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Pain in babies
From Citizendium, the Citizens' Compendium
Up until the last thirty years medicine seems to have been unable to make up its mind about whether babies feel pain. Doctors followed whatever the prevailing expert opinion was, and before the late nineteenth century it was generally considered that babies hurt more easily than adults. Then the opinion changed, and until the mid 1970s doctors “knew” that babies do not feel much pain. For much of the history of modern scientific medicine children and babies were therefore denied the benefits of the steadily improving medical techniques of treating pain. Fortunately for the linguistically challenged young human, having only a frowning face, fierce cry and angry movements with which to convey hurt, science has in the last quarter of the 20th century established beyond reasonable doubt that neonates and babies definitely do experience pain – probably more than adults – and has developed reliable means of measuring and of treating it.
This article sets out to review the main difficulties involved in assessing and treating pain in the newborn and the pre-verbal toddler. It aims to dispel those myths and fallacies which have caused whole generations of children to suffer unnecessarily, and to inform caregivers about the possibilities for helping the baby in pain.
However could we think babies don’t hurt?
Before the late nineteenth century babies were considered to be more sensitive to pain than adults. In the pre-scientific medicine era, this was patently obvious, by virtue of everyday observations and logic. Doris Cope quotes from The Children's Book, by surgeon and pediatrician Felix Würtz of Basel, published in 1656, to illustrate this logic: "If a new skin in old people be tender, what is it you think in a newborn Babe? Doth a small thing pain you so much on a finger, how painful is it then to a Child, which is tormented all the body over, which hath but a tender new grown flesh?" The ease with which an apparently trifling hurt can set off a piteous crying spell in the young child had made its impression on Dr Wurtz, and set him a-wondering, as it has turned out, on the right path.
But then the whole idea did a turn-about. Suddenly, in the late nineteenth and first half of the twentieth century, doctors were being taught that babies did not experience pain, and they were treating their young patients according to this unproven idea. From needle sticks to tonsillectomies to heart operations were done with no anaesthesia or analgesia, other than muscle relaxation for the surgery.
When one realises that a horse lover is prepared to put his beloved mount "out of its misery" when it sustains an incurable injury, this callous attitude of humans towards the young of their own species seems inexplicable. Cope considers it probable that the idea was born in the latter half of the nineteenth century, out of scientific misinterpretation of the findings of the new science of embryology – where Dr Paul Flechsig equated the non-myelinisation of much of a baby’s nervous system with an inability to function – taken together with the writings of Charles Darwin in his book The Expression of Emotions in Man and Animal, that babies (as well as animals, "savages" and the insane) were incapable of experiencing pain. "These new scientific theories based on Darwin's theories and the anatomical and histological data from embryology were applied to clinical practice by surgeons and neurologists." Whatever the real cause for the myth was, doctors were taught that in babies the expression of "pain is merely reflexive and … owing to the immaturity of the infant brain, the pain could not really matter." At the same time there was the unscientific belief that use of opiates would lead to addiction, that babies would not remember any pain that they happened to feel, and that lack of conscious memory meant lack of long-term harm. Scientific studies on animals with various brain lesions were interpreted as supporting the idea that the responses seen in babies were merely spinal reflexes. Furthermore, the whole effort of relieving pain was considered futile since it was thought to be impossible to measure the child's pain. No doubt the perceived risk of opiates, and the time and effort needed to provide adequate analgesia to the newborn, contributed to the doctor clinging to the "sensible and safe" doctrine of "carry on regardless of the crying", rather than worrying about the ethics of not providing pain relief – and the practical difficulties of providing it..
While there were always doctors who treated young patients’ pain at face value, the revolution in the study and treatment of pain in babies happened in the mid 1980s. Parents and doctors became aware of the then common practice of performing surgery on newborns using no drugs to induce unconsciousness or provide analgesia - foremost experts considered them to be "dangerous". In the United States, a major change in practice was brought about by events surrounding one operation. Infant Jeffrey Lawson underwent open heart surgery in 1985. His mother, Jill R. Lawson, subsequently discovered that her child had been operated on without any anaesthesia other than a muscle relaxant. She started a vigorous awareness campaign about the practice which had up to then been virtually unknown to the public. The public and medical uproar about the practice of surgery while the neonate was fully conscious, with no analgesia, lead to a remarkably swift response from the medical community. By 1987 The New York Times could publish a lead article entitled "Infants' Sense of Pain Is Recognized, Finally." The medical opinion about the significance of pain in the neonate had come a full circle, so that the number of studies on the measurement of pain in young children, and on ways of reducing the injury response, began to increase dramatically. Publications on the hormonal and metabolic responses of babies to noxious stimuli began to appear, demonstrating the harmful effects of what previously was considered good practice, and confirming that the provision of adequate anaesthesia and analgesia was better medicine on both humanitarian and physiological grounds.
We now know that the neonate responds more extensively to pain than the adult does, and that exposure to severe pain, without adequate treatment, can have long-term consequences. In spite of the difficulty of assessing how much pain a baby has, and the problem of finding the correct dosage or technique for treating a feeling which can be gauged but indirectly, modern medicine is firmly committed to improving the quality of pain relief for the very young. Science is catching up with what the caring mother has always known about her child, by the tone of her offspring’s cry.
The developmental neurobiology of pain
Pain can only be assessed by self-reporting of the person experiencing it. Lacking that, it may be inferred from activation of nociceptor nerve pathways, by biochemical changes, by changes seen during functional neuroimaging, or by physiological and behavioural assessments. In deciding whether and when babies become capable of experiencing pain, one cannot take biopsies of babies’ nerves or brain tissue in order to study the neuronal anatomy and chemistry. If it were to become practical to turn the powerful tools of functional neuroimaging to use in the study of neonates, it may well mean a second revolution in our understanding of pain in the newborn, but this has not yet been done. The reader has therefore to interpret this section in the light of the fact that beliefs about the development of the nociceptive component of the human nervous system frequently are deduced from findings in animal models of neonatal nociception.
One of the critical scientific events which lead to the present improved understanding of pain in the newborn was the realisation that the fetal and newborn unmyelinated nerve fibres are quite capable of relaying information, albeit slower than would be the case with myelinated fibres. The dictum that “babies don’t feel pain because their nerve pathways are not yet completely myelinated”, originating in the nineteenth century, was eventually, almost a century later, shown by experiment in animal models to be false.
At birth a human has developed the neural pathways for nociception and for experiencing pain, but the pain responses of a newborn baby is not simply a miniaturised or immature version of that of an adult. There are a number of differences in both nerve structure and in the quality and extent of nerve responses which are considered to be pertinent to understanding neonatal pain.
For one, the nerves of young babies respond more readily to noxious stimuli (lower threshold to stimulation), than those of adults. Secondly, their threshold for sensitisation is also decreased. Sensitisation refers to to the phenomenon that a noxious event increases the sensitivity of the nociceptor system to another such event – or to a much milder or even entirely non-noxious event. The experience of severe pain to a mildly painful stimulus is called hyperalgesia, and pain in response to a stimulus which would normally not be painful is called allodynia. This happens in adults and babies, but in babies this occurs more quickly and the sensitised area is larger than in adults, for the same initial stimuli. A third factor which deserves mention is the fact that the pathways that descend from the brain to the spinal cord are not well developed in the newborn, so that the ability to reduce or inhibit nociception via central brain mechanisms is limited. For all these known reasons, and probably many which still need to be discovered, a noxious event which appears minor to adults (for instance, an intramuscular injection) can have unexpectedly widespread effects in the baby’s nervous system; it is sensed more intensely and potentially more diffusely than it would be in the adult.
In addition to being more sensitive to start with, the neonate's nervous system seems much more active than that of an adult in transforming its connections and central nerve pathways in response to stimuli. This is intuitively obvious, if one considers that the nervous system is actively growing and maturing - a sapling changes its shape more readily than a rigid old oak. This reshaping - also called plasticity - involves both structural and chemical changes of the nervous system. It has been shown to occur in response to noxious events in the short term, and there are indications that such changes, once established, can persist until adult life. What precisely this implies for later childhood and adult life is as yet unclear, but the present feeling is that this potential for long term harm is a valid reason for working towards more effective management of neonatal pain.
Why treat pain?
If it made no difference to a person whether he or she experienced repeated and severe pain as a baby, then it would be a senseless exercise for the care-givers to look for ways of relieving such pain. But it does make a difference.What is known about the pain response and the effects of pain on the baby, both immediate and long term, argues strongly for the view that the effective treatment of pain benefits the baby immediate, reduces some medium-term negative consequences, and likely prevents a number of adult psycho-physiological problems.
Some of the immediate effects of pain are obvious to the observer, requiring no special equipment or training. The baby is crying and irritable when awake, develops a disturbed sleep pattern, feeds poorly, and shows a fearful, distrustful reaction towards care-givers. These all have implications for the well-being of the child, not least because the relationship between care-givers and neonate may suffer, with the necessary caring and tenderness being replaced by mutual irritation.
What the observer may not notice, however, is the number of metabolic and homeostatic changes that are caused by untreated pain. The neonate in pain develops an increased requirement for oxygen, while at the same time the gas exchange between air and blood in the lungs becomes less efficient. The combination can lead to inadequate oxygen supply to the cells. The damage that hypoxemia does to cells is well known, and may be permanent, but in the neonate it may be impossible to quantify. Another unseen disadvantage is the rise in stomach acidity that accompanies the stress reaction precipitated by the pain. The sick neonate, in pain, is at risk of aspirating this acid into the lungs, further endangering lung integrity and tissue oxygenation.
The undesirable effects of pain go further. For the duration of the period of persistent pain (for instance after an operation), or of repeated episodes of acute pain (for instance from the procedures in an intensive care unit), the metabolism becomes predominantly catabolic, that is, the baby is not building up its own protein and tissues, but breaking them down through the action of the stress hormones. This same pain and stress response reduces the efficiency of the immune system. Taken together with the reduced oxygen available, it would not be surprising if healing of damaged or infected tissue is impaired, and morbidity and mortality increased. This has been shown to be true in trials of analgesia in newborns with pain.
The neuropsychological effect of untreated pain on the bonding between mother and child, on later contact with health professionals, and on personal and social psychological well-being is difficult to quantify, but research indicates that babies exposed to pain in the neonatal period have more difficulties in all these areas of function, to their possible detriment as older children and adults. Professionals working in the field of neonatal pain have even speculated that adolescent aggression and self-destructive behaviour – including suicide – may in some cases be caused by untreated neonatal pain and stress.
Diagnosis and assessment of a baby's pain
The classical IASP definition of pain as a subjective, emotional experience that is “described in terms of tissue damage”, a definition which depends on the sufferer being able to self-report pain. This is of little use to a person faced with decisions about whether a baby is suffering from pain, how severe it is, and whether treatment is necessary. Care-givers have therefore had to look to non-verbal responses which may be used to identify the experience of pain. The two kinds of responses used are gross physical movements and measurement of physiological responses to stress. The former entails simple direct observation, while the latter depends on measurements which generally require specific equipment, including blood pressure and blood stress hormone levels.
To all but the deaf, the most familiar consequence of hurting a baby is the baby’s cry. Mothers are able to interpret their babies’ cries, while researchers are able to differentiate between different kinds of cry, roughly classed as “hungry”, “angry”, and “fearful or in pain”. Unfortunately a specific baby’s cry is difficult to quantify. It depends on a certain sensitivity in the listener, and the interpretation varies between observers. Quite apart from difficulties of measuring the degree of pain from the type of cry, there is the problem of whether the pain is caused by physical hurt, by fear or by separation. Crying on its own, therefore, is not sufficient a measure of a baby’s pain - clearly it would be inappropriate to treat separation anxiety with morphine, or the pain of acute otitis media by coddling, clucking and cooing.
Additional visible and easily definable evidence of pain have been sought. Combinations of crying with facial expressions, posture and movements, as well as with physiological measurements, have been tested and found to be reliable indicators of pain, and of successful treatment of pain. A number of such measurements and observational scales have been published and verified, with some differences in the ease of use and applicability to different clinical situations (a parameter such as the baby’s blood pressure is of little use to a mother at home, while a person in pain cannot wait for the result of a measurement of plasma cortisol level, before being treated). Behavioral observations include changes in crying, facial expressions, body posture, limb movements and muscle tone. Physiological measurements related to stress, distress or pain include the heart rate, blood pressure, breathing, transcutaneous oxygen saturation, sweating (palms of hands), vagal tone and stress hormone levels (cortisol and norepinephrine).
As an illustration of the pain scales commonly used, we can consider one that may be used at home or during hospitalisation. The CHIPPS (Children’s and Infants’ Postoperative Pain Scale) does not use special measurements to obtain a score, so that these same sort of observations could be made by any care-giver, more or less anywhere. (Note that this example is not an endorsement that this scale is any better or worse than other scales mentioned in the reference section) It was described as recently as 2000, and uses a scale of five items, each rated as 0, 1, or 2: Item “Crying” could be none, moaning, or screaming. Item “Facial expression” could be relaxed smiling, wry mouth, or grimacing about face and mouth. Item “Posture of the trunk” could be neutral, variable, or rear up. Item “Posture of the legs” could be neutral, kicking about, or tightened legs. Item “Motor restlessness” could be none, moderate, or restless. The scores are totalled and the baby managed according to the rule that 0 to 3 indicates no requirement for treating pain, and 4 to 10 indicates progessively greater need for analgesia.
Two aspects of the neonate’s observed pain response deserve special mention. One is that all observations – both movements and physiological parameters – tend to decrease when the neonate is exposed to persistent pain, becoming less reliable as indicators of ongoing pain. This may be the same as the older person’s “strict bedrest” – a response to the increased metabolic requirements of stress and injury. The second, which may seem to be working against the forementioned, is that hyperalgesia, as well as the occurrence of allodynia, happens more quickly and more extensively than in adults.  Day to day changes in the response to a specific injury may therefore become somewhat unpredictable and variable.
The recognition that babies experience pain as much as – and probably more than – adults has two important consequences. In the first place, the idea that babies can be allowed to undergo painful procedures without adequate analgesia or anesthesia is rapidly becoming unacceptable to care-givers, in both lay and professional sections of the population. The second is that the diagnosis and treatment for established pain is becoming part of the everyday duty of care-givers.
As far as the prevention of pain caused by planned procedures goes, the parent or responsible adult is fully justified in asking about what steps a health worker will take to reduce the pain to the minimum. In some circumstances it may be not be possible to remove all pain, due to specific limiting circumstances such as lack of proper facilities, drugs, expertise, or funding, but consideration should always be given to of what pain-reducing steps can be taken.
Where the baby has established pain, due to an illness, accident or procedure, a graded sequence of treatment is becoming established as standard practice. Research is making it easier and simpler to provide the necessary care with some confidence, with a clearer understanding of the possible risks and side-effects. In this ongoing process, some old fashioned ideas and treatments have been confirmed as good practice, some have been refined or used in novel ways, some have been rejected as not worth while, and some entirely new techniques have been developed.
Measures not involving medications
Touching, holding, stroking, keeping warm, talking and singing/music are ways in which adults have been comforting babies since the start of human history. This way of managing pain is shared with other primates, where the actions are performed both by female and male adults. It works to reduce anxiety and distress, but its effect on actual physical pain is less certain. This has been found in children who are able to verbalise pain, and it is assumed to be true of neonates. While the hurt of a procedure may not be much reduced, the fear is visibly reduced, so that the negative effects of fear for health care situations may less readily be established. Therefore it is considered good practice to involve parents or care-givers directly with the handling of the baby, and to have them present and directly in contact with the baby whenever possible. In the absence of the mother or father, the role may be taken over by another adult, such as a nursing sister.
As management before a minor single painful procedure – for the drawing of blood by an experience venepuncturalist - this may be all that is required. It may be used before a local anaesthetic injection is given to establish anaesthesia for a procedure like circumcision, and is useful for keeping the baby restful before a general anaesthetic.
Breastfeeding, the use of a pacifier and the administration of sugar orally has been proven to reduce the signs of pain in babies. Even electroencephalographic changes are reduced by sugar, but the mechanism for this remains unknown; it does not seem to be endorphin mediated. As is the case with comforting, it is not possible to ask the baby whether it is the physical hurt itself, or the anxiety and/or fear reduction which causes the reduced incidence of pain-related behaviours. However, since in present practice pain is defined by the baby's behaviour, and even biochemical tests cannot distinguish between pain or severe anxiety in the baby, the effect is interpreted as a reduction of pain. The reduction in pain behaviour is assumed to be accompanied by a reduction in pain-related disorders, both immediate and longer term.
Having established that such old-fashioned techniques can be scientifically validated, other "granny-class" maneuvers are being tested. “Facilitated tucking”, swaddling and “kangaroo care” have been shown to reduce the response of babies to painful or distressful circumstances, while a comprehensive technique of nursing called “developmental care” has been developed for managing preterm infants so as to reduce distress and pain.
Measures involving medication
Topical anaesthesia refers to a local anaesthetic agent that is applied directly on to skin or tissue (that is, without injecting it). A variety of creams have been developed and used for this, ranging from older single agents with good skin penetration, to eutactic mixtures of agents, to technologically modern formulations of lignocaine in microspheres. They are effective for suitable procedures, if correctly and timeously applied. The main disadvantages are the slow onset of adequate anaesthesia, inadequate analgesia for larger procedures, and toxicity of absorbed medication. Improved agents are actively being researched, since some of the more effective agents cannot be used safely more than once a day, which is inadequate for the requirements in a neonatal intensive care unit. On the other hand, where frequent or prolonged painful events have lead to hypersensitivity of pain nerves – as for instance where repeated heel pricks have caused the whole foot to become over-sensitive – the daily use of such an ointment can return the sensitivity of the foot to normal.
Local infiltration anesthesia refers to the infiltration of agent into the skin and subcutaneous tissue where the painful procedure is to be undertaken, and may be equally effectively used to reduce pain after a procedure under general anesthesia. To reduce the pain of the initial injection, a topical anesthetic ointment may be applied to the skin an hour before the procedure.
Regional anesthesia entails the injection of local anaesthetics around the nerve trunks that supply a limb, or into the epidural space surrounding the spinal cord. It is used for pain relief after surgery, but may require special facilities for observation of the baby until the effect has worn out.
Since a baby in pain is unable to tell one about the site and nature of the hurt, it is unwise to give analgesics before one has a diagnosis of what is causing the apparently pain-related behaviour. In many cases excessive crying and distress after two weeks of age is infantile colic, where analgesics are not indicated. Other painful conditions may need specific treatments, with the use of analgesics being a measure to decrease the distress while specific treatment helps to heal the problem. There is always the risk that the use of analgesics can, in the absence of a known cause for pain, delay the proper diagnosis and treatment.
There are basically three kinds of medications which reduce pain in babies, paracetamol (acetaminophen), the non-steroidal anti-inflammatory drugs, and the opiates. Paracetamol is safe and effective if given in the correct dose, and frequently enough. The same is true of the non-steroidal anti-inflammatory drugs such as ibuprofen (aspirin, the prototype of this class of drugs is seldom used). Of the opiates, morphine and fentanyl is most often used in the hospital setting, while codeine is affective for use at home. For all these drugs, the immaturity of the baby’s nervous system and metabolic pathways, the different way in which the drugs are distributed, and the reduced ability of the baby to excrete the drugs though the kidneys have to be taken into account when dosages are worked out. A correct dosage by mass for a baby of 6 months old would be quite wrong for a premature neonate.
The side-effects and potentially harmful effects of analgesic drugs are essentially the same for babies as they are for adults, they are known and they are manageable. While many procedures where the pain is short lived may be managed by physical comforting techniques and topical anesthesia, additional systemic analgesic drugs are indicated for longer term pain, such as after an operation. In a suitable environment there are no good reasons for denying the benefits of proper analgesia to a baby in pain.
There is good scientific evidence that babies feel as much pain as adults do, if not more. Research has shown that treating established pain, and ensuring adequate analgesia before painful procedures, improves the outcome of injuries and procedures. On the other hand, untreated pain in the newborn may have harmful effects which last into childhood and possibly longer. Ordinary loving physical care and comforting has been scientifically shown to be effective, and remains the mainstay of managing infants in pain. For non-minor pain, appropriate local anesthesia and systemic analgesic drugs are needed, and health workers should learn to use them appropriately. Infant should not be given analgesics without a diagnosis of their pain.
- ↑ 1.0 1.1 1.2 1.3 Cope DK. Neonatal Pain: The Evolution of an Idea. The American Association of Anesthesiologists Newsletter, September 1998. Electronic text available at www.asahq.org/Newsletters/1998/09_98/Neonatal_0998.html. Accessed 20070312.
- ↑ The electronic text of the book is available at Project Gutenberg. The etext is of a later edition than the 1872 one quoted by Cope, the title page reading: "THE EXPRESSION OF THE EMOTIONS IN MAN AND ANIMALS. BY CHARLES DARWIN M.A., F.R.S., ETC. WITH PHOTOGRAPHIC AND OTHER ILLUSTRATIONS. NEW YORK. D. APPLETON AND COMPANY, 1899. Authorized Edition." Download at: http://www.gutenberg.org/etext/1227.
- ↑ 3.0 3.1 Chamberlain DB. Babies Remember Pain. Pre- and Peri-natal Psychology. 1989;3(4):297-310. Electronic text available at the Circumcision Reference Library. Accessed 20070221.
- ↑ Wagner AM. Pain control in the pediatric patient. Dermatol Clin 1998;16:609-17. PMID 9704215
- ↑ 5.0 5.1 Mathew PJ, Mathew JL. Assessment and management of pain in infants. Postgraduate Medical Journal 2003;79:438-443 PMID 12954954
- ↑ Lawson JR. The politics of newborn pain - includes related article on newborn surgery and list of resource groups. Mothering. Fall, 1990 Fall. Reprinted at [http://findarticles.com/p/articles/mi_m0838/is_n57/ai_8915398. Accessed 20070323
- ↑ Boffey PM. LEAD: Infants' Sense of Pain Is Recognized, Finally. The New York Times, November 24, 1987. http://query.nytimes.com/gst/fullpage.html?sec=health&res=9B0DE1D71139F937A15752C1A961948260 Accessed 20070323.
- ↑ 8.0 8.1 Anand KJS, Hickey PR. Pain and its effects in the human neonate and fetus. The New England Journal Of Medicine, 1987, Volume 317, Number 21: Pages 1321-1329.
- ↑ Anand KJS, et al. Summary Proceedings From the Neonatal Pain-Control Group. Pediatrics, 2006, Vol. 117 No. 3, pp. S9-S22 doi:10.1542/peds.2005-0620C.
- ↑ 10.0 10.1 Fitzgerald M, Beggs S. The neurobiology of pain: developmental aspects. Neuroscientist. 2001;7:246-57.
- ↑ Howard RF. Developmental Factors and Acute Pain in Children. in Pain 2005 – An Updated Review: Refresher Course Syllabus, ed. Justins DM. IASP Press, Seattle, 2005.
- ↑ Walco GA, Cassidy RC, Schechter NL. Pain, Hurt and Harm: The ethics of pain control in infants and children. N Engl J Med 331(8), Aug 25 1994, 541-544.
- ↑ American Academy of Pediatrics, Committee on Fetus and Newborn and Section on Surgery, Canadian Paediatric Society and Fetus and Newborn Committee. ‘’Prevention and Management of Pain in the Neonate: An Update.’’ Pediatrics Vol. 118 No. 5 November 2006, pp. 2231-2241. doi10.1542/peds.2006-2277
- ↑ Anand KJS, Sippell WG, Aynsley-Green A. Randomized trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on stress response. Lancet 1987;1:62-66.
- ↑ Anand KJS, Scalzo FM. Can Adverse Neonatal Experiences Alter Brain Development and Subsequent Behavior? Biology of the Neonate, 2000: 77(2); 69-82
- ↑ Koeslag J. The Human Lifecycle, Part 19. Development Of Communication. Division of Medical Physiology, Department of Biomedical Sciences, University of Stellenbosch. Available at http://academic.sun.ac.za/medphys/Life19.html
- ↑ Zeskind PS. Cross-Cultural Differences in Maternal Perceptions of Cries of Low- and High-Risk Infants. Child Development, 1983;Vol. 54, No. 5, 1119-1128. DOI 10.2307/1129668
- ↑ Other scales that the interested reader may wish to look out for, go by the acronyms of: BPS, CHEOPS, CRIES, DAN, DEGR, FACES, FLACC, MBPS, MOPS, NFCS, NIPS, N-PASS, OPS, PEPPS, PIPP, POCIS, POPS, RIPS, TPPPS
- ↑ Buttner W, Finke W. Analysis of behavioral and physiological parameters for the assessment of postoperative analgesic demand in newborns, infants and young children: a comprehensive report on seven consecutive studies. Paediatric Anaesthesia. 2000; 10: 303-318.
- ↑ Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA. 2002;288 :857 –861
- ↑ Craig KD, Whitfield MF, Grunau RVE, Linton J, Hadjistavropoulos HD. Pain in the preterm neonate: behavioral and physiological indices. Pain. 1993;52 :287 –299
- ↑ Carbajal R, Veerapen S, Couderc S, Jugie M, Ville Y. Analgesic effect of breastfeeding in term neonates: randomized controlled trial. BMJ. 2003;326 :13
- ↑ Blass EM, Watt LB. Suckling- and sucrose-induced analgesia in human newborns. Pain. 1999;83 :611 –623
- ↑ Fernandez M, Blass EM, Hernandez-Reif M, Field T, Diego M, Sanders C. Sucrose attenuates a negative electroencephalographic response to an aversive stimulus for newborns. J Dev Behav Pediatr. 2003;24 :261 –266
- ↑ Taddio A, Shah V, Shah P, Katz J. B-Endorphin concentration after administration of sucrose in preterm infants. Arch Pediatr Adolesc Med. 2003;157 :1071 –1074
- ↑ Porter FL, Grunaue RE, Anand KJ. Long-term effects of pain in infants. J Dev Behav Pediatr. 1999;20 :253 –261
- ↑ Ward-Larson C, Horn RA, Gosnell F. The efficacy of facilitated tucking for relieving procedural pain of endotracheal suctioning in very low birthweight infants. MCN Am J Matern Child Nurs. 2004;29 :151 –156
- ↑ Johnston, C., Stevens, B., Pinelli, J., Gibbins, S., Filion, F., Jack, A., Steele, S., Boyer, K., & Veilleux, A. (2003). Kangaroo care is effective in diminishing pain response in preterm neonates. Archives of Pediatrics and Adolescent Medicine, 157 (11), 1084-1088
- ↑ Sizun J, Ansquer H, Browne J, Tordjman S, Morin JF. Developmental care decreases physiologic and behavioral pain expression in preterm neonates. J Pain. 2002;3 :446 –450