Auditory facsimiles of maternal presence While infants are in utero , sensory learning is t aking place, so that following birth, they have some knowledge of their mother \200\231s id enti- fi cation, notably auditory and olfactory (see later sections). During the third trim ester ( \211 27 weeks GA) fetuses are able to hear and respond behaviourally to sound and auditory stimuli (DeCasper and Fifer, 1980; Ockleford et al., 1988). DeCasper and Spence Goubet and colleagues conducted three studies on familiar odors versus non-familiar odors o n pain response in full-term infants (Goubet et al., 2003, 2007; Rattaz et al., 2005). All stud- ies demonstrated the eff ectiveness of a familiar smell, be it from mother or from co nditioning the infant to the smell of vanillan. One study compared odors of mother \200\231 s own milk, another wom- an \200\231s milk, formula milk, or no odor control on grimacing, crying, SECTION 8 physical interventions 602 Table 58.1 Studies examining the e \200 ect of kangaroo care (KC) on pain response Study Sample Design and intervention Provider Procedure Outcome measures Results in KMC N , GA Cry \206\223 by 82%, grimacing \206\223 by 65%, smaller \206\221 in beats/minute during blood collection (8 \200\22310 vs 36 \200\22338) (Gray et al., 2000) 30, full term RCT, 10 \200\22315 min, KC vs swaddled in cot Mother Heel lance Duration of cry, grimacing, HR PIPP scores signi \201 cantly \206\223 at 30 sec (MD, 1.5 points; P = 0.04), 60 sec (MD, 2.2 points; P = 0.002), and 90 sec (MD, 0.6 point; P = 0.37) after heel-lancing procedure. Heart rate and oxygen saturation similar in both conditions. Facial actions contributed sig ni \201 cantly to total pain score (0.000 <P <0.005), with facial actions averaging 20% gr eater in control vs KC condition. (Johnston et al., 2003) 74, 32 \200\22336 weeks GA RCT, crossover 30 min KC vs swaddled in incubator Mother Heel lance PIPP: facial actions, heart rate, oxygen saturation, gestational age, behavioral state (Ludington-Hoe et al., 2005) 23, mean 31 weeks GA RCT, crossover 3 h of KC vs incubator Mother Heel lance HR, respiratory rate, oxygen saturation, \206\223 crying, length of crying, behavioral sta te Mean rise in heart rate (F(1,32) = 3.01, P = 0.047) from baseline to heel lance was less in the KC condition than in the warmer condition Crying length during KC heel lance signi \201 cantly less than during warmer heel lance (F(1,32) = 7.38, P = 0.003) and post-lance p eriod (P = 0.02). 100 full term RCT, 10 min KC vs cot Mother IM injection Duration of cry, NIPS score Mean duration of crying post injection was longer, 24.61 in the control group vs 14.55 sec in the KC group p = 0.001. NIPS scores signi \201 cantly \206\223 immediately following i njection in KC, p <0.001 (Kashaninia et al., 2008; Sajedi et al., 2007) a NFCS score signi \201 cantly \206\223 at heel lance ( \210\222 1.140; p = 0.23) and sque eze phase ( \210\222 1.872; p <0.001). Cry \206\223 by 37.4%. No di \200 erence in HR (Castral et al., 2008) 59, 30 \200\22337 weeks GA RCT, 15 min KMC vs swaddled in incubator Mother Heel lance Facial action, NFCS score, behavioral state, duration of cry, HR (Freire et al., 2008) 95, 28 \200\22336 weeks GA RCT. 15 min KC vs oral glucose vs prone position in incubator Mother Heel lance Behavioral state, HR variation, Oxygen saturation, PIPP scores for facial actions No di \200 erence in behavioral state, \206\223 variation in (p<0.0001) and HR in oxygen saturation (p <0.0012), \206\223 scores for facial actions (p <0.0001) PIPP scores \206\223 at 90 sec (8.871 versus 10.677; p <0.001). Time to recover \206\223 in KC (123 sec (95%CI 103 \200\223142)) vs 193 sec for incubator (95% CI 158 \200\223227) ( F (61,1) = 13.6, p <0.000) (Johnston et al., 2008) 61 28 \200\22331 weeks GA RCT cross-over 15 min KC versus swaddled in incubator Mother Heel lance PIPP, time to recover (heart rate return to baseline), facial actions, HR, oxygen saturatio n \206\223 combined crying time during heel stick (55 vs 96.2 sec; p = 0.001) and during rec overy (5.8 vs 25.5 sec; p <0.01). Inaudible cry was minimal in each phase, in both conditio ns 0 \200\2231.34 sec (Kostandy et al., 2008) 10 Preterm 30 \200\22332 weeks GA RCT, crossover, 30 min KC vs nested in incubator Mother Heel lance Audible and inaudible crying (Anderson Behavioral State Scoring system) RCT, 45 min KC \227 5 days-procedure on 5th day. PIPP scores were \206\223 in the KC group, at the 1st, 2nd and 3rd min of the painful proc edure, 7.0, 4 and 4 in infants in KC group vs 15.0, 15.5 and 15.0 (p <0.001, p = 0.001, p = 0.047, respectively) (Akcan et al., 2009) 50, Preterm 26 \200\22336 weeks GA Mother Heel stick/ venepuncture PIPP score at 60, 90, 120 seconds following procedure (Continued) CHAPTER 58 mother care for procedural pain in infants 603 Table 58.1 (Continued) Study Sample Design and intervention Provider Procedure Outcome measures Results in KMC N , GA Chermont (Chermont et al., 2009) 640 Full term RCT. 2 min KC vs standard care vs 25% dextrose vs KC/dextrose Mother IM injection PIPP score. NFCS and NIPS Mean PIPP scores for the 4 groups were standard care, 6.9 2.3; KC, 6.2 2.0; 25% dextrose treatment, 6.8 1.6; KC plus 25% dextrose treatment, 5.9 2.1 (Cong et al., 2009) 14 Preterm 30 \200\22332 weeks RCT, crossover 60 min KC vs incubator (IC) Mother Heel lance Infant behavioral state, HR, HRV HR signi \201 cantly lower in the KC condition (146 9 bpm) than in IC (152 13 bpm) durin g baseline period (p <0.05) and Heel Stick period (KC 159 bpm vs IC 165 14 bpm, p <0. 05). HRV \206\221 stable in KC at baseline (p <01) and at heel lance (p <0.001) \206\223 motor disorganization F(129) = 6.716, p = 0.002; extension movements (F(1, 29) = 8.554, p < 0.0001); and an \206\221 in attention signs negative attention signs (F(1.29) = 27.000, p = 0.018) and positive attention signs ([F(1,29) = 3.077, p <0.05) during KC (Ferber and Makhoul, 2008) 30 Preterm 28 \200\22334 weeks RCT Crossover, 10 min KC vs incubator Mother Heel lance NIDCAP (Johnston et al., 2009) 90 32 \200\22336 weeks GA RCT, crossover, 30 min KC with additional rocking, singing, and sucking vs KC without addit ional stimulation Mother Heel lance PIPP, time to recover No signi \201 cant di \200 erences in PIPP scores or time to recover signi \201 cant, di \200 erences across sites (Cong et al., 2011) 28 Preterm 30 \200\22332 weeks RCT, crossover 14 infants, 80 min KC (Study 1); 10 infants, 30 min KC (Study 2) vs incubato r Mother Heel lance PIPP salivary and serum cortisol at baseline, heel warming, heel stick and recovery Study 1: no di \200 erences Study 2: \206\223 PIPP during recovery (p <0.05 to p <0.001), \206\223 salivary cortisol at the end of recovery (p <0.05) and \206\223 serum cortisol during heel lance condition during heel lance \206\223 PIPP in MKC, mean di \200 erence 1.4 at 30 sec, 1.5 at 60 sec. No di \200 erenc e at 90 sec and 120s sec. \206\223 time to recover (204 sec MKC, 246 sec FKC). PIPP scores \206\223 in both groups vs historical controls (Johnston et al., 2011) 62 Preterm 28 \200\22336 weeks RCT, crossover 30 min MKC vs FKC Mother Father Heel lance PIPP, time to recover a Same study bpm = beats per minute; FKC =father kangaroo care; GA = gestational age; HR = heart rate; H RV = heart rate variability; IM = intramuscular injection; KC = kangaroo care; MD = mean di \200 erence; MKC = mother kangaroo care; NFCS = Neonatal Facial Coding System; NIDCAP = N ewborn Individualized Developmental Care and Assessment Program; NIPS = Neonatal Infant Pai n Scale; PIPP = Premature Infant Pain Pro \201 le; RCT = randomized controlled trial. motor activity, and salivary cortisol levels in full-term neonates undergoing heel lance (N ishitani et al., 2009). Infants exposed to mothers \200\231 own milk odor had signifi cantl y lower scores and values for all outcome measures when compared to controls. Th ere were n o signifi cant diff erences noted in the other groups for any of the outcomes compared to t he controls. infant undergoing a stressful or painful procedure. While typically performed by nurses, it has been used by mothers (Axelin et al., 2006, 2010). Th e infant is generally held in a s ide-lying, fl exed fetal-type position (Axelin et al., 2006, 2009b; see Holstii et al., Cha pter 57, this volume, for a more detailed description of facili- tated tucking). Facilitate d tucking alone, studied in both preterm and very preterm infants, has been associated with diminished pain scores following heel lance and endotracheal suctioning (Axelin et al., 20 06; Ward-Larson et al., 2004) when compared to placebo. Similarly, when used in combination with non-nutritive sucking, Facilitated tucking Facilitated tucking consists of a care provider or parent using their h ands to provide containment and a supportive boundary to an SECTION 8 physical interventions 604 34 preterm infants receiving facilitated tucking during heel lance had signifi cantly lower mean (standard deviation) pain scores dur- ing heel-stick procedures (6.39 (3.35) and 7.15 (3.88), respectively) than those receiving routine care (9.52 (4.95)) (Liaw et al., 2012). Facilitated tucking is also more benefi cial when compared to oxy- codone (Axelin et al., 2009b). Following endotracheal suctioning, facilitated tucking by parents was equivalent to glucose (Axelin et al., 2009a); however, this was not the case following repeated heel lan ce. In a study examining preterm infants between 24 and 32 weeks GA randomized to receive f acilitated tucking, sucrose or combination of sucrose and facilitated tucking following ove r time for repeated heel lances, facilitated tucking alone was less eff ective than sucrose ; however, Bernese Pain Scale for Neonates (Cignacco et al., 2004) scores were lowest when combined with the sweet taste (Cignacco et al., 2012). a signifi cant predictor across all phases of the immunization proce- dure (Pillai Riddell et al., 2011). Pillai Riddell and colleagues sug- gested that this ability of the mother to accurately use the infant cues, as well as the infant \200\231s ability to display learned cues resulting in maternal caring response, is directly related to maternal-infant attachm ent, which typically peaks at 1 year of age (Ainsworth, 1969). For an in-depth discussion o n psychological theories and models, see Pillai Riddell et al. (Chapter 9, this volume). Other providers KMC or SSC provides a multisensorial context encompassing tac- tile, olfact ory, and relational systems (Campbell-Yeo et al., 2011). Consistent fi ndings from numerous studies clearly support the comforting role of a mother. What is less known, is whether th is comfort relates only to a mother or whether other providers, (e.g. an adult who cares fo r you or someone familiar) could provide a similar comforting eff ect. In the fi rst study to address this question, alternate women (n = 22), biologically unrelated to the mother, w ere compared to infants \200\231 own mothers using a cross-over design (Johnston et al., 20 12). PIPP scores were lower in the infant \200\231s own mother group (8.3 versus 6.0 at 90 sec post-lance) although this diff erence was not statistically signifi cant due to the sma ll pilot sample, but eff ect size was greater than other studies at 90 and 120 sec supporti ng the eff ectiveness of the biological mother. Although highly plausible, these fi ndings need to be interpreted with caution due to the small sample size. Sensorial saturation Combining strategies, including talking to the infant, massaging or st roking the infant as well as giving a sweet solution, has been coined sensorial saturation by Bellieni and his group (Bellieni et al., 2001, 2002). Typically, sensorial saturation is performed by nurs- ing staff ; however, in one study with full-term neonates, mothers did the sensorial saturation (Bellieni et al., 2007). Both mothers doing it for the fi rst time and experienced nurses doing sensorial saturation were more eff ective than glucose and pa cifi er, but there were no signifi cant diff erences between the two. It could be that the experience of the nurses waived diff erences or it could be that, it did not matter who did the intervention. Using a similar crossover design, comparison between fathers or mothers who provided KMC fo r 30 min was made prior to and during heel lance (Johnston et al., 2011). Although PIPP sco res were lower in both groups compared to historical controls, moth- ers provided more anal gesic eff ect and infants recovered faster than when with fathers (mean diff erence of 1.4 at 30 sec, 1.5 at 60 sec; no diff erence at 90 sec and 120 sec; time to recover 204 sec ver sus 246 sec), respectively. Maternal \200\223infant interactions related to pain experience As infants develop and have more interactions with their mothers, patterns of interactions become established. Healthy infants who do not experience hospitalization beyond normal nursery care in the fi rst few days of life, are subjected to immunization pain. Mothers, perhaps as a refl ection of the stress associated with their infant expe- riencing pain from an elective procedure, will i ntuitively apologize, empathize, and give reassurance such as \200\230don \200\231t worry \200\231 or \200\230it will be okay \200\231 (McMurtry et al., 2010). Th ese actions, have been found to be less eff ective than distraction approaches that might include sing- ing, off ering a toy in reducing both intensity and duration of pain response (Blount et al., 2 008, 2009; also see Cohen et al., Chapter 53, this volume). Similar to the eff ect in prete rm neonates, proximal strat- egies, such as the mother rocking (Campos, 1994) also reduced pain response. Furthermore, controlling for factors such as age, previous pain exposure, me dical history, in a sample of 4- and 6-month-old infants, mothers and fathers made more pro ximal coping promoting behaviors prior to the immunization than health care professionals w hich signifi cantly decreased facial actions of their infants during the immunization (Piir a et al., 2007). Interestingly, the PIPP scores were very low but not statistically diff erent between prete rm twins who were co-bedding (being cared for together in the same incubator allowing skin contact between them) prior and during heel lance and provided sucrose compared to a simila r population receiving sucrose alone, considered standard care (SC) in the fi rst minute po st heel lance (7.1(SD2.8), 6.1(SD3.0) versus 7.2 (SD3.4), 5.2 (2.0)) (Campbell-Yeo et al., 2012). At 90 sec, PIPP scores were higher in the co-bedding group 6.0 (SD 3.0) com- pared t o 5.0 (SD1.8) (p <0.05), in the SC group. Although higher, the clinical signifi cance of th is diff erence at 90 sec post lance is uncertain. Reasons for the lack of analgesic eff ect may be due to the lack of full ventral contact and the upright position present during kan garoo care which is not possible during co-bedding. Or, it may be that mother \200\231s abi lity to eff ectively provide pain relief is unique. Further research is needed to elucidate these fi ndings. Nevertheless, co-bedding was associated with the twins \200\231 ability t o better regulate the pain associated with heel lance. Th e co-bedding twins recovered more than a minute faster than the SC group, mean time of 75.6 sec, compared to 142.1 sec durin g SC. Further analysis using general- ized estimating equation modeling (GEE) and including corrected GA less than 32 weeks at heel lance did not change these fi ndings and resulted in a p value of 0.005. Salivary cortisol levels, a reliable biomarker of stress, were signi fi cantly lower, mean levels 0.28 mcg/ dL (SD 0.25) versus 0.50 mcg/dL (SD 0.73), in the co -bedding twins (see Table 58.2 ). It is perhaps less the specifi c behaviors that mothers use as opposed to maternal sensitiv ity to the infant cues that is impor- tant. Th is only becomes strongly associated with dec reased pain response as mother and infant have longer time together. For exam- ple, in Swee t \200\231s prospective study of 6- and 18-month-old infants undergoing immunization, mater nal sensitivity was a signifi cant predictor of lower distress only at the 18-month visit ( Sweet et al., 1999). Similarly, Pillai Riddell following a cohort of infants across the fi rst year of life, found that maternal availability/sensitivity was CHAPTER 58 mother care for procedural pain in infants 605 Table 58.2 Th e e \200 ectiveness of maternal- or family-driven non-pharmacological strate gies for reduction of procedural pain Intervention Gestational age Procedure Findings E \200 ect \206\223 crying time and smaller increase in HR with breastfeeding compared to swaddling \206\223 PIPP scores with breastfeeding compared to placebo. Mixed results when comparing b reastfeeding to sweet solutions Breastfeeding and expressed breast milk (Codipietro et al., 2008; Efe and Ozer, 2007; Gray et al., 2002; Osinaike et al., 2007; Shah et al., 2008) Full term Preterm Venepuncture Heel stick Breastfeeding is e \200 ective; con \202 icting results regarding expressed breast milk \206\223 crying, less variation in HR \206\223 PIPP scores Better results when combined w ith breastfeeding or sweet taste Kangaroo care (or skin-to-skin contact) (Akcan et al., 2009; Castral et al., 2008; Cong et al., 2009, 2011; de Sousa Freire et al., 2008; Ferber and Makhoul, 2008; Gray et al., 2000; Johnston et al., 2008; Kashaninia et al., 2008; Kostandy et al., 2008; Ludington-Hoe et al ., 2005) Full term Preterm Very preterm Heel stick Venepuncture Intramuscular injection Kangaroo care or skin-to-skin care is e \200 ective \206\223 physiological and behavioral pain responses. Less e \203 cacious than sucrose Containment/facilitated tucking (Axelin et al., 2006, 2009b; Cignacco et al., 2012; Cor \200 et al., 1995, Obeidat et al., 2009; Ward- Larson et al., 2004) Term Preterm Endotracheal/ pharyngeal suctioning/ heel Lance Containment and swaddling are e \200 ective for single procedures. May be optimal as adjuv ant strategy for repeated procedures \206\223 HR, \206\221 oxygenation and quicker recovery Strongest e \200 ect combined wit h NNS Auditory recognition: maternal heart rate (Kurihara et al., 1996) recorded maternal voice ( Johnston et al., 2007) Full term Preterm Heel stick Maternal heart beat e \200 ective but not recorded maternal voice \206\223 crying and grimacing during venepuncture Olfactory recognition: own mother \200\231s milk or familiar odor (Goubet et al., 2003, 200 7; Nishitani et al., 2009; Rattaz et al., 2005) Full term Preterm Heel stick Venepuncture Mothers own milk or familiar odor was e \200 ective during venepuncture but not heel lance HR = heart rate; NNS = non-nutritive sucking; PIPP = Premature Infant Pain Pro \201 le. Mechanisms underlying maternal comforting e \200 ectiveness Th ere are likely several unde rlying mechanisms for the eff ectiveness of maternal comfort on infant pain. Th e two mecha nisms with the most compelling data related to endogenous opiates and oxytocin. In the anim al literature, there is a strong relationship between endogenous opiates and social affi li ation (Panksepp et al., 1980, 1994), including mother \200\223infant bonding. Endorphins ar e excreted in milk and the levels are augmented by suckling. Young animals, of several spec ies, removed from their mothers display distress behav- iours including specifi c crying, o r distress vocalizations. When given opiates exogenously, the number of these distress beha viors decrease, as when they are reunited with the mother. Furthermore, naloxone, in many e xperiments, though not all, decreases the number of distress vocalizations when the young a re separated. Th ere is congruence of areas in the brain responsible for distress behaviors and opiate receptors. Th e important point is that the behaviors and the opiate excretion are mediated by maternal presence. Th e opiate-affi liative system is also bi-directional: dams (mother rats) given naloxone are slower to retrieve their young scattered about the ne st. Carter et al., 1992; Insel, 1997; Konner, 2004). Th e role of oxytocin in the mediation of pain has been tested in animals. Based on the knowledge that gentle stroking has a pleasura ble anti-nociceptive function, the injection of an oxytocin antagonist blocked that func- t ion (Agren et al., 1995). Further studies revealed that: (1) strok- ing did increase the la tency withdrawal to mechanical or thermal noxious stimulation; (2) there were increased lev els of circulating oxytocin and oxytocin in the periaqueductal gray (PAG), an area importan t in pain processing, following stroking sessions; and (3) an opiate antagonist, naloxone, injected directly into the PAG, decreased the withdrawal latency. In adults, the administra tion of oxytocin has decreased pain (Madrazo et al., 1987; Yang, 1994). Recommendations for practice Given the current evidence regarding the comforting role of mo thers and families in the NICU and the lack of reported adverse events, we recommend that f or healthy full-term and preterm infants, KMC and breastfeeding should be considered as the behavioral pain strategy of choice for single painful events. Where possible, breastfeedin g infants should establish an eff ective latch prior to the procedure and have as much dire ct skin contact with the mother as possible. Th e second hypothesized mechanism is related to oxytocin. Oxytocin is thought to be of maj or importance in mother \200\223infant bonding; being released at delivery, with the commen cement of suckling, with touch, and is found in breast milk (Carter, 1998; In infants who are unable to breastfeed, KMC is benefi cial. Infants should be placed diape r clad in an upright position with full ventral contact with their mother prior to and duri ng the painful proce- dure. Th e optimal duration of SSC prior to a procedure remains SECTION 8 physical interventions 606 unknown. Th e majority of studies used 15 to 30 min and had posi- tive results, and as litt le as 10 min seems to be eff ective. Madeline \200\231s mother, Sarah, also becomes visibly upset when she watches during these procedures and describes, \200\230feeling helpless \200\231. Madeline \200\231s nurse disc usses the comforting benefi ts of SSC with Sarah and asks if she would like to hold Madelin e in this way before and during her next heel lance. Sarah agrees and her nurse tells expla ins to her this would mean holding Madeline, while her baby wears only a diaper, and placin g her upright in a ventral position on her bare chest, than covering them both with a blan- ket (for an example see Figure 58.1 ). Th e nurse also told her that even a small amount o f SSC before the heel lance can be helpful, as little as 10 to 15 min, but that it is impor tant to allow Madeline to recover from the transfer from the incubator to her mother \200 \231s chest which may take a few extra minutes. In the situations where it is impossible to hold the infant, alter- native strategies empha sizing maternal presence such as olfactory or auditory stimuli, or facilitated tucking may be used as adju- vant therapy in conjunction with sweet taste or in combination as more hol istic sensorial saturation. Further studies are required to determine the effi cacy of thes e strategies for repeated procedures over time. Some benefi t is derived from KMC with other providers who are not the mother; however, unt il further studies are conducted, addi- tional strategies in combination should be consider ed. For infants undergoing multiple painful procedures or those who demonstrate high behavi oral pain response, adjuvant strategies used in com- bination specifi cally sweet taste, no n-nutritive sucking, swaddling or containment in addition to breastfeeding or SSC are likel y to be benefi cial, although there remains a paucity of evidence regarding an optimal comb ination. Th e next day, Sarah held Madeline in SSC during her heel lance. Sarah displayed only minim al facial response during the procedure and did not require additional oxygen. Both the nur se and Sarah felt that Madeline benefi ted from the SSC. Sarah also expressed that she \200\230truly felt like a parent since she was able to actively help her daughter \200\231 that she \200\230would like to be able to continue helping Madeleine in this way \200\231. Feasibility Some outstanding issues remain regarding the implementation of KMC during painf ul procedures. We know that the uptake of any clinical practice change generally lags behin d dissemination of the research fi ndings (Graham et al., 2006; also see Yamada and Hutchin son, Chapter 61, this volume). Using mothers and families as providers of comfort presents several additional several chal- lenges, requiring a paradigm shift . Health care providers will need to further relinquish their traditional care model to consider parents as partne rs in provision of care rather than bystanders; thus placing increased emphasis and time fo r the coordination of care, sched- uling, and timing of procedures to enhance parental invo lvement. Th e skill of the health care providers conducting the procedure also needs to be considered in relation to feasibility. Issues regard- ing safety and ergonomic needs of the care providers have also been reported (Campbell-Yeo et al., 2008b) and require further re search. Th e nurse shares with the neonatal team that Sarah would like to be an active participant in Madeleine \200\231s pain management and the team agrees that all non-emergent blood coll ections and procedures can be scheduled around Sarah \200\231s availability. Conclusion Mothers have a unique relationship with their infant and a spe- cial role in com forting their infant in the face of pain. Data exist to support that mothers are better tha n others at comforting their infant, either through some biological mechanism or because of the profound caring they have for their infant, normally stronger than others. Given their eff ectiveness, it is highly recommended that mothers be included in comforting their infa nt during painful procedures whenever possible. Figure 58.1 Skin-to-skin contact during a heel lance. References Agren, G., Lundeberg, T., Uvnas-Moberg, K., and Sato, A. (1995). Th e oxytocin a ntagonist 1-deamino-2-D-Tyr-(Oet)-4-Th r-8-Orn-oxytocin reverses the increase in the withdr awal response latency to thermal, but not mechanical nociceptive stimuli following oxytocin administration or massage-like stroking in rats. Neurosci Lett , 187 , 49 \200\22352 . Case example Ainsworth, M. D. (1969). Object relations, dependency, and attachment: a theoretical review of the infant-mother relationship. Child Dev , 40 , 969 \200\2231025 . Madeline is a 7-day-old preterm neonate who was delivered 11 weeks early at 29 weeks gestat ional age. Madeline undergoes numerous painful procedures, as part of her medical care in t he NICU. For example, heel lance for blood collection, the most common, occurs one to two t imes a day. Madeline becomes very distressed during the heel lance as exhib- ited by her fa cial actions and changes in her physiological sta- bility. She oft en requires additional s upplemental oxygen during the heel lance. 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