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Paracetamol (acetaminophen) for prevention or treatment of pain in newborns.

BACKGROUND
Newborn infants have the ability to experience pain. Newborns treated in neonatal intensive care units are exposed to numerous painful procedures. Healthy newborns are exposed to pain if the birth process consists of assisted vaginal birth by vacuum extraction or by forceps and during blood sampling for newborn screening tests.


OBJECTIVES
Primary objectiveTo determine the efficacy and safety of paracetamol for the prevention or treatment of procedural/postoperative pain or pain associated with clinical conditions in neonates. Secondary objectiveTo review the effects of various doses and routes of administration (enteral, intravenous or rectal) of paracetamol for the prevention or treatment of pain in neonates. We designed the main comparisons according to intention of use, that is, paracetamol for prevention or treatment of pain. We included separate comparisons based on the painful intervention/procedure/condition (heel lance, insertion of nasogastric tube, insertion of intravenous catheter, lumbar puncture, assisted vaginal birth, postoperative pain, birth trauma, congenital anomalies such as myelomeningocoele and open cutaneous lesions) and the mode of administration of paracetamol. Within these comparisons, we planned to assess in subgroups (when possible) effects based on postmenstrual age (PMA) at the birth of randomly assigned infants (< 28 weeks, 28 weeks to 31 + 6 weeks, 32 weeks to 36 + 6 weeks and ≥ 37 weeks) or based on birth weight (or current weight) categories (≤ 1000 grams, 1001 to 1500 grams, 1501 to 2500 grams and ≥ 2501 grams)


SEARCH METHODS
We used the standard search strategy of the Cochrane Neonatal Review Group including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (October 2014), MEDLINE (1966 to October 2014), EMBASE (1980 to October 2014) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to October 2014). We applied no language restrictions.We conducted electronic searches of abstracts from meetings of the Pediatric Academic Societies (2000 to 2014) and the Perinatal Society of Australia and New Zealand (2010 to 2014).We searched clinical trial registries for ongoing trials and the Web of Science for articles quoting identified randomised controlled trials. We searched the first 200 hits on Google Scholar(TM) to identify grey literature.


SELECTION CRITERIA
We included randomised and quasi-randomised controlled trials of paracetamol for the prevention or treatment of pain in neonates (≤ 30 days of age).


DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data from the full-text articles using a specifically designed form. We used this form to decide trial inclusion/exclusion, to extract data from eligible trials and to request additional published information from authors of the original reports. We entered and cross-checked data using RevMan 5.3.3 software. When noted, we resolved differences by mutual discussion and consensus.


MAIN RESULTS
We included eight trials with low risk of bias, which assessed paracetamol use for the treatment of pain in 614 infants. Painful interventions studied included heel lance, assisted vaginal birth, eye examination for ascertainment of retinopathy of prematurity (ROP) and postoperative care following major surgery. Results of individual studies could not be combined in meta-analyses as the painful conditions, the use of paracetamol and comparison interventions and the outcome measures differed. Paracetamol compared with water, cherry elixir or EMLA cream did not significantly reduce pain following heel lance. The Premature Infant Pain Profile score (PIPP) within three minutes following lancing was higher in the paracetamol group than in the oral glucose group (mean difference (MD) 2.21, 95% confidence interval (CI) 0.72 to 3.70; one study, 38 infants). Paracetamol did not reduce "modified facies scores" after assisted vaginal birth (one study, 119 infants). In another study (n = 123), the Échelle de Douleur et d'Inconfort du Nouveau-Né score at two hours of age was significantly higher in the group that received paracetamol suppositories than in the placebo suppositories group (MD 1.00, 95% CI 0.60 to 1.40). In that study, when infants were subjected to a heel lance at two to three days of age, Bernese Pain Scale for Neonates scores were higher in the paracetamol group than in the placebo group, and infants spent a longer time crying (MD 19 seconds, 95% CI 14 to 24). For eye examinations, no significant reduction in PIPP scores in the first or last 45 seconds of eye examination was reported, nor at five minutes after the eye examination. In one study (n = 81), the PIPP score was significantly higher in the paracetamol group than in the 24% sucrose group (MD 3.90, 95% CI 2.92 to 4.88). For postoperative care following major thoracic or abdominal surgery, the total amount of morphine (µg/kg) administered over 48 hours was significantly less among infants randomly assigned to the paracetamol group than in those randomly assigned to the morphine group (MD -157 µg/kg, 95% CI -27 to -288). No adverse events were noted in any study.


AUTHORS' CONCLUSIONS
Paracetamol does not significantly reduce pain associated with heel lance or eye examinations. Paracetamol given after assisted vaginal birth may increase the response to later painful exposures. Paracetamol should not be used for painful procedures given its lack of efficacy and its potential for adverse effects. Paracetamol may reduce the total need for morphine following major surgery, and for this aspect of paracetamol use, further research is needed.