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Nonnutritive Sucking and Oral Sucrose Relieve Neonatal Pain During Intramuscular Injection of Hepatitis Vaccine

Open AccessPublished:May 27, 2011DOI:https://doi.org/10.1016/j.jpainsymman.2011.02.016

      Abstract

      Context

      Newborns are subject to pain during routine invasive procedures. Pain caused by immunization injections is preventable, but remains untreated in neonates.

      Objectives

      The purpose of the study was to compare the effectiveness of three nonpharmacological pain relief strategies on newborns’ pain, physiological parameters, and cry duration before, during, and after hepatitis B intramuscular (IM) injection.

      Methods

      In this prospective, randomized clinical trial, we enrolled 165 newborns (gestational age, ≥36 weeks). The infants received IM injections and were randomized to three treatment groups: nonnutritive sucking (NNS), 20% oral sucrose, or routine care. Pain was measured by the Neonatal Facial Coding System, physiological signals by electrocardiogram monitors, and cry duration using a stopwatch.

      Results

      Pain was significantly lower among infants in the NNS (B=−11.27, P<0.001) and sucrose (B=−11.75, P<0.001) groups than that in controls after adjusting for time effects, infant sleep/wake state, number of prior painful experiences, and baseline pain scores. Infants in the NNS and sucrose groups also had significantly lower mean heart and respiratory rates than the controls. Cry duration of infants receiving sucrose was significantly shorter than those in the NNS (Z=−3.36, P<0.001) and control groups (Z=−7.80, P<0.001).

      Conclusion

      NNS and oral sucrose can provide analgesic effects and need to be given before painful procedures as brief as a one-minute IM injection. Sucrose orally administered two minutes before injection more effectively reduced newborns’ pain during injection than NNS. Both nonpharmacological methods more effectively relieved newborns’ pain, stabilized physiological parameters, and shortened cry duration during IM hepatitis injection than routine care.

      Key Words

      Introduction

      From birth, normal newborns are subject to procedural pain from routine care, such as injection of vitamin K and vaccines, circumcision, and heel sticks.
      • Hockenberry P.
      • Wilson L.
      Maternal child nursing.
      Newborns can perceive pain, process pain sensation, and respond to pain through facial expressions, behavioral responses, and physiological signals.
      • Fitzgerald F.
      • Beggs S.
      The neurobiology of pain: developmental aspects.
      • Bellieni C.V.
      • Iantornao L.
      • Perrone S.
      • et al.
      Even routine painful procedures can be harmful for the newborn.
      Early exposure of newborns to repeated procedural pain is considered a major factor contributing to negative physiological, cognitive, behavioral, and psychological consequences.
      • Grunau R.E.
      • Holsti L.
      • Peters J.W.B.
      Long-term consequences of pain in human neonates.
      • Grunau R.E.
      • Whitfield M.F.
      • Petrie-Thomas J.
      • et al.
      Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants.
      To promote newborns’ well-being and development, clinicians are obliged to offer them pain relief.
      Pain can be managed by pharmacological and nonpharmacological interventions. Using analgesics to relieve short-term procedural pain in newborns is questionable because of these agents’ poor effectiveness and potential side effects.
      • Anand K.J.
      • Hall R.W.
      • Desai N.
      • et al.
      Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial.
      • Axelin A.
      • Salanterä S.
      • Kirjavainen J.
      • et al.
      Oral glucose and parental holding preferable to opioid in pain management in preterm infants.
      • Carbajal R.
      • Lenclen R.
      • Jugie M.
      • et al.
      Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates.
      Nonpharmacological pain relief strategies are not only convenient, inexpensive, and can be used without prescriptions, but also are well tolerated by infants. Procedural pain in newborns has been relieved by nonpharmacological interventions, such as nonnutritive sucking (NNS),
      • Liaw J.J.
      • Yang L.
      • Yin T.
      • et al.
      Non-nutritive sucking relieves pain for preterm infants during heel stick procedures in Taiwan.
      • South M.M.T.
      • Strauss R.A.
      • South A.P.
      • et al.
      The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial.
      • Liu M.
      • Lin K.
      • Chou Y.
      • Lee T.
      Using non-nutritive sucking and oral glucose solution with neonates to relieve pain: a randomized controlled trial.
      swaddling,
      • Huang C.M.
      • Tung W.S.
      • Kuo L.L.
      • Chang Y.J.
      Comparison of pain responses of premature infants to the heelstick between containment and swaddling.
      facilitated tucking,
      • Axelin A.
      • Salanterä S.
      • Kirjavainen J.
      • et al.
      Oral glucose and parental holding preferable to opioid in pain management in preterm infants.
      • Ward-Larson C.
      • Horn R.A.
      • Gosnell F.
      The efficacy of facilitated tucking for relieving procedural pain of endotracheal suctioning in very low birthweight infants.
      • Axelin A.
      • Salanterä S.
      • Lehtonen L.
      Facilitated tucking by parents’ in pain management of preterm infants—a randomized crossover trial.
      oral sucrose,
      • Stevens B.
      • Yamada J.
      • Beyene J.
      • et al.
      Consistent management of repeated procedural pain with sucrose in preterm neonates: is it effective and safe for repeated use over time?.
      • Taddio A.
      • Shah V.
      • Hancock R.
      • et al.
      Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures.
      • Harrison D.
      • Loughnan P.
      • Manias E.
      • Gordon I.
      • Johnston L.
      Repeated doses of sucrose in infants continue to reduce procedural pain during prolonged hospitalizations.
      • Taddio A.
      • Shah V.
      • Atenafu E.
      • et al.
      Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants.
      breast feeding,
      • Tansky C.
      • Lindberg C.E.
      Breast feeding as a pain intervention when immunizing infants.
      • Razek A.A.
      • Ei-Dein N.A.Z.
      Effects of breast-feeding on pain relief during infant immunization injections.
      and skin-to-skin contact.
      • Castral T.C.
      • Warnock F.
      • Leite A.M.
      • Haas V.J.
      • Scochi G.S.
      The effects of skin-to-skin contact during acute pain in preterm newborns.
      • Kashaninia Z.
      • Sajedi F.
      • Ragozar M.
      • Noghabi F.A.
      The effect of kangaroo care on behavioral responses to pain of an intramuscular injection in neonates.
      • Johnston C.C.
      • Filion F.
      • Campbell-Yeo M.
      • et al.
      Kangaroo mother care diminishes pain from heel lance in very preterm neonates: a crossover trial.
      Most of these studies examined effects on pain caused by heel sticks, venipuncture, eye examination, and circumcision. Only two studies have examined the effects of oral sucrose and kangaroo care on newborn pain during intramuscular (IM) injection.
      • Taddio A.
      • Shah V.
      • Hancock R.
      • et al.
      Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures.
      • Kashaninia Z.
      • Sajedi F.
      • Ragozar M.
      • Noghabi F.A.
      The effect of kangaroo care on behavioral responses to pain of an intramuscular injection in neonates.
      However, all newborns require injections of hepatitis B vaccine around 48 hours after birth to prevent hepatitis B virus infection.
      • Kroger A.T.
      • Atkinson W.L.
      • Marcuse E.K.
      • Pickering L.K.
      Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      Thus, promoting infant health requires considering and treating the pain caused by injecting hepatitis B vaccine soon after birth. Neonatal clinicians also need to consider which strategies better relieve pain caused by routine injections.
      Among nonpharmacological pain relief strategies for newborns, the most appropriate for use during thigh IM injections are NNS and oral sucrose because they do not impede the procedures. NNS is hypothesized to produce analgesia by stimulating orotactile and mechanoreceptors in the mouth, thus modulating transmission or processing of nociception by the endogenous nonopioid system.
      • Gunnar M.R.
      • Connors J.
      • Isensee J.
      • Wall L.
      Adrenocortical activity and behavioral distress in human newborns.
      • Bellieni C.V.
      • Buonocore G.
      • Nenci A.
      • et al.
      Sensorial saturation: an effective analgesic tool for heel-prick in preterm infants: a prospective randomized trial.
      Sucrose is thought to activate endogenous opiates through tactile stimulation by the sweet fluid in the mouth, which releases endogenous opiates,
      • Blass E.M.
      • Watt L.B.
      Suckling- and sucrose-induced analgesia in human newborns.
      • Gradin M.
      • Finnström O.
      • Schollin J.
      Feeding and oral glucose—additive effects on pain reduction in newborns.
      and the presence of opioid receptors on the tongue.
      • Shide D.J.
      • Blass E.M.
      Opioid-like effects of intraoral infusions of corn oil and polycose on stress reactions in 10-day-old rats.
      The analgesic effect lasts approximately 10 minutes, peaking two minutes after administration.
      • Leslie A.
      • Marlow N.
      Non-pharmacological pain relief.
      Despite their different pain relief mechanisms, NNS and sucrose are both effective pain relief interventions. For example, NNS effectively reduced preterm infants’ pain during heel sticks.
      • Liaw J.J.
      • Yang L.
      • Yin T.
      • et al.
      Non-nutritive sucking relieves pain for preterm infants during heel stick procedures in Taiwan.
      Sucrose also was shown in 45 studies to be effective and safe in reducing newborns’ procedural pain.
      • Stevens B.
      • Yamada J.
      • Ohlsson A.
      Sucrose for analgesia in newborn infants undergoing painful procedures.
      However, sucrose was reported to be ineffective in reducing infants’ pain during IM injection of vitamin K in the first hour after birth.
      • Taddio A.
      • Shah V.
      • Hancock R.
      • et al.
      Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures.
      Thus, it remains unknown whether NNS or sucrose can effectively relieve newborn pain caused by IM injection of hepatitis B vaccine around 48 hours after birth and which pain relief strategy better relieves pain.
      To address these gaps in knowledge, this study offered newborns receiving their first IM injection for hepatitis B three nonpharmacological pain relief strategies: routine care measures, NNS, or sucrose. The purpose of the study was to compare the efficacy of these three strategies on newborns’ pain, physiological parameters, and cry duration, before, during, and after their first IM injection of hepatitis B vaccine. We hypothesized that pain caused by IM injection would be better managed in infants receiving NNS and sucrose than in those receiving routine care. We also hypothesized that sucrose would be more effective than NNS in relieving newborns’ pain, stabilizing physiological parameters, and in reducing cry duration during injection procedures.

      Methods

      Participants

      Infants were recruited by convenience sampling from the neonatal nursery at a medical center in Taipei, Taiwan. Healthy newborns were included if they met these criteria: 1) gestational age (GA) greater than or equal to 36 weeks; 2) birth weight greater than or equal to 2200 g; 3) Apgar score greater than or equal to 7 at the first and fifth minute after birth; 4) underwent IM injection for hepatitis B; and 5) mothers healthy without substance abuse. Newborns were excluded by these criteria: 1) congenital anomalies; 2) neurological impairment; 3) documented congenital or nosocomial sepsis; 4) surgery; 5) substance-abusing mother; 6) had been administered sedatives, analgesics, or naloxone; and 7) no need for injection against hepatitis B. Parents of infants who met the study criteria received a pamphlet that briefly introduced the study. Interested parents returned the response sheet to the research nurse, who then explained the study in more detail and obtained parental consent. This study was approved by the study site's institutional review board.
      Of 220 newborn infants screened for participation from 2007 to 2008, 193 infants met the study criteria (Fig. 1). Twenty-eight parents refused participation because they did not want their infants to be filmed during data collection, leaving 165 newborn infants who received IM injection. Infants who did and did not participate in the study were not significantly different in terms of sex, GA, age (days since birth), and birth weight. The sample size was sufficient to power the study, based on estimates using G∗Power (Heinrich Heine University, Dussëldorf, Germany).
      • Faul F.
      • Erdfelder E.
      • Lang A.G.
      • et al.
      G∗Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
      The effect size of outcome variables, according to differences in means and standard deviations (SDs) of pain scores within each study group, was 0.54. For this effect size, 98.95% actual power, and a significance level of 0.05, a sample of 55 newborn infants was required. Each infant enrolled in the study was randomly assigned to one of three pain relief methods by a statistician blind to the study purpose and using random allocation software.
      • Saghaei M.
      Random allocation software for parallel group randomized trials.
      The software generated a permutated three-block randomization list, which was used to assign each qualified subject to one of the three pain relief measures.

      Design

      A randomized clinical trial was used to compare the efficacy of NNS, oral sucrose, and routine care on newborn infant pain, physiological parameters (heart rate [HR] and respiratory rate [RR]), and cry duration associated with IM injection.

      Pain Relief Interventions

      All newborn infants were placed in a side-lying position. The injection procedures included nine steps: 1) prepare the materials needed and select the site for injection; 2) stabilize the infant’s leg; 3) cleanse the injection site with alcohol cotton balls; 4) pinch up the infant’s muscle between the thumb and forefinger; 5) insert the needle into the vastus lateralis at a 90° angle; 6) release the muscle and gently withdraw the syringe plunger; 7) if no blood is aspirated in Step 6, inject the hepatitis vaccine; 8) after injection, quickly withdraw the needle; and 9) press the site with gauze and cover with an adhesive bandage.
      • Hockenberry P.
      • Wilson L.
      Maternal child nursing.
      During injection procedures, infants in the routine care group (control group) received gentle touch and verbal comfort, whereas infants in the experimental group received NNS or sucrose two minutes before the injection procedures. Infants in the NNS group (one experimental group) were given a standard silicone newborn pacifier manufactured with natural scent (Super Soothie, Natural Scent; Philips Children’s Medical Ventures, Monroeville, PA) to stimulate sucking two minutes before touching the thigh to initiate the injection procedures. Infants in the sucrose group (the other experimental group) were fed 2 mL of 20% sucrose through a syringe two minutes before the injection procedures.

      Measures

      Outcome variables included newborn infants’ pain, physiological responses (HR and RR), and cry duration.

      Pain

      Procedural pain, the major outcome, was assessed by a research assistant (RA) trained to use the Neonatal Facial Coding System (NFCS), which has been successfully used with preterm and full-term infants between 25- and 42-week GAs.
      • Grunau R.V.E.
      • Craig K.D.
      Pain expression in neonates: facial action and cry.
      The NFCS is an observational measure of infant facial expressions in response to pain. Facial response is widely recognized as a reliable and valid indicator for measuring infant pain.
      • Grunau R.V.E.
      • Craig K.D.
      Pain expression in neonates: facial action and cry.
      • Grunau R.E.
      • Oberlander T.
      • Holsti L.
      • Whitfield M.F.
      Bedside application of the facial coding system in pain assessment of premature neonates.
      The NFCS scores the presence (1) or absence (0) of 10 discrete facial expressions: brow bulge, eye squeeze, nasolabial furrow, open lips, vertical mouth stretch, horizontal mouth stretch, lip purse, taut tongue, tongue protrusion, and chin quiver. Because infants receiving NNS had a pacifier in their mouths, it was difficult to observe the actions of their lips, mouth, and tongue. Thus, measurement of facial expressions focused only on actions that could be clearly and consistently observed in all infants, that is, brow bulge, eye squeeze, nasolabial furrow, and chin quiver. Facial actions were measured by time-triggered coding. Infants’ facial actions were coded at 10-second intervals during the baseline, IM injection, and recovery phases by the blinded RA, who typed the facial codes in Word files. Each code was scored and summed for every minute of each injection phase (see Data Collection).
      Each facial action is scored from 0 to 2 (0=face relaxed; 1=slight facial actions; 2=intense/continuous facial actions).
      • Grunau R.V.E.
      • Craig K.D.
      Pain expression in neonates: facial action and cry.
      For each 10-second interval, the possible score is 0–8; scores are then summed over one minute for a total possible score of 0–48. A higher total score indicates more intense pain. To ensure fidelity of behavioral measurements, videotapes were coded in random order. All infant facial actions on the videotapes were coded and scored in a quiet room to maintain consistency and accuracy of data analysis. The NFCS interrater reliability (between the RA and first author [J.- J. L.]) was 0.88–0.92, and the intrarater reliability was 0.93–0.96.

      Physiological Parameters

      HR and RR were continuously monitored (HP M1166A Monitor; Hewlett-Packard, Palo Alto, CA) and recorded by custom software. Electrocardiogram (ECG) monitors were regularly calibrated by certified technicians, and computer function was checked before data collection. HR and RR were recorded from ECG leads attached to the infant’s chest and digitally sampled at 15-second intervals by computer. The mean HR and RR values were calculated and compared among the control, NNS, and sucrose groups across the seven phases of the injection procedures (see Data Collection).

      Cry Duration

      The RA who was trained to code infants’ facial expressions watched the video of each injection a second time and measured the infant’s cry duration in seconds using a stopwatch. The interrater reliability for measuring cry duration (between the RA and J.- J. L.) was 96% for a random sample of 33 newborns.

      Data Collection

      Data were collected on newborn infants’ pain, HR, RR, and cry duration (see Measures for details). Data collection procedures were based on the first author’s preliminary observations that newborns who received IM injections in the nursery took almost five minutes to completely recover from pain. Therefore, all data were collected for five minutes without stimuli (mean baseline, T1); during injection procedures (T2); and after injection procedures (five minutes of recovery starting from when the nurse finished the IM injection and lifted her hands). Pain scores, HR, and RR were measured every minute during baseline (T1) and injection procedures (T2), and during recovery at the first (T3), second (T4), third (T5), fourth (T6), and fifth (T7) minutes. The duration of crying was measured in seconds from the video recording using a stopwatch from the start of the injection procedures to the fifth minute of recovery.
      Data were collected by two trained RAs. One RA, who was informed about the research purpose and plans, was trained to select participants and collect infants’ background data and prior painful experiences by reviewing medical and nursing charts. A painful experience was defined as an invasive, tissue-damaging cutaneous procedure, including heel stick, intravenous or arterial line insertion, and IM injection in this study. The other RA, blinded to the study purpose and the infants’ clinical information and intervention group, was trained to code facial actions, to score pain using the NFCS (see Measures), and to measure cry duration.
      Two neonatal research nurses also were trained to conduct experimental procedures on newborns. The senior research nurse was trained to skillfully follow the nursery’s standard procedures for IM injections of hepatitis vaccine. The IM injection procedures were controlled to be administered within one minute in all newborns of the three groups. The other research nurse was trained to adeptly offer NNS or oral sucrose to infants in the experimental groups before the IM injection procedures. All personnel were trained separately by J.- J. L.
      Study fidelity was established by weekly meetings between the authors and senior research nurse to review the exact procedures and discuss any problems. The other research nurse worked regularly with one author (T. Y.) to confirm that NNS and sucrose oral administration were consistently provided to each newborn and to discuss any problems. As described earlier, infants were placed in a side-lying position, with the video camera (Sony DCR-DV42, Sony Taiwan Limited) lens focused on the infant’s entire face to record facial actions. Facial actions and cry duration were recorded using a real-time color video recorder. Video signals were directly transmitted to a computer, and a time code was recorded and entered into videotapes by software (Ulead Videostudio, Tapei, Taiwan).

      Data Analysis

      Data were analyzed using SPSS for Windows, Version 15.0.0 (IBM SPSS Inc., Ardsley, NY). Background data of infants in the three groups (routine care, NNS, and sucrose) were compared by nonparametric Kruskal-Wallis tests. Data were described using means (SDs) for continuous variables and frequencies for categorical variables. NFCS pain scores, HR, and RR of infants in the three groups were compared by the generalized estimating equation method’s generalized linear models.
      • Liang K.Y.
      • Zeger S.L.
      Longitudinal data analysis using general linear models.
      As a result, potential influencing factors, such as infants’ sleep/wake state,
      • Anand K.J.S.
      Pain assessment in preterm neonates.
      number of prior pain experiences, phase of the injection procedure, and lag time to prior pain exposure or feeding (breast or bottle), were not significantly related to infants’ pain responses. Cry durations among the three groups were compared by Kruskal-Wallis tests and Mann-Whitney U tests. NFCS inter- and intrarater reliabilities were measured by intraclass correlation coefficients. P-values less than 0.05 were considered statistically significant.

      Results

      Infant Characteristics

      The study participants were 28 male and 27 female newborn infants in each of the three groups (n=55), for a total sample of 165. Infants’ basic characteristics did not differ significantly among the three groups (Table 1).
      Table 1Characteristics of Newborn Infants in Control, Nonnutritive Sucking, and Sucrose Groups (n=165)
      CharacteristicControl (n=55)Nonnutritive Sucking (n=55)Sucrose (n=55)χ2P
      Kruskal-Wallis test.
      MeanSDRangeMeanSDRangeMeanSDRange
      Gestational age (weeks)39.191.2536.43–41.2839.211.2736.43–42.2839.221.0936.85–41.850.110.945
      Birth weight (g)3247.8386.362240–41553172.00355.832500–38503256.98435.941775–41902.200.333
      Body weight during injection (g)3045.64373.212181.76–4088.522975.45349.752133.50–3661.353059.19403.511670.28–4001.452.190.334
      Age (days)2.500.372–32.570.312–32.450.312–33.980.137
      Number of prior painful experiences3.240.852–53.360.772–53.270.802–65.880.06
      Time since previous feeding (hours)2.560.741–32.290.831–32.490.841–34.210.122
      Time since last painful stimuli12.9911.861–4810.206.101–2812.897.905–302.020.364
      Apgar score
       First minute8.000.008–87.950.237–87.960.197–82.870.238
       Fifth minute9.000.009–99.000.009–99.000.009–90.001.000
      Gender0.001.000
       Male272727
       Female282828
      Delivery methods0.160.924
       NSD363534
       Cesarean section192021
      NSD=normal spontaneous delivery.
      a Kruskal-Wallis test.

      Neonatal Facial Coding System Pain Score

      Infants in the NNS and sucrose groups had significantly lower NFCS pain scores (B=−11.27, P<0.001 and B=−11.75, P<0.001, respectively) than controls after adjusting for the effects of time, infant sleep/wake state before injection, number of prior painful experiences, and baseline NFCS pain scores (Table 2). The NFCS pain scores of infants receiving NNS and sucrose were significantly lower than those of infants in the control group at all seven phases of IM injection procedures (Fig. 2). Infants’ pain scores increased during and in the first minute after IM injection procedures and significantly decreased afterward (Table 2). The pain scores in newborn infants were significantly related to their sleep/wake state before injection and baseline pain score. Infants’ facial expressions of pain during injection procedures were not significantly influenced by the number of prior painful experiences.
      Table 2Changes in NFCS Pain Scores of Control, Nonnutritive Sucking, and Sucrose Groups, Predicted by Generalized Estimating Equation Method Multiple Regression Model (n=165)
      VariableBSEWald Chi-squareP95% Confidence Interval
      LowerUpper
      Group
       Sucrose−11.751.14105.56<0.001−13.99−9.51
       NNS−11.271.2088.56<0.001−13.62−8.92
       Control0
      Time of observation
       Fifth minute after IM (7)
      Numbers in parentheses refer to times shown in Fig. 2.
      −5.471.1024.50<0.001−7.63−3.30
       Fourth minute after IM (6)−5.171.1021.93<0.001−7.33−3.00
       Third minute after IM (5)−5.121.0722.95<0.001−7.22−3.03
       Second minute after IM (4)−4.271.1214.59<0.001−6.46−2.08
       First minute after IM (3)0.591.180.250.617−1.732.91
       The one minute during IM (2)0.591.180.250.617−1.732.91
       Baseline: no stimulation (1)0
      Infant state before injection
       Fussy or crying−1.480.753.880.049−2.940.008
       Active awake2.461.025.800.0160.464.47
       Quiet awake2.601.174.970.0260.314.89
       Active sleep2.011.153.090.079−0.234.26
       Quiet sleep2.961.513.860.0500.015.91
      Number of prior painful experiences
       6−1.551.560.990.321−4.611.51
       53.792.232.880.090−0.598.16
       40.681.500.210.647−2.253.62
       30.101.390.010.943−2.622.82
       20
      Baseline score0.590.1128.52<0.0010.380.81
      IM=intramuscular injection; SE=standard error.
      a Numbers in parentheses refer to times shown in Fig. 2.
      Figure thumbnail gr2
      Fig. 2NFCS pain scores of newborns receiving routine care, nonnutritive sucking, and sucrose during intramuscular injection of hepatitis B vaccine. T1=baseline (no stimulation); T2=during injection; T3=first minute after injection; T4=second minute after injection; T5=third minute after injection; T6=fourth minute after injection; T7=fifth minute after injection. CI=confidence interval.

      Physiological Parameters

      Infants in the NNS and sucrose groups had significantly lower mean HR (B=−13.28, P<0.001 and B=−17.01, P<0.001, respectively) than those in the control group after adjusting for the effects of time, infant sleep/wake state before injection, number of prior painful experiences, and baseline HR (Table 3). Infants’ mean HR significantly increased over time during the IM injection procedures and gradually decreased thereafter. The infants’ mean HR was significantly related to their state before injection except the state of fussing or crying. Furthermore, infants’ mean HR was only significantly influenced by the number of prior painful experiences when they had experienced six painful events (B=−14.84, P<0.001).
      Table 3Changes in Heart Rates of Control, Nonnutritive Sucking, and Sucrose Groups, Predicted by Generalized Estimating Equation Method Multiple Regression Model (n=165)
      VariableBSEWald Chi-squareP95% Confidence Interval
      LowerUpper
      Group
       Sucrose−17.012.2059.60<0.001−21.33−12.69
       NNS−13.282.0740.97<0.001−17.34−9.21
       Control0
      Time of observation
       Fifth minute after IM (7)
      Numbers in parentheses refer to times shown in Fig. 2.
      −15.122.0653.67<0.001−19.16−11.07
       Fourth minute after IM (6)−11.432.0331.80<0.001−15.41−7.46
       Third minute after IM (5)−6.452.0210.170.001−10.41−2.49
       Second minute after IM (4)−2.802.071.830.176−6.851.25
       First minute after IM (3)7.961.9117.28<0.0014.2111.72
       The 1 minute during IM (2)26.871.63270.83<0.00123.6730.06
       Baseline: no stimulation (1)0
      Infant state before injection
       Fussy or crying−0.540.760.500.482−2.030.96
       Active awake10.952.6916.62<0.0015.6816.21
       Quiet awake10.632.7215.32<0.0015.3115.96
       Active sleep10.082.7213.77<0.0014.7615.41
       Quiet sleep9.852.8611.820.0014.2415.46
      Number of prior painful experiences
       6−14.842.8028.20<0.001−20.32−9.37
       53.873.451.260.263−2.9010.63
       41.862.600.510.473−3.236.95
       30.082.340.0010.974−4.504.65
       20
      Baseline heart rate0.430.5559.41<0.0010.320.54
      IM=intramuscular injection; SE=standard error.
      a Numbers in parentheses refer to times shown in Fig. 2.
      Infants in the NNS and sucrose groups had a significantly lower RR (B=−2.76, P=0.005 and B=−3.47, P<0.001, respectively) than those of the control group after adjusting for the effects of time, infant sleep/wake state before injection, number of prior painful experiences, and baseline RR (Table 4). Infants’ mean RR significantly increased during the IM injection procedures and decreased thereafter, but not significantly. Infants’ mean RR was not significantly related to their state before injection and number of prior painful experiences.
      Table 4Changes in Respiratory Rates of Control, Nonnutritive Sucking, and Sucrose Groups, Predicted by Generalized Estimating Equation Method Multiple Regression Model (n=165)
      VariableBSEWald Chi-squareP95% Confidence Interval
      LowerUpper
      Group
       Sucrose−3.470.8616.26<0.001−5.16−1.78
       NNS−2.760.978.060.005−4.67−0.86
       Control0
      Time of observation
       Fifth minute after IM (7)
      Numbers in parentheses refer to times shown in Fig. 2.
      −0.630.730.750.388−2.060.80
       Fourth minute after IM (6)−0.520.730.500.479−1.940.91
       Third minute after IM (5)−0.420.720.350.553−1.830.98
       Second minute after IM (4)−0.850.761.230.267−2.350.65
       First minute after IM (3)−0.320.680.230.635−1.651.00
       The 1 minute during IM (2)2.900.7216.40<0.0011.504.31
       Baseline: no stimulation (1)0
      Infant state before injection
       Fussy or crying0.220.330.430.511−0.440.87
       Active awake0.761.130.450.502−1.462.98
       Quiet awake0.671.160.330.565−1.612.95
       Active sleep1.111.180.890.347−1.203.42
       Quiet sleep0.431.260.110.735−2.042.89
      Number of prior painful experiences
       61.191.181.010.314−1.133.50
       5−2.291.731.760.185−5.681.10
       4−0.181.040.030.862−2.221.86
       3−0.541.000.300.585−2.501.41
       20
      Baseline respiration rate0.560.0680.72<0.0010.430.68
      IM=intramuscular injection; SE=standard error.
      a Numbers in parentheses refer to times shown in Fig. 2.

      Cry Duration

      The average cry duration in the three groups was shown by Kruskal-Wallis test to be significantly different (χ2=79.22, P<0.001). Multiple comparisons showed that the cry durations of the infants in the NNS and sucrose groups were significantly shorter (Z=−66.8, P<0.001 and Z=−7.80, P<0.001, respectively) than the cry durations of the infants in the control group (Table 5). The cry duration of infants receiving sucrose was significantly shorter (Z=−3.36, P<0.001) than the cry duration of infants in the NNS group.
      Table 5Comparison of Cry Duration During and After Immunization Injection in Control, Nonnutritive Sucking, and Sucrose Groups (n=165)
      Study GroupnAverage Pain ScoreRoutine CareNonnutritive SuckingSucrose
      Mean (SD)RangeZP
      Mann-Whitney U tests.
      ZP
      Mann-Whitney U tests.
      ZP
      Mann-Whitney U tests.
      Routine care55203.81 (100.16)18–328−66.8<0.001−7.80<0.001
      Nonnutritive sucking5564.56 (56.82)0–246−66.8<0.001−3.360.001
      Sucrose5539.98 (42.46)0–223−7.80<0.001−3.360.001
      a Mann-Whitney U tests.

      Discussion

      Our study demonstrated that both NNS and sucrose are effective pain management methods during IM injection of hepatitis B vaccine. These findings support our hypothesis that pain because of IM injection would be relieved better in infants receiving NNS and sucrose than in those receiving routine care. Indeed, we found that oral sucrose and NNS reduced newborns’ pain scores, HR, RR, and cry duration during IM hepatitis injection. In contrast, sucrose was previously reported to be ineffective in reducing pain during IM vitamin K injection in the first hour after birth.
      • Taddio A.
      • Shah V.
      • Hancock R.
      • et al.
      Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures.
      This difference might be because sucrose usually generates analgesic effects beyond one day of birth.
      • Stevens B.
      • Yamada J.
      • Ohlsson A.
      Sucrose for analgesia in newborn infants undergoing painful procedures.
      For newborns younger than one day, NNS is the best choice to relieve pain. Others have reported that sucrose can reduce pain associated with immunization beyond the neonatal period, that is, in two- to six-month-old infants.
      • Hatfield L.
      Sucrose decreases infant biobehavioral pain response to immunizations: a randomized controlled trial.
      • Mörelius E.
      • Theodorsson E.
      • Nelson N.
      Stress at three-month immunization: parents’ and infants’ salivary cortisol response in relation to the use of pacifier and oral glucose.
      Sucrose also has been shown in more than 40 studies to be safe and effective for reducing newborns’ procedural pain.
      • Stevens B.
      • Yamada J.
      • Ohlsson A.
      Sucrose for analgesia in newborn infants undergoing painful procedures.
      However, the use of oral sucrose to relieve pain is still controversial in some infants. For example, preterm infants who received more than 10 doses of sucrose over 24 hours were found to be at risk of poorer neurodevelopmental scores than infants who received less than 10 doses in 24 hours.
      • Johnston C.C.
      • Filion F.
      • Snider L.
      • et al.
      How much sucrose is too much sucrose?.
      • Johnston C.C.
      • Filion F.
      • Snider L.
      • et al.
      Routine sucrose analgesia during the first week of life in neonates younger than 31 weeks postconceptional age.
      These findings indicate the need to avoid overuse of sucrose in preterm infants and guide clinicians to avoid the complications of using sucrose by alternating its use with NNS in infants who have received more than 10 painful procedures.
      In this study, sucrose was more efficacious than NNS in relieving pain during IM hepatitis injection, in contrast to previous reports that NNS relieves procedural pain better than sucrose.
      • Liu M.
      • Lin K.
      • Chou Y.
      • Lee T.
      Using non-nutritive sucking and oral glucose solution with neonates to relieve pain: a randomized controlled trial.
      • Mathai S.
      • Natrajan N.
      • Rajalakshmi N.R.
      A comparative study of nonpharmacological methods to reduce pain in neonates.
      These different results might be because of the different types of stimuli, sucrose concentrations, ways of administering sucrose, and infants’ GAs. Another reason for the different findings might be the pain measurement used. Most previous studies have measured infant pain using the Premature Infant Pain Profile,
      • Liaw J.J.
      • Yang L.
      • Yin T.
      • et al.
      Non-nutritive sucking relieves pain for preterm infants during heel stick procedures in Taiwan.
      • Stevens B.
      • Yamada J.
      • Beyene J.
      • et al.
      Consistent management of repeated procedural pain with sucrose in preterm neonates: is it effective and safe for repeated use over time?.
      • Taddio A.
      • Shah V.
      • Atenafu E.
      • et al.
      Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants.
      and some used the NFCS,
      • Piira T.
      • Champion G.D.
      • Bustos T.
      • Donnelly N.
      • Lui K.
      Factors associated with infant pain responses following an immunization injection.
      Neonatal Infant Pain Scale,
      • Liu M.
      • Lin K.
      • Chou Y.
      • Lee T.
      Using non-nutritive sucking and oral glucose solution with neonates to relieve pain: a randomized controlled trial.
      or Leuven Pain Scale.
      • Dilen B.
      • Elseviers M.
      Oral glucose solution as pain relief in newborns: results of a clinical trial.
      Choosing NNS or sucrose to relieve procedural pain depends on the infant’s condition, the type of pain, clinical situation, and availability of materials. Although using multiple doses of sucrose or repeated use of NNS has not been found to lead to any adverse events, such as hyperglycemia,
      • Taddio A.
      • Shah V.
      • Hancock R.
      • et al.
      Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures.
      necrotizing enterocolitis,
      • Stevens B.
      • Yamada J.
      • Beyene J.
      • et al.
      Consistent management of repeated procedural pain with sucrose in preterm neonates: is it effective and safe for repeated use over time?.
      or nipple confusion,
      • Howard C.R.
      • Howard F.M.
      • Lanphear B.
      • et al.
      Randomised clinical trial of pacifier use and bottle-feeding or cup-feeding and their effect on breastfeeding.
      great care must still be taken in using oral sucrose and NNS, especially in newborns of diabetic mothers, with necrotizing enterocolitis, gastrointestinal disorders, or after surgery. Furthermore, for extremely painful procedures, such as eye examination or circumcision, NNS or sucrose may need to be combined with a pharmacological strategy. For infants receiving suctioning, clinicians can provide facilitated tucking. In addition, some investigators have reported that combining sucrose with NNS has an additive analgesic effect
      • Stevens B.
      • Yamada J.
      • Beyene J.
      • et al.
      Consistent management of repeated procedural pain with sucrose in preterm neonates: is it effective and safe for repeated use over time?.
      • Bellieni C.V.
      • Bagnoli F.
      • Perrone S.
      • et al.
      Effect of multisensory stimulation on analgesia in term newborns: a randomized controlled trial.
      because of synergism between pacifiers and sweet solution. The effectiveness of NNS and sucrose appears to be reinforced by multisensory stimulation of tactile, taste, and scent sensory pathways.
      • Bellieni C.V.
      • Bagnoli F.
      • Perrone S.
      • et al.
      Effect of multisensory stimulation on analgesia in term newborns: a randomized controlled trial.
      Our findings that NNS and sucrose significantly stabilized newborns’ HR and RR are comparable with reports that the HR of newborns receiving NNS, sucrose, facilitated tucking, swaddling, or kangaroo care increased less than that of infants not receiving such interventions during painful procedures.
      • Catelin C.
      • Tordjman S.
      • Morin V.
      • Oger E.
      • Sizun J.
      Clinical, physiological, and biological impact of environmental and behavioral interventions in neonates during a routine nursing procedure.
      • Boyle E.M.
      • Freer Y.
      • Khan-Orakzai Z.
      • et al.
      Sucrose and non-nutritive sucking for the relief of pain in screening for retinopathy of prematurity: a randomized controlled trial.
      During IM hepatitis injection in our study, newborns’ HR and RR decreased and returned to baseline when they received sucrose and NNS compared with those of routine care, in contrast to a report that newborns’ HR was not affected by NNS during circumcision.
      • South M.M.T.
      • Strauss R.A.
      • South A.P.
      • et al.
      The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial.
      These different findings might have been the result of all infants in the other study receiving acetaminophen plus penile nerve block before circumcision,
      • South M.M.T.
      • Strauss R.A.
      • South A.P.
      • et al.
      The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial.
      which might have interfered with the effect of NNS on HR. More studies are needed to explore the effects of NNS on physiological parameters.
      Cry duration was shorter during and after IM injection in newborns who received sucrose and NNS than that in routine care, comparable to previous studies.
      • South M.M.T.
      • Strauss R.A.
      • South A.P.
      • et al.
      The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial.
      • Harrison D.
      • Loughnan P.
      • Manias E.
      • Gordon I.
      • Johnston L.
      Repeated doses of sucrose in infants continue to reduce procedural pain during prolonged hospitalizations.
      Pain-related crying in newborns increases HR, blood pressure, and diaphragmatic splinting that might lead to greater blood volume and lower vagal tone, possibly resulting in intraventricular hemorrhage in fragile and immature infants.
      • Hall W.R.
      • Anand K.J.S.
      Short- and long-term impact of neonatal pain and stress: more than an ouchie.
      Such neurological impairment in newborns can be avoided during invasive painful procedures by using sucrose and NNS.
      Considering the consequences of pain in newborns, pain relief should be offered for all painful procedures. NNS and oral sucrose must be given before painful procedures begin, even a one-minute IM injection. In general, neonatal clinicians need to become familiar with the mechanisms of the nonpharmacological pain-relief strategies and the methods for administering them, and should wisely select the one that is available and appropriate for the infant and the clinical situation or combine the appropriate strategies to enhance their analgesic effects.
      Our findings suggest that newborns who had received six painful stimuli before the IM injection had significantly lower HR than those with fewer prior pain experiences. In contrast, newborns repeatedly exposed to pain were found to develop hyperalgesia and lower thresholds to pain.
      • Taddio A.
      • Shah V.
      • Gilbert-Macleod C.
      • Katz J.
      Conditioning and hyperalgesia in newborns exposed to repeated heel lances.
      These different findings might be the result of the different numbers of newborns’ prior painful experiences and the observational contexts of the two studies. In our study, infants’ facial responses to pain and HR were also significantly influenced by their sleep/wake state before IM injections. Regardless of whether the infants were asleep or awake, they perceived pain as indicated by significant increases in NFCS pain scores and HR.
      Furthermore, the study time effects suggest that newborns’ HR and RR significantly increased during hepatitis injection, but NFCS pain scores did not increase significantly. This lack of effect on pain scores might be explained by newborn infants having insufficient time to express facial responses to pain during the very short IM injection. Although grimace is a very sensitive pain indicator, it is not the only one. Thus, infant pain should be assessed by multiple pain dimensions, such as HR, RR, and cry duration.
      • Stevens B.J.
      • Riddell R.R.P.
      • Oberlander T.E.
      • Gibbins S.
      Chapter 6: Assessment of pain in neonates and infant.

      Study Limitations

      Despite the contributions of this study, it had some limitations. Infant behavioral responses to injection procedures varied greatly at each observation. Infant facial responses to pain as well as physiological responses and cry duration might have been influenced by multiple confounding factors, such as infant hunger or discomfort, temperament, sleep/wake state, and prior painful experiences. Although some of these variables were controlled in our analyses, future studies should consider these factors in selecting newborns and in data analysis. Although outcome assessors and interveners were different, they could not be completely blind to all research processes because they could clearly distinguish among routine care, NNS, and oral sucrose administration. The effects of NNS and sucrose were examined separately during injection procedures. Thus, we do not know whether the combination of NNS and sucrose can additively relieve pain in painful procedures. This study selected only the four items of the NFCS that could be observed clearly and consistently. These items might not capture the full expression of neonatal pain. Future studies should include more pain indicators. The outcome variables of this study focused on pain, cry duration, and physiological changes. Future research should examine the effectiveness of sucrose, NNS, or other nonpharmacological interventions on other outcomes, such as sleep, or neurodevelopmental indicators. The pain relief effectiveness of NNS and sucrose plus other supportive or pharmacological interventions could also be examined during different invasive procedures.

      Conclusions

      Pain caused by IM injection procedures, as brief as one minute, was lower after administering NNS or 20% oral sucrose than that after routine care. Using NNS and sucrose also enhanced infants’ physiological stability and shortened their cry duration during injections. Furthermore, administering sucrose two minutes before the injection more effectively reduced newborns’ pain during injection than NNS. Clinicians should incorporate NNS and sucrose into caregiving while newborns undergo painful procedures. These study results add to evidence supporting the use of NNS and sucrose for pain relief in newborns during immunization injection.

      References

        • Hockenberry P.
        • Wilson L.
        Maternal child nursing.
        Mosby Elsevier, Maryland Heights, MO2010
        • Fitzgerald F.
        • Beggs S.
        The neurobiology of pain: developmental aspects.
        Eur J Pain. 2007; 11: 139-152
        • Bellieni C.V.
        • Iantornao L.
        • Perrone S.
        • et al.
        Even routine painful procedures can be harmful for the newborn.
        Pain. 2009; 147: 128-131
        • Grunau R.E.
        • Holsti L.
        • Peters J.W.B.
        Long-term consequences of pain in human neonates.
        Semin Fetal Neonatal Med. 2006; 11: 268-275
        • Grunau R.E.
        • Whitfield M.F.
        • Petrie-Thomas J.
        • et al.
        Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants.
        Pain. 2009; 143: 138-146
        • Anand K.J.
        • Hall R.W.
        • Desai N.
        • et al.
        Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial.
        Lancet. 2004; 363: 1673-1682
        • Axelin A.
        • Salanterä S.
        • Kirjavainen J.
        • et al.
        Oral glucose and parental holding preferable to opioid in pain management in preterm infants.
        Clin J Pain. 2009; 25: 138-145
        • Carbajal R.
        • Lenclen R.
        • Jugie M.
        • et al.
        Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates.
        Pediatrics. 2005; 115: 1494-1500
        • Liaw J.J.
        • Yang L.
        • Yin T.
        • et al.
        Non-nutritive sucking relieves pain for preterm infants during heel stick procedures in Taiwan.
        J Clin Nurs. 2010; 19: 2741-2751
        • South M.M.T.
        • Strauss R.A.
        • South A.P.
        • et al.
        The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial.
        Am J Obstet Gynecol. 2005; 193: 537-542
        • Liu M.
        • Lin K.
        • Chou Y.
        • Lee T.
        Using non-nutritive sucking and oral glucose solution with neonates to relieve pain: a randomized controlled trial.
        J Clin Nurs. 2010; 19: 1604-1611
        • Huang C.M.
        • Tung W.S.
        • Kuo L.L.
        • Chang Y.J.
        Comparison of pain responses of premature infants to the heelstick between containment and swaddling.
        J Nurs Res. 2004; 12: 31-39
        • Ward-Larson C.
        • Horn R.A.
        • Gosnell F.
        The efficacy of facilitated tucking for relieving procedural pain of endotracheal suctioning in very low birthweight infants.
        MCN Am J Matern Child Nurs. 2004; 29: 151-158
        • Axelin A.
        • Salanterä S.
        • Lehtonen L.
        Facilitated tucking by parents’ in pain management of preterm infants—a randomized crossover trial.
        Early Hum Dev. 2006; 82: 241-247
        • Stevens B.
        • Yamada J.
        • Beyene J.
        • et al.
        Consistent management of repeated procedural pain with sucrose in preterm neonates: is it effective and safe for repeated use over time?.
        Clin J Pain. 2005; 21: 543-548
        • Taddio A.
        • Shah V.
        • Hancock R.
        • et al.
        Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures.
        CMAJ. 2008; 179: 37-43
        • Harrison D.
        • Loughnan P.
        • Manias E.
        • Gordon I.
        • Johnston L.
        Repeated doses of sucrose in infants continue to reduce procedural pain during prolonged hospitalizations.
        Nurs Res. 2009; 58: 427-434
        • Taddio A.
        • Shah V.
        • Atenafu E.
        • et al.
        Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants.
        Pain. 2009; 144: 43-48
        • Tansky C.
        • Lindberg C.E.
        Breast feeding as a pain intervention when immunizing infants.
        J Nurse Pract. 2010; 6: 287-295
        • Razek A.A.
        • Ei-Dein N.A.Z.
        Effects of breast-feeding on pain relief during infant immunization injections.
        Int J Nurs Pract. 2009; 15: 99-104
        • Castral T.C.
        • Warnock F.
        • Leite A.M.
        • Haas V.J.
        • Scochi G.S.
        The effects of skin-to-skin contact during acute pain in preterm newborns.
        Eur J Pain. 2008; 12: 464-471
        • Kashaninia Z.
        • Sajedi F.
        • Ragozar M.
        • Noghabi F.A.
        The effect of kangaroo care on behavioral responses to pain of an intramuscular injection in neonates.
        J Spec Pediatr Nurs. 2008; 13: 275-280
        • Johnston C.C.
        • Filion F.
        • Campbell-Yeo M.
        • et al.
        Kangaroo mother care diminishes pain from heel lance in very preterm neonates: a crossover trial.
        BMC Pediatrics. 2008; 8: 13
        • Kroger A.T.
        • Atkinson W.L.
        • Marcuse E.K.
        • Pickering L.K.
        Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).
        MMWR Recomm Rep. 2006; 55: 1-48
        • Gunnar M.R.
        • Connors J.
        • Isensee J.
        • Wall L.
        Adrenocortical activity and behavioral distress in human newborns.
        Dev Psychobiol. 1988; 21: 297-310
        • Bellieni C.V.
        • Buonocore G.
        • Nenci A.
        • et al.
        Sensorial saturation: an effective analgesic tool for heel-prick in preterm infants: a prospective randomized trial.
        Biol Neonate. 2001; 80: 15-18
        • Blass E.M.
        • Watt L.B.
        Suckling- and sucrose-induced analgesia in human newborns.
        Pain. 1999; 83: 611-623
        • Gradin M.
        • Finnström O.
        • Schollin J.
        Feeding and oral glucose—additive effects on pain reduction in newborns.
        Early Hum Dev. 2004; 77: 57-65
        • Shide D.J.
        • Blass E.M.
        Opioid-like effects of intraoral infusions of corn oil and polycose on stress reactions in 10-day-old rats.
        Behav Neurosci. 1989; 103: 1168-1175
        • Leslie A.
        • Marlow N.
        Non-pharmacological pain relief.
        Semin Fetal Neonatal Med. 2006; 11: 246-250
        • Stevens B.
        • Yamada J.
        • Ohlsson A.
        Sucrose for analgesia in newborn infants undergoing painful procedures.
        Cochrane Database Syst Rev. 2010; 1 (CD001069, 1–114)
        • Faul F.
        • Erdfelder E.
        • Lang A.G.
        • et al.
        G∗Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
        Behav Res Methods. 2007; 39: 175-191
        • Saghaei M.
        Random allocation software for parallel group randomized trials.
        BMC Med Res Methodol. 2004; 9: 26
        • Grunau R.V.E.
        • Craig K.D.
        Pain expression in neonates: facial action and cry.
        Pain. 1987; 28: 395-410
        • Grunau R.E.
        • Oberlander T.
        • Holsti L.
        • Whitfield M.F.
        Bedside application of the facial coding system in pain assessment of premature neonates.
        Pain. 1998; 76: 277-286
        • Liang K.Y.
        • Zeger S.L.
        Longitudinal data analysis using general linear models.
        Biometrika. 1986; 73: 13-22
        • Anand K.J.S.
        Pain assessment in preterm neonates.
        Pediatrics. 2007; 119: 605-607
        • Hatfield L.
        Sucrose decreases infant biobehavioral pain response to immunizations: a randomized controlled trial.
        J Nurs Scholarsh. 2008; 40: 219-225
        • Mörelius E.
        • Theodorsson E.
        • Nelson N.
        Stress at three-month immunization: parents’ and infants’ salivary cortisol response in relation to the use of pacifier and oral glucose.
        Eur J Pain. 2009; 13: 202-208
        • Johnston C.C.
        • Filion F.
        • Snider L.
        • et al.
        How much sucrose is too much sucrose?.
        Pediatrics. 2007; 119: 206
        • Johnston C.C.
        • Filion F.
        • Snider L.
        • et al.
        Routine sucrose analgesia during the first week of life in neonates younger than 31 weeks postconceptional age.
        Pediatrics. 2002; 110: 523-528
        • Mathai S.
        • Natrajan N.
        • Rajalakshmi N.R.
        A comparative study of nonpharmacological methods to reduce pain in neonates.
        Indian Pediatr. 2006; 43: 1070-1075
        • Piira T.
        • Champion G.D.
        • Bustos T.
        • Donnelly N.
        • Lui K.
        Factors associated with infant pain responses following an immunization injection.
        Early Hum Dev. 2007; 83: 319-326
        • Dilen B.
        • Elseviers M.
        Oral glucose solution as pain relief in newborns: results of a clinical trial.
        Birth. 2010; 37: 98-105
        • Howard C.R.
        • Howard F.M.
        • Lanphear B.
        • et al.
        Randomised clinical trial of pacifier use and bottle-feeding or cup-feeding and their effect on breastfeeding.
        Pediatrics. 2003; 113: 511-519
        • Bellieni C.V.
        • Bagnoli F.
        • Perrone S.
        • et al.
        Effect of multisensory stimulation on analgesia in term newborns: a randomized controlled trial.
        Pediatr Res. 2002; 51: 460-463
        • Catelin C.
        • Tordjman S.
        • Morin V.
        • Oger E.
        • Sizun J.
        Clinical, physiological, and biological impact of environmental and behavioral interventions in neonates during a routine nursing procedure.
        J Pain. 2005; 6: 791-797
        • Boyle E.M.
        • Freer Y.
        • Khan-Orakzai Z.
        • et al.
        Sucrose and non-nutritive sucking for the relief of pain in screening for retinopathy of prematurity: a randomized controlled trial.
        Arch Dis Child Fetal Neonatal Ed. 2006; 91: F166-168
        • Hall W.R.
        • Anand K.J.S.
        Short- and long-term impact of neonatal pain and stress: more than an ouchie.
        NeoReviews. 2005; 6: e69-e75
        • Taddio A.
        • Shah V.
        • Gilbert-Macleod C.
        • Katz J.
        Conditioning and hyperalgesia in newborns exposed to repeated heel lances.
        JAMA. 2002; 288: 857-861
        • Stevens B.J.
        • Riddell R.R.P.
        • Oberlander T.E.
        • Gibbins S.
        Chapter 6: Assessment of pain in neonates and infant.
        in: Anand K.J.S. Steven B.J. McGrath P.J. Pain in neonates and infants. 3rd ed. Mosby Elsevier, St. Louis, MO2007

      Linked Article

      • Sucrose During Single Painful Procedures—No Longer a State of Equipoise
        Journal of Pain and Symptom ManagementVol. 43Issue 4
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          The recent study by Liaw et al.1 in the December 2011 issue showed that sucrose effectively reduced pain in newborn infants during a single, short-lasting, painful procedure. This is now the 145th published study of sweet solutions for infants and the 131st study where a placebo or no treatment group has been used (Harrison et al., unpublished data).
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