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A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with prega balin . J Pain , 11 , 462 \200\223471. Vondracek , P. , Oslejskova , H. , Kepak , T. , Mazanek , P. , Sterba , J. , Rysava , M. , et al . ( 2009 ). Effi cacy of pregabalin in neuropathic pain in pediatric oncological pati ents . Eur J Paediatr Neurol , 13 , 332 \200\223336. Walco , G. A. , Dworkin , R. H. , Krane , E. J. , Lebel , A. A. , and Treede , R. D. ( 2010 ). Neuropathic pain in children: Special considerations . Mayo Clin Proc , 85 , S33 \200 \22341. CHAPTER 49 Sucrose and sweet taste Denise Harrison , Vanessa C. Z. Anseloni , Janet Yamada, and Mariana Bueno Summary Abundant evidence demonstrates pain-reducing eff ects of sweet solutions in human i nfants and animals. Analgesic eff ects persist up to around 1 year of age in human infants, although the eff ects are more moderate than seen in the neonatal period. Eff ects are con sidered to be due to the relationship between sweet taste and the endogenous opiate system. Yet, despite extensive research, knowledge gaps remain relating to the exact mechanisms, t he eff ec- tiveness and safety of sweet solutions when given over prolonged periods to pret erm and sick infants, the eff ectiveness in sick infants receiving concomitant analgesics, and the eff ectiveness in children older than 12 months of age. Based on the extensive evid ence to support sweet solutions, their use can be recommended prior to commonly performed s hort lasting minor painful procedures in newborn and young infants. knowledge/evidence practice gap are in all likelihood multifacto- rial, but may be related to remaining knowledge and research gaps or prevailing myths or controversies concerning an algesic eff ects of sweet solutions. Th is chapter will review (1) the mechanisms of sweet taste induced analgesia and (2) the evidence obtained from bench to bedside studies in anim als, human infants, toddlers, pre-school children, and school-aged children. Uncertainties, knowledge gaps, and current controversies will be highlighted and translation of knowledge concerning eff ectiveness of sweet solutions in diverse patient populations and settings w ill be dis- cussed. Finally, this chapter will provide implications for practice and direct ions for future research. Sweet taste-induced analgesic mechanisms: the animal studies Analgesic, calming, and distre ss-reducing eff ects of sweet taste were fi rst demonstrated in rodent pups in 1987 (Blass et al., 1987 ). Eff ects of sweet solutions were demonstrated to occur rapidly, last for se veral minutes, and were blocked by systemic opioid receptor antagonists. Introduction Calming and pain-reducing eff ects of sweet-tasting solutions in infants have been demonstrated in more than 150 published stud- ies, and are one of the most extensively studied interventions in infant care (Harrison and Bueno, 2012 ; Harrison et al., 2010a ). With few exceptions, fi ndings of trials, systematic reviews, and meta-analyzes have consi stently shown that sucrose and glucose reduce behavioral responses during commonly performe d pain- ful procedures in diverse populations of preterm and term new- born infants, and in fants up to 12 months of age ( Table 49.1 ) (Harrison et al., 2010a , 2010b ; Stevens et al ., 2010 ; Tsao et al., 2007 ). Based on this evidence, sweet solutions are recommended by n ational and international organizations (American Academy of Pediatrics Committee on Fetus and Newborn et al., 2006 ; Anand and International Evidence-Based Group for Neonatal Pain, 2001 ; Harrison and Australian College of Neonatal Nurses, 2006 ; Henderson-Smart and Austr alian & New Zealand Neonatal Network, 2007 ; Royal Australasian College of Physicians, 2005 ). Yet, despite such compelling evidence and recommendations, use of sucrose or glucose du ring painful procedures has not been translated into widespread consistent utilization in c linical practice in hospitals (Carbajal et al., 2008 ; Johnston et al., 2011 ; Losacco et a l., 2011 ; Stevens et al., 2011 ) or ambulatory care set- tings (Harrison et al., 2013 ; Ta ddio et al., 2009 ). Reasons for this Th e eff ects were reported to be age dependent with a decline in eff ectiveness as the rod ents aged. Analgesic and calming eff ects of oral sucrose were demonstrated as early as pos tnatal day 2 to 3, peaked at postnatal day 10, then declined by postnatal day 14, and were ineff ective by postnatal day 21; the weaning time of rodents. In the presence of infl amma tion, the analgesic eff ects of sucrose (7.5%) are initially present on postnatal day 3 for infl amed fore- paw and postnatal day 13 for infl amed hindpaw. By postnatal day 17, the a nalgesic eff ects of sucrose were no longer present for both infl amed fore- and hindpaws. Th ese fi ndings support that sucrose is age dependent and also has diff erential maturatio nal eff ects that work in parallel to the changes in the endogenous analgesic mecha- nisms and the developmental features between gustatory and pain pathways in neonatal rats (Anselo ni et al., 2002 ). Reports from studies of rodents also showed that amongst sweet-tasting solutions there is a rank-order of potency in which sucrose is more analgesic and calming than glucose, and the latter is more eff ective than fructose and lactose had no analgesic eff ects (Blass and S hide, 1994 ). Studies also investigated a possible dose \200\223 response function of sugar concentrations; however, increasing the CHAPTER 49 sucrose and sweet taste 509 Table 49.1 Systematic reviews of sweet solutions for analgesia in infants and children Reference Population and details Summary of \201 ndings/recommendations Stevens, B., Yamada, J., Lee, G. Y., and Ohlsson, A. (2013). Sucrose for analgesia in newbo rn infants undergoing painful procedures. Cochrane Database Syst Rev , 1, CD001069 \227\206 Sucrose is e \200 ective and safe for reducing procedural pain in neonates from single events \227\206 NNS and other non-pharmacological methods of pain relief should be considered in combination with sucrose \227\206 Further research on sucrose in combination with other behavioral (e.g. facilitated tucking, kangaroo care) and pharmacological (e.g. morphine, fentanyl) interventions for more invasive procedures is warranted \227\206 Th e use of repeated dosing of sucrose and its impact on clinical development is required N = 57 RCTs, 4,730 infants Population: term (29), preterm (27), both preterm and term (1) n eonates Procedures: HL (30); eye examination (6); VP (9); circumcision (3); subcutaneous in jection (2); combination of procedures (2); all procedures (2); NGT insertion (2), urethral catheterization (1) \227\206 Glucose is e \200 ective and safe for reducing procedural pain in neonates from single events \227\206 Concentrations from 20 \200\22330% and higher were e \200 ective \227\206 Small volumes were required \227\206 Glucose can be incorporated into clinical se ttings as an alternative when sucrose is not readily available. Bueno, M., Yamada, J., Harrison, D., Kahn, S., Adams- Webber, T., Beyene, J., et al . (2013 ). A systematic review and meta-analyzes of non-sucrose sweet solutions sucrose for pain re lief in neonates. Pain Res Manage N = 38 RCTs, 3785 infants Population: term (23), preterm (10), both preterm and term (5) ne onates Procedures: HL (19); VP (10); IM injections (3); eye examination (1); circumcision ( 1); subcutaneous injection (1); PICC (1); combination of procedures (2) \227\206 Sucrose or glucose is e \200 ective for reducing immunization pain. \227\206 Ot her recommended pain reduction strategies, such as NNS, breastfeeding, and distraction shou ld be consistently utilized for immunization, and considered for other painful procedures \227\206 Total dose of sweet solution should be given in aliquots commencing 1 \200\2232 mi n prior to painful procedure, immediately prior to procedure, and at intervals throughout p rocedure to ensure sustained analgesic e \200 ects Harrison, D., Stevens, B., Bueno, M., Yamada, J., Adams- Webber, T., Beyene, J., et al . (2 010). E \203 cacy of sweet solutions for analgesia in infants between one and 12 months of age: A systematic review. Arch Dis Child , 95(6), 406 \200\223413 N = 14 RCTs, 1674 injections in 1618 infants Population: infants 1 \200\22312 months during immunization Discussion included 3 other RCTS: HL, VP and urethral catheterization \227\206 Con \202 icting evidence in toddlers aged 12 \200\22318 months. Insu \203 cient evidence to recommend use \227\206 No evidence of e \203 cacy in school aged children Harrison, D., Yamada, J., Adams-Webber, T., Ohlsson, A., Beyene, J., and Stevens, B., et al . (2011). Sweet tasting solutions for reduction of needle-related procedural pain in child ren aged 1 to 16 years. Cochrane Database Syst Rev , 10, CD008408 N = 4 RCTs, 330 children Population: children 12 months \200\22316 years during IM injectio n (3), venepuncture (1) since distilled water, saline, or other salty solutions do not produce analgesia (Anseloni et al., 2002 , 2005 ; Blass, 1997 ; Blass et al., 1987 ; Ren et al., 1997 ; Shide and Blass , 1989 ). concentration of sucrose did not result in increased analgesic and calming eff ects (Blass and Shide, 1994 ). Opioid basis of e \200 ects Th e neurochemical basis of the sweet-taste analgesia has been investigated both in human and animal newborns. Studies reported that the eff ects of oral ly administered sugars and fats are mediated by endogenous opioids (Anseloni et al., 2002 ; Blass et al., 1987 , 1991 ). Analgesic and calming eff ects of sweet solutions and milk we re reversed by injections of naloxone and naltrexone, non-selec- tive opioid receptor antag onists (Anseloni et al., 2002 ; Blass and Fitzgerald, 1988 ; Blass et al., 1987 , 1991 ; Sh ide and Blass, 1989 ). Several studies reported the mechanisms underlying sweet-taste analg esia. Th e stimulation of the taste buds in the oral cavity remains the main mechanistic ex planation due to the rapid onset of the eff ects of sweet solutions given orally. It is cle ar that oral infusion of sweet solutions do not happen due to somatosensory stimulation in the oral cavity or gustatory stimulation in general, Further evidence is needed to describe the mechanisms in which sweet-taste stimulation of t he taste buds involve specifi c nerve branches. One study showed that, in rodents, sweet-ta ste receptors are located mainly on the palate, which is consistent with reports on the gre ater involvement of the greater petrosal nerve fi bres instead of the chorda tympani fi bre s (Travers, 1993 ). Th e question of the possible contribution of post-ingestional mechanis m remains unclear since there has been only one study in human infants and none in animal m odels. Ramenghi and colleagues (Ramenghi et al., 1999 ) reported that direct administration of sucrose to the stomach via a nasogastric tube (NGT) had no analgesic eff ects during he el lance. Another remarkable fi nding relating to the basic neurobiology of sucrose analgesia was tha t oral sucrose did not require involve- ment of the forebrain, but was dependent on brainst em activity SECTION 6 pharmacological interventions 510 (Anseloni et al., 2005 ). Sucrose was seen to activate neurons in the two main brainstem st ructures involved in descending modulation of pain; the caudal periaqueductal gray matter a nd the raphe mag- nus. Th ese fi ndings contribute signifi cantly to the knowledge con- cer ning mechanisms of sweet taste analgesia. Th ese fi rst studies conducted over two decades ago, clearly dem- onstrating profound and sustained calming and analgesic eff ects of sweet solutions, set the scene for the conduct and subsequent pub- lication of large numbers of studies, reviews, systematic reviews, comm entaries, and guidelines concerning eff ects of sweet taste in diverse populations of human infants (Harrison et al., 2010a ). In the next section, systematic reviews of randomized c ontrolled trials (RCTs) evaluating sweet solutions for reducing procedural pain in the neon atal period will be reviewed. Sweet taste-induced analgesic mechanisms: the human infant studies Th e early animal labora tory studies discussed in the preceding sec- tion set the scene for more than 150 studies o f sweet taste-induced analgesia in human infants conducted over two decades (Harrison and B ueno, 2012 ; Harrison et al., 2010a ). Th e fi rst published study identifi ed showing calm ing eff ects of sweet solutions in human infants was published in 1989 by Blass and colleag ues (Blass et al., 1989 ), the same authors responsible for many of the early inves- tigati ons into the stress moderating and analgesic eff ects of sweet taste in rodents. In this ea rliest study, 0.2 ml 12% sucrose solution given in two aliquots 2 min apart, to healthy cry ing, term newborn infants, resulted in immediate calming, immediate cessation of cry- ing, and vigorous mouthing and hand to mouth activity. Sustained calming persisted for up to 5 m in. Successive trials continued to demonstrate calming eff ects of small volumes of oral su crose on healthy crying infants (Barr et al., 1994 , 1999a , 1999b ; Blass and Smith, 1992 ; Graillon et al., 1997 ; Smith and Blass, 1996 ; Smith et al., 1992 ). Such profound calmi ng eff ects were considered to be non-sedating, with most of the infants remaining alert fo llowing sucrose administration (Blass and Ciaramitaro, 1994 ). E \200 ectiveness of sweet taste in newborn infants Sucrose has been the most commonly inv estigated strategy for reduction of procedural pain in infants. As already mentioned, the f i rst study evaluating sucrose during a painful procedure was pub- lished in 1991(Blass and Hoff meyer, 1991 ) and was the forerun- ner for extensive evaluation of sweet solutions fo r procedural pain management in infants and children over the next two decades. Six years a ft er this fi rst trial, the fi rst systematic review and meta- analysis of studies of sucr ose included 13 trials and 982 neonates (Stevens et al., 1997 ). Procedures investigated we re HL (11 studies) and one study each evaluated venepuncture (VP), immunization, and circum cision. Findings were that sucrose reduced cry duration, facial expressions, pain intensity scores, and heart rate compared to water or no intervention, with the exception of one stu dy in which an 18% sucrose solution was used. Fift een years later, this system- atic revie w has been substantially updated a number of times, with the most recent update in 2013 inc luding 57 studies with 4730 term or preterm infants (Stevens et al., 2013 ). Predominantly, HL was studied (29) while other painful procedures included VP (nine), eye examination for retinopathy of prematurity (six), combination of procedures (four), circumcision (three), subcutaneous injec- tion (two), NGT insertion (two), bladder catheterization (one), and hee l stroke (one). Sucrose consistently and statistically signifi - cantly decreased individua l behavioral pain indicators, unidimen- sional, multidimensional and composite pain scores compared to water or no treatment. A meta-analysis including four studies (264 neonates) sh owed that a range of doses ranging from the pacifi er dipped in 24% sucrose up to administe ring 0.5 ml 24% sucrose signifi cantly reduced Premature Infant Pain Profi le (PIPP) scores compared to control or no treatment (1) at 30 sec following HL (weighted mean diff erence (WMD) \210\2221.76 (95% confi dence inter- val (CI) \210\2222.54 to \200\2230.97; p <0.0 01)), and (2) at 60 sec following HL (WMD \200\2232.05 (95% CI \200\2233.08 to \200\2231 .02; p <0.001)). Another meta- analysis including only two trials and 88 neonates showed th at sucrose also reduced total crying time following HL. Based on the meta-analyzes of four studies, the authors recommended the rou- tine use of sucrose 0.012 to 0.12 g (0.05 ml of 2 4% sucrose to 0.5 ml of 24% sucrose) be administered approximately 2 min prior to single pa inful procedures. However, given the broad range of eff ec- tiveness of sucrose doses and t he heterogeneity of studies in this review, further research is needed to identify a more p recise dose for the diff erent gestational ages. Th e authors also recommended further rese arch in extremely preterm, sick ventilated infants, and relationships between validated pai n assessment tools and indica- tors that measure nociceptive brain activity. Further research established that calming eff ects were dependent on sweet taste rather tha n volume. A step-wise sweetness eff ect on calming was clearly demonstrated, with the sweet est solutions of sucrose and fructose resulting in more rapid and sustained calming compare d to the less sweet sugars of glucose and lactose (Blass and Smith, 1992 ). Lactose was no more eff ective than water and in fact, led to some infants to cry more. As volumes of 0.2 ml sucrose were equally as eff ective in soothing infants as larger volumes of 0.6 ml and 1 .0 ml, calming eff ects were considered to be independent of volume (Blass and Smith, 1992 ). To further explore the endogenous opioid basis of sweet taste-in- duced calming, the eff ec ts of sucrose on infants with chronic ante- natal exposure to opiates were evaluated (Blass and Ciaramitaro, 1994 ). Sucrose was hypothesized to be ineff ective in infants with anten atal methadone exposure and suff ering from withdrawal symptoms, due to low circulating end ogenous opioid levels pre- cluding an increase in response to sweet taste. Findings were th at sucrose was less eff ective in this population compared to infants with no antenatal met hadone exposure, further confi rming the association between sweet taste, an intact endogen ous opioid sys- tem, and analgesia. Following these studies demonstrating calming eff ects of sweet taste, the questions turned to whether sweet solutions, if given prior to painful procedures could in fact be analgesi c. In the fi rst published placebo controlled trial of sucrose for reducing procedural pain in human newborn infants, Blass and Hoff meyer demonstrated that 2 ml of a 12% sucrose sol ution signifi cantly reduced crying duration during capillary sampling via heel lance (HL), compared to water, and 24% sucrose solution combined with non-nutritive sucking (NNS) sign ifi cantly reduced crying duration during circumcision, compared to water with NNS (Blass a nd Hoff meyer, 1991 ). Sweet-tasting solutions other than sucrose have also been inves- tigated. A systematic revi ew and meta-analysis exploring the eff ects CHAPTER 49 sucrose and sweet taste 511 of solutions other than sucrose included 38 studies, 3785 infants, and eight diff erent pro cedures (Bueno et al., in press). Glucose was the most frequently investigated solution (35 , 92% of trials) with one study each including artifi cial sweetener, fructose, glycine, ho ney, and maltitol. Nineteen studies evaluated non-sucrose solu- tions during HL; ten studie s during VP, and three during intramus- cular (IM) injections ( Table 49.1 ). Results were analogous to the sucrose systematic review; glucose of suffi cient concentrations con- sist ently reduced individual behavioral responses and unidimen- sional, multidimensional and co mposite pain scores compared to water or no treatment in preterm and term newborn infants d uring single episodes of painful procedures. A meta-analysis showed that glucose (20 \200 \22350%) given prior to HL resulted in a 36 sec reduction in duration of cry (two studies, 90 infants, 95% CI \210\22243.3, \210\22229.5; p <0.001), and a 3.6-point reduction in me an PIPP scores (two studies, 124 infants, 95% CI \210\2224.6, \210\2222.6; p <0.001) comp ared to water or no treatment. However, this recommendation needs to be viewed with caution given the large number of stud ies demonstrating eff ectiveness of a broad range of sucrose doses (e.g. 0.02 \200\2232.0 m l) that were excluded from these analyzes. In conclusion, systematic reviews and meta-analyzes of large numbers of trials show that su crose and glucose consistently and signifi cantly reduce behavioral responses and unidimens ional, multidimensional and composite pain scores in newborn preterm and term infants compa red to water or no treatment, during single episodes of commonly performed short lasting pa inful procedures. Evidence to support use of sucrose or glucose during procedures of longer duration is less clear. As analgesic eff ects of sucrose persist for around 2 to 5 min in newborn infants (Barr et al., 1994 ; Blass et al., 1989 ; Smith et al., 1990 ), and for a s horter period of around 1min in 6-week old infants (Barr et al., 1994 ), administering solu - tions in divided doses throughout procedures that are prolonged for more than a few minut es may be more eff ective than single doses. Further research is warranted to confi rm this hypothesis. Further knowledge gaps include safety and effi cacy of repeated doses of sweet solutions for extremely preterm infants and term infants requiring prolonged hospitalizati on. Both systematic reviews highlighted that analgesic eff ects were independent of volume of s weet solutions; as small volumes were as eff ective as larger volumes, yet the eff ects wer e reported to be sweet-taste dependent. Sweeter, more concentrated solutions more eff ectiv ely reduced pain responses compared to less sweet solutions (Bueno et al., in press; Steven s et al.,2013). Although sucrose and glucose consistently reduced behavioral indicators, bo th reviews reported inconsistent eff ects of sweet solutions on reducing physi- ological re sponses. Inconsistency between behavioral, physiologi- cal, and even cortical responses (No rman et al., 2008 ; Slater et al., 2010 ) highlights the diff erent mechanisms and actions of sweet solutions as well as the loose correlation in infants between physi- ological and behavioral responses to pain (Barr, 1998 ).