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 ). E \200 ectiveness of sweet taste in infants beyond the newborn period Does the same sweet taste-induced analgesic eff ect persist beyond the neonatal period? As highlighted in the f i rst section of this chap- ter, analgesic eff ects of sweet taste in rodents declined as t he rodents aged. However, this same age-related decline of eff ectiveness is not as clear c ut in human infants. As highlighted in a systematic review and meta-analysis of 14 trials o f sweet solutions during immuni- zation in infants aged 1 to 12 months of age ( Table 49.1 ), sweet solutions at suffi cient concentrations (at least 30% glucose or 24% sucrose) cons istently reduced pain scores and individual behav- ioural indicators during or following im munization (Harrison et al., 2010b ). Eff ect sizes were however smaller than reported in n eonatal studies (Stevens et al., 2013 ). Confl icting results were also reported concerning ; (1) eff ectiveness of a weak 12% sucrose con- centration, and (2) eff ectiveness of singl e doses of sucrose for pro- longed procedures. Th e large majority of studies included in the systematic reviews were single episodes of s hort lasting painful procedures, with fewer studies evaluating sucrose or glucose during pr ocedures of more prolonged duration such as eye examination for retinopathy of pre- maturit y. In addition, very few studies investigated repeated use of sucrose over days, weeks, or months of use. Only three studies to date have examined repeated use of sucrose and showed that sucrose was eff ective and safe over time (Harrison et al., 2009 ; Mucignat et al., 20 04 ; Stevens et al., 2005 ). However, one study of consist- ent use of sucrose for preterm infants during the fi rst 7 days of life showed that more than ten doses of sucrose in a 24 h period was associated with poorer neurodevelopmental outcomes compared to ten or less do ses for infants less than 31 weeks gestational age (Johnston et al., 2002 , 2007 ). In cont rast, there were no diff erences in neurodevelopmental outcomes in preterm infants who rece ived multiple doses of sucrose compared to water over a 4-week period (Stevens et al., 2005 ). To date, these are the only two studies exam- ining neurodevelopmental outcomes followi ng repeated use of sweet solutions for procedural pain management in infants. A single dose of 12% sucrose, given 2 min prior to immunization, was no more eff ective tha n water in reducing pain in infants beyond the newborn period in two trials (Allen et al., 1996 ; Poulsen, 2009 ), yet the same dose was eff ective in a third study (Dilli et al., 20 09 ). Dilli et al. reported that 12% sucrose not only substantially reduced immunization pa in in infants, but also in children up to 4 years of age. Th ese confl icting results may b e attributed to possible cultural diff erences, or maternal interventions, including holdin g, com- forting, and distraction techniques which may have potentiated the sucrose eff ects (Harrison et al., 2010b ). As there are no other published studies of analgesic eff ects o f sucrose in pre-school chil- dren during medically related painful procedures, comparison with other fi ndings is not possible at this time. Th e most important limitation of the systematic reviews was that inconsistencies across st udies in outcome measures and met- rics used to report results meant that the number of out comes that could be pooled for meta-analysis was severely restricted. In fact, despite the inclusion of 57 individual studies of sucrose in the 2013 review, the largest number of stu dies included in any meta-analysis was only four, highlighting the large variability in stu dy outcomes and reporting of statistics. Based on the results of the meta-anal- yses only, the use of 24% sucrose within a range of 0.05 \200\2230.5 ml was recommended prior to singl e episodes of painful procedures. Whether the analgesic eff ects of a single dose of sucrose given prior to procedures can be sustained throughout the duration of painful procedures, especially in infants beyond the newborn period, is questionable. Single doses of sucrose given 2 min prior to venepuncture (Curtis et al., 2007 ) and urethral catheterization (Rogers et al., 2006 ) were ineff ectiv e in reducing pain in infants SECTION 6 pharmacological interventions 512 E \200 ectiveness of sweet taste in school-aged children Five published studies have evalu ated whether sweet taste reduces pain in school-aged children (Lewkowski et al., 2003 ; Mil ler et al., 1994 ; Mennella et al., 2010 ; Pepino and Mennella, 2005 ). Lewkowski and colle agues compared sweetened and unsweetened chewing gum during immunization and VP or fi nger prick (Lewkowski et al., 2003 ). Results showed no diff erences in self-report of pain for children who chewed sweet gum either prior to, or during the procedures compared to childre n chewing non-sweet gum. Th ree studies were conducted during CPT and results were confl ic ting (Mennella et al., 2010 ; Miller et al., 1994 ; Pepino and Mennella, 2005 ). Miller et al ( 1994 ) reported that pain threshold (time until pain/discomfort was reported) was redu ced, but neither pain toler- ance (removal of arm from the water), or self-report of pain w ere eff ected by 24% sucrose (Miller et al., 1994 ). Limitations to the study included inco mplete data collection with over half the chil- dren having no pain tolerance or self-repor t data. Similar problems with incomplete data collection were also reported in the two othe r studies of sucrose during CPT in children (Mennella et al., 2010 ; Pepino and Mennella, 2 005 ). In addition to examining analgesic eff ects of sucrose, the two more recently publis hed studies also reported that preference for sweet taste infl uenced whether sucrose exert ed analgesic eff ects. Based on the fi ndings from these fi ve published studies including school aged children, sucrose or other sweet substances are not suffi ciently eff ective as a pain management strategy in this population and their use cannot be recommended. beyond the newborn period (Curtis et al., 2007 ; Rogers et al., 2006 ). Although neither st udy reported the duration of the proce- dures, it is well known that these procedures can t ake a long time to successfully complete. Single doses of sucrose given 2 min prior to thes e more prolonged procedures may not result in sustained analgesic eff ects in older infants . In fact, a key important diff erence in eff ectiveness of sweet solutions in infants beyo nd the neonatal period compared to newborn infants, is the shorter peak eff ect time and du ration of eff ect, reported to be 1 min only in 6-week- old infants, compared to around 5 m in for newborn infants (Barr et al., 1994 ). Th is diff erence has important implications a s, based on previous studies showing the peak onset of analgesic eff ects fol- lowing sucro se administration is 2 min (Blass and Shah, 1995 ; Blass et al., 1987 ); the large majority of study protocols use this timing, regardless of the age of the infants. For infants beyo nd the newborn period, dividing the dose of sucrose and administering throughout the durati on of painful and distressing procedures is recommended to ensure sustained analgesic eff e cts (Harrison et al., 2010b ). E \200 ectiveness of sweet taste throughout childhood Th ere are few studies of sweet tast e for pain reduction in children beyond 1 year of age, and results of these studies are con fl icting. Seven published studies investigating sweet taste during painful procedures in t oddlers and children aged from 1 to 16 years have been identifi ed (Allen et al., 1996 ; Di lli et al., 2009 ; Lewkowski et al., 2003 ; Mennella et al., 2010 ; Miller et al., 1994 ; P epino and Mennella, 2005 ). Four trials involved needle-related procedures (Allen et al., 1 996 ; Dilli et al., 2009 , Lewkowski et al., 2003 ) and were included in a recent Cochrane systematic review of sweet- tasting solutions for needle-related pain in children ( Table 4 9.1 ) (Harrison et al., 2011 ). Th ree further trials involved experimental pain invoked by cold pressor testing (CPT) (Mennella et al., 2010 ; Miller et al., 1994 ; Pepino and Menne lla, 2005 ). Uncertainties, knowledge gaps, and current controversies Despite over 150 studies, predomin ately including neonates, the use of sweet solutions for painful procedures has not been tr ans- lated into consistent clinical practice (Carbajal et al., 2008 ; Harrison et al., 2013 , Johnston et al., 2011 ; Losacco et al., 2011 ; Stevens et al., 2011 ). Additionally, the re are a number of key knowledge gaps concerning mechanisms of action and eff ectiveness an d safety of sucrose in specifi c populations of infants. Th ese gaps include: E \200 ectiveness of sweet taste in toddlers and pre-school children Only two studies have included toddlers, both of which investi- gated 12% sucrose during immunization (Allen et al., 1996 ; Dilli et al., 2009 ). Both studies included children aged 15 and 18 months of a ge, but Dilli et al., 2009 also included children up to 4 years of age. Dilli et al. report ed that sucrose signifi cantly reduced crying duration and pain scores across all ages of c hildren, while Allen et al. reported a lack of analgesic eff ects of sucrose compared to wa ter, in infants beyond the newborn period. Possible reasons for the confl icting fi ndings were proposed, including cultural diff er- ences and diff erences in comfort strategies use d by parents during the immunization procedure (Harrison et al., 2011 ). Valid conclu- sion s from these two trials, both of which used 12% sucrose which is considerably less concentr ated and less sweet than the 24% rec- ommended for eff ective pain reduction in newborn inf ants (Stevens et al., 2013 ), and both of which included small numbers of children in this age bracket, are unable to be drawn. Children in this age group oft en become exceedingly d istressed during procedures and eff ective pain management is problematic. Further research deter- mining eff ective interventions, including use of sucrose, is strongly recommended in this age group. 1. Physiological mechanisms of sucrose. 2. Effectiveness and safety of sucrose given repeatedly over pro- longed periods to preterm and sick infants. 3. Effectiveness and utilization of sucrose for managing non-proce- dural pain and distress in sick infants. 4. Effectiveness of sucrose in sick infants receiving concurrent opi- oid or equivalent analgesics. 5. Effectiveness of consistent use of sucrose in addition to non- pharmacological pain mana gement interventions in reducing or preventing long-term adverse outcomes of repeated painf ul pro- cedures in sick hospitalized infants. 6. Effectiveness of sucrose in children older than 12 months of age. Physiological mechanisms of sucrose Despite the current understanding of a sweet taste, ora lly-induced endogenous opioid eff ect, considered to be due to a beta-endorphin response (A nseloni et al., 2002 ; Blass et al., 1987 ; Dum et al., 1983 ; McKay et al., 1981 ), the ex act mechanism has not been defi nitively CHAPTER 49 sucrose and sweet taste 513 confi rmed in human infants (Taddio et al., 2003 ). Further research aimed to elucidate the calming and analgesic mechanism of oral sucrose in infants is warranted. could be fl awed reasoning. Nevertheless, close follow-up of preterm and sick infants follo wing discharge from hospital, which includes all relevant behavioral and developmental outc omes including pain responses to future procedures such as immunization, and pain sensitivi ty, will contribute to the knowledge gap regarding long-term eff ects of eff ective early p ain management. E \200 ectiveness and safety of sucrose given repeatedly over prolonged periods to preterm and sick infants Only three disparate studies, two trials and one longitudinal study, have evaluated the use of sucrose for prolonged periods (Harrison et al., 2009 ; Mucignat et al ., 2004 ; Stevens et al., 2005 ). All three studies showed that sucrose remained eff ective and safe when used for 4 weeks or longer, however further research is warranted to cor- ro borate these fi ndings. E \200 ectiveness of sucrose in children older than 12 months of age Young children oft en become extremely distressed during medical procedures. Eff ective management of procedural pain and distress in this age-group is challenging. Whether sucrose can be of benefi t bey ond 1 year of age is an important question warranting further investigation. E \200 ectiveness and utilization of sucrose for managing non-procedural pain and distress in sick infants Th is is a key unexplored question which has not been addressed in any pub lished reports to date. Although, anecdotally sucrose is used to calm crying, distressed, a gitated hospitalized infants, the eff ectiveness of sucrose, in this context, as well as th e extent of this practice is unknown. As eff ects of sweet solutions are short lasting, con sistent use for ongoing pain and distress could potentially lead to excessive volumes being given over the course of the hospitalization. Setting maximum daily doses may reduce this risk. Tracking the utilization of sweet solutions in hospital- ized infants is imperative f or furthering our understanding of the degree of sucrose exposure which can in turn, inform if there are any long-term eff ects based on degree of exposure. Currently there is little evidence to inform the question \200\230How much is too much? \200\231. When tracking suc rose use, it is important to be cogni- zant that sucrose is also present in commonly admini stered pro- prietary syrups, including antibiotics, vitamins, and antipyretics (Harrison, 2 008 ). Due to the abundant research consistently showing eff ectiveness of oral sucrose or glucose in newborns and infants up to 1 year of age during single episodes of short-lasting painfu l procedures, there is no longer uncertainty regarding benefi ts of using sweet solutions. It is therefore no longer ethical to conduct further no treatment or placebo-controlled tri als of sweet solutions during commonly performed painful procedures in this population (Har rison et al., 2010a ). Sweet solutions, with NNS if possible, should be considered a standa rd of care, along with breastfeeding and skin-to-skin care when feasible. Further research needs to focus on addressing exist- ing knowledge gaps. Clinical practice implications Practice pointers \200\224guidelines for use \227\206 Sweet solutions only work if given orally. Administer in small doses on the top o f the tongue, with a pacifi er if the infant is able to suck. E \200 ectiveness of sucrose in sick infants receiving concurrent opioid or equivalent ana lgesics As the proposed mechanism of oral sweet taste in infants is the invoking of an endo genous opioid response, whether this response can occur in the context of exogenous opioid delivery is an impor- tant question. As maintenance doses of continuous opioid anal- gesics , given for postoperative pain management or for sedation, do not suffi ciently reduce pain during acute painful procedures (Carbajal et al., 2005 ), it important that the eff ective ness of sucrose in this context is evaluated. \227\206 Solutions need to be suffi ciently sweet for endogenous opioid eff ect (24% sucrose or 25 \200\22330% glucose). \227\206 Suggested doses range from 0.05 to 2 ml in total for single painful procedures. \227\206 Delivery: only small volumes are required. For newborn infants, a single dose giv en 2 min before a painful procedure reduces pain during procedures. For infants beyond the newborn period \200\224ad- minister about one-fourth of the dose on the anterior part of th e infant \200\231s tongue, one min before the procedure and give remaining dose immediately prior to, and throughout the procedure. E \200 ectiveness of consistent use of sucrose in addition to non-pharmacological pain man agement interventions in reducing or preventing long-term adverse outcomes of repeated pain ful procedures in sick hospitalized infant Adverse long-term eff ects of repeated painful p rocedures have been reported. Th e question whether consistent use of eff ective pain manag ement strategies including sucrose with NNS and breastfeeding or skin-to-skin care, can ame liorate such eff ects is not known. Th e design of such a study is challenging, as a contro l group would be considered to be unethical, given what is currently known. Furthermore, us ing historical controls is problematic as rapid changes have been made in many NICU care pr actices; thus attributing diff erences in outcomes to pain management practices \227\206 For more painful or prolonged procedures, such as eye examina- tion, use addition al pain-relieving strategies as recommended. \227\206 Sucrose or glucose should be considered as adjuvant pain man- agement strategies for procedures associated with moderate to severe pain intensity (e.g. circumcision) and us ed in conjunc- tion with topical and regional anesthetics such as dorsal penile block. \227\206 Document the administration and eff ectiveness of sucrose. \227\206 Use additional strategies as feasible such as skin-to-skin care, facilitated tucking, and NNS if part of infant \200\231s care. \227\206 Support parents to provide pain management and advise of addi- tional ways they c an help reduce their baby \200\231s pain (e.g. breast- feeding or skin-to-skin care during non-urgent blood draws, SECTION 6 pharmacological interventions 514 newborn screening, and immunization) (see Johnston and Campbell-Yeo, Chapter 58 , this volu me on mothercare). management practices. Guidelines should highlight how to achieve optimal eff ectiveness of sweet solutions over the course of pain- ful procedures. Examples of mini pocket clinical p ractice guide- line cards developed during the course of a Canadian Institutes of Health Re search knowledge synthesis and dissemination project are shown in Figures 49.1 and 49.2 . \227\206 Parent education may need to include recommendations to avoid using sucrose for crying in the home. Availability and accessibility of sweet solutions in all settings where infants undergo pai nful procedures is necessary to enable their use. Sucrose may be purchased pre-manufactured or made by hospital drugstore departments or independent pharmacists. Sucrose recipes are available from most large pediatric hospi- tal drugstore departments. Glucose for intraveno us use is readily available in hospitals and can be used orally, as an alternative to sucro se when sucrose is not available. Clearly written, user-friendly clinical practice guidelin es which have been approved by rel- evant stakeholders are necessary to promote consistent best pain Infants no longer need to suff er unnecessarily during painful pro- cedures. Sucrose or glu cose, alongside other eff ective pain manage- ment strategies including pacifi er, breastfe eding, and skin-to-skin care cost little to use, are eff ective, and can easily be incorpor ated into infants \200\231 care during painful procedures. Health professionals have an eth ical responsibility to consistently use best pain manage- ment practices and to support par ents to do the same. Researchers have an ethical responsibility to work at eff ectively dis seminating their research and to address existing research gaps. (a) (b) HOW and WHEN should I use Sucrose? Most e \200ective in infants up to 1 year of age. Only works if given orally. Suggested dose: 0.1 \200\2232mL over duration of procedure. Administer about 1/4 of the dose on the anterior part of the infant \200\231s tongue, 2 minutes before the procedure. Give rema ining dose just prior to, and throughout the procedure. For more painful or prolonged procedures, such as circumcision or eye examination, use addi tional strategies as recommended. Document the administration and e \200ectiveness of sucrose. Figure 49.1 Clinical practice guideline (CPG) care in English. Republished with kind permis sion of the author Denise Harrison, Copyright 2013. Guidelines designed by Hospital for SickKids Toronto. Advise parents about additional ways they can help reduce their baby \200\231s pain (a) (b) QUAND et COMMENT utiliser le Sucrose? Figure 49.2 Clinical practice guideline (CPG) care in French. Republished with kind permiss ion of the author Denise Harrison, Copyright 2013. Guidelines designed by Hospital for S ickKids Toronto. CHAPTER 49 sucrose and sweet taste 515 References Allen , K. D. , White , D. D. , and Walburn , J. N. 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