J. Paediatr.

Child Health (2003) 39, 591597

Oral sucrose for procedural pain in sick hospitalized infants: A randomized-controlled trial
D Harrison,1,2,3 L Johnston1,2,3 and P Loughnan1
1

Department of Neonatology Royal Childrens Hospital, 2Murdoch Childrens Research Institute, 3 School of Nursing, The University of Melbourne, Victoria, Australia

Objective: To determine the efficacy of 25% oral sucrose in the reduction of pain during a heel lance procedure in sick hospitalized infants. Methodology: In a blinded randomized- controlled trial, hospitalized infants were given either 1 mL 25% sucrose or 1 mL water 2 min prior to a heel lance procedure. Pain assessment comprised a four-point facial expression score, incidence and duration of crying, heart rate and oxygen saturation changes. Results: A total of 128 infants were included. Facial scores immediately upon heel lance, and at 1 and 2 min in the recovery period were reduced in the treatment (sucrose) group compared to the placebo (water) group (P < 0.05). At other observation points, the differences in facial scores between the two groups of infants did not reach statistical significance. Neither incidence nor duration of crying whilst the blood collection was in progress was significantly reduced by sucrose. In the 3-min recovery period following completion of the blood collection, incidence and duration of crying were significantly less in the treatment group of infants (P < 0.05). Physiological responses of heart rate and oxygen saturation were not attenuated by sucrose at any time point during or following the blood collection. Conclusion: Oral sucrose was effective in reducing behavioural responses to pain upon heel lance and in the period following completion of a heel lance procedure in this group of sick hospitalized infants. This simple strategy can be promoted in institutions caring for sick babies, as a method of reducing behavioural responses to procedural pain. Key words: analgesia; blood specimen collection; infant; newborn; pain; sucrose. Heel lancing is a frequently performed invasive procedure for hospitalized infants,1 and is associated with both behavioural and physiological changes.2 In the last 10 years, the administration of oral sucrose has been the most frequently studied nonpharmacological intervention for reduction of procedural pain in neonates.3 There are two mechanisms by which sucrose works. The first is an immediate and short acting attentiongaining response due to a strong taste, resulting in instant calming and cessation of crying.4 The second and principal mechanism is due to the release of endogenous opioids, causing an analgesic-like effect, which peaks at 2 min,5 and lasts around 5 min.69 These ongoing effects are sweet taste mediated, and are also seen when non-sucrose sweet tasting solutions are administered orally.1012 However, the calming and analgesic effects are reduced when less sweet solutions are administered, such as lower concentrations of sucrose and other sugars, expressed breast milk, artificial milk formula, fats or proteins, or less sweet sugars such as lactose and polycose.4,10,1216 The analgesic effects of sucrose are orally mediated, as demonstrated by the lack of effect if sucrose is given directly into the stomach via a nasogastric tube.7 The analgesic effect of sweet tasting solutions is dependent on a functioning endogenous opioid system, as evidenced by the lack of effect in infants of mothers on methadone6 and the reversal of the calming response with administration of opioid antagonists.17 The use of sucrose in reducing pain associated with minor painful procedures has been studied in well term infants and in medically stable low birth-weight infants.3 In a small number of studies,15,18 sweet tasting solutions resulted in less of an analgesic effect compared with other studies.3 The lower concentrations of sucrose administered in these trials may have been insufficiently sweet to stimulate release of endogenous opioids.10 Other studies in which oral sucrose was less effective in calming crying infants, or reducing pain responses during procedures, have included older infants between 2 and 6 months.19,20 In one study of infants aged 26 months, a 75% sucrose solution was used as a 50% sucrose solution was found to be ineffective in a pilot study.21 In the studies undertaken to date examining the efficacy of sucrose and other sweet solutions, infants with congenital abnormalities, those who have undergone surgery and infants with chronic medical problems were excluded. As a result, the efficacy and safety of oral sucrose for analgesic purposes in this population of infants has not been established. The aim of this study was to determine the effectiveness of 25% oral sucrose in reducing pain during heel lancing in sick hospitalized infants. METHODS This study was a blinded randomized-controlled trial of 1 mL of sucrose (treatment) or water (placebo) administered orally 2 min prior to a heel lance procedure. The study was approved by the Ethics in Human Research Committee at the Royal Childrens Hospital.

Correspondence: Ms D Harrison, Neonatal Unit, Royal Childrens Hospital, Flemington Road, Parkville, Vic. 3052, Australia. Fax: +61 3 9345 5315; email: denise.harrison@rch.org.au Accepted for publication 15 April 2003.

592 Study population Participants considered for entry included all infants admitted to the Neonatal Unit, and infants less than 2 months corrected age admitted to the Cardiac Unit. The Neonatal Unit is a 24-bed tertiary neonatal intensive care and special care nursery, which provides care for infants with complex medical and surgical, genetic and metabolic conditions. The Cardiac Unit provides cardiac medical and surgical services for infants and older children. Infants were eligible for entry into the trial if the collection of a capillary blood sample was anticipated, unless one of the following exclusion criteria were present: (i) proven or suspected central nervous system disease; (ii) altered swallow or gag reflexes; (iii) spinal cord malformation (myelomeningocele, sacral teratoma); (iv) proven or suspected necrotising enterocolitis; (v) administration of narcotic analgesics, muscle relaxants, sedatives, anticonvulsants, or other drugs likely to affect responses to painful stimuli within the previous 48 h; and (vi) infants of methadone dependent mothers. Randomization A computer generated randomization system was used to assign infants in random blocks of two, four, six or eight to the sucrose or water group. The Pharmacy Department at the participating institution held the codes of group assignment and made up the test solutions accordingly in consecutively numbered identical syringes with a label obscuring the syringe contents. The codes were not released to the investigator until completion of the trial. Intervention The infants received either the treatment solution of 1 mL 25% sucrose or the placebo solution of 1 mL of sterile water. For infants weighing 1500 g or less on the day of participation in the trial, the dose was reduced to 0.5 mL. Blinding Administration of the study solution was performed by the nurse caring for the infant. The nurse administered the solution onto the infants anterior tongue over 1 min, commencing 2 min prior to the heel lance. The nurse was asked not to comment upon the infants response to the solution, thus ensuring that the investigator remained blinded to the solution being administered. If a pacifier was a normal part of the individual infants care, it was offered and supported in the infants mouth to elicit non-nutritive sucking. Outcome measures A combination of behavioural and physiological parameters was utilized to measure the infants responses to the heel lance procedure. The first behavioural measure was a four-point subset of the Neonatal Facial Coding System (NFCS),22 comprising visual assessment of brow bulge, eye squeeze, nasolabial furrow and stretched mouth opening. This subset of the NFCS has been shown to be a reliable and valid method to assess procedural pain in infants.2325 The second behavioural parameter was

D Harrison et al. incidence and duration of crying, measured by audiotaping the infants cry. During playback of the tape, the following crying characteristics were measured: (i) duration of first cry until a 5 s pause; (ii) incidence and duration of crying during the heel lance and squeeze; and (iii) in the 3-min recovery period following completion of the blood collection. The percentage of crying time during the heel lance and heel squeeze and in the 3-minute recovery period was calculated. Physiological parameters measured were heart rate and oxygen saturation (SpO2). All infants had cardiorespiratory and pulse oximetry status monitored continuously using a Hewlett Packard Transport Monitor, model M1276A (Hewlett Packard, Andover, MA, USA). Application of leads was completed at least 1 hour prior to the study. Assessment and documentation of facial expression scores, and documentation of physiological parameters occurred at baseline, upon the heel lance, and at set points throughout both the heel squeeze phase and the recovery period following completion of the procedure (Fig. 1). In some infants, a second heel lance was required to complete the blood collection. If this occurred, observation points continued to be timed from the initial heel lance. The same investigator, skilled in using the NFCS, completed all pain assessments throughout the study. Baseline observations also included behavioural state,26 and severity of illness as determined by the Neonatal Therapeutic Intervention Scoring System (NTISS).27 The heel lance procedure was performed in a standardized manner by one of four experienced phlebotomists using a 1.9 1.0 mm spring-loaded lancet (Microtainer Brand Safety Flow Lancets, Becton Dickinson, NJ, USA). Statistical analysis Stata 7.0 statistical software was used for analysis of the data. (Stata Corporation, College Station, TX, USA). A two-sample Students t-test was used for normally distributed continuous variables, Pearsons Chi-squared test for categorical variables with large frequencies, and Fishers exact test for categorical variables with small frequencies. The non-parametric twosample Wilcoxon rank sum (MannWhitney) test was employed for analysis of non-normally distributed continuous data. In the event of significant confounding variables, a regression analysis was used. Probability values of less than 0.05 were considered statistically significant. Data from a previous pain assessment pilot study were used for a sample size calculation.24 A 20% reduction in mean facial expression pain scores was considered clinically meaningful. Sixty-four infants in each group were required to detect this difference assuming 80% power and two-sided of 0.05. RESULTS Recruitment and enrolment Data collection commenced in May 2000 in the Neonatal Unit, and August 2000 in the Cardiac Unit, and was completed in July 2001. The numbers of infants potentially eligible and subsequently randomized are summarized in Figure 2. Potentially eligible infants were not studied if there was no further requirement for blood tests by a heel lance once they had met the eligibility criteria, or if the infants were transferred out of the participating units, or if the sole investigator was unavailable for data collection when blood collections were taking

Sucrose for sick infants prior to heel lance

593

Fig. 1

Timeline depicting administration of intervention and points at which pain assessments were documented.

Fig. 2 Numbers of infants who were admitted to the Neonatal Unit (NNU) and Cardiac Unit during the study periods, and who were eligible and randomly assigned to the sucrose (treatment) and water (placebo) groups.

place. A total of 128 infants were enrolled in the study, 100 in the Neonatal Unit and 28 in the Cardiac Unit.

Main outcome measures Total facial scores were significantly lower in the treatment group than the placebo group upon heel lance (2 4, P = 0.02), and at 1 and 2 min during the recovery period (2 3, P = 0.04) and (2 3, P = 0.046, respectively). Figure 3 presents the distribution of facial expression scores at these time points. In contrast, during and upon immediate completion of the heel squeeze phase of the procedure, there were no significant differences in facial scores between the two groups. By the final observation point of the recovery period, the distribution of facial scores between the two groups of infants was no longer significantly different (2 3, P = 0.21) (Fig. 3d). Crying characteristics were measured in 123 of the total 128 infants, as there were five infants (two in the treatment group

Study participant demographics The baseline characteristics of the infants in the two groups were similar and are presented in Table 1. Two characteristics differed significantly between the groups. First, there was an increased number of infants in the sucrose group using a pacifier (P = 0.04). Second, infants in the placebo group had a higher mean NTISS score indicating increased severity of illness (P = 0.02).

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D Harrison et al.

Table 1

Characteristics of infants in the treatment and placebo groups Treatment group n = 65 [%]/(SD) 19 46 2647 36.6 49 21 19 8 17 33 14 55 20 17 12 4 3 8.4 33 17 145 8 [29] [71] (841) (3.6) [75] [33] [29] [12] [26] [51] (11) [85] [36] [31] [22] [7] [4] (4.2) (44) (15.9) (95) [13] Placebo group n = 63 [%]/(SD) 24 39 2546 35.7 37 20 14 11 18 34 12 57 24 18 10 4 1 10.1 32 23 167 15 [38] [62] (986) (4.4) [59] [32] [22] [17] [29] [54] (10) [90] [42] [32] [18] [7] [2] (4.4) (36) (24) (101) [23] P

Infant characteristics

Gender Female Male Birthweight (g) Gestational age (weeks) Use of pacier Sleep state 1 2 3 4 Previous surgery Mean number of days since most recent surgery On enteral feeds If on enteral feeds: hours since last feed 1 2 3 4 5 NTISS score Length of stay (days) Age at day of study (days) Duration of procedure (s) Repeat heel lance required

0.29 0.53 0.22 0.04 0.74

0.72 0.44 0.32 0.93

0.02 0.79 0.09 0.22 0.13

Results presented as absolute numbers or mean values. Figures in square brackets are percentages of total, and Figures in parentheses are standard deviations of the mean values. NTISS, Neonatal Therapeutic Intervention Scoring System.

and three infants in the placebo group) unable to vocalize due to the presence of either an endotracheal tube or tracheostomy. The median percentage of crying during the blood collection was no different between the two groups (60% for infants in the treatment group vs 69% for infants in the placebo group; P = 0.43) (Fig. 4). The median duration of the first cry until a 5 s pause was also not different between the groups (37 s for infants in the treatment group vs 45 s for infants in the placebo group; P = 0.26). However, during the 3-min recovery period, the percentage of time spent crying was significantly less in the treatment group compared to infants in the placebo group (P = 0.01) (Fig. 4). There was no difference in the mean heart rate between the two groups of infants at any time during or following the heel lance procedure. Mean heart rate for infants in both groups increased from baseline, and remained constantly elevated above baseline levels throughout the duration of the procedure. By the 3-min observation point during the heel squeeze, the mean heart rate of both groups of infants had reached maximum values. Subsequently the mean heart rate of both groups decreased steadily until the final observation point, yet remained elevated above baseline levels. There was also no difference in the mean SpO2 between the two groups of infants at any point, either during or following completion of the heel lance procedure. DISCUSSION The administration of 1 mL of 25% sucrose to this cohort of sick hospitalized infants, prior to a heel lance procedure,

resulted in a reduction in behavioural pain responses. This was demonstrated by reduced facial scores in the treatment group upon heel lance, and at the 1 and 2-min observation points in the recovery period. This suggests that the analgesic effect of sucrose blunted the initial response to pain; was less effective in reducing pain while the heel lance procedure was in progress; and reduced distress in the period following completion of the procedure. The lack of significant difference in facial scores at the final observation point may have been due to the endorphin effect being diminished by this time.28,29 Crying duration was significantly reduced in the treatment group of infants in the 3-min recovery period following completion of the blood collection, but was not demonstrated during the lance and squeeze phase of the procedure itself. The lack of treatment effect in reducing crying duration whilst the blood test was in progress differs from that of similar trials previously conducted. In this present trial, unlike most trials examining heel lancing, the study population included sick and older infants. Ninety infants (73%) included in the trial were beyond 1 week of postnatal age, and 30 (23%) were beyond the neonatal period of 28 postnatal days. Studies of the analgesic effects of oral sucrose in older infants examined the infants response to immunization injections.19,21 Results of these studies showed decreased efficacy of similar doses of oral sucrose in reducing crying compared to those studies of younger infants. It was concluded that the use of oral sucrose beyond the neonatal period was less effective; increased sucrose doses were required, and the effect was limited to the period following recovery from the procedure rather than while the procedure was in progress.19 This is consistent with the results of this trial.

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Duration of the first cry, following the initial heel lance, was not significantly reduced by oral sucrose in this study. Other comparable trials demonstrated that the administration of oral sucrose prior to a heel lance procedure resulted in significant reductions in the duration of the first cry, depending on the concentration of sucrose used.18,30,31 Possible reasons for this discrepancy include the inclusion of older infants, or the reduced ability of the sicker infants in the placebo group to cry for a prolonged period of time. In this trial, 25% oral sucrose did not result in a significant reduction of physiological responses to the heel lance procedure at any time, either during or following completion of the blood collection. The efficacy of sucrose in reducing

Fig. 4 Percentage crying time during (a) lance and squeeze (P = 0.43) and (b) during 3-min recovery period (P = 0.01) (MannWhitney ranksum). Circles represent individual infants.

Fig. 3 Distribution of facial scores at (a) heel lance (P = 0.02); (b) 1 min into recovery time (P = 0.04); (c) 2 min into recovery time (P = 0.046); and (d) at the final 3-min recovery period (P = 0.21). Bars represent the actual numbers of infants in each group who scored each facial score, on a zero to four scale. Percentages of infants with each score are presented above each bar. For each Figure, P < 0.05 with the exception of the final observation point in the recovery period (Fishers exact Chi-squared). ( ), Treatment; ( ), placebo.

596 physiological responses to pain has been variable in previous studies.3 In this study, the lack of a physiological effect may have been due to the infants in the placebo group being more ill thus having reduced ability to mount as strong a physiological response as the less ill infants in the treatment group. This has been previously described.32 Consistent with results of most previous studies, this study also demonstrated a lack of response to sucrose in attenuating SpO2 changes occurring in response to a painful procedure.3,18,30,33,34 Limitations to this study include the unequal distribution of both the incidence of pacifier use between the two groups of infants and the severity of illness as measured by the mean NTISS scores (Table 1). A post hoc logistic regression analysis was performed to examine whether either of these factors confounded the relationship between sucrose and the response to the heel lance procedure. Without adjustment for pacifier use, the odds ratio (OR) for crying following the heel lance procedure in the treatment group of infants was 0.36 (95% CI 0.17, 0.78). Following adjustment, the OR remained the same (0.36, 95% CI 0.17, 0.78). Therefore there was a 64% reduction in crying in the treatment group of infants, regardless of whether infants were sucking on a pacifier. Severity of illness scores as denoted by the NTISS score, were also significantly different between the two groups (P = 0.02). Compared to the unadjusted OR of 0.36, when the NTISS score was included in the regression model, the OR for crying following completion of the procedure in the treatment group was further reduced to 0.29 (95% CI 0.13, 0.65). This suggests that, when the NTISS scores were not adjusted for, the analgesic effects of oral sucrose may have been underestimated. The other limitation to this study is that the examination of the efficacy of oral sucrose was limited to a single episode of heel lancing. Infants responses have been shown to vary over time2,3537 and also to vary with context, depending on factors such as the time since the most recent painful procedure35 and the number of previous painful procedures.38,39 Further studies are required to examine the efficacy and safety of repeated doses of oral sucrose in the continued reduction of pain during procedures in sick hospitalized infants. CONCLUSION This trial has demonstrated that sick hospitalized infants, in whom oral sucrose was administered prior to a blood collection by a heel lance, exhibited reduced behavioural responses to pain in the period following completion of the procedure, compared to a group receiving placebo. Physiological responses to the heel lance procedure, as measured by heart rate and SpO2 were not attenuated by the oral sucrose. These findings, although more modest than seen in similar studies of the use of oral sucrose for analgesia, further strengthen existing evidence of the benefits of administering oral sucrose to infants prior to painful procedures. This simple strategy can be promoted in institutions caring for sick infants, as a method of reducing behavioural responses to heel lance procedures. ACKNOWLEDGEMENTS The authors thank the families of infants who participated as well as the participating staff at the Royal Childrens Hospital. Special thanks also go to staff at The Clinical Epidemiology and Biostatics Unit, K Hynes in the Drug Information Centre,

D Harrison et al. members of the Pathology Collection Team plus C Evans, R Wallace and T McConnell. Sources of support: Murdoch Childrens Research Institute (Trainee Research Scholarship and Minor Grant), Australian Nurses Federation (Elizabeth Hulme Special Interest Group Clinical Research Grant), and Neonatal Unit Charity Group; Tiny Miracles. REFERENCES
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32 Field T, Goldson E. Pacifying effects of non-nutritive sucking on term and preterm neonates during heel stick procedures. Pediatrics 1984; 74: 10125. 33 Bucher HU, Moser T, von Siebenthal K, Keel M, Wolf M, Duc G. Sucrose reduces pain reaction to heel lancing in preterm infants: a placebo-controlled, randomized and masked study. Pediatr. Res. 1995; 38: 3325. 34 Abad F, Diaz NM, Domenech E, Robayna M, Rico J. Oral sweet solution reduces pain-related behaviour in preterm infants. Acta Pdiatr. 1996; 85: 8548. 35 Johnston CC, Stevens BJ, Franck LS, Jack A, Stremler R, Platt R. Factors explaining lack of response to heel stick in preterm newborns. J. Obstet. Gynecol. Neonatal Nurs. 1999; 28: 58794. 36 Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain response. Pediatrics 1996; 98: 92530. 37 Johnston CC, Stevens BJ, Yang F, Horton L. Developmental changes in response to heelstick in preterm infants: a prospective cohort study. Dev. Med. Child. Neurol. 1996; 38: 43845. 38 Stevens B, Johnston C, Franck L, Petryshen P, Jack A, Foster G. The efficacy of developmentally sensitive interventions and sucrose for relieving procedural pain in very low birth weight neonates. Nurs. Res. 1999; 48: 3543. 39 Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity following peripheral tissue damage in newborn infants and its reversal with topical anaesthesia. Pain 1989; 39: 316.