Objective: To determine whether lingual sucrose modifies the pain response to nasogastric tube insertion in preterm infants.
Design: Randomised, double-blind, placebo controlled clinical trial.
Setting: Special care baby unit.
Patients: 20 stable preterm infants who required nasogastric tube insertion for feeding, randomised on 51 occasions.
Intervention: Lingual 24% sucrose or water placebo (0.5–2 ml varying with body weight) administered 2 min before nasogastric tube insertion.
Outcome measures: Heart rate, oxygen saturation (SaO2), Neonatal Facial Coding Score and presence or absence of cry.
Results: Infants who received sucrose demonstrated a significantly lower Neonatal Facial Coding Score during nasogastric tube passage compared with the placebo group (median 1 (range 0–4) vs 3 (0–4), p = 0.004). There was a trend for sucrose-treated infants to have little change in heart rate during nasogastric tube passage compared with the placebo group (mean (SD) −0.73 (23) vs +11 (17), p = 0.055). Mean SaO2 did not change significantly. Pain response measurements quickly returned to baseline after nasogastric tube insertion. Adverse effects, such as apnoea or oxygen desaturation, were few and occurred equally in each group.
Conclusions: Nasogastric tube insertion induces a pain response comparable with previously reported responses to heel lance in neonates. Single-dose lingual 24% sucrose is effective in reducing the behavioural and physiological pain response to nasogastric tube insertion in preterm infants and it appears to be safe.
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Nasogastric tube (NGT) insertion is a painful procedure in adults1 and this is likely to be the same in infants. NGT insertion is a frequently performed procedure on neonatal units; on average each infant has a NGT inserted once every 2 days.2 A recent consensus statement on neonatal pain made recommendations for analgesia for neonatal procedures including NGT insertion.3
Oral sucrose has been shown to be an effective and safe analgesic for some common neonatal procedures such as blood sampling by heel lance and venepuncture.4 5 Sucrose has a rapid-onset, brief analgesic action thought to be mediated by activation of lingual sweet taste receptors and release of endogenous brain opioids.6 The neonatal pain response to NGT insertion has not previously been investigated and the use of sucrose for its analgesic effect on NGT insertion has not been evaluated.
The aim of this randomised, placebo controlled clinical trial was to determine the effect of lingual 24% sucrose on the physiological and behavioural pain responses generated by NGT insertion in stable preterm infants.
We conducted this study on our neonatal unit. Infants were eligible for inclusion in the study if they were clinically stable, on full volume bolus nasogastric feeds and required routine NGT reinsertion. Infants were excluded if they required ventilatory support or supplemental oxygen, had any facial congenital anomalies or neurological impairment, were receiving opiates or were infants of opiate-using mothers.7
Parents of eligible infants were approached by nursing or medical staff and given verbal and written information about the study. Those who agreed to participate gave written consent and their infant was enrolled into the trial. Enrolled infants could be randomised on more than one occasion provided they remained eligible. This was not a cross-over study. In each instance where NGT reinsertion was required, the infant was randomised separately and independently of any previous allocation to receive either placebo (sterile water) or 24% sucrose solution (Sweet-Ease; Inspiration Healthcare Ltd, UK) prior to the NGT procedure.
Randomisation was performed by the pharmacy department using a computer-generated random number lists in blocks of 10 for 50 trials. The test solutions were prepared fresh each day in 2 ml syringes and placed in sealed opaque envelopes in consecutive sets of five and kept in the neonatal unit refrigerator and used in trial number order. The volume of test solution administered to each baby was adjusted for current body weight based on doses used in previously published studies of low birthweight infants.4 8 9 We chose 2 ml for infants greater than 2 kg in weight, 1.5 ml for those between 1.5 kg and 2 kg and 0.5 ml for those below 1.5 kg.
For each NGT passage the following procedure was followed. Before the baby was disturbed, baseline behavioural state was recorded using a modified Prechtl score10 11 (1–5 by the presence or absence of combinations of spontaneous movement, eye opening and cry). Behavioural state (alertness) is known to correlate positively with neonatal pain response.12 A pulse oximeter (Nellcor; Tyco Healthcare, UK) was then placed to record heart rate and oxygen saturation (SaO2).
Behavioural pain responses were measured using the Neonatal Facial Coding Score (NFCS) as the primary outcome measure for this study. The presence or absence of cry was also recorded.12 13 The NFCS uses four facial responses: brow bulge, eye squeeze, deepened nasolabial furrow and open lips (possible score 0–4). The NFCS has been extensively validated and used in neonatal pain research.11 14–16
The test solution was administered by 2 ml syringe to the front of the infant’s tongue, slowly over 1–2 min. The presence or absence of adverse effects, as judged by the neonatal nurse administering the test solution, was recorded. Two minutes later the NGT was passed, following our standard unit procedure (an unlubricated 6 Fr neonatal feeding tube passed through the nostril that had not most recently been used for tube placement). A second nurse, who had not witnessed or been involved in the lingual administration of the test solution, recorded the NFCS, maximum/minimum heart rate and lowest SaO2 during the NGT insertion. The presence or absence of adverse effects was again judged by the second neonatal nurse, and recorded, together with a judgment about the ease of passage of the NGT (easy, difficult or failed). NFCS, SaO2 and heart rate measurements were repeated at the end of the procedure after the NGT had been secured.
There are no previously published data on neonatal pain response to NGT insertion. Hence, the range of NFCS responses was unknown and a power calculation for this study could not be performed. However, we planned to perform an analysis after 50 NGT reinsertions (25 water and 25 sucrose).
We compared the two study groups for significant differences by using a two-tailed Mann–Whitney U test for unpaired data (NFCS, Prechtl score) and a two-tailed unpaired t test for the remaining normally distributed data. Group proportions were compared by using a two-tailed test of significance for proportions in unpaired samples.
A total of 30 infants were eligible for inclusion in the study, of which 25 were enrolled and 20 actually took part. In the study period, measurements were made during 51 NGT reinsertions in these 20 infants. The median frequency of NGT reinsertions studied was 2 per infant with 6 infants studied on more than two occasions, although never more than once in any 12-h period. The 20 infants studied (11 boys and 9 girls) had a mean (SD) birth weight of 1.63 kg (0.55) and a mean birth gestation of 30.7 weeks (2.3). The infants randomised to receive sucrose had a significantly higher baseline heart rate and a non-significant trend to a more alert behavioural state (higher Prechtl score) (table 1).
Behavioural pain responses
Table 2 summarises the behavioural and physiological pain responses during NGT insertion. The sucrose group had a significantly lower median NFCS score during NGT insertion compared with the placebo group (1 (range 0–4) vs 3 (range 0–4), median difference 1 (95% CI 0 to 2) p = 0.004). There was a non-significant trend (p = 0.069) for fewer sucrose-treated infants to cry during NGT insertion (8/26), compared with the placebo group (14/25). After NGT passage, the NFCS fell to a median of 0 in both groups, with a similar proportion of babies still manifesting cry (four in each group).
We were unsure whether the facial responses measured by the NFCS would be a reliable indicator of pain or whether they would be merely a local reflex response to tactile stimulation of the nose by the NGT. To explore this, we analysed the four individual components of the NFCS and were reassured to find that the response most likely to reflect this, namely deepening of the nasolabial folds, did indeed show significant inhibition in the sucrose group (present in 4/26 (15%) compared with 12/25 (48%) in the placebo group; p = 0.012). Hence, the NFCS is a reliable method of monitoring pain response in neonates, even when the stimulus involves the face and, specifically, the nasal mucosa.
Infants in the trial group randomised to later receive sucrose had a higher mean pretreatment baseline heart rate than the placebo group, but they showed no change in heart rate during NGT insertion (mean change –0.7 bpm). In contrast, in the placebo group the heart rate increased during NGT insertion (mean change +11 bpm); this difference approached statistical significance when compared with the sucrose group (p = 0.055) (see fig 1 and table 1). There were no significant changes in mean SaO2 during NGT insertion in infants in both groups nor was there any significant difference between the two groups.
Adverse effects/ease of NGT insertion
There were no significant differences between the two groups with regard to the number of adverse events attributable to either solution administration or NGT passage (table 2). Both groups had similar proportions of “difficult” NGT insertions. Brief apnoea or self-limiting bradycardia was seen in a handful of infants; none was clinically important or required intervention.
What is already known on this topic
Oral sucrose is an effective analgesic in neonates for brief procedural pain, such as with venepuncture and heel lance.
Sucrose has a rapid-onset, short-lived effect thought to be mediated by endogenous brain opioid release.
What this study adds
Nasogastric tube insertion generates a pain response similar to that shown previously for heel lance.
Lingual 24% sucrose reduces the behavioural and physiological pain response to nasogastric tube insertion in preterm infants.
Our study has shown that NGT insertion in stable preterm infants elicits a measurable pain response. This is similar in magnitude, using the NFCS pain score, to the pain response observed during heel lancing in other studies.8 9 11 Lingual 24% sucrose was effective in reducing this pain response to NGT insertion when compared with water placebo, as measured by our primary outcome measure, the NFCS.
As well as measuring the infants’ behavioural response to pain (NFCS and cry), we also measured two physiological responses—heart rate and SaO2. We found that baseline heart rate was higher in the infants who would later receive sucrose, before any intervention. This was an unexpected finding, so the changes in heart rate in response to NGT-induced pain, seen in our study, must be interpreted with caution. Nevertheless, we found that heart rate in the sucrose group changed little from baseline and during and after NGT insertion, whereas the placebo group demonstrated a rise in heart rate during NGT insertion, falling thereafter (fig 1). This is in keeping with an analgesic effect of sucrose. A Cochrane review on the use of sucrose analgesia, in which results of studies were pooled, showed no significant differences in changes in heart rate or oxygen saturation between infants receiving sucrose and those receiving placebo.4
Despite careful attention to randomisation and blinding, the infants in the sucrose group in our study seemed to be in a higher state of alertness before any intervention. This was manifest by a significantly higher heart rate and a non-significant trend towards higher median Prechtl score before sucrose was administered. We have no explanation for this finding. Nevertheless, it does not invalidate our results or conclusions. Previous studies have shown that infants in a higher state of arousal manifest an enhanced behavioural pain response to heel lancing.12 Hence, in our study the sucrose group might have been expected to show a greater pain response than the placebo group but we found the reverse. Therefore the differences seen in the NFCS between the two groups may represent an underestimate of the true treatment effect of sucrose.
Researchers in the field of neonatal pain have used a variety of multidimensional pain assessment tools.17 18 We chose to use the NFCS as our primary outcome measure to assess behavioural pain response because of its simplicity and reproducibility. To this, we added the simple observation of presence or absence of cry. Other studies have included more complex cry measures such as duration of cry, cry latency and the acoustic quality of crying using video/audio recording and other specialist equipment.9 12 19–21 Our study demonstrates that simple cot side observation of the four-point NFCS, with presence or absence of cry, can successfully discriminate a significant analgesic effect of sucrose without the need for more complex methods.
Facial expression has been shown to be relatively specific to pain and the most consistent response in infants.22 The NFCS was adopted from the Facial Action Coding System of Grunau and Craig.13 It can differentiate between painful and non-painful stimuli and has well-founded validity.14 Studies have shown that 96–99% of term infants will demonstrate brow bulge, eye squeeze, deepening of the nasolabial furrow and open lips in response to heel lancing.12 13 Refining the score to just these four items plus presence/absence of cry maintains its specificity for pain assessment without reducing the sensitivity and validity of detecting changes in pain.15 The score has high interobserver reliability and can be used at the bedside.11 16 The response to painful stimuli is consistent and not influenced by gestational age or postnatal age.11 17
Our study design was not that of a cross-over study. Instead, we allowed infants, who remained eligible, and who required NGT reinsertion, to be randomised on multiple occasions. Infants in whom this occurred were not randomised more than once in any 12-h period to avoid the possibility of any carry-over effect. Sucrose is known to have a very brief period of analgesic action (about 10 min) so we do not think that our study design introduced any carry-over effect that could have biased our findings.
The mechanism by which sucrose exerts its analgesic effect in neonates is only partially understood.6 The effect is mediated by activation of sweet taste receptors on the anterior tongue; no effect is seen when sucrose in administered intragastrically.23 The analgesic effect of lingual sucrose has rapid onset (1–2 min) and short duration (7–8 min), making it ideally suited for brief painful procedures.24 Studies in rat models have shown that sucrose activates two key brainstem sites which are important in descending pain modulation.25 Other animal studies have suggested the involvement of indirect inactivation of μ1-opiod receptors by endogenous opioid release.26 27 Some studies, though not all, have shown that the effect is blocked by the opioid antagonist naloxone.6 Further animal evidence suggests involvement of monoamine and 5-hydroxytryptamine (5-HT)2A serotonergic/α1 noradrenergic receptors in the central regulation of the analgesia produced by sweet substances.26 28 It is clear that the sweet taste itself does not simply operate through a direct calming effect, but rather it triggers a more complex analgesic action, as the effect continues long after the sweet taste has dissipated.29 A measurable analgesic effect of sweet taste is preserved in older children and adults although with a much diminished effect, waning with age and apparently correlated with sweet taste preference.30
A legitimate concern about frequent or repeated use of sucrose for neonatal procedures is the possibility of short-term and long-term adverse effects. Six studies from a Cochrane review4 evaluated short-term adverse effects, but only one study17 reported the frequency and episodes of desaturation or choking with an increased frequency seen in the least mature infants. These adverse effects resolved spontaneously without any medical intervention. The Cochrane review concluded that the use of sucrose had minimal to no side effects. Our study was not rigorously designed to detect the frequency of adverse effects; we relied on reporting by clinical observation of experienced neonatal nurses. We found that there was no significant difference in the number of adverse effects in the two study groups with regard to either test solution administration or NGT insertion. We observed occasional self-limiting bradycardia, transient oxygen desaturation, and choking or coughing; none of these events required medical intervention. Thus, single use of sucrose seems to be safe.
Repeated use of sucrose over a period of time raises different safety issues. Studies have raised the possibility of an increased risk of necrotising enterocolitis due to the hyperosmolality.31 Other unconfirmed reports have raised concern about late adverse neurobehavioural outcomes.20 A more recent study addressed this concern in infants of gestational age 26–30 weeks receiving sucrose and pacifier for any painful procedure until 28 days of age.32 This study showed no associated increase in either immediate or long-term complications with the regular use of sucrose.
Among adults, NGT insertion has been identified as one of the most painful procedures commonly performed in the accident and emergency department—for example, NGT insertion was rated by patients and practitioners as more painful than abscess drainage and urethral catheterisation.1 It is reasonable to assume that the procedure will be at least as painful in neonates. Local anaesthesia, such as lidocaine (nebuliser, spray or gel), has been shown to reduce the pain in NGT insertion in adults,33 34 but this has not been investigated in infants.
Although our study has demonstrated pain responses to NGT insertion that are quantitatively comparable with other neonatal procedures such as heel lance, it is possible that the discomfort of NGT insertion may be qualitatively different from these needle procedures. It is likely to have at least two components, namely the immediate pain from the sensitive nasal mucosa and the subsequent unpleasant sensation of gagging arising from the contact between the tube and the pharynx and upper oesophagus. Our study does not differentiate between these two pathways.
Our study has demonstrated that preterm infants manifest a pain response to NGT insertion which is similar in magnitude to other painful neonatal procedures. Pretreatment with lingual 24% sucrose acts quickly to reduce but not abolish this pain response. This simple intervention may have a clinically useful role in reducing the burden of pain associated with repeated procedures in preterm infants. Research and surveillance to confirm the long-term safety of repeated sucrose administration in the newborn period should continue.
We are grateful to parents and neonatal unit nursing staff for participating in the study, and to A Wilson who provided secretarial support to the project.
Competing interests: None.
Ethics approval: The regional ethics committee approved the study.