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Pain – INFANT updated: 4/5/2014

______________,2013 FT, PT, Review of non-pharmacologic strategies to reduce pain, KC and BF reduce pain and says that parental involvement in pain reduction is important.

Abdel Razek et al., 2009 FT, infants in 1st year of life who got maternal KC +BF (n=60) or standard clinic(n=60) immunization. Sig shorter duration of crying during and after injection in KC + BF group. HR lower and less variability in KC. Lower NIP score. Not RCT because did not randomize to groups.

Acad BF Med2010 Coordinating breastfeeding with pain is best to reduce pain, but KC is 2nd best

Akcan et al., 2009 PT, RCT PIPP scores lower in 25 maternal KC infants(30 mins before and 10 mins after invasive procedure –but not during the procedure) during and after procedure compared to 25 controls

AAP/CanadPedSoc, 2006 Policy. Recommends KC for pain reduction with neonates

Anand et al., 2006 PT, FT, Summary of proceedings from consensus group meeting. KC is one way to treat procedural pain and is recommended by this group.

Anand, 2008 Review, concerns about infant pain have led to the development of non- pharmacologic therapies such as sucrose, massage and kangaroo care for neonatal pain,

Ancora, 2010 PT, Review, pain control is essential to make NICU developmentally appropriate

Axelin- See axelin below

Bakewell-Sachs et al ‘03 Review of pain management, more research on pain management strategies needed

Batton et al 2006 PT aap & cps recommend kc to reduce painBauer K , 2005 PT review, KC is a time when infants are protected from painful interventions

Bulfone et al 2011 PT and FT review of 19 articles - some show that KC reduces pain

Bunik et al., 2010 PT,FT., policy of combining breastfeeding and KC to reduce procedure pain

Burkhammer et al 2004 FT, case study, kc reduces nipple pain

Byaruhanga et al 2008 FT, qualitative, 5 focus groups, moms reported that KC distracted them from post delivery pain (episiotomy and contractions)MATERNAL PAIN

Bystrova 2009 Review of physiology of the C-Afferent nerves which is a second tactile system

and the pleasant touch that stimulates the c afferent nerves release oxytocin and oxytocin reduces pain, - a physiologic KC mechanism

Canadian Ped Soc 2012 PT, Position statement that says that KC reduces pain and it proposed that this is done through sensory saturation and says that KC should be used for bedside painful procedures for preterm infants.

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Campbell-Yeo etal. 2009 PT, RCT. of cobedding skin to skin in 128 twins because skin to skin between mom and baby reduces pain. This is abstract of what is planned, not what has been done. NOT A KC STUDY yet

Campbell-Yeo et al 2011 Review of mother-driven pain interventions. KC reduces pain perception; other strategies do too. Mother’s presence is very important for pain reduction.

Campbell-Yeo et al., 2013 PT Proposal of three group comparative study of repeated use of KC alone, 24% sucrose alone, or KC+sucrose for procedural pain in NICU. PIPP for pain, NAPI for neurobehavioral develop at term age and cortisol being measured.

Carbajal et al., 2004 Review of pain. Same as 2005 publication but in English. Describes pathways by which KC may directly and indirectly affects pain response. MECHANISMS

Carbajal et al., 2005 Review of pain management strategies and reviews Gray and Johnson’s articles and states that skin to skin contact is a part of BF and provides the direct (by blocking nociceptive transduction or transmission or activation of descending inhibitory pathways or by activating attention and arousal systems that modulate pain (pg. 114) and indirect mechanisms (reduce total amount of noxious stimuli to which infants are exposed) of how SSC reduces pain. MECHANISMS

Carbajal et al., 2008 Review that says infants do not get relief from procedural pain

Castral et al., 2008 PT, RCT of 15 min of KC before, during and after heel stick. Facial coding less in KC group, and less heart rate increase and less behavioral state agitation in KC group.

Castral et al. 2012 PT, correlational, infant’s HR and salivary cortisol pain responses to heel stick were influenced by mother’s ability to regulate her own stress (maternal salivary cortisol level) but mother’s depression and anxiety did not affect infant pain response. This is also a CO-REGULATION STUDY

Celeste et al 2008 Very PT, Randomized cross over trial, kc diminishes heel lance pain MICROPREEMIES

Chermont et al., 2009 FT, RCT, KC is effective to reduce pain, and when added to oral 25% dextrose it acted synergistically to reduce pain even more. Hepatitis B vaccination given

Chidambaram, 2013 PT, RCross over of KC that reduced pain better than no KC group.

Childrens Hosp Philly2007 PT, should document pain score during ventilated KC for all infants

Chroma &Sikorova 2012 Review of non-pharmacologic methods of pain reduction and KC comes in second to nutritive sucking and works better when combined with other non-pharmacologic methods. See also Johnston Cochrane of 2012 and 2014

Cignacco et al.,2007 Review of non-pharmacologic interventions and mentions that KC appears to be effective and should be used to minimize pain.

Cignacco et al. 2008 NOT A KC STUDY. RCT of morphine and MSS (multisensory stimulation = nurse massages baby’s face and back, gently talk to baby, and put vanilla oil on nurses hands during massage for orogustatory stim and sucrose on cotton stick in baby’s mouth for sucking. Neither morphine nor MSS after endotracheal suctioning eased pain. So comparing parts of maternal like experience to morphine for pain reduction did nothing. Similar to Johnston’s maternal voice study. Cignacco E, Hamers JP, van Lingen Ra, Zimermann LJI, Muller R,

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Gesler P. Nelle M. Pain relief in ventilated preterm infants during endotracheal suctioning: a randomized controlled trial. Swiss Med Weekly, 2008, vol 138 #45-44, pg. 635-645. SIMULATED KC

Cignacco et al., 2009 NOT KC, but is REPEATED heel sticks (over days) study with sucrose. Clifford et al., 2004 FT, Review article, KC effectively reduces fullterm infant pain and is

recommended as a pain reduction intervention.

Cong et al., 2006 PT, heel stick in KC and then in incubator or vice versa. Much less pain as measured by PIPP when received 30 minutes of KC and heelstick in KC than in incubator. Heart rate variability and SaO2 better with KC heelstick.

Cong et al., 2009 PT, randomized cross over of 60 min of KC before KC heelstick vs 60 mins of incubator before incubator heelstick. Lower HR rise during heelstick in KC and and lower HR during KC baseline. Many HRV changes too. More stable autonomic functioning with KC heelstick.

Cong, L-Hoe et al., 2011 PT, Randomized cross over trial of 80 and 30 minutes of KC on Cortisol and PIPP. Babies had less pain in KC heelstick than incubator heelstick, regardless of sequence.

Cong et al 2012 PT, case study, 28 weeks, KC and heel stick, infant had better outcomes when they had KC for 15 or 30 minutes in comparison to incubator but no difference in PIPP between KC for 15 minutes to KC for 30 minutes. DOSAGE STUDY

Cong, et al. 2012 PT randomized cross-over trial of 15 and 30 min of KC vs incubator on heart rate variability, both longer and shorter periods of kc stabilized autonomic control during pain better than incubator

Cong & L-H, 2013 PT, FT, ergonomic step by step procedure for personnel to conduct venipuncture and injections during KC

D’Apolito, 2006 Review, cortisol and B-endorphin level were significantly reduced for infant in KC, thus MECHANISMS

deSousa Freire et al., 2008 PT, RCT of 3 groups. KC group had lower PIPP, less variation in HR and SaO2 and shorter duration of facial action with 10-15 min of KC before and during stick than incubator alone or incubator + oral glucose groups. Same as Freire ref.

Dodds, 2003 PT, Survey of nurses- RNs don’t use pharma treatments because they think that they are harmful to infants. We need non-pharmacologic interventions

Ferber & Makhoul 2008 PT, R cross over. NIDCAP signs of neurobehavioral stress were less with heel stick when heelstick was done in KC than in an incubator. Randomized cross-over design. Got 15 mins of KC.

Freire et al., 2008 PT, RCT, see de Sousa Freire above. Same article. This is the one that pubmed uses, but the words “de Sousa” appear in actual article, not pubmed citation.

Gibbins et al.2008 PT, Review of universe of developmental care and how KC is listed in the comfort care planet because Kc reduces pain.

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Golianu et al., 2007 Review of non-pharmacologic techniques and mentions that KC should be used to alleviate acute pain, but cannot provide analgesia for moderate or severe pain in neonate. KC needs to be included in a graduated multidisciplinary algorithm for pain management.

Gray, Watt, Blass 2000 FT, RCT, 10-15 min KC B4 heelstick, KC heelstick vs. swaddled in crib B4 andDuring heelstick. HR increased 8-10 (KC) vs 36-38 (C), crying time dropped 82% KC, facial grimacing dropped 64% KC. Not opioid mediated but pain blockade. Effects of KC seen once infant had relaxed in KC and that took 15 mins.

Gray et al., 2002 FT, mat KC & simultaneous BF (two minute baseline before stick) reducedpain response as compared to cot heel stick.

Hall, 2012 PT, Review. Pain is undertreated, common, and has adverse effects and mostcommon non-pharmacologic treatments are nonnutritive sucking with/without sucrose, KC, swaddling and massage.

Hall & Kirsten, 2008 PT, study of # of kc vs incubator infants who needed blood transfusions. The article ends with a Review of lit that says KC reduces pain.

Hardy 2011 FT, PT, Review, KC reduces pain, in KC a combination of enzymes & hormones are released and raise pain thresholds . KC reduces

behavioral response to pain

Hardy,2011 FT, review of L-H’s Developmental Care chapter and relates that. KC reduces pain.

Harrison et al 2010 PT, FT review, kc mentioned on 118-119. In all studies KC reduces pain, kc isBetter than sucrose, enhanced KC with rocking etc did not have more benefits,more research is needed to study kc on pain, policies for use of KC for all non-emergency for pain situation needed

Hensel, et al. 2013 FT, PT, Review of pain relief strategies for newborns. Says KC is effective and KC can be combined with sucrose to alleviate pain.

Hung and Berg 2011 FT, one mother said “when they put the baby on my arms I forgot about the pain” during cesarean birth

Hunseler & Roth, 2008 PT, FT Review of pain strategies and states that KC is effective in reducing Pain in fullterms and preterm.

Johnson 2005 Review for Advanced Practice Nurses use of KC and cites that KC reduces pain

Johnston et al., 2003 PT. Heelstick pain decreased PIPP by 2 points in 30 mins of KC heelstick vs.incubator. Some infants did not cry at all during the KC heelstick

Johnston, Nuyt ,2007 PT, heelstick pain did NOT decrease on PIPP when infants heard recording of filtered mother’s voice. The skin-to-skin modality of maternal presence is needed to blunt pain response to heel stick. SIMULATED KC

Johnston et al., 2007 PT, FT, review in text. Says effects of fathers on reducing pain has not been studied.

Johnston et al., 2008a PT, VLBW, RCT, less pain and faster recovery in KC (10-15 mins) than

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incubator

Johnston et al., 2008b PT Rcross over of KC +singing, rocking, sucking and then KC alone. No diffs in pain relief between two conditions. KC alone is sufficient to decrease pain response.

Johnston et al 2010 PT, FT first report of planned Cochrane analysis for kc pain reductionJohnston et al 2014 PT, FT, completed pain Cochrane and shows that KC reduces pain

Johnston et al.,2011 PT R cross over. Maternal KC reduces pain perception better than paternal KC. MAT vs PAT

Johnston et al. 2011 Rev of pharmacologic interventions and says that KC will be reviewed in part 2 which is under Campbell-Yeo et al., 2011.

Johnston, F, C-Y, 2011 Physiology of pain review in Pain. Pertains to PT and FT infants

Johnston, Byron et al. 2012 PT, R cross over of 18 preterms 15 mins of KC with mom one day and 15 mins of nurse KCing on other day before heel stick. Surrogate woman not as good as maternal KC.

Johnston et al. 2014 PT, FT, Cochrane meta-analysis shows that KC reduces pain.

Jonson et al 2004 review, research shows that KC reduces pain responses

Kashaninia et al., 2008 FT, RCT, less NIPS pain and less crying with 10 min of mat KC (+2 min during shot) than in crib

Klaus 2009 review, oxytocin release during kc reduces pain MECHANISM

Klaus & Klaus, 2007 A preface review that states that KC increases oxytocin production which in turn raises the pain threshold. This is a mechanism of KC’s impact on pain.MECHANISM

Kostandy et al., 2008 PT, descriptive, 30 mins of KC + KC heelstick cut audible and inaudible crying.

Kostandy & GCA 2003 FT. RCT Some KC infants did not cry at all during hepatitis shot. See 2013 ref.

Kostandy 2005 FT, Dissertation results: KC reduced infant crying during Hepatitis C vaccine

Kostandy & LH 2012?? FT, case report of how one newborn girl responded to two heelsticks and oneshot given in cluster and used pretest-test-posttest design. HR, behavior state (sleep) and crying all improved with KC during the clustered procedures.

Kostandy et al. 2013 FT, RCT of KC for Hep B vaccine injection and KCers had less crying during injection and recovery and returned to calm state sooner than controls. Heart rate trended to being lower during injection in KCers than in controls.

Lago et al., 2009 Review, recommends KC to manage procedural pain

Leslie & Marlow, 2006 PT, FT Review of non-pharmacologic pain relief measures. Reviews studies Showing that KC reduces pain responses in preterm and fullterm infants.

Lindgren et al. 2011 Descrip. Study that showed that human skin-to-skin touch (without movement) is a pleasant sensation and that skin to skin touch with movement (massage) isan even stronger pleasant sensation and that touch with or without movement

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most strongly activates the pregenual anterior cingulate cortex, an area that when activated (usually by opioid analgesia or by oxytocin) reduces pain,anxiety, stress and increases sense of well-being..

Lisle-Porter 2009 Clin article about dying babies and it says to do KC to keep parents involvedand reduces stress/pain (see Lindgren above) – this is all in the table, not in the text. PALLIATIVE CARE

Long 2010 Commentary on Chermont 09 study and agrees that kc with sucrose may beBetter than KC alone

Ludington-Hoe 2011 Review, kc reduces pain

Ludington- Hoe 2011 30 years of review, kc reduces pain

Ludington, 1994 PT, descriptive crossover of 3 hr KC then KC Heelstick then 3 hrs incubator with incubator heel stick. Crying time was 5 seconds with KC heelstick; 45 seconds in Incubator heel stick.. Abstract of El Salvador study.

Ludington-Hoe et al. 2005 PT R cross over. Crying time was sig. less during 2-3 hours of KC + KCheel stick than incubator. 3/11 infants did not cry at all with KC heelstick. HR did not rise as much in KC. Big SECTION ON MECHANISMS

Ludington-Hoe et al.’08 PT, national USA guidelines recommend KC for pain reduction and reviews all studies to March 2008

Lundberg 2009 skin to skin contact provides analgesia

Mallet et al., 2007 Descriptive study of French health professionals knowledge and use of KC.Pain effects of KC were not known by anyone.

Marin Gabriel 2009/2010 FT no difference in episiotomy pain between birth kc and no KC

Marin Gabriel, et al. 2013 FT, RCT of KC+BF, KC+Sucrose, KC alone and sucrose alone showed KC+BF far superior to others in reducing pain and crying to heel stick. No effect on HR.

McGrath JM 2006 Editorial that states that family presence during procedures is needed and should be followed, and states in Guideline #3 that parents be encouraged to “..touch and sooth infants.” Does not mention KC per se, but talks about touch and presence.

McGrath & Brock, 2002 Review. Recommends KC for pain reduction and says after lit review that nurses do not use it for this reason.

Meek & Huertas, 2012 PT, FT, Cochrane meta-analysis that shows that KC reduces pain and does it better than swaddling and facilitative tucking. This is the study that talks about Fabrizi’s work about KC handling the brain’s pain better than sucrose which just eradicates behavioral signs of pain, and does not eradicate brain memory and pathways for long term adverse effects of pain like pleasing human touch can do. FABRIZI

Merenstein & Gardner 2002 Text book, KC is a good analgesic

Messerer et al.,2014 PT,children adolescent Review of non-pharmacologic pain treatments. KC can be used for slightly painful procedures More research needed for its effectiveness in children.

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Miles et al., 2006 PT, RCT, vlbw, daily KC for 4 wks starting in 1st week, 20 mins of KC each time. Pain profile at 4 and 12 months during an immunization; no difference between grps (KC vs. non-KC) on pain response at 4 and 12 months (standard care), but did not get KC during immunization at 4 and 12 months. Long term effects of KC, but did not get KC during pain procedures in hospital either.

Mitchell et al. 2013 PT 2 studies address painMorelius et al., 2005 PT. Used PIPP to measure pain/discomfort during 1 hours of KC. Found first

session of KC was more stressful/behaviorally agitating than 4th session of KC.

Montirosa et al,, 2013 PT, quasi-exp, maternal stress was related to infant’s pain

Morrow et al 2010 FT, RCT, not KC held full upright swaddled reduced pain than in crib

Nanavati et al., 2013 PT, RCT, VLBW 50 infants got either KMC or expressed breast milk for pain reduction with adhesive tape removal. No differences in PIPP Pain scores after removal of the tape between the groups.

NANN, 2008 2nd Edition of Pain Assessment and Management Guidelines that includes KC for procedural pain management.

Naughton 2005 Review. Says KC can be used to reduce pain.

Nimbalkar et al. 2012 PT, RCT cross over of 15 mins of KMC in 50 preterms 32-36 wks GA who had heel stick. HR, behavior, facial scores, PIPPs were 4.85 lower in KMC, but SaO2 did not differ between groups. PIPP was 4.85 points lower.

Nyqvist et al., 2010 Universal article, Recommendations from 7th INK meeting. Says that KMC reduces pain and cites Johnston’s studies.

Okan et al 2010 FT, RCT, kc with breastfeeding group, kc group, and control group. no differences in the kc with breastfeeding and kc only

Parsons et al, 2010 functional neuroanatomy of newborn review page 229 says skin-to-skin has analgesic effects and mechanism is sensory saturation (simultaneous multi senses stimulation) . MECHANISM

Pillai Riddell et al. 2011 FT, PT, Cochrane review of pain management in infants and says that maternal presence reduces use of pain medication and reduces pain of infant. META=ANALYSIS Also, did standardized mean differences and found that KC mean differences in reduction of pain were greater than what they were for facilitated tucking and any other non-pharmacologic pain relief strategy.

Saeidi et al., 2011 FT, Quasi-experimental but random assignment to 2 min of Kc before vaccination and 3 mins Kc after vaccination. study of videotaped pain and crying time. Pain significantly less in KC group,

Sajedi et al., 2007 FT, RCT of 10 minutes of KC before, during and after injection. Mean HR was lower and mean SaO2 was higher in the KC infants than in no-KC infants.

Schultz et al, 2009 PT survey of 33 NICU doctors who knew that breastfeeding and sucrose affect pain but a fewer number knew about kc effects

Shah 2006 Cochrane review. Says BM is not as good as sucrose in reducing HR and pain responses. NOT KC study

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Shah & Jefferies, 2012 PT, Commentary on Johnston 2011 study in which infants having heel lance have lower pain scores and quicker time to return to baseline HR when held in KC by mom than by father. MAT vs PAT

Stevens and Franck, 2001 Review. Say further investigation of KC as a potential source of analgesia in human neonates is most certainly warranted

Stevens et al. 2004 PT, Cochrane review and at end says Sucrose should be tested with KC

Stevens et al., 2007 PT, FT, review in Text. Reviews Johnston’s study and then says the effectiveness of KC in reducing procedural or chronic pain in unstable and vulnerable infants requiring multiple supportive therapies has not been established.

Suresh et al 2009 Not a kc study, lay review that shows massage reduces pain

Terhaar & Starr, 2007 A review for physicians revealing that KC should be routine practice but is not, reviews all “strong” literature supporting KC and gives docs a test at end so it is a continuing education offering too. Cites pain reduction.

Thiel &Ostermann, 2010 Systematic review of pain studies and concludes that KC is simple and effective method to reduced mild to moderate pain in neonates.

Torowitz et al 2010 FT, Case report, congenital heart disease newborn, kc reduce pain measured by FLACC

Tsao et al., 2007 PT,FT review says KC is natural, non-invasive analgesic, gives good identification of research limitations, says it has effect through state and maternal touch, and that further research on generalizability and maternal attitudes is warranted.

Tsao et al., 2008 PT,FT, review, part two that reviews KC (part 1 reviewed sucrose and NNS) and KC studies are reviewed on pg 402 and on pg. 405 says KC is an appealing method.

Uvnas-Moberg 2003 book, cites studies about oxytocin releases during kc in neonates MECHANISM

Uvnas-Moberg 2005 Review, oxytocin released during KC increases pain threshold MECHANISM

Van Sleuwen et al. 2007 Review of 78 swaddling studies. Swaddling is not as good as KC for pain reduction

Vivancos et al, 2010 FT, quasi- experimental, neonates did not cry during the hep B shot (put this study in the new study discussion, they said that babies did not cry at all during the injection while all my babies did cry).

Walden & Jorgansen 2010 book chapter review, kc decreases pain response to heel stick

Walter-Nicolet et al 2010 FT and PT review, kc reduces pain response, breastfeeding

Walter et al 2007 FT descriptive , kc distracted mother from episiotomy repair

Warnock, et al., 2010 Review, systematic narrative review of 12 KC and pain studies and said could not do meta-analysis because no standard errors were reported. They call for better descriptions of KC, use of a guiding framework, better explanation of

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study methods and analyses, and reporting effect sizes, but conclude that KC is safe and effective method to reduce mild to moderate pain in neonates.

Yamada et al., 2008 Review of systematic reviews. KC is a holding technique that was in systematic reviews. States that more research is needed on single, repeated, and combined pharm and non-pharm interventions, including KC.

PAIN – MATERNAL

Axelin et al.,2010 Not KC, but a study of maternal attitude on holding to reduce pain, some do some do not want to hold, but holding is better than sucrose

Byaruhanga et al. 2008 FT. qual.study: Moms felt that Kc distracted them from episiotomy repairJohnson 2005 PT review. Recommends testing KC on maternal pain effectsMarin et al., 2010 FT, RCT of birth KC, no difference in episiotomy pain between groupsHenderson, 2011 FT. KC during C/S and cites Walter’s study for decreased sensations during

surgeryHung and Berg 2011 FT, one mother said “when they put the baby on my arms I forgot about the

pain”Lindgren et al. 2011 Not a KC study. Theory. Adult, human skin to skin massage is a pleasant

sensation even more so than just human skin to skin touch without movement and that the skin to skin touch stimulates the pregenual anterior cingulate cortex, an area that when activated by opioids reduces adults’ pain, anxiety, stress and increase sense of well-being.

Walters et al. 2007 FT, Birth KC. Md’s reported that maternal pain management was better with birth KC for episiotomy repair.

Svenson et al., 2013 FT,RCT.maternal pain before and during breastfeeding was being measuredbut no differences in nipple pain between kc+BF vs BF alone group were evident.

MATERNAL vs PATERNAL ABILITY TO REDUCE PAIN

Johnston et al. 2011 PT, original article showing mothers are better at relieving painShah & Jefferies, 2012 Commentary on Johnston et al. 2011 study

Related Literature

Andrews, K., & Fitzgerald, M. (1994). The cutaneous withdrawal reflex in human neonates: Sensitization, receptive fields, and the effects of contralateral stimulation. Pain, 56, 95-101.

Arias MC, Guinsburg R.(2012). Differences between uni-and multidimensional scales for assessing pain in term newborn infants at the bedside. Clinics (Sao Paulo). 2012 Oct;67(10):1165-70. This study sought to determine the level of agreement between behavioral and multidimensional pain assessment scales in term newborn infants submitted to an acute nociceptive stimulus.This cross-sectional study was performed on 400 healthy term newborns who received an intramuscular injection of vitamin K during the first 6 hours of life. Two behavioral pain scales (the Neonatal Facial Coding System and the Behavioral Indicators of Infant Pain) and one multidimensional tool (the Premature Infant Pain Profile) were applied by a single observer before the procedure, during cleansing, during injection and two minutes after injection. The Cochran Q, McNemar and kappa tests were used to compare the presence and degree of agreement between the three scales. The Hotelling T2 test was used to compare the groups of newborns for which the scales showed agreement or disagreement. A generalized linear regression was used to compare the results of the Neonatal Facial Coding System and the Behavioral Indicators of Infant Pain across the four study time points.The neonates studied had a gestational age of 39±1 weeks, a birth weight of 3169±316 g and and postnatal age of 67±45 minutes. During the stimulus procedure, 80% of the newborns exhibited pain behaviors according to the Neonatal Facial Coding System and the Behavioral Indicators of Infant Pain,

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and 70% experienced pain according to the Premature Infant Pain Profile (p<0.001). The frequencies of the detection of pain using the Behavioral Indicators of Infant Pain and the Neonatal Facial Coding System were similar. The characteristics of the neonates were not associated with the level of agreement between the scales.The Neonatal Facial Coding System and the Behavioral Indicators of Infant Pain behavioral scales are more sensitive for the identification of pain in healthy term newborn infants than the multidimensional Premature Infant Pain Profile scale.

Bartocci M, Bergqvist LL, Lagercrantz H, Anand KJ.(2006). Pain activates cortical areas in the preterm newborn brain. Pain. 2006 May;122(1-2):109-17. Epub 2006 Mar 13. Neonatal Research Unit, Astrid Lindgren's Children's Hospital, Karolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden. marco.bartocci@kbh.ki.se. To study the patterns of supraspinal pain processing in neonates, we hypothesized that acute pain causes haemodynamic changes associated with activation of the primary somatosensory cortex. Forty preterm neonates at 28-36 weeks of gestation (mean=32.0) and at 25-42 h (mean=30.7) of age were studied following standardized tactile (skin disinfection) and painful (venipuncture) stimuli. Changes in regional cerebral haemodynamics were monitored by near infrared spectroscopy (NIRS) over both somatosensory cortices in 29 newborns, and over the contralateral somatosensory and occipital areas in 11 newborns. Heart rate (HR) and peripheral oxygen saturation (SaO2) were recorded simultaneously with NIRS parameters: oxygenated [HbO2], deoxygenated, and total hemoglobin. Tactile stimulation produced no changes in HR or SaO2. HR increased in the first 20s (p<0.001), while SaO2 decreased during the 40s after venipuncture (p<0.0001). Following tactile or painful stimulation, [HbO2] increased bilaterally regardless of which hand was stimulated (p<0.0001). Pain-induced [HbO2] increases in the contralateral somatosensory cortex (p<0.05) were not mirrored in the occipital cortex (p>0.1). Pain-related [HbO2] increases were more pronounced in male neonates (p<0.05 on left, p<0.001 on right), inversely correlated with gestational age (r=-0.53 on left, p<0.01; r=-0.42 on right, p<0.05) and directly correlated with postnatal age (r=0.75 on left, p<0.0001; r=0.67 on right, p<0.0001). Painful and tactile stimuli elicit specific haemodynamic responses in the somatosensory cortex, implying conscious sensory perception in preterm neonates. Somatosensory cortical activation occurs bilaterally following unilateral stimulation and these changes are more pronounced in male neonates or preterm neonates at lower gestational ages.

Bergqvist LL, Katz-Salamon M, Hertegård S, Anand KJ, Lagercrantz H. (2009). Mode of delivery modulates physiological and behavioral responses to neonatal pain. J of Perinatol. 2009 Jan;29(1):44-50. Delivery mode needs to be monitored in future studies because physiological events associated with a normal delivery reduce the physiologic and sympathoadrenal activation by nociceptive mechanisms. Pain and stress reactivity appear to be inhibited during fetal life and sensory inputs during vaginal delivery may reverse this inhibition. To minimize neonatal pain, we recommend that postnatal invasive procedures to be performed shortly after vaginal birth (Bergqvist et al., 2009)

Brummelte S., Grunau RE, Chau V, Poskitt KJ, Brant R, Vinall J, Grover A,Synnes AR, Miller SP. (2012). Procedural pain and brain development in premature newborns. Annals of Neurology 71(3): 385-396. 86 infants born 24-32 weeks were followed from birth with MRI, 3-dimensional MRspectroscopy imaging, and diffusion tensor imaging. First scan at 32.1wks, scan 2 at term age. Calcuated N-acetylaspartate to choline ratios , lactate to choline ratios, average diffusivity, white matter fractional anisotrophy from 7 white and 4 subcortical gray matter sites. Procedural pain was quantified as the number of skin breaking events. After comprehensively adjusting for illness severity, morphine exposure, brain injury, surgery and other factors, greater neonatal procedural pain was assoc with reduced WHITE MATTER and reduced GRAY MATTER. Reduced WHITE MATTER was predicted by EARLY PAIN before scan #1; reduced GRAY MATTER was predicted by pain exposure throughout the neonatal course. Early and continuing pain reduces brain matter. Early procedural pain in very preterm infants contributes to impaired brain development.

Butt ML & Kisilevsky BS. (2000). Music modulates behavior of premature infants following heel lance. Can J Nurs Res 31(4), 17-39. 14 preterms 29-36 wks GA tested on 2 occasions, one with music and then no music.videotaped for baseline, heel lance, and recovery and data separated according to two age groups <31 wks pma and > 31 weeks pma. ANOVA showed that heel lance elicited a stress response (increased

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HR, decreased SaO2, increased arousal, increased facial actions) in both age groups. STRESS reponse greater in older infants. During recovery older infants had faster return on heart rate, behavioral state and facial expression to baseline in the music group. Music is an effective stress reducing intervention.

Chik & Sluka. 2012. Massage and swaddling reduce pain in infants. Paper presented at American Pain Society, 31st Annual Scientific Meeting, May 16, 2012, Abstract 333 and 455. Cited in Ridky 2012 on KC bib

Fabrizi L, Slater R, Worley A, Meek J, Boyd S, Olhede S, Fitzgerald M.(2011) A shift in sensory processing that enables the developing human brain to discriminate touch from pain. Curr Biol. 2011 Sep 27;21(18):1552-8. doi: 10.1016/j.cub.2011.08.010.

Fabrizi L, Worley A, Patten D, Holdridge S, Cornelissen L, Meek J, Boyd S, Slater R.(2011) Electrophysiological measurements and analysis of nociception in human infants.J Vis Exp. 2011 Dec 20;(58). doi:pii: 3118. 10.3791/3118.

Fabrizi L, Slater R. (2012). Exploring the relationship of pain and development in the neonatal intensive care unit. Pain. 2012 Jul;153(7):1340-1341. doi: 10.1016/j.pain.2012.03.013.

Slater R, Cornelissen L, Fabrizi L, Patten D, Yoxen J, Worley A, Boyd S, Meek J, Fitzgerald M.(2010). Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet. 2010 Oct 9;376(9748):1225-32. doi: 10.1016/S0140-6736(10)61303-7.

Worley A, Fabrizi L, Boyd S, Slater R. (2012). Multi-modal pain measurements in infants. J Neurosci Methods. 2012 Apr 15;205(2):252-7. doi: 10.1016/j.jneumeth.2012.01.009.

Fearon I, Kisilevsky BS, Hains SM, Muir DW, Trammer J 1997. Swaddling after heel lance: age-specific effects on behavioural recovery in preterm infants. J Dev. Behav Pediatr 18(4), 222-232. 15 infants in two age groups (<31 wks pma and >31 wks pma)

(Fernandez M, Blass EM, Hernandez-Reif, M, Field, T., Diego, M., Sanders C. 2003. Sucrose attenuates a negative electroencephalographic response to an aversive stimulus for newborns. Dev Behav Pediatr 24, 261-266)

Fernandez,A., Campbell-Yeo, M. & Johnston, C.C. (2010 or 2011) Procedural pain management for neonates using non-pharmacologic strategies: Part 1: sensorial interventions. Advances in Neonatal Care, 11(4), 235-241. This speaks to how auditory and olfactory recognition are helpful in reducing pain and it also reviews facilitated tucking, containment, swaddling, positioning,nonnutritive sucking and sweet solutions. These are nurse driven strategies and they are grossly underutilized. This only says in the introduction that KC will be reviewed in part2 which is published under Campbell-Yeo in 2011.

Fitzgerald, M. & de Lima, J. (2001). Hyperalgesia and allodynia in infants. In: Finley GA, McGrath, PJ. Eds. Acute and Procedural Pain in Infants and Children. Seattle: IASP Press. 1-12. The more the number of previous painful experiences, the more likely the infant is to have hypersensitization to pain (Andrews and Fitzgerald, 1994;Fitzgerald nd de Lima, 2001). Hypersensitivity to pain is an inability to implement inhibitory mechanisms, thus the infant demonstrates an exaggerated pain response to subsequent pain experiences.

Franck L & Gilbert, R 2002. Review. Should test KC as a pain reducing strategy. Reducing pain during blood sampling in infants. Clinical Evidence 7, 352-366.

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Franck,L.S., Oulton, K., & Bruce, E. (2012). Parental involvement in neonatal pain management: an empirical and conceptual update. Journal of Nursing Scholarship, 44(1), 45-54. Provides a new theory of the levels of parental involvement in managing NICU infant pain and clearly states that parents see their” role as a VITAL ROLE in which they want full involvement” (pg. 48) and to help with infant pain as much as possible, want to be informed of painful procedure before it occurs and then help baby through painful procedure and even use specific treatments like change diaper frequently, give sucrose, , pacifier, proper rest opportunities, more skill in health workers for putting lines in, create calm surroundings etc (pg 49 chart).. They don’t want to be told that they should wait outside. Page 48 relates the stages of parental involvement: 1. None (views infant comfort as nurse or doctor’s role only, 2. Be Informed, 3. Be present, 4. Provide comfort by touch, voice, specific comforting techniques, 5 Informant for NICU staff (tells staff what works for baby), 6. Active decision maker, 7. Advocate for infant – primary responsibility in partnership with clinical team

Gibbins S, Stevens B etal. 2008. Changes in physiological and behavioural pain indicators over time in preterm and term infants at risk for neurologic impairment. Early Human Dev epub before print.

Gibbins S, Stevens B, McGrath PJ, Yamada J, Beyene J, Breau L et al., 2007. Comparison of pain responses in infants of different gestational ages. Neonatology (former Biol Neonate) 93(1), 10-18.

Gibbins S, Stevens B, Beyene J, Chan PC, Bagg M, Asztalos E.(2008). Pain behaviours in Extremely Low Gestational Age infants. Early Hum Dev. 2008 Jul;84(7):451-8. doi: 10.1016/j.earlhumdev.2007.12.007. Epub 2008 Feb 19. A prospective crossover design with 50 ELGA infants from one Canadian tertiary level NICU was conducted. Infants were assessed in random order during standardized painful (heel lance) and non-painful (diaper change) procedures. Physiological (heart rate, oxygen saturation) and behavioural (facial and body movement) indicators were continuously collected during 4 phases of the procedures. Biochemical (salivary cortisol) indicators were collected immediately before and 20 min following the procedures. Four facial actions (brow bulge, eye squeeze, nasolabial furrow, vertical mouth stretch) increased immediately following the heel lance. There were no specific changes in physiological, body movement or cortisol indicators following the heel lance. ELGA infants demonstrated greater body movements during the diaper change, which may reflect immature motor coordination. No differences in pain responses were found for infants born between 23-25 6/7 weeks GA and those between 26-28 weeks GA. Similarly, no gender differences were found.

Gray L, & Michalska, K. 2004. Sucrose effect on infant metabolism. Paper presented at ICIS, Chicago, Illl, April 2004. Sucrose results in decreased rate of metabolism dur to an average 10 bp. Decrement in heart rate following sucrose taste.

Harrington JW, Logan S, Harwell C et al., 2012. Effective analgesia using physical interventions for infant immunizations. Pediatrics, 129(5): 815-822) tested the 5 S’s (swaddling, side/stomach position, shushing, swinging, and sucking) on 2 and 4 month old infants and resulted in decreased crying time and decreased pain scores for infants getting immunizations. The addition of sucrose did NOT lessen pain scores or crying further (given 2 ml water or 2 ml of 24% sucrose before immunization and either parental comfort or the 5 S’s after immunization. The 5 S group had lower pain scores than parental comfort group and no diff between 5S’s with water and 5 S;s with sucrose. Pain reduction from physical intervention was significantly greater than pain reduction from sucrose alone. IMMUNIZATION

Johnston, C. (2011). Pain control in infants and young children. Pain Research and Management. 16(5): 320.

Johnston C, Barrington KJ, Taddio A, Carbajal R, Filion F.(2011). Pain in Canadian NICUs: have we improved over the past 12 years? Clinical J of Pain, 27(3), 225-232.

Johnston, C.C., Fernandes, A.M., Campbell-Yeo, M. (2011). Pain in neonates is different. Pain 152(3 suppl): S65-S73. Doi: 10.1016/j.pain.2010.10.008 Pain processing and management in neonates,

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especially preterm neonates, differs from older populations. In this review, a brief background on pain processing in neonatal life, pain exposure in Neonatal Intensive Care Units (NICU), the consequences of untreated pain, and the difficulties in treating procedural pain pharmacologically will be presented. A more detailed review of non-pharmacological interventions for procedural pain in neonates will include sensory stimulation approaches, oral sweet solutions, and maternal interventions. Some possible mechanisms for the effectiveness of non-pharmacological interventions are offered. Finally, avenues of research into similar interventions as adjuvant therapies or drug-sparing effects in older populations are suggested. THIS MAY BE KC, GET AT SCHOOL. Variation in pain in neonates. Pain processing and management in neonates, especially preterm neonates, differs from older populations. In this review, a brief background on pain processing in neonatal life, pain exposure in Neonatal Intensive Care Units (NICU), the consequences of untreated pain, and the difficulties in treating procedural pain pharmacologically will be presented. A more detailed review of non-pharmacological interventions for procedural pain in neonates will include sensory stimulation approaches, oral sweet solutions, and maternal interventions. Some possible mechanisms for the effectiveness of non-pharmacological interventions are offered. Finally, avenues of research into similar interventions as adjuvant therapies or drug-sparing effects in older populations are suggested

Campbell-Yeo ML, Johnston CC, Joseph KS, Feeley N, Chambers CT, Barrington KJ(2012). Cobedding and recovery time after heel lance in preterm twins: results of a randomized trial. Pediatrics. 2012 Sep;130(3):500-6. doi: 10.1542/peds.2012-0010. Epub 2012 Aug 27 Women’s and Newborn Health Program, IWK Health Centre, Halifax, Nova Scotia, Canada. marsha.campbellyeo@iwk.nshealth.ca Cobedding of preterm twin infants provides tactile, olfactory, and auditory stimulation and may affect pain reactivity. We carried out a randomized trial to assess the effect of cobedding on pain reactivity and recovery in preterm twin neonates.Stable preterm twins (n = 67 sets) between 28 and 36 weeks of gestational age were randomly assigned to a cobedding group (cared for in the same incubator or crib) or a standard care group (cared for in separate incubators or cribs). Pain response (determined by the Premature Infant Pain Profile [PIPP]) and time to return to physiologic baseline parameters were compared between groups with adjustment for the nonindependence of twin infants. Maternal and infant characteristics were not significantly different between twin infants in the cobedding and standard care groups except for 5-minute Apgar <7 and postnatal age and corrected gestational age on the day of the heel lance. Mean PIPP scores were not different between groups at 30, 60, or 120 seconds. At 90 seconds, mean PIPP scores were higher in the cobedding group (6.0 vs 5.0, P = .04). Recovery time was shorter in the cobedding group compared with the standard care group, (mean = 75.6 seconds versus 142.1 seconds, P = .001). No significant adverse events were associated with cobedding. Adjustment for nonindependence between twins and differences in baseline characteristics did not change the results.Cobedding enhanced the physiologic recovery of preterm twins undergoing heel lance, but did not lead to lower pain scores.

Latimer, M., Jackson, P., Johnston, C. & Vine, J. (2011). Examining nurse empathy for infant procedural pain: Testing a new video measure. Pain Research and Management, 16(4), 228-233.

Maneyapanda SB & Venkatasubramanian, A. (2005). Relationship between significant perinatal events and migraine severity. Pediatrics 116(4), e555-e558. Nociceptive neuronal circuits are formed during embryonic and postnatal times, so insult during these periods may result in long term altercations to pain circuitry via synaptic plasticity. One long term result is central hyperexcitability, which is assoc with migraines. 280 pediatric migraine patient records were reviewed. A significant relationship betw being an NICU patient and having migraine medication existed but no relationship between patients who were not NICU patients. NICU patients also had significantly earlier onset of migraines. Pain experienced as a neonate alters later experience of pain (happens through neuronal plasticity and central hyperexcitability. Early pain experience can affect subsequent pain syndromes and pain in neonates needs to be TREATED to avoid long lasting neuronal alterations.

Milazzo W, Fielder, J., Bittel A, Coil, J., McClulre M, Tobin, P. and Vande Kamp, V. (20110. Oral sucrose to decrease pain associated with arterial puncture in infants 3036 weeks’ gestation: a randomized clinical trial. Advances in Neonatal Care, 1196), 406-411.

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Ranger M, Johnston CC, Limperopoulos C, Rennick JE, du Plessis AJ. (2011) Cerebral near-infrared spectroscopy as a measure of nociceptive evoked activity in critically ill infants. Pain Res Manag. Sep-Oct;16(5):331-6. Review

Rao M, Blass EM et al., 1997. Reduced heat loss following sucrose ingestion in premature and normal human newborns. Early Hum Dev. 48 (1-2), 109-116.

Rattaz et al., 2005. Scent of mother’s milk reduces pain response. Rattaz C,Goubet N, Bullinger A. (2005). The calming effect of a familiar odor on full-term newborns. J Dev Behav Pediatr 26, 86-92. And run pubmed on Goubet 2003 for her familiar odor (but was not mother’s milk).

Rennick, J.E., Lambert. S., Childerhose, J., Campbell-Yeo, M., Filion, F. & Johnston, C.C. (2011). Mother’s experiences of a Touch and Talk nursing intervention to optimize pain management in the PICU: A qualitative descriptive study. Intensive Critical Care Nursing, 27(3), 151-157. Doi:10.1016/j.iccn.2011.03.005 Parents consistently express a desire to support their child and retain a care-giving role in the paediatric intensive care unit (PICU). Qualitative data gathered as part of a PICU intervention study were analysed to explore mothers' experiences using a Touch and Talk intervention to comfort their children during invasive procedures.To describe how mothers experienced involvement in their children's care through a Touch and Talk intervention and whether they would participate in a similar intervention again. RESEARCH METHODOLOGY AND SETTING: A qualitative descriptive design was used and semi-structured interviews conducted with 65 mothers in three Canadian PICUs. Data were subjected to thematic analysis.The overarching theme centered on the importance of comforting the critically ill child. This included being there for the child (the importance of parental presence); making a difference in the child's pain experience; and feeling comfortable and confident about participating in care. All but two mothers would participate in the intervention again and all would recommend it to others. Giving parents the choice of being involved in their child's care using touch and distraction techniques during painful procedures can provide an invaluable opportunity to foster parenting and support the child during a difficult PICU experience.

Santos LM, Ribeiro IS, Santana RC.(2012). [Identification and treatment of pain in the premature newborn in the intensive care unit]. Rev Bras Enferm. 2012 Apr;65(2):269-75. This study aimed to analyze the parameters used by the nursing staff of a public hospital in Bahia for pain assessment in premature newborns and to describe the interventions used to relieve the pain. This is a qualitative descriptive study that was carried out through semi-structured interviews with ten participants, in the period from December 2008 to January 2009. The data were analyzed through content analysis. The results showed the use of crying and facial expression as the clinical indications of pain premature newborns and that the interviewed participants use, on a non-systematic basis, non-pharmacological measures in order to ease this process. We suggest the introduction of pain as the fifth vital sign to be evaluated and the use of scales, contributing to excellence and humane care.

Stevens BJ, Abbott LK, Yamada J, Harrison D, Stinson J, Taddio A, Barwick M, Latimer M, Scott SD, Rashotte J, Campbell F, Finley GA; CIHR Team in Children's Pain. (2011). Epidemiology and management of painful procedures in children in Canadian hospitals. Canadian Medical Assoc.Journal, April 19 , 183(7): E403-E410,

Stevens and Franck, 2001 Review. Say further investigation of KC as a potential source of analgesia in human neonates is most certainly warranted

Stevens BJ, Yamada J, Ohlsson A. 2001. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Databae Systematic Reviews, #4,CD001069. “The use of repeated administrations of

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sucrose in neonates needs to be investigated as does the use of sucrose in combination with other behavioural (facilitated tucking, kangaroo care) and pharmacologic (morphine, fentanyl) interventions.” SUCROSE &KC

Uvnas-Moberg K, Bruzelius G, Alster P, Lundeberg T. 1993. The antinociceptive effect of non-noxious sensory stimulation is partly mediated through oxytocinergic mechanisms. Acta Physiologica Scandinavica, 149, 199-204. Non-noxious stimulation such as stroking, skin-to-skin contact, touch, massage, and pleasant warm temperature causes a release in oxytocin which enhances the antinociceptive effects of these treatments. This is in animal studies. ANIMAL STUDIES OF SKIN TO SKIN

Vinall J, Miller SP, Synnes AR, Grunau RE. (2013). Parent behaviors moderate the relationship between neonatal pain and internalizing behaviors at 18 months' corrected age in children born very prematurely. Pain . 2013 Jun 5. pii: S0304-3959(13)00292-3. doi: 10.1016/j.pain.2013.05.050. [Epub ahead of print].Children born very preterm (⩽32weeks' gestation) exhibit greater internalizing (anxious/depressed) behaviors compared to term-born peers as early as 2years; corrected age (CA); however, the role of early stress in the etiology of internalizing problems in preterm children remains unknown. Therefore, we examined the relationship between neonatal pain and internalizing behavior at 18months' CA in children born very preterm and examined whether parent behavior and stress moderated this relationship. Participants were 145 children (96 very preterm, 49 full term) assessed at 18months' CA. Neonatal data were obtained from medical and nursing chart review. Neonatal pain was defined as the number of skin-breaking procedures. Cognitive ability was measured with the Bayley Scales of Infant Development II. Parents completed the Parenting Stress Index III, Child Behavior Checklist 1.5-5, and participated in a videotaped play session with their child, which was coded using the Emotional Availability Scale IV. Very preterm children displayed greater Internalizing behaviors compared to full-term control children (P=.02). Parent Sensitivity and Nonhostility moderated the relationship between neonatal pain and Internalizing behavior (all P<.05); higher parent education (P<.03), lower Parenting Stress (P=.001), and fewer children in the home (P<.01) were associated with lower Internalizing behavior in very preterm children, after adjusting for neonatal medical confounders, gender, and child cognitive ability (all P>.05). Parent Emotional Availability and stress were not associated with Internalizing behaviors in full-term control infants. Positive parent interaction and lower stress seems to ameliorate negative effects of neonatal pain on stress-sensitive behaviors in this vulnerable population. PARENT STRESS TOO!

Weller & Feldman, 2003 – KC contact is a form of touch that promotes infant self regulation and the infant’s ability to moderate the effects of some risk (painful) factors. Serum cholecystokinin (CCK) and opiod peptides might be going up (or whichever direction is beneficial) when in KC.

Weller A, Rozin et al. 2002 pituitiary thyroid axis and adrenal function in preterm infants raised by KMC

BIOMARKERS OF PAIN

Shibata M, Kawai M, Matsukura T, Heike T, Okanoya K, Myowa-Yamakoshi M.(2013). Salivary biomarkers are not suitable for pain assessment in newborns. Early Hum Dev. 2013 Jul;89(7):503-6. doi: 10.1016/j.earlhumdev.2013.03.006. Epub 2013 Apr 10.Department of Pediatrics, Kyoto University Hospital, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan. mishibat@kuhp.kyoto-u.ac.jp Newborns admitted to the neonatal intensive care unit are repeatedly subjected to painful or stressful procedures; therefore, objective assessment of their pain is essential. An increasing number of scales for neonatal pain assessment have been developed, many of which are based on physiological and behavioral factors. Recently, salivary biomarkers have been used to assess stress in adults and older infants. This study aimed to determine whether salivary biomarkers can be useful objective indices for assessing newborn pain. A total of 47 healthy newborns were enrolled 3-4days after birth. Heel lancing was performed to collect blood for a newborn screening test. Before and after heel lancing, saliva was collected to analyze hormone levels, a video was recorded for behavioral observations, and heart rate was recorded. Two investigators independently assessed newborn pain from the video observations using the Neonatal Infant

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Pain Scale (NIPS). Salivary chromogranin (sCgA) and salivary amylase (sAA) levels were measured using an enzyme-linked immunosorbent assay kit and a dry chemistry system, respectively.No definite changes in salivary biomarkers (sCgA or sAA) were detected before and after heel lancing. However, newborn sCgA levels were markedly higher than reported adult levels, with large inter- and intra-subject variability, whereas newborn sAA levels were lower than adult levels. NIPS score and heart rate were dramatically increased after heel lancing.NIPS score (behavioral assessment) and heart rate are useful stress markers in newborns. However, neither sCgA nor sAA is suitable for assessing newborn pain.

Circumcision Pain

Bellieni CV, Alagna MG, Giuseppe B. (2013)Analgesia for infants' circumcision. Ital J Pediatr. 2013 Jun 13;39(1):38-?? Male circumcision (MC) is one of the oldest and most common operations performed all over the world. It can be performed at different ages, using different surgical techniques, with or without analgesia, for different religious, cultural and medical reasons.Our aim is to examine and compare the various methods of analgesia and different surgical procedures reported in literature that are applied in infant MC. We performed a PubMed, MEDLINE, EMBASE and Cochrane search in the papers published since 2000: 15 studies met the inclusion criteria, most of them showing that a combined pharmacological and non-pharmacological intervention is the best analgesic option, in particular when the dorsal penile nerve block is combined with other treatments. The Mogen surgical procedure seems to be the less painful surgical intervention, when compared with Gomco clamp or PlastiBell device. Only 3 papers studied groups of at least 20 babies each with the use of validated pain scales. Data show a decrease of pain with dorsal penile nerve block, plus acetaminophen associated to oral sucrose or topic analgesic cream. However, no procedure has been found to eliminate pain; the gold standard procedure to make MC totally painfree has not yet been established.

Taddio A.(2001). Pain management for neonatal circumcision. Paediatr Drugs. 2001;3(2):101-11. Circumcision is the most common surgical procedure performed in the neonatal period in North America. If untreated, the pain of circumcision causes both short and long term changes in infant behaviours. The most widely studied pharmacological intervention for pain management during circumcision is dorsal penile nerve block (DPNB) by injected lidocaine (lignocaine). Randomised controlled trials have demonstrated its efficacy; infants premedicated with lidocaine have significantly smaller changes in physiological and pain-related behaviours compared with infants who are not given analgesics. A meta-analysis of injection-related adverse effects (bruising/haematoma) yielded a risk of 6.7% (95% confidence interval, 0.5 to 12.9%). Systemic toxicity from injected local anaesthesia has not been reported. Less effective modalities include topical anaesthesia with lidocaine-prilocaine cream [Eutectic Mixture of Local Anaesthetics (EMLA)], lidocaine cream and oral administration of sucrose. The good tolerability of lidocaine-prilocaine cream has been demonstrated by a lack of clinically significant methaemoglobinaemia when used appropriately. Nonpharmacological interventions (pacifier, specially designed restraint chair) reduce distress during the procedure, and paracetamol (acetaminophen) may provide postoperative analgesia. No single agent has been demonstrated to ameliorate pain for all infants undergoing circumcision. A multimodal approach of pharmacotherapy is currently recommended. Studies evaluating the efficacy of combined analgesia have demonstrated significant benefits for combinations of 2 or more forms of treatment (such as DPNB and sucrose-dipped pacifier) compared with single interventions. The instrument used to perform the circumcision is also important. The Mogen clamp has been shown to be associated with a shorter procedure time and less pain compared with the Gomco clamp. If circumcision is to be performed on infants, it is, therefore, recommended that combined analgesia and the Mogen clamp technique are used, and nonpharmacological stress reducing interventions such as pacifiers and comfortable restraining chairs should also be employed.

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New heel stick procedure is in:Folk LA. 2007. Guide to capillary heelstick blood sampling in infants. Adv Neonatal Care 7(4): 171-178. Gives step by step guide to capillary blood sampling along with evidence-based pradtie incorporating neonatal appropriate disinfection and non-pharmacological analgesia that contribute to improved infant safety and comfort during the procedure.

SUCROSEHatfield LA. 2008. Sucrose decreases infant biobehavioral pain response to immunizations : a randomized controlled trial. J. Nrsg. Scholarship, 40(3), 219-225. Used old Gate Controlled Theory of Pain by Melzack & Wall, 1965. Says in article that “the plasticity of the developing brain and the long term changes that occur in response to unmanaged pain in infants can contribute to altered perceptions of pain later in life” (Grunau RV, Holsti L, Peters JW 2006, Long term consequences of pain in human neonates. Sem Fetal Neonatal Med 11(4), 268-275), permanent impairment of learning,memory, behavior and increased sensitization in childhood (Grunau RV, Whitfield MF, PetrieJH & Fryer EI 1994,Early pain experience, child and family factors as precursors of somatization- a prospective study of extremely premature and fullterm children. Pain 56(3) 353-359). Also says crying is considered an indicator for the presence of pain (Ramenghi IA, Webb AV, Shevlin PM Green M Evans DJ, Levene MI. 2002, Intra-oral administration of sweet tasting substances and infants’ crying response to immunizations: a RCT. Biol Neonate 81(3), 163-169; Reis EC, Roth EK, Syphan JL, Tarbell SE, Holubkov R, 2003,Effective pain reduction for multiple immunization injections in young infants. Arch Pediatr Adolesc Med 157(11),1115-1120), but presence of crying does not confirm nor deny pain in infants.

SUCROSE SIDE EFFECTS: Naughton, 2013 (see MOD article for citation)

Stevens B, Craig K, Johnston C, Harrison D, Ohlsson A.(2011). Oral sucrose for procedural pain in infants. Lancet, 377(9759), 25-26, author reply 27-28.

Stevens BJ, Yamada J, Ohlsson A. 2001. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Systematic Reviews, #4,CD001069. “The use of repeated administrations of sucrose in neonates needs to be investigated as does the use of sucrose in combination with other behavioural (facilitated tucking, kangaroo care) and pharmacologic (morphine, fentanyl) interventions.”

WHY NURSES DON’T USE PAIN INTERVENTIONS.Latimer MA, Ritchie JA, Johnston CC., (2010). Individual nurse and organizational context considerations for better Knowledge Use in Pain CareJ Pediatr Nurs. 2010 Aug;25(4):274-81. THIS HAS A MODEL FOR GETTING NURSES TO USE TREATMENTS BECAUSE THEY DON’T NOW (10/8/2011).

MATERNAL CARE AND PAIN PERCEPTION.________________,2013. Review that says maternal involvement reduces pain.

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de Medeiros CB, Fleming AS, Johnston CC, Walker CD (2009). Artificial rearing of rat pups reveals the beneficial effects of mother care on neonatal inflammation and adult sensitivity to pain. Pediatr Res. 2009 Sep;66(3):272-7. Repeated pain during brain development can have long-term consequences in both humans and animals. We previously showed that maternal care provided to pups experiencing pain reduced adult pain sensitivity. This study tested whether sensory stimulation was responsible for this effect. Rat pups were either mother-reared controls (MR-CON) or artificially reared (AR) with minimal (AR-MIN) or maximal (AR-MAX) stimulation provided daily. In each rearing condition, pups were either uninjected or injected from postnatal day (PND) 4 to 14 with saline (0.9%) or formalin (0.2-0.4%). Pain behavior and paw inflammation were scored. Thermal sensitivity and responses to formalin were tested in adulthood (PND 70). AR neonates, irrespective of sensory stimulation received, exhibited a pain response (p < 0.001), even with a mild formalin dose. Maternal rearing reduced inflammation during the second week of life compared with AR pups (p < 0.05). Early pain exposure did not modify adult pain sensitivity. However, rearing altered adult pain sensitivity such that uninjected MR-CON rats had lower pain sensitivities than uninjected AR rats (p < 0.05). This suggests that the beneficial effects of maternal rearing can be obliterated if additional stimulation/stress occurs during the early neonatal period. In addition, this suggests that optimal level of maternal stimulation exists that determines adult pain sensitivity.

Walker CD, Xu Z, Rochford J, Johnston CC (2008). Naturally occurring variations in maternal care modulate the effects of repeated neonatal pain on behavioral sensitivity to thermal pain in the adult offspring. Pain. 2008 Nov 15;140(1):167-76. Epub 2008 Sep 17 Source:Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada. waldom@douglas.mcgill.ca Abstract:Repeated pain during a critical period of development can have long-term behavioral and physiological consequences in both human and animals. We previously showed that rat mothers caring for pups subjected to mild pain in neonatal life increased pup licking and grooming behavior. Therefore, we tested whether naturally occurring variations in maternal behavior would modulate the effects of repeated mild inflammatory pain on behavioral responses to pain and stress in the adult male offspring. Rat pups were either uninjected (UI) or injected twice daily between PND3 and PND14 with either saline (0.9%) or formalin (0.2-0.4%) in the footpad of the hindpaw. Maternal behavior (pup licking and grooming) was recorded under basal conditions and after reunion with the litter post injection to determine maternal phenotype (High, Middle, Low licking). Adult offspring (PND60) were tested for their thermal sensitivity, inflammatory pain responses after formalin injection and neuroendocrine responses to formalin injection. Maternal phenotype significantly altered pain sensitivity after thermal stimulation, but not formalin injection. Offspring from the High licking mothers displayed increased withdrawal latencies compared to offspring from Low mothers, regardless of neonatal treatment. Pain responses after formalin injection were higher in offspring receiving formalin as neonates compared to saline-treated or uninjected rats, demonstrating a long lasting increased sensitivity to inflammatory pain. Neuroendocrine responses to pain stress were not affected by neonatal treatment. These data suggest that changes in maternal behavior can influence some modalities of pain sensitivity and that repeated mild inflammatory pain in neonatal period causes hypersensitivity to formalin in the adult offspring.

Also get Veenema, AH. (2012). Toward understanding how early life social experience alters oxytocin and vasopressin-regulated social behaviors. Homones and Behavior, 61(3), 34-312 THIS IS ALSO FOR SEPARATION>

PAIN SCALESStevens B, Johnston C, Petryshen P, Taddio A (1996). Premature Infant Pain Profile: development and initial validation. Clin J Pain. 1996 Mar;12(1):13-22.

Stevens B, Johnston C, Taddio A, Gibbins S, Yamada J. (2010)The premature infant pain profile: evaluation 13 years after development. Clin J Pain. 2010 Nov-Dec;26(9):813-30. doi: 10.1097/AJP.0b013e3181ed1070.)

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Neonatal Infant Pain Scale (NIPS). {Santos LM, Ribeiro IS, Santana RC. [Identification and treatment of pain in the premature newborn in the intensive care unit] Rev Bras Enferm. 2012 Apr;65(2):269-75This study aimed to analyze the parameters used by the nursing staff of a public hospital in Bahia for pain assessment in premature newborns and to describe the interventions used to relieve the pain. This is a qualitative descriptive study that was carried out through semi-structured interviews with ten participants, in the period from December 2008 to January 2009. The data were analyzed through content analysis. The results showed the use of crying and facial expression as the clinical indications of pain premature newborns and that the interviewed participants use, on a non-systematic basis, non-pharmacological measures in order to ease this process. We suggest the introduction of pain as the fifth vital sign to be evaluated and the use of scales, contributing to excellence and humane care}

PAIN OUTCOMES ON DEVELOPMENT

Jillian Vinall, Steven P. Miller, Vann Chau, Susanne Brummelte, Anne R. Synnes, Ruth E. Grunau (2012) Neonatal pain in relation to postnatal growth in

infants born very preterm

PAIN, Volume 153, Issue 7, July 2012, Pages 1374-1381

Fabrizi, L.S. (2012) Exploring the relationship of pain and development in the neonatal intensive care unit. Pain 153(7): 1340-1341.doi: 10.1016/j.pain.2012.03.013

Why are premature babies admitted to the neonatal intensive care unit (NICU)? The obvious answer is to ensure their survival. The time that a premature infant spends in NICU is a critical and delicate stage for the overall growth and neurodevelopment of the individual. For this reason, the clinical procedures required to assure survival may affect the neurological development during the relatively short hospitalization period and even later in life. Invasive medical interventions are often required to diagnose and treat life-endangering pathophysiological conditions. As a result, pain is an unavoidable aspect of neonatal intensive care and is an experience that deviates most dramatically from what would occur physiologically at an equivalent gestational age in the womb. So the question arises, what are the short and long-term effects of early exposure to painful procedures on the developmental outcomes of premature infants?

The effect of early exposure to pain is often studied with regards to its long-term consequences. Pain in the NICU is associated with worse motor and cognitive development [4] and, particularly following surgery, with persistent changes in sensory processing in ex-premature children [3], [6] and [10]. These studies, however, have to take into account the social and environmental factors that follow prematurity, which may themselves affect the developmental outcomes – i.e. these

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factors are potential confounds [8]. It is therefore important to look at the influence of noxious experiences on early developmental indicators and pain perception, since this analysis may provide information as to whether successive alterations are primed while the infants are still in the NICU. Because neurodevelopmental indices cannot be measured in neonates, the observed indicators are bound to be indirect. Indeed, the importance of these indicators resides in their relation to subsequent outcomes. In this complex clinical population, any study that attempts to relate the number of painful procedures to long-term effects, is thus inherently complicated.

hy are premature babies admitted to the neonatal intensive care unit (NICU)? The obvious answer is to ensure their survival. The time that a premature infant spends in NICU is a critical and delicate stage for the overall growth and neurodevelopment of the individual. For this reason, the clinical procedures required to assure survival may affect the neurological development during the relatively short hospitalization period and even later in life. Invasive medical interventions are often required to diagnose and treat life-endangering pathophysiological conditions. As a result, pain is an unavoidable aspect of neonatal intensive care and is an experience that deviates most dramatically from what would occur physiologically at an equivalent gestational age in the womb. So the question arises, what are the short and long-term effects of early exposure to painful procedures on the developmental outcomes of premature infants?

The effect of early exposure to pain is often studied with regards to its long-term consequences. Pain in the NICU is associated with worse motor and cognitive development [4] and, particularly following surgery, with persistent changes in sensory processing in ex-premature children [3], [6] and [10]. These studies, however, have to take into account the social and environmental factors that follow prematurity, which may themselves affect the developmental outcomes – i.e. these factors are potential confounds [8]. It is therefore important to look at the influence of noxious experiences on early developmental indicators and pain perception, since this analysis may provide information as to whether successive alterations are primed while the infants are still in the NICU. Because neurodevelopmental indices cannot be measured in neonates, the observed indicators are bound to be indirect. Indeed, the importance of these indicators resides in their relation to subsequent outcomes. In this complex clinical population, any study that attempts to relate the number of painful procedures to long-term effects, is thus inherently complicated.

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This complexity is primarily due to the numerous confounding factors associated with prematurity, which are difficult to control for and to separate. Often, to assess the effect of one factor, it is normal practice to control for the others by selecting a subsample of hospitalized infants and comparing groups whose only difference is the aspect under investigation. For example, in a trial to investigate the effect of pre-emptive morphine analgesia, more than a third of the screened infants were excluded from the study so that the effect of morphine analgesia was only tested on ventilated infants [1]. In the present issue of PAIN, Vinall et al. [9] instead, made an elegant attempt to disentangle the relation of pain experience with postnatal body weight and head growth, – measurements commonly used in the NICU to monitor the developmental trajectory – while including a wide cross-section of the premature population. The authors designed a generalised linear model (GLM) to include most of the key factors known to influence body growth. Using this approach they could successively assess each relationship independently, with a particular focus on the number of painful procedures. This approach has the advantage of not biasing the estimated correlations by cherry-picking a selected sample population, and provides a framework to explore simultaneously the relationships between individual factors and body growth, eventually uncovering possible interactions. It is clear that the feasibility of the model is limited by the amount and nature of the variables taken into account and by the underlying connections between them, but this is common to most clinical research. Unconsidered factors, such as nutrition, fall into the unexplained variance of the data, but since the number of painful procedure is linked to multiple medical aspects, rather than to one in particular, the correlation with the outcome measure has been shown to be significant. Bearing in mind these considerations, the authors found that body growth at 32 weeks gestational age is inversely related to the number of painful procedures delivered since birth. This represents the time when the infants received the greatest number of skin-breaking procedures. Changes later on (between 32 weeks and 40 weeks gestational age) appear to be less related to painful procedures, but more to postnatal infection, such that when considering the overall period from birth to term-age-equivalence, body growth is not associated with painful experience. The study suggests, therefore, that the extremely early postnatal period for the very early pre-term infants represents a time of high susceptibility to growth retardation, and that this is related to painful experiences. It should be pointed out that as no physiological or causal interpretation can be given to the observed relationship, these findings are important from a strictly epidemiological point of view. Moreover the interpretation of this study relies on the

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validity of the chosen indicators, body weight and head growth, as predictors of neurodevelopmental outcome. Although these have been found to be associated with incidence of cerebral palsy and neurodevelopmental retardation [2], the significance of measurements such as birthweight and body growth is not evident and still under investigation [11].

It is nevertheless interesting that the period when body growth is most directly influenced by the number of painful procedures (from birth to 32 weeks gestational age) corresponds with a period in which dramatic structural and functional changes are taking place in the central nervous system [5] and [7]. For example, thalamo-cortical connections that are growing into the cortical plate are highly plastic and possibly shaped by external inputs, such as noxious stimuli. The work of Vinall et al. [9] provides further evidence that early exposure to noxious procedures may adversely influence neonatal development and also demonstrates the importance of considering short-term effects of early exposure to pain. These early changes – which can be observed when infants are still in the NICU – may give an indication about the subsequent neurodevelopmental trajectory of premature infants

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