The Effectiveness of Glucose in Reducing Needle-Related Procedural Pain in Infants

Article Outline

• Abstract
• Methods
  • Search Strategy/Study Identification
  • Study Selection
  • Assessment of Study Quality and Data Management
• Results
  • Literature Search and Descriptive Characteristics of Included Studies
  • Effectiveness of Glucose: Physiological Measures
  • Effectiveness of Glucose: Behavioral Measures
  • Effectiveness of Glucose: Composite Measures
• Discussion
• Acknowledgments
• References
• Copyright

This systematic review examined the effectiveness of glucose in relieving needle-associated pain in infants. Meta-analysis was not undertaken, and there was variation in dose, administration method, concentration, and outcome measurement. Glucose was more effective than placebo in relieving infant pain as measured by behavioral outcomes, but there were mixed findings for physiological outcomes. Based on these findings, 25%–50% glucose appears effective for infant pain management.

Key words: Analgesia, Infant, Glucose, Systematic review

ACUTELY PAINFUL PROCEDURES such as heel pricks for blood samples and immunization injections are administered frequently in both ill and healthy infants. There has been concern about the impact of performing such procedures without analgesia, with findings suggesting that exposure to painful stimuli in infancy is associated with increased sensitivity to pain (Andrews & Fitzgerald, 1999, Porter et al., 1999, Taddio et al., 2002) and heightened responsiveness and pain avoidance in later life (Fitzgerald & Howard, 2003, Grunau et al., 2001, Johnston & Stevens, 1996, Johnston et al., 2003, Porter et al., 1998). Cumulative pain experiences are believed to change the developing nociceptive system (Andrews & Fitzgerald, 1999, Overgaard & Knudsen, 1999, Porter et al., 1999, Ramenghi et al., 1996), which can lead to an enhanced response to painful stimuli (Schechter, Berde, & Yaster, 2003) after infancy. Pain relief for infants exposed to painful procedures is thus an important issue.

In this review, we define a pain-relieving effect as the reduction of short-term behavioral and physiological measures associated with painful procedures. We acknowledge the challenge of differentiating between calming effects and analgesic effects (Fitzgerald, 2009), as well as new research that suggests that sweet solutions such as sucrose may be calming, rather than analgesic, agents and may not be able to have a long-term effect (Taddio, Shah, Atenafu, & Katz, 2009). However, to date, the literature has focused on short-term behavioral and physiological measures for assessing pain relief (Taddio et al., 2009), and the implications of Taddio et al.'s (2009) findings have yet to be addressed fully in the research literature. We have therefore adopted this definition to carry out a narrative systematic review of the literature.

Because infancy is a time of rapid cortical development, there has been research interest in the impact of procedural pain and methods for procedural pain management (Derbyshire, 1999, Stevens & Koren, 1998) and immunization in particular (Abu-Arafeh et al., 1998, Choonara & Beyer, 1998, Hatfield et al., 2008, Lewindon et al., 1998, Ramenghi et al., 2002, Thyr et al., 2007). Immunization is an important source of procedural pain because it is a common and frequently performed procedure in healthy infants; for example, the Australian immunization schedule recommends a number of injections within the first few months of life, such as hepatitis B, diphtheria, pertussis, tetanus, polio, and rotavirus (Australian Government Department of Health and Ageing., 2009).

There has been interest in using nonpharmacological treatment options such as breast-feeding (Gormally et al., 2001), nonnutritive sucking (NNS; Gormally et al., 2001), and sweet solution administration (Blass & Hoffmeyer, 1991, Grabska et al., 2005) for immunization pain management. Sucrose in particular has garnered interest as a method for reducing procedural pain among neonates (Blass & Watt, 1999, Gormally et al., 2001, Haouari et al., 1995).

Sweet solutions have several potential mechanisms of action for their pain-relieving effects (Kracke, Uthoff, & Tobias, 2005), and the release of endogenous opioids in the central nervous system appears to be the most likely mechanism (Blass et al., 1987, Blass & Hoffmeyer, 1991; Gibbins et al., 2002, Kracke et al., 2005, Pomonis et al., 2000, Skogsdal et al., 1997). Research suggests that the taste of these solutions causes the release of beta-endorphins (Blass & Hoffmeyer, 1991, Blass & Shah, 1995, Carbajal et al., 1999, Skogsdal et al., 1997), which could reduce the transmission of a pain signal to the central nervous system (Blass & Shide, 1994).

Sucrose sweet solutions have a pain-relieving effect in both term and preterm newborns if administered preprocedure (Stevens, Yamada, & Ohlsson, 2004), with positive results found for heel lancing (Eriksson et al., 1999, Skogsdal et al., 1997), venipuncture (Gradin, Eriksson, Holmqvist, Holstein, & Schollin, 2002), intramuscular and subcutaneous injections (Barr et al., 1995), and circumcision (Kaufman, Cimo, Miller, & Blass, 2002). Sucrose is considered a simple and fast-acting nonpharmacological method for alleviating pain in the neonatal population during painful procedures (Barr et al., 1995, Eriksson & Finnstrom, 2004). A recent Cochrane systematic review (Stevens et al., 2004) demonstrated that sucrose is a safe and effective pain-relieving agent in infants.

Because glucose is believed to act along a common sensory pathway (Guala et al., 2001) and stimulate the same endogenous pain-relieving opioids as sucrose (Carbajal et al., 1999, Isik et al., 2000, Jatana et al., 2003), it may be a useful alternative to sucrose. Sucrose is often used in many economically developed countries and is primarily used in neonatal intensive care units (NICUs) for procedural analgesia, whereas glucose tends to be used for intravenous nutrition (Okan, Coban, Ince, Yapici, & Can, 2007). Glucose is more likely to be found in non-NICU settings such as outpatient maternal and child health care centers or other primary health care settings, particularly in economically developing countries. In her experience as a neonatal nurse in a major hospital in Jordan, the first author found sucrose to be infrequently available, suggesting that its use in community-based settings for relief from procedures such as immunization may be limited. In contrast, glucose was widely available in most pediatric clinical settings including outpatient clinics, consistent with reports from other economically developing countries (Gharehbaghi & Ali, 2007, Isik et al., 2000). Reports of difficulties experienced in economically developing countries in accessing other pain-relieving measures such as lidocaine/prilocaine (Shadkam & Lotfi, 2008) further underscore the importance of research into glucose.

Sucrose has been studied much more frequently (Okan et al., 2007), including the aforementioned Cochrane review, but similar levels of evidence have yet to be established specifically for glucose. It is important to establish this evidence base, given the greater availability and thus likelihood of use of glucose in non-NICU settings, particularly in economically developing countries.

In light of the existing systematic assessment of the literature on sucrose, as well as the lack thereof for glucose despite its more widespread use in economically developing countries, this narrative systematic review focuses on the effectiveness of glucose in order to build this knowledge base. The primary aim of this review was to assess the effectiveness of glucose in reducing procedural pain in infants. The secondary aims were to determine (a) the effective concentration and method of administration of glucose and (b) if glucose and sucrose are equivalent as pain-relieving agents for infant procedural pain management.

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Methods 

Search Strategy/Study Identification 

We searched the databases OVID (MEDLINE, PubMed, PsycINFO), ProQuest, Blackwell, Cochrane (Central Register of Controlled Trials and Databases of Systematic Reviews), CINAHL (EBSCO), and EMBASE for articles from 1987 to 2010 using the terms pain or procedural pain and oral sucrose or oral glucose or sweet solutions and newborn neonates or infants. The same terms were also used to search conference abstracts from the Dissertation and Proceedings of the World Congress on Pain (2003–2010), the European Academy of Pediatrics (2006–2010), European Society for Pediatric Research (2003, 2006, and 2008), and the European Society of Pediatric and Neonatal Intensive Care (2003–2010). We searched abstracts from the Pediatric Academic Societies (2000–2009) using the terms pain and oral glucose and infant because it was not possible to add in additional terms with the search engine. We searched the following clinical trial registries: the WHO International Clinical Trials Registry Platform Search Portal, the metaRegister of Clinical Trials (www.controlled-trials.com), and the NIH trial registry (www.clinicaltrials.gov). We hand-searched the bibliographies of any identified systematic reviews.

Study Selection 

Inclusion criteria for studies were as follows: (a) randomized controlled trial (RCT) design, (b) study population was full-term infants up to the age of 12 months, (c) the sweet solution intervention was for a needle-related painful procedure, and (d) pain outcomes were measured using either behavioral and/or physiological outcomes. We excluded studies if they were (a) duplicate citations, (b) dissertations that were later published, (c) conference abstracts that were later published, (d) only testing sucrose, (e) conducted in preterm infants, (f) systematic reviews, (g) nonexperimental studies, or (h) not in English. The first author reviewed most of the titles and abstracts (if available) of the identified studies to determine if they warranted inclusion for full text review. The second author reviewed the titles and/or abstracts from the clinical trial registry searches and the Pediatric Academic Societies search to ascertain inclusion for full text review, with the first author confirming the decisions. We obtained the full text for studies for which eligibility could not be determined from the abstract and/or title alone.

Assessment of Study Quality and Data Management 

The first and second authors appraised the quality of the included studies. We used tables with columns for randomization, blinding, allocation concealment, flow of participants through the study, and use of intention-to-treat analysis to abstract data for quality assessment. Any disagreements over quality assessment were resolved by consensus.

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Results 

Literature Search and Descriptive Characteristics of Included Studies 

Of the 766 citations identified by the search, 160 were selected for possible inclusion and 18 studies were ultimately included following full text review. Fifteen of these studies evaluated glucose alone, and 3 evaluated both glucose and sucrose. Although the review aimed to assess only RCTs, a number of included studies did not clearly describe their randomization process, and so we cannot exclude the possibility that quasi-randomized trials were also included (Table 1).

Table 1. Characteristics of Included Studies

Note: BF = breast-fed; EBM = expressed breast milk; PIPP = premature infant pain profile; NFCS = Neonatal Facial Coding Scale; NIPS = Neonatal Infant Pain Scale; DAN = Douleur aiguë du Nouveau-né; MBPS = Modified Behavioral Pain Scale.

Eight of the included studies were undertaken in economically developing countries (Akçam & Ormeci, 2004, Chermont et al., 2010, Gharehbaghi & Ali, 2007; Isik et al., 2000, Jatana et al., 2003, Ling & Rostenberghe, 2005, Sajedi et al., 2006, Shadkam & Lotfi, 2008), and the remaining 10 were undertaken in economically developed countries in Europe (Bauer et al., 2004, Carbajal et al., 1999, Eriksson et al., 1999, Gradin et al., 2002, Gradin et al., 2004, Guala et al., 2001, Mörelius et al., 2009, Skogsdal et al., 1997, Thyr et al., 2007). Seven studies compared glucose alone to a placebo, usually water, or no treatment; 4 compared glucose alone to a placebo and another pain-relieving measure that was not sucrose; 3 compared glucose to sucrose and a placebo; and 4 compared glucose in combination with another pain-relieving measure to a placebo, another pain-relieving measure, or both. The included studies used a range of outcome measures, from more objective physiological ones, such as heart rate changes, to more subjective behavioral ones, such as scales. In addition, some studies used a combination of behavioral and physiological outcomes, whereas some used exclusively behavioral or physiological outcomes.

The comparison of glucose and sucrose to placebo meant that the three trials comparing the two solutions were not formal equivalence or noninferiority trials (Piaggio et al., 2006, Ware & Antman, 1997) and so we could not fulfill our aim of assessing the equivalence of glucose and sucrose. Two studies allowed additional interventions to occur during the procedure. Thyr et al., 2007 allowed parents to hold and comfort infants during the procedure, and NNS was encouraged in Gradin et al. (2002). NS occurred more frequently in the glucose group compared to the lidocaine/prilocaine group (Gradin et al., 2002, Thyr et al., 2007 did not report on the frequency or distribution of additional interventions. Seven studies (Carbajal et al., 1999, Eriksson et al., 1999; Gharehbaghi & Ali, 2007, Gradin et al., 2002, Guala et al., 2001, Ling & Rostenberghe, 2005, Shadkam & Lotfi, 2008) assessed if adverse effects occurred as a result of the sweet solution interventions, and none identified any adverse effects associated with glucose administration (Table 2).

Table 2. Results of Quality Assessment

None of the studies mentioned the use of intention-to-treat analysis. Twelve of the studies had complete follow-up, with no losses or exclusions (Akçam & Ormeci, 2004, Bauer et al., 2004, Carbajal et al., 1999, Chermont et al., 2010, Eriksson et al., 1999; Gharehbaghi & Ali, 2007, Guala et al., 2001, Isik et al., 2000, Jatana et al., 2003; Ling & Rostenberghe, 2005, Sajedi et al., 2006, Skogsdal et al., 1997); the exclusions or losses that occurred in the 6 other studies ranged from 2 to 10 infants in total. Thirteen studies explained and had approaches to blinding in place (Akçam & Ormeci, 2004, Bauer et al., 2004, Carbajal et al., 1999, Chermont et al., 2010, Eriksson et al., 1999, Gradin et al., 2002, Gradin et al., 2004, Guala et al., 2001, Isik et al., 2000, Lindh et al., 2003, Ling & Rostenberghe, 2005; Mörelius et al., 2009, Skogsdal et al., 1997, Thyr et al., 2007); 12 explained their allocation concealment methods, which were adequate (Akçam & Ormeci, 2004, Bauer et al., 2004, Carbajal et al., 1999, Chermont et al., 2010, Eriksson et al., 1999, Gradin et al., 2002, Gradin et al., 2004, Guala et al., 2001, Lindh et al., 2003, Lindh et al., 2003, Mörelius et al., 2009, Thyr et al., 2007); and 9 explained their sequence generation for randomization, which was adequate (Akçam & Ormeci, 2004, Bauer et al., 2004, Carbajal et al., 1999, Eriksson et al., 1999, Gradin et al., 2002, Guala et al., 2001, Lindh et al., 2003; Ling & Rostenberghe, 2005, Skogsdal et al., 1997).

Effectiveness of Glucose: Physiological Measures 

One study did not find a statistically significant effect for glucose compared to placebo for oxygen consumption or energy expenditure (Bauer et al., 2004). No significant differences were found between glucose and sucrose for physiological outcomes in two studies (Guala et al., 2001, Isik et al., 2000). In one study, the combination of 1 ml 30% oral glucose and a pacifier was effective in reducing the salivary cortisol response compared to water and a pacifier (Mörelius et al., 2009). Although transcutaneous oxygen saturation fell with administration of 1 ml glucose at a range of concentrations (10%, 25%, 50%), expressed breast milk and sterile water, the fall was smallest with 1 ml 50% glucose (Jatana et al., 2003). Data regarding heart rate were inconsistent, with one study identifying an increase in heart rate with the administration of 30% glucose (Eriksson et al., 1999); six studies identifying no significant difference in heart rate between glucose and comparators, including placebo (Bauer et al., 2004, Gharehbaghi & Ali, 2007; Gradin et al., 2002, Guala et al., 2001, Isik et al., 2000, Lindh et al., 2003); and three studies finding that glucose significantly attenuated increases in heart rate (Jatana et al., 2003, Sajedi et al., 2006, Skogsdal et al., 1997). In these studies, concentrations of 10%, 25%, 30%, and 50% glucose were used; 50% had the largest attenuation compared to 10% and 25%, and more than water or expressed breast milk (Jatana et al., 2003), and 30% also appeared effective, compared to water (Sajedi et al., 2006) and no treatment or expressed breast milk (Skogsdal et al., 1997; Table 3).

Table 3. Results for Physiological Outcomes

Note: CI = confidence interval; ANOVA = analysis of variance; EBM = expressed breast milk.

Effectiveness of Glucose: Behavioral Measures 

Twenty-five to fifty percent glucose had a better effect on crying behavior than placebo, no treatment, lidocaine/prilocaine, or expressed breast milk (Bauer et al., 2004, Eriksson et al., 1999, Gharehbaghi & Ali, 2007; Gradin et al., 2002, Jatana et al., 2003, Ling & Rostenberghe, 2005, Shadkam & Lotfi, 2008; Skogsdal et al., 1997, Thyr et al., 2007). Two studies found no significant effect of glucose on crying behavior (Isik et al., 2000, Mörelius et al., 2009). The combination of glucose and breast-feeding (Gradin et al., 2004) and glucose and lidocaine/prilocaine (Lindh et al., 2003) was also effective, with the glucose and breast-feeding group having a lower median crying time than breast-feeding and placebo or glucose alone (Gradin et al., 2004). Thirty percent sucrose alone had a lower crying time than 30% or 10% glucose alone (Isik et al., 2000). One study explicitly evaluated the effect of 30% glucose across different age groups and found that the effects in crying behavior were significant for the 5- and 12-month age groups but not the 3-month age group (Thyr et al., 2007; Table 4).

Table 4. Results for Behavioral Outcomes

Note: EBM = expressed breast milk; ANOVA = analysis of variance; BF = breast feeding; NB = Nota Bene.

Twenty-five to fifty percent glucose was effective in reducing pain scores compared to water, lidocaine/prilocaine, or standard care (Akçam & Ormeci, 2004, Carbajal et al., 1999, Chermont et al., 2010, Sajedi et al., 2006, Shadkam & Lotfi, 2008). The one study that directly compared spray and syringe administration of glucose found no difference between the two methods in terms of impact on pain scores (Akçam & Ormeci, 2004). However, the combination of glucose and skin-to-skin contact significantly reduced pain scores more than 25% glucose alone (Chermont et al., 2010); likewise, the combination of pacifier and 30% sucrose reduced pain scores than 30% or 10% glucose alone (Carbajal et al., 1999).

Effectiveness of Glucose: Composite Measures 

Infants receiving 25%–30% glucose had significantly lower composite pain scores than those receiving placebo or lidocaine/prilocaine (Bauer et al., 2004, Eriksson et al., 1999, Gharehbaghi & Ali, 2007, Gradin et al., 2002). Two studies compared the effect of combining 30% glucose with another intervention, and in both studies, the combined intervention group had lower composite pain scores than other intervention groups or the placebo/standard care group (Chermont et al., 2010, Gradin et al., 2004; Table 5).

Table 5. Results for Composite Outcomes

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Discussion 

Our findings suggest that glucose is an effective pain-relieving agent. Its effects were seen more consistently with behavioral outcomes, typically measured on pain scales or by an assessment of crying. However, it is concerning that not all studies comparing glucose to a placebo or other nonsweet solution comparator had clear and well-described blinding measures when evaluating behavioral outcomes, particularly with more subjective outcome measures such as pain scales.

Glucose had less consistent effects for physiological outcomes, which were measured by a variety of metrics including heart rate and oxygen saturation. The use of heart rate as an assessment measure for glucose may be somewhat problematic because of the association between glucose administration and an increase in heart rate, even in the absence of a painful procedure (Gradin, 2005). One possible explanation is that the heart rate is increased by the sweet taste and the pleasure it gives to the infant (Gradin, 2005). The heart rate outcomes of the studies using this measure (Gharehbaghi & Ali, 2007, Guala et al., 2001, Isik et al., 2000, Jatana et al., 2003, Sajedi et al., 2006, Skogsdal et al., 1997) may therefore need to be interpreted with caution.

Another concern is the use of other unplanned additional interventions such as cuddling or NNS during the painful procedure or sweet solution administration, which occurred in two studies (Gradin et al., 2002, Thyr et al., 2007). Although these other interventions could also impact infant pain responses and potentially confound the findings, we could not find any indication of adjustment for confounding in the analysis.

Although both glucose and sucrose appear to have pain-relieving effects in infants compared to placebo, there is insufficient evidence at this stage to ascertain equivalence. The similarity of mechanisms of action makes it plausible that the two are equivalent in terms of pain-relieving effects, but the small number of identified studies comparing the two solutions and the lack of formal equivalency trials prevents drawing definitive conclusions.

Our findings also suggest that combining glucose with another intervention such as skin-to-skin contact, NNS, or breast-feeding may be more effective than glucose alone. Further studies in this area would be beneficial. However, not all these additional interventions are appropriate for all cultural groups; for example, breast-feeding would be problematic for Muslim women in an open hospital setting. In such circumstances, glucose alone would be preferable.

The one included study that compared the effects of glucose across age groups found that 30% glucose was more effective in 5- and 12-month-old infants than in 3-month-old infants for reducing the duration of crying time (Thyr et al., 2007). Although three other included studies (Carbajal et al., 1999, Guala et al., 2001, Sajedi et al., 2006) had older infant participants, they did not compare responses across age groups. Several studies assessing the impact of age have been conducted using sucrose, but the findings have been inconclusive. There are indications that the pain-relieving effect decreases with age (Allen et al., 1996, Barr et al., 1995), with the calming effects appearing greater in the newborn infants than those older than 6 weeks (Barr et al., 1994, Barr et al., 1995). It has been suggested that sucrose may only be reliably effective in infants 30 days or younger (Barr et al., 1995, Gibbins & Stevens, 2003, Lewindon et al., 1998, Rogers et al., 2006), with only a modest effect at 2 months of age (Barr et al., 1995). However, studies in infants older than 2 months have not detected any consistent pain response trends (Allen et al., 1996, Barr et al., 1995, Lewindon et al., 1998, Lindh et al., 2003, Reis et al., 2003). Further research in this area is necessary, particularly in older infants.

A limitation of this review is the relatively small number of RCTs that met the criteria for inclusion; this may be due to the emphasis on sucrose in the research literature. In addition, several studies did not describe important methodological steps such as randomization and blinding, which made it difficult to fully assess study quality. Finally, we acknowledge that we cannot comment on the long-term effect of glucose as a pain-relieving agent, and so, the recommendations made in this article relate to the immediate short-term pain-relieving effect as measured by specific outcome measures only, as this is what exists in the literature at this time.

Although no meta-analysis was undertaken, this review contributes to the existing literature on the use of sweet solutions for pain relief in infants. Another review was recently undertaken regarding the use of sucrose and glucose for infants aged 1–12 months during immunization (Harrison et al., 2010) and found that the solutions positively affected the incidence and duration of crying, consistent with our results. Our study differs from Harrison et al.'s review in that it includes a much larger number of studies assessing the effect of glucose as well as more studies from economically developing countries.

Our narrative systematic review suggests that glucose is effective at relieving needle-associated pain in infants, with the most consistent effects seen in behavioral as opposed to physiological measures. It would be useful to conduct further research using a range of outcome measures and more consistent concentrations. Our findings have identified that concentrations ranging from 25% to 50% are associated with pain-relieving effects. Oral administration by either syringe or spray appears effective.

The lack of adverse events noted in the included studies suggests that glucose is safe, although only a small number of studies looked at this issue. Greater assessment and reporting of adverse events in glucose trials are important for confirming the safety of glucose.

In summary, glucose appears to be an effective agent for relieving immediate pain from painful needle-related procedures with no adverse effects associated with its administration, and it has similar effects to sucrose when both are compared to placebo. We therefore recommend the use of glucose for needle-related procedural pain relief in infants.

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Acknowledgments 

We would like to thank Dr. Sandie Bredemeyer and the anonymous reviewers for providing helpful feedback.

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