.85 to 12.58; 124 participants, 2 studies; very low-certainty evidence) and after the procedure (RR 2.71, 95% CI 0.11 to 64.96; 124 participants, 2 studies; very low-certainty evidence) and on hypotension (RR 1.34, 95% CI 0.32 to 5.59; 204 participants, 3 studies; very low-certainty evidence). The other main outcomes were not reported. We identified no studies comparing different opioids (e.g. morphine versus fentanyl) or different routes for administration of the same opioid (e.g. morphine enterally versus morphine intravenously).

Authors' conclusions: Compared to placebo, opioids probably reduce pain score assessed with PIPP/PIPP-R scale during the procedure; may reduce NIPS during the procedure; and may result in little to no difference in DAN one to two hours after the procedure. The evidence is very uncertain about the effect of opioids on pain assessed with other pain scores or at different time points. No studies reported if any harms occurred. The evidence is very uncertain about the effect of opioids on episodes of bradycardia or hypotension. Opioids may result in an increase in episodes of apnea. No studies reported parent satisfaction with care provided in the NICU. The evidence is very uncertain about the effect of opioids on any outcome when compared to non-pharmacological interventions or to other analgesics. We identified no studies comparing opioids to other opioids or comparing different routes of administration of the same opioid.

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Conflict of interest statement

MK works as a physician in the Department of Pediatrics, Yokohama Municipal Citizens' Hospital.

EO works clinically (part‐time) as a registered nurse at Örebro University Hospital, and therefore cares for newborns exposed to procedural pain.

FB has started a neonatology residency in II Department of Neonatology in GPSK clinical hospital, Poznan University of Medical Sciences, Poznan, Poland.

MB is an Associate Editor for the Cochrane Neonatal Group. However, his participation in the editorial group has not impacted this review.

Figures

1
1
Screen4Me summary diagram.
2
2
Study flow diagram.
3
3
Risk of bias graph.
4
4
Risk of bias summary.
5
5
Funnel plot for PIPP/PIPP‐R during procedure, opioids versus placebo.
1.1
1.1. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 1: PIPP/PIPP‐R during procedure
1.2
1.2. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 2: PIPP/PIPP‐R up to 30 min after procedure
1.3
1.3. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 3: PIPP/PIPP‐R 1 to 2 hours after procedure
1.4
1.4. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 4: DAN 1 to 2 hours after procedure
1.5
1.5. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 5: NIPS during procedure
1.6
1.6. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 6: Mortality
1.7
1.7. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 7: Episodes of bradycardia
1.8
1.8. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 8: Episodes of desaturation
1.9
1.9. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 9: Episodes of apnea
1.10
1.10. Analysis
Comparison 1: Opioids versus no treatment/placebo, Outcome 10: Hypotension
2.1
2.1. Analysis
Comparison 2: Opioids versus oral sweet solution or non‐pharmacological intervention, Outcome 1: CRIES
3.1
3.1. Analysis
Comparison 3: Opioids versus other analgesics, Outcome 1: PIPP/PIPP‐R during procedure
3.2
3.2. Analysis
Comparison 3: Opioids versus other analgesics, Outcome 2: PIPP/PIPP‐R up to 30 min after procedure
3.3
3.3. Analysis
Comparison 3: Opioids versus other analgesics, Outcome 3: PIPP/PIPP‐R 1 to 2 hours after procedure
3.4
3.4. Analysis
Comparison 3: Opioids versus other analgesics, Outcome 4: Episodes of apnea
3.5
3.5. Analysis
Comparison 3: Opioids versus other analgesics, Outcome 5: Hypotension
See this image and copyright information in PMC

References

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References to studies awaiting assessment

ACTRN12612000385842 {published data only}
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References to ongoing studies

CTRI/2017/12/011035 {published data only}
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References to other published versions of this review

Kinoshita 2021
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