Elsevier

The Lancet

Volume 363, Issue 9422, 22 May 2004, Pages 1673-1682
The Lancet

Articles
Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial

https://doi.org/10.1016/S0140-6736(04)16251-XGet rights and content

Summary

Background

Opioid analgesia is commonly used during neonatal intensive care. We undertook the Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial to investigate whether pre-emptive morphine analgesia decreases the rate of a composite primary outcome of neonatal death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL) in preterm neonates.

Methods

Ventilated preterm neonates (n=898) from 16 centres were randomly assigned masked placebo (n=449) or morphine (n=449) infusions. After a loading dose (100 μg/kg), morphine infusions (23–26 weeks of gestation 10 μg kg−1 h−1; 27–29 weeks 20 μg kg−1 h−1; 30–32 weeks 30 μg kg−1 h−1) were continued as long as clinically justified (maximum 14 days). Open-label morphine could be given on clinical judgment (placebo group 242/443 [54.6%], morphine group 202/446 [45·3%]). Analyses were by intention to treat.

Findings

Baseline variables were similar in the randomised groups. The placebo and morphine groups had similar rates of the composite outcome (105/408 [26%] vs 115/419 [27%]), neonatal death (47/449 [11%] vs 58/449 [13%]), severe IVH (46/429 [11%] vs 55/411 [13%]), and PVL (34/367 [9%] vs 27/367 [7%]). For neonates who were not given open-label morphine, rates of the composite outcome (53/225 [24%] vs 27/179 [15%], p=0·0338) and severe IVH (19/219 [9%] vs 6/189 [3%], p=0·0209) were higher in the morphine group than the placebo group. Placebo-group neonates receiving open-label morphine had worse rates of the composite outcome than those not receiving open-label morphine (78/228 [34%] vs 27/179 [15%], p<0·0001). Morphine-group neonates receiving open-label morphine were more likely to develop severe IVH (36/190 [19%] vs 19/219 [9%], p=0·0024).

Interpretation

Pre-emptive morphine infusions did not reduce the frequency of severe IVH, PVL, or death in ventilated preterm neonates, but intermittent boluses of open-label morphine were associated with an increased rate of the composite outcome. The morphine doses used in this study decrease clinical signs of pain but can cause significant adverse effects in ventilated preterm neonates.

Introduction

Guidelines published in the past few years have endorsed the use of opioid analgesia for mechanically ventilated preterm neonates,1, 2 despite the limited evidence on the best drug and dose regimens, the safety and efficacy of these regimens, and scientific assessment of the need for analgesia in preterm neonates.3 Opioid analgesia can be recommended for ventilated preterm neonates because of increased pain sensitivity resulting from immature pain modulatory mechanisms, hyperalgesia of long duration after tissue injury, acute physiological and behavioural responses to painful stimuli, and humane and ethical considerations for providing comfort.

Some studies have shown that periods of hypoxaemia and blood-pressure fluctuations are significantly reduced in ventilated preterm neonates receiving opioid analgesia.4, 5 Other trials have shown prolongation of ventilation,6 decreased behavioural and hormonal stress responses,6, 7 increased ventilator synchrony and shortened duration of oxygen therapy,8 or improved neurological outcomes7, 9 in preterm neonates. Despite these effects, randomised trials of fentanyl or morphine analgesia have shown no differences in the frequency of severe intraventricular haemorrhage (IVH) or other outcomes,6, 10, 11 perhaps because of insufficient sample size or delay in initiation of opioid therapy after birth. Moreover, sample sizes in those trials were inadequate for investigation of the safety of routine opioid therapy in preterm neonates.4, 5, 6, 7, 8, 9, 10, 11, 12 No dose-ranging studies have been done (apart from one study on diamorphine13), and the clinical effects of continuous infusions or bolus doses have not been explored in preterm neonates.

On the basis of the behavioural and biological effects of acute pain in preterm neonates and a temporal relation between the invasive procedures necessary just after birth14, 15, 16 and the early frequency of IVH and periventricular leucomalacia (PVL), we developed a physiological rationale (figure 1) linking repetitive acute pain with early neurological injury in ventilated preterm neonates. A pilot study suggested that morphine infusions decreased the frequency of early neurological injury in ventilated preterm neonates, whereas midazolam infusions had no effect.9 We report here the results of a multicentre, blinded, randomised trial (Neurologic Outcomes and Pre-emptive Analgesia in Neonates; NEOPAIN) designed as a pragmatic test of the hypothesis that pre-emptive morphine analgesia, compared with a placebo control, would significantly reduce the frequency of early neurological injury in ventilated preterm neonates. The primary outcome for this trial was defined as a composite of neonatal death, severe IVH, or PVL (panel 1).

Section snippets

Neonates

Eligible infants were born at 23–32 weeks of gestation, were intubated within 72 h of birth, and had been ventilated for less than 8 h at enrolment. After exclusion of neonates born with major congenital anomalies, birth asphyxia, intrauterine growth retardation, or maternal opioid addiction, and those participating in other clinical trials (panel 2), patients were enrolled from 12 American and four European centres.

The protocol and data collection were approved by local hospital and university

Results

Of 4254 preterm neonates screened, 2236 were eligible for enrolment (figure 2). 898 were randomised, with equal numbers assigned morphine and placebo infusions. There were no differences in clinical and demographic characteristics between the two randomised groups, except for greater use of antenatal magnesium in the placebo group (table 1).

Open-label morphine analgesia was given to fewer neonates in the morphine group than in the placebo group (202 [45·3%] vs 242 [54·6%], p=0·0054). To examine

Discussion

The decision to use opioid analgesia in ventilated preterm neonates is often based on expert opinions,1, 2 institutional protocols,30 or personal preferences among clinicians.22, 31, 32, 33 We report primary outcomes from a large, multicentre, placebo-controlled clinical trial designed to investigate the effects of morphine analgesia on the neurological outcomes of ventilated preterm neonates. The study was designed as a pragmatic clinical trial as well as a dose-ranging study for continuous

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