Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: A randomized trial

doi:10.1016/S0022-3476(99)70407-5

The Journal of Pediatrics

Volume 134, Issue 2, February 1999, Pages 144-150

https://doi.org/10.1016/S0022-3476(99)70407-5 Get rights and content

Abstract

Objective: To compare the efficacy and adverse effects of fentanyl or morphine analgesia during the first 2 days of life in newborn infants who underwent mechanical ventilation. Study design: In a randomized double-blind trial, 163 infants were allocated to receive a continuous infusion of fentanyl (10.5 μg/kg over a 1-hour period followed by 1.5 μg/kg/hr) or morphine (140 μg/kg over a 1-hour period followed by 20 μg/kg/hr) for at least 24 hours. The severity of pain was assessed with physiological parameters, a behavioral pain scale, and stress hormone concentrations before and 2 and 24 hours after the start of treatment. Results: The analgesic effect was similar in both groups, as judged by the pain scale. Plasma adrenaline and noradrenaline concentrations decreased significantly from 0 to 24 hours in both groups. Median adrenaline decrease was –0.5 nmol/L (interquartile range [IQR] –1.1;0.0) in the fentanyl and –0.7 nmol/L (IQR –1.3;0.1) in the morphine group, noradrenaline –2.1 nmol/L (IQR –9.0;0.2), and –3.0 nmol/L (IQR –7.5;0.3), respectively. β-endorphin decreased significantly only in the fentanyl group (–14 pmol/L (IQR –28;–7), P < .05). Decreased gastrointestinal motility was less frequent in the fentanyl group (23% vs 47%, P < .01). Conclusions: With at least as effective analgesia as with morphine, fentanyl had fewer side effects. Fentanyl may be superior to morphine for short-term postnatal analgesia in newborn infants. (J Pediatr 1999;134:144-50)

Section snippets

METHODS

The study was performed between January 1994 and March 1996 in the Neonatal Intensive Care Unit of the Hospital for Children and Adolescents, University of Helsinki. The study was approved by the ethical committee of the hospital, and written parental informed consent was obtained.

RESULTS

In total, 163 babies were enrolled, of whom 83 were randomized to the fentanyl and 80 to the morphine group. Two babies in the fentanyl group did not receive the infusion. Their data are included in an intention to treat analysis. Fentanyl and morphine groups were similar at enrollment (Table I).

. Clinical characteristics and physiologic variables before trial infusion (baseline)

Variable	Fentanyl (n = 83)		Morphine (n = 80)
Variable	n	%	n	%
Antenatal steroids	23	40	26	42
Cesarean section	52	63	47	59
Male	50	60	54	67

Empty Cell	Median	IQR	Empty Cell

DISCUSSION

We designed the study to be performed in only 1 neonatal intensive care unit to achieve strict adherence to the protocol and to standardize evaluation of pain and adverse effects. With this design enrollment of a large sample size for evaluating subtle differences between the treatment groups was not possible. Inclusion of a third trial arm, a placebo group, was not ethically acceptable because of frequent need of analgesia in these patients. Administration of fentanyl resulted in a significant

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This systematic review and meta-analysis aimed to investigate the association of neonatal exposure to pain, stress, opiate administration alone, as well as opiate administration prior to a painful procedure on neuronal cell death, motor, and behavioral outcomes in rodents. In total, 36 studies investigating the effect of pain (n = 18), stress (n = 15), opiate administration (n = 13), as well as opiate administration prior to a painful event (n = 7) in rodents were included in our meta-analysis. The results showed a large effect of pain (g = 1.37, 95% CI 1.00–1.74, p < .001) on neuronal cell death. Moreover, higher number of neonatal pain events were significantly associated with increased neuronal cell death, increased anxiety (b = −1.18, SE = 0.43, p = .006), and depressant-like behavior (b = 1.74, SE = 0.51, p = .027) in rodents. Both opiates and pain had no impact on motor function (g = 0.26, 95% CI 0.18–0.70, p = .248).
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Newborns are highly susceptible to pain stimuli, which may cause anomalies in respiration, heart rate and blood pressure.24 Fentanyl is generally the preferred opiate agent in this patient population, primarily because it has less gastrointestinal effects due to histamine release, compared to morphine.25 In our results, fentanyl prescription increased the risk of major DDI during the NICU stay.
To characterize the prevalence and profile of drug–drug interactions (DDIs), the drugs most related to major DDIs and risk factors of their prescription in a neonatal intensive care unit (NICU).
Neonates admitted to a NICU who had at least one medication prescribed and a hospital stay >24 h were included in a prospective cohort study (August 2017 to July 2018). All medications prescribed during the hospitalization were collected from all neonates (n = 220), with the screening for DDIs. Prevalence and type of DDIs was identified. Network analysis was used to identify the drugs more implicated with DDIs. Logistic regression was used for the analysis of risk factors (p < 0.05).
Over 70% of neonates were exposed to DDIs and 29% were exposed to major DDIs. The network analysis identified furosemide, fentanyl, aminophylline and fluconazole as most implicated with DDI, fentanyl was especially associated with major DDIs. The number of drugs (OR 1.60, p < 0.01), caesarean delivery (OR 2.68, p < 0.05), gestational age (OR 1.03, p < 0.01) and APGAR score (OR 0.78, p < 0.01) were identified as risk factors for exposure to DDI.
Neonates in intensive care have a high exposure to DDIs and the occurrence of major DDIs is related specifically to the prescription of fentanyl. The number of prescribed drugs, gestational age, cesarean delivery and low APGAR score in the first minute were identified as risk factors for DDIs in NICU.
Evaluations of Morphine and Fentanyl for Mechanically Ventilated Patients With Respiratory Disorders in Intensive Care: A Systematic Review of Methodological Trends and Reporting Quality
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Mechanically ventilated patients with respiratory disorders may require sedatives, such as opioids.
To define methodological trends, gaps, and the reporting quality of the comparative clinical and economic evaluations of fentanyl and morphine in ventilated patients in the intensive care unit.
We conducted a literature review of the MEDLINE, Embase, OVID, ScienceDirect, Springer Link, and EconLit databases, comparing studies in the management of ventilated patients with respiratory disorders in the intensive care unit using either fentanyl or morphine, or both. We assessed the methodological aspects of the literature characteristics and trends of, for example, modeling, data sources, cost calculation, and data analysis, appraising the quality of reporting via the CONsolidated Standards Of Reporting Trials, STrengthening the Reporting of OBservational studies in Epidemiology, and the Consolidated Health Economic Evaluation Reporting Standards checklists.
Among 1327 articles, 33 (comprising 22 in adults, 8 in neonates, and 3 in pediatrics) met the inclusion criteria. No head-to-head morphine versus fentanyl evaluations explicitly confined to subjects with respiratory conditions were undertaken. Studies relied on various scales to measure the sedation level as a primary study outcome, limiting the comparability of study conclusions. Seven articles of adults were identified to be economic studies from the hospital perspective. On the basis of different endpoints, the same sedation regimen performed differently in various studies. None of the randomized controlled trials, observational cohorts, or pharmacoeconomics studies met most of the assessed reporting quality criteria.
Our review identified poor reporting quality and high heterogeneity of methods used, potentially limiting the degree to which studies could be interpreted, decisions could be influenced, and findings could be generalized.
Clinical and Economic Analysis of Morphine Versus Fentanyl in Managing Ventilated Neonates With Respiratory Distress Syndrome in the Intensive Care Setting
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As discussed in Patients and Methods, neonates with mild pain did receive pharmacologic intervention to avoid anticipated pain and associated agitation due to MV. The only study that directly compared morphine and fentanyl as monotherapies was a 1999 randomized controlled trial (RCT) conducted by Saarenmaa et al,18 which reported no significant differences between the drugs except in the β-endorphin level in favor of fentanyl. RCTs may not be generalizable to local practices; moreover, morphine and fentanyl were evaluated in neonates with different overlapping disorders, including RDS, infection, and persistent pulmonary hypertension.
Morphine and fentanyl opioids are common analgesic agents for consideration in the neonatal intensive care unit (NICU) for neonates with respiratory distress syndrome (RDS) and undergoing mechanical ventilation (MV). The aim of this study was to evaluate the clinical and economic impact of morphine versus fentanyl in neonates with RDS undergoing MV.
Retrospective cost-effectiveness analysis of critically ill neonates with RDS receiving standard doses of morphine versus fentanyl at Women's Wellness and Research Center, Qatar. Clinical data of neonates were extracted from medical records of patients from 2014 to 2016. A decision analytic model based on the hospital's perspective was constructed to follow possible consequences of the initial dosing of analgesia, before potential titration. Primary end points were successful pain relief rate based on the Premature Infant Pain Profile scale and overall direct medical cost of therapy. Study population of 126 neonates was used to achieve results with 80% power and 0.05 significance. Sensitivity analysis was conducted to enhance robustness of conclusions against input uncertainties and to increase generalizability of results.
Morphine achieved a success of 68% versus 43% with fentanyl (risk ratio = 1.72; 95% CI, 1.16–2.56; P = 0.0075). Morphine was associated with a minimal incremental cost-effectiveness ratio of USD 135 per additional case of successful pain relief over fentanyl. Higher morphine cost was reported in 2% of cases. Sensitivity analysis found model insensitivity to input uncertainties except NICU stay and cost of MV.
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^☆☆: Submitted for publication Sept 21, 1998.

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Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: A randomized trial☆,☆☆,★

Abstract

Section snippets

METHODS

RESULTS

DISCUSSION

Lancet

J Pediatr

Lancet

J Pediatr

J Pediatr

J Cardiothorac Anesth

J Pediatr

J Pediatr

J Chromatogr

J Pediatr

Early Hum Dev

Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response

Lancet

A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care units

Clin J Pain

Clinical pharmacokinetics of sedatives in neonates

Clin Pharmacokinet

Morphine pharmacokinetics in early infancy

Anesthesiology

Pharmacokinetic-pharmacodynamic relationships of morphine in neonates

Clin Pharmacol Ther