Opioids for managing pain in babies exposed to painful procedures

Key messages

• Due to a lack of strong evidence, the benefits and risks of opioids for managing pain in babies exposed to painful procedures are unclear.

• Compared to placebo (a 'dummy' treatment, or sham treatment, that does not contain any medicine but looks identical to the medicine being tested), opioids may reduce pain assessed with certain scales during the procedure, but may not make a difference with other scales 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, episodes of bradycardia (slow heart rate), or hypotension (low blood pressure). Opioids may increase episodes of breathing stops.

Why are opioids given to manage pain during procedures in babies?

Babies (particularly in the first four weeks after birth) are frequently exposed to painful procedures during hospitalization. Similar to adults, they require uninterrupted pain management and control during these procedures. Opioids, a broad group of pain-relieving medications that work by interacting with opioid receptors in the body's cells, are commonly used in babies.

What did we want to find out?

We wanted to find out the effect of opioids in babies exposed to painful procedures, compared to:

• no treatment or placebo;

• non-drug treatments (such as sweet solutions);

• other drugs;

• different types of opioids;

• or same opioid administered by a different route, for example by mouth compared to by injection.

What did we do?

We searched for studies looking at the five comparisons described above. We compared and summarized study results and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We included 13 studies involving a total of 823 babies. The largest study was in 150 babies, and the smallest in 12 babies. All studies were performed in a hospital. Four studies were conducted in India, two each in Italy and the UK, one each in Canada, Finland, Iran, and the USA, and one was an international study conducted in France and the USA.

Seven studies compared opioids to placebo; two studies compared opioids to oral sweet solution or other treatments such as touching the baby's body; and five studies compared opioids to another drug.

Compared to placebo, opioids probably result in a reduction in pain score assessed with certain scales during the procedure, but in little or no difference between groups with other scales 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.  The evidence is very uncertain about the effect of opioids on episodes of bradycardia, hypotension or breathing stops requiring resuscitation. Opioids may increase episodes of breathing stops. No studies reported parent satisfaction with medical care.

The evidence is very uncertain about the effect of opioids on any outcome when compared to other treatments, such as touching the baby's body or giving other drugs.

What are the limitations of the evidence?

We are not confident in the evidence because there are not enough studies to be certain about the results of our outcomes. Moreover, it is possible that people in the studies were aware of what treatment they were giving to the babies. Few studies provided data about everything that we were interested in.

How up-to-date is this review?

We searched for studies up to December 2021.

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. The evidence is very uncertain about the effect of opioids on episodes of bradycardia, hypotension or severe apnea. 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.

Read the full 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 strategy: 

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). 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): with one study reporting a concerning increase in severe apnea (RR 7.44, 95% CI 0.42 to 132.95; 31 participants, 1 study; very low-certainty). 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).