Paracetamol and morphine for infant and neonatal pain; still a long way to go?

Figures & data

Figure 1. Depiction of pain multimodality according to Loeser. Adapted with permission from: Loeser JD. Pain and suffering. Clin J Pain 2000; 16(2 Suppl): p. S2-6.

Table 1. Validated pain assessment tools according to age and their indication.

Pain assessment tool	Indication	Age category	Type of tool
Premature Infant Pain Profile (PIPP) [14–16]	Procedural and postoperative pain	Premature infants >24 weeks GA	Behavioral, contextual, physiological parameters
Revised Premature Infant Pain Profile (PIPP-Revised) [17,18]	Procedural pain	Premature infants >28 weeks GA	Behavioral and physiological parameters
Neonatal Pain, Agitation and Sedation Scale(N-PASS) [19]	Procedural and prolonged pain Sedation level	Premature infants >23 weeks GA	Behavioral and physiological parameters
COMFORTneo scale [20]	Prolonged pain Sedation level	Premature infants >24 weeks	Behavioral parameters
COMFORT scale [21,22]	Postoperative pain Sedation level	Children 0–18 years	Behavioral and physiological parameters
COMFORT behavior scale [23]	Postoperative pain Sedation level	Children 0–3 years Children 0–18 years	Behavioral parameters
Faces, Legs, Arms, Cry, Consolability (FLACC) scale [24,25]	Postoperative pain	Children 2 months–7 years	Behavioral parameters
Multidimensional Assessment of Pain Scale (MAPS) [26]	Postoperative pain	Infants 0–31 months	Behavioral and physiological parameters

GA: gestational age.

Table 2. Potential pharmacodynamic markers in neonates and infants.

Potential outcome measures	Advantages	Limitations
NIRS [27,28]	Noninvasive, continuously monitoring	Measures only cortical response
aEEG [29]	Continuous monitoring	Not validated for pain in children <2 years
Skin conductance [30–33]	Noninvasive, continuously monitoring	Sympathetic activity may be caused by anxiety and/or distress as well
SSEP [34,35]	Noninvasive, continuously monitoring (when repetitive stimuli are being given)	Only reflects sensory response, not validated in infants
Pupillary reflex dilatation [36,37]	Promising bedside application in older children	Sympathetic activity may be caused by anxiety and/or distress, practical difficulties in infants
HRV (including ANI) [38–50]	Noninvasive, continuously monitoring	Sympathetic activity may be caused by anxiety and/or distress
fMRI [51,52]	Good overlap between findings in infants and adults, insight in pain beyond the sensory cortex	Not suitable for clinical application
Salivary cortisol levels	Noninvasive collection of sample	Delay in laboratory results
Plasma cortisol levels [53–55]	Suitable for both short- and long-term pain	Delay in laboratory results, sampling restricted in neonates
Plasma adrenalin levels [53,56]		Delay in laboratory results, sampling restricted in neonates, less sensitive than noradrenalin
Plasma noradrenalin levels [53,56]	Significantly reduced by analgesics	Delay in laboratory results, sampling restricted in neonates

aEEG: amplitude-integrated electroencephalography; ANI: Analgesia Nociception Index; fMRI: functional magnetic resonance imaging; HRV: heart rate variability; NIRS: near-infrared spectroscopy; SSEP: somatosensory evoked potentials.

Figure 2. Schematic diagram of clinical research wi th morphine and paracetamol (white boxes) in practice. Black boxes represent new drugs to be studied. Dose finding and population PK/PD modelling with both ion into clinical practice will be possible. RCT: randomized controlled trial; pop PK/PD: population pharmacokinetics/pharmacodynamics; PCM: paracetamol.

Table 3a. Randomized controlled trials with morphine in the young pediatric population.

Authors	Year	Sample size	RCT study design	Outcome	Major limitation(s)
Barker et al. [75]	1995	27	Low vs. high loading dose diamorphine	Adequate analgesia in both groups, high loading dose produced greater respiratory depression	Pain was not the primary end point and assessed by hormonal stress response
Wood et al. [76]	1998	88	Morphine vs. diamorphine in ventilated preterm neonates	Reduced stress response in both groups, more hypotension in morphine group	High morphine dose: 200 mcg/kg in 2 h and 25 mcg/kg.hr in preterm neonates Pain assessed by hormonal stress response, no placebo control group
Anand et al. [77]	1999	67	Morphine vs. midazolam vs. placebo in ventilated preterm neonates (NOPAIN pilot trial)	Morphine and midazolam reduced PIPP scores, only morphine improved neurological outcome	High midazolam loading dose and high morphine maintenance doses
Lynn et al. [78]	2000	83	Morphine continuous targeting predefined plasma level vs. intermittent bolus in infants postsurgery	Continuous morphine provided better analgesia, morphine dosing was higher	Power calculation performed on ventilatory end point
Van Dijk et al. [72]	2002	181	Morphine continuous vs. intermittent postsurgery aged 0–3 year	No difference in pain scores or morphine consumption	No power calculation performed
Simons et al. [74]	2003	150	Morphine continuous vs. placebo in ventilated preterm neonates	No beneficial effect on pain, less IVH in morphine group, comparable composite outcome	Rescue morphine not based on pain assessments
Anand et al. [79]	2004	898	Morphine continuous vs. placebo in ventilated preterm neonates (NEOPAIN trial)	No beneficial effect on neurological outcome measures	High morphine dose, no baseline for primary composite outcome
Carbajal et al. [80]	2005	42	Morphine boluses vs. placebo for procedural pain	No adequate analgesia in morphine group	Continuous morphine used for procedure
Taddio et al. [81]	2006	132	Morphine vs. placebo vs. tetracaine for central catheter insertion in premature neonates	Beneficial effect of both morphine and tetracaine	Morphine infusion allowed during intervention

PIPP: Preterm Infant Pain Profile.

Table 3b. Randomized controlled trials with paracetamol in the young pediatric population.

Authors	Year	Sample size	RCT study design	Outcome	Major limitation(s)
Howard et al. [82]	1994	44	Paracetamol vs. placebo in neonates undergoing circumcision	Minimal effect of paracetamol	Sweet solutions (both PCM and placebo) may have biased the results Crying time as pain end point
Shah et al. [83]	1998	75	Paracetamol vs. placebo 90 min before heel lance	No effect of paracetamol	No validated pain assessment tool
Van der Marel et al. [73]	2007	54	Morphine vs. rectal paracetamol in postsurgery infants	No effect of paracetamol	High continuous morphine doses could have masked a clean paracetamol effect
Van Lingen et al. [84]	2001	122	Rectal paracetamol vs. placebo after vacuum extraction	No analgesic effect of paracetamol	No validated pain assessment tool, rectal administration unreliable in neonates
Bonetto et al.	2008	76	Oral glucose vs. oral paracetamol vs. topical EMLA vs. placebo	No effect of paracetamol	No comment on interobserver variability of pain assessment tools
Badiee et al. [85]	2009	72	Oral paracetamol vs. placebo 90 min before heel lance	No effect of paracetamol	Time of administration could possibly be too early: no clear PK data on start of study
Manjunatha et al [86]	2009	18	Oral paracetamol vs. oral morphine vs. placebo 60 min before ROP screening	No significant effect of morphine or paracetamol	Underpowered (calculated sample size was n = 63)
Tinner et al [87]	2013	123	Rectal paracetamol vs. placebo after forceps or vacuum extraction delivery	No effect of paracetamol	Only 2 doses of paracetamol: no steady state
Seifi et al [88]	2013	120	Oral acetaminophen vs. oral sucrose vs. placebo	No effect of paracetamol	Paracetamol administered 30 min before ROP screening
Ceelie et al [3]	2013	71	Morphine vs. IV paracetamol in postsurgery infants	Significant reduction of morphine consumption	Single-center study

IV: intravenous; ROP: retinopathy of prematurity.

Figure 3. (a, d) Morphine concentrations, (b, e) morphine-3-glucuronide (M3G) concentrations, and (c,f) morphine-6-glucuronide (M6G) concentrations predicted in model-based simulations in children weighing 0.5, 1, 2, 2.5 and 4 kg and a postnatal age of <10 days (dotted lines) and children weighing 0.5, 1, 2, 2.5,4, 10 and 17 kg and a postnatal age of >10 days (solid lines) based on (a–c) a dosing regimen with a loading dose of 100 mg/kg and maintenance dose of 10 mg/kg/h and (d–f) a regimen with a loading dose of 100 mg/kg followed by an infusion of 10 mg/kg1.5/h with a 50% reduction in the maintenance dose for children with a postnatal age <10 days. Reprinted with permission from: Knibbe, C.A, et al., Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin Pharmacokinet, 2009. 48(6): p. 371–85.

Figure 4. Metabolic pathways of paracetamol. Reprinted with permission from: Roofthooft, D.M.E., Paracetamol and Preterm Infants: a painless liaison? PhD thesis, 2015, Erasmus University.

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