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CONTEXT: Abundant evidence of sweet taste analgesia in neonates exists, yet placebo-controlled trials continue to be conducted. OBJECTIVE: To review all trials evaluating sweet solutions for analgesia in neonates and to conduct cumulative meta-analyses (CMAs) on behavioral pain outcomes. DATA SOURCES: (1) Data from 2 systematic reviews of sweet solutions for newborns; (2) searches ending 2015 of CINAHL, Medline, Embase, and psychINFO. DATA EXTRACTION AND ANALYSIS: Two authors screened studies for inclusion, conducted risk-of-bias ratings, and extracted behavioral outcome data for CMAs. CMA was performed using random effects meta-analysis. RESULTS: One hundred and sixty-eight studies were included; 148 (88%) included placebo/no-treatment arms. CMA for crying time included 29 trials (1175 infants). From the fifth trial in 2002, there was a statistically significant reduction in mean cry time for sweet solutions compared with placebo (−27 seconds, 95% confidence interval [CI] −51 to −4). By the final trial, CMA was −23 seconds in favor of sweet solutions (95% CI −29 to −18). CMA for pain scores included 50 trials (3341 infants). Results were in favor of sweet solutions from the second trial (0.5, 95% CI −1 to −0.1). Final results showed a standardized mean difference of −0.9 (95% CI −1.1 to −0.7). LIMITATIONS: We were unable to use or obtain data from many studies to include in the CMA. CONCLUSIONS: Evidence of sweet taste analgesia in neonates has existed since the first published trials, yet placebo/no-treatment, controlled trials have continued to be conducted. Future neonatal pain studies need to select more ethically responsible control groups.

BACKGROUND: Procedural pain assessment and management have been extensively studied through multiple research studies over the past decade. Results of this research have been included in numerous pediatric pain practice guidelines. OBJECTIVE: To systematically review the quality of existing practice guidelines for acute procedural pain in children and provide recommendations for their use. METHODS: A systematic search was conducted on Medline, Embase, CINAHL, PsycINFO, and Scopus from 2000 to July 2013. A gray literature search was also conducted through the Translating Research Into Practice database, Guidelines International Network database, and National Guideline Clearinghouse. Four reviewers rated relevant guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument. Screening of guidelines, assessment of methodological quality, and data abstraction were conducted by 2 pairs of raters. Disagreements in overall assessments were resolved through consensus. RESULTS: Eighteen guidelines from 4930 retrieved abstracts were included in this study. Based on the AGREE II domains, the guidelines generally scored high in the scope and purpose and clarity of presentation areas. Information on the rigor of guideline development, applicability, and editorial independence were specified infrequently. Four of the 18 guidelines provided tools to help clinicians apply the recommendations in practice settings; 5 were recommended for use in clinical settings, and the remaining 13 were recommended for use with modification. CONCLUSIONS: Despite the increasing availability of clinical practice guidelines for procedural pain in children, the majority are of average quality. More transparency and comprehensive reporting are needed for the guideline development process.

Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

OBJECTIVE: The goal was to review published studies of analgesic effects of sweet solutions, to ascertain areas with sufficient evidence of effectiveness and areas of uncertainty. METHODS: Databases searched included Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature database, and PsycINFO, using the terms pain*, infant*, neonat*, newborn*, sucrose, glucose, and alternative sugars. Publications were sorted according to type, year, painful procedure studied, placebo/no-treatment groups, population studied, and country of publication. RESULTS: A total of 298 relevant unique publications involving human infants were identified; 125 (42%) were primary research studies, of which 116 (93%) were randomized controlled trials. Healthy preterm or term newborns were included in 82 studies (65%), and sick or very low birth weight infants were included in 22 (18%). Most studies included single episodes of painful procedures, with only 3 (2%) conducted over long periods. Procedures investigated most frequently were heel lance (49%), venipuncture (14%), and intramuscular injection (14%). Placebo or no-treatment groups were included in 111 studies (89%); in 103 (93%) of those studies, sweet solutions reduced behavioral responses, compared with placebo/ no treatment. CONCLUSION: Clinical equipoise relating to analgesic effects of sweet solutions no longer exists for single episodes of procedures for healthy preterm and term newborn infants. Uncertainties include outcomes after prolonged use of sweet solutions, concomitant use of other analgesics, and effectiveness beyond the newborn period. Future research should focus on addressing these knowledge and research gaps.

This statement is intended for health care professionals caring for neonates (preterm to 1 month of age). The objectives of this statement are to: 1. Increase awareness that neonates experience pain;2. Provide a physiological basis for neonatal pain and stress assessment and management by health care professionals;3. Make recommendations for reduced exposure of the neonate to noxious stimuli and to minimize associated adverse outcomes; and4. Recommend effective and safe interventions that relieve pain and stress.

Objective. To determine the effect of being in the neonatal intensive care unit (NICU) on pain responses in infants of 32 weeks' postconceptual age (PCA). Design. A cross-sectional comparative design was used. Setting. Two level III NICUs, each in metropolitan, university teaching hospitals. Patients. Infants of 32 weeks' PCA born within the past 4 days (the newly born group; n = 53) were compared with infants of the same PCA who had been born 4 weeks earlier (the earlier-born group; n = 36) and had spent that time in an NICU. Outcome Measures. Heart rate, oxygen saturation levels, and facial actions were used as outcomes in a between-group repeated measures analysis of variance across the heel stick procedure. Background variables of Apgar, weight at birth and data collection, severity of illness, age group, and total number of invasive procedures were entered into a stepwise regression. Results. The two groups responded differently to the heel stick: the earlier-born infants had less behavioral manifestations of pain than the newly born infants. The number of invasive procedures was the primary factor that explained those behavioral differences, with Apgar as a second explanatory factor. The earlier-born infants had higher heart rates and lower oxygen saturation than the newly born infants before as well as during the procedure. These physiological differences were explained by the perinatal factors of age at birth and birth weight. Conclusion. Preterm infants who spend PCA weeks 28 through 32 in an NICU are less mature in their pain response than newborn premature infants of 32 weeks' PCA. Greater frequency of invasive procedures is associated with behavioral immaturity, whereas birth factors are associated with physiological immaturity.

The use of oral sucrose has been the most extensively studied pain intervention in newborn care to date. More than 150 published studies relating to sweet-taste-induced calming and analgesia in human infants have been identified, of which 100 (65%) include sucrose. With only a few exceptions, sucrose, glucose, or other sweet solutions reduced pain responses during commonly performed painful procedures in diverse populations of infants up to 12 months of age. Sucrose has been widely recommended for routine use during painful procedures in newborn and young infants, yet these recommendations have not been translated into consistent use in clinical practice. One reason may be related to important knowledge and research gaps concerning analgesic effects of sucrose. Notably, the mechanism of sweet-taste-induced analgesia is still not precisely understood, which has implications for using research evidence in practice. The aim of this article is to review what is known about the mechanisms of sucrose-induced analgesia; highlight existing evidence, knowledge gaps, and current controversies; and provide directions for future research and practice.

OBJECTIVE: The study goal was to compare the efficacy of expressed breast milk (EBM) versus 25% glucose on pain responses of late preterm infants during heel lancing. METHODS: In a noninferiority randomized controlled trial, a total of 113 newborns were randomized to receive EBM (experimental group [EG]) or 25% glucose (control group [CG]) before undergoing heel lancing. The primary outcome was pain intensity (Premature Infant Pain Profile [PIPP]) and a 10% noninferiority margin was established. Secondary outcomes were incidence of cry and percentage of time spent crying and adverse events. Intention-to-treat (ITT) analysis was used. RESULTS: Groups were similar regarding demographics and clinical characteristics, except for birth weight and weight at data collection day. There were lower pain scores in the CG over 3 minutes after lancing (P < .001). A higher number of infants in the CG had PIPP scores indicative of minimal pain or absence of pain (P = .002 and P = .003 on ITT analysis) at 30 seconds after lancing, and the mean difference in PIPP scores was 3 (95% confidence interval: 1.507–4.483). Lower incidence of cry (P = .001) and shorter duration of crying (P = .014) were observed for CG. Adverse events were benign and self-limited, and there was no significant difference between groups (P = .736 and P = .637 on ITT analysis). CONCLUSIONS: Results based on PIPP scores and crying time indicate poorer effects of EBM compared with 25% glucose during heel lancing. Additional studies exploring the vol and administration of EBM and its combination with other strategies such as skin-to-skin contact and sucking are necessary.

Objective. Neonates routinely undergo painful cutaneous procedures as part of their medical treatment. Lidocaine-prilocaine 5% cream (EMLA) is a topical anesthetic that may be useful for diminishing the pain from these procedures. EMLA is routinely used in children and adults. There is substantial apprehension about its use in neonates because of concerns that it may cause methemoglobinemia. The objective of this review was to determine the efficacy and safety of EMLA as an analgesic for procedural pain treatment in neonates and provide evidence-based recommendations for clinical practice. Methods. Systematic review techniques were used. Studies were identified using manual and computer-aided searches (Medline, EMBASE, Reference Update, personal files, scientific meeting proceedings). Behavioral (eg, facial action, crying) and physiologic (eg, heart rate, oxygen saturation, blood pressure, respiratory rate) outcome data from prospective nonrandomized controlled studies and randomized controlled trials in full-term and preterm neonates were accepted for inclusion to establish efficacy of EMLA. The risk of methemoglobinemia (defined as methemoglobin concentration >5% and requiring medical intervention) was estimated from all prospective studies. Results. Eleven studies of the efficacy of EMLA were included in the analysis. Infant gestational age at the time of delivery ranged from 26 weeks to full-term. Two studies included data from both neonates and older infants. The following procedures were studied: circumcision (n = 3), heel lancing (n = 4), venipuncture (n = 1), venipuncture and arterial puncture (n = 1), lumbar puncture (n = 1), and percutaneous venous catheter placement (n = 1). Nine studies were randomized controlled trials. The total sample size for each study ranged from 13 to 110 neonates. The dose of EMLA used was 0.5 g to 2 g in 9 studies, and was not specified in the others. The duration of application ranged from 10 minutes to 3 hours. The three studies that investigated the efficacy of EMLA for decreasing the pain of circumcision used a randomized controlled trial design. All of them demonstrated significantly reduced crying time during the procedure in the infants in the EMLA group compared with the infants in the control group. Facial grimacing, assessed in two of the studies, was also significantly lower in the EMLA group. Using meta-analytic techniques, the heart rate outcome data for two studies was summarized. Increases in heart rate compared with baseline values were 12 to 27 beats per minute less for the EMLA group than in the placebo group during various stages of the surgical procedure. Three studies that investigated the pain from heel lancing were randomized controlled trials; the other was a nonrandomized controlled study. None demonstrated a significant benefit of EMLA for any of the outcome measures used to assess pain (ie, behavioral pain scores, infant crying, heart rate, blood pressure, respiratory rate, oxygenation parameters). One randomized controlled study of the pain from venipuncture showed that infants treated with EMLA had significantly lower heart rates and cry duration compared with infants treated with a placebo. In one nonrandomized study, a significantly lower behavioral pain score was observed for infants treated with EMLA compared with the control group. Infant heart rate, however, did not differ between the groups. In one randomized controlled study of pain from percutaneous venous catheter placement, EMLA resulted in a significantly lower increase in heart rate and respiratory rate. Behavioral pain scores were significantly lower during arterial puncture in one nonrandomized controlled study. EMLA did not reduce physiologic changes or behavioral pain scores in one randomized controlled trial in infants undergoing lumbar puncture. Meta-analytic techniques revealed that methemoglobin concentrations did not differ between EMLA-treated and placebo-treated infants (weighted mean difference, −0.11%; 95% confidence interval, −0.31% to 0.10%). The incidence of clinically important methemoglobinemia from all prospective studies was 0% (95% confidence interval, 0.0% to 0.2%). There was insufficient data to assess the risk with multiple doses of EMLA. Four studies measured concentrations of lidocaine in the plasma of neonates who had been treated with EMLA. In all cases, concentrations were Conclusions. EMLA diminishes pain during circumcision. It may also diminish the pain from venipuncture, arterial puncture, and percutaneous venous catheter placement; however, efficacy data for these procedures are limited. EMLA does not diminish the pain from heel lancing. Based on available data, EMLA is recommended for the treatment of pain from circumcision but not heel lance. There is insufficient data to recommend its use for other procedures. Single doses do not cause methemoglobinemia. Additional research is recommended in neonates before EMLA is used routinely for procedures other than circumcision and to determine the safety of repeated administration.