PEDIATRIC

PAIN: CURRENT NEW DIRECTIONS

STATUS

AND

It has been almost 5 years since Schechter wrote a monograph on pediatric pain for Current Problems in Pediatrics. During the ensuing years, three textbooks,1-3 an issue of Pediatric Clinics of North America,4 a special issue of Pediatrician,5 and chapters in other textbook&’ have been published on the topic of pain in infants, children, and adolescents. Research in this area is beginning to blossom, especially in the areas of fetal/neonatal pain,s-1’ pain assessment in infants,*” l3 and the development of laboratory models of pain in children for the study of developmental and inherent individual characteristics that contribute to the pain experience.14-I5 No longer is it necessary to defend the importance of this topic and the clinical relevance of research. Preliminary but seminal work in neonatal pain led to the recommendation by the American Academy of Pediatrics that invasive and painful procedures on neonates, including preterms, should be accompanied by appropriate anesthesia.16 In this regard, the research questions no longer focus on documenting the need but rather on determining what drugs, dose ranges, and routes of administration are safe and effective in this population. A chief question is how best to tailor a treatment strategv to the individual needs of a child patient, especially an infant, to ensure maximal likelihood of efficacy. Documentation of the undertreatment of pain in children’7-‘s has led to the emergence of pain clinics and pain consultation services that are geared to the unique needs of children.20 These pediatric pain services are typically interdisciplinary, with pediatrics, anesthesiology, nursing, and psychology/psychiatry as the core specialties and rehabilitation medicine, neurosurgery, orthopedics, physical therapy, education, and other specialties involved as necessary. Research questions now focus on pain management, (e.g., how to use different behavioral techniques, analgesics, and sedatives effectively and safely to manage different types of pain problems, such as postoperative pain, pain associated with suturing of lacerations, bone marrow aspirations, and debridement in children with burns, and disease-related pain (e.g., headaches, arthritis, cancer pain, Curr

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sickle cell pain, etc.). Effective management is based on pain assessment. dew do you know if a child is hurting enough to warrant pain management and how do you know if the pain treatment is effective? For the preverbal child (infant, toddler) this issue is salient since assessment relies on behavioral and physiologic indices of pain. Self-~po~s in school-aged children rely on the child’s cognitive abilities to translate the personal experience of suffering into a qualitative descriptor or mathematical (i.e., relational) quantification using some type of measurement scale. Issues in interpreting these reports include assessment of affective and motivational contributors to the child’s responses. For example, to what degree does the response represent anxiety. 7 What else is the child expressing through his/her pain ratings or complaints? The importance of past pain experiences and the behavior of the people in the child’s environment, particularly the family, is of increasing interest to investigators as the impact of these factors in children’s experience of and response to pain is recognized. Additionally, there is increasing recognition of the importance of the child’s individual characteristics, such as “reactivity” to the environment and the ability to modulate his/her response to environmentmediated pain perturbations. Some of the early critical work in this area has come from studies of nonhuman primate?’ ” and young infants.““-“” Longitudinal studies of infants and children have identified a conglomerate of biologic and behavioral characteristics of children called “temperament” that interacts with the environment so as to influence whether an environmental “event” is experienced as “stressful.“zg For example, in Kagen’s studies, an “inhibited” child might become behaviorally withdrawn, with high autonomic arousal and increased stress hormones, in response to being alone in a room with a stranger, while an “uninhibited” child might rapidly initiate conversation that may serve to quickly reduce the potential “stress” of this type of situation3”‘“’ The influence of temperament and learned coping styles on children’s experience of “suffering” in potentially painful and anxietyprovoking situations is one of the newest areas of study for those interested in pediatric pain, although this has previously been of interest primarily to researchers in child development. We are seeing the emergence of a “cross-fertilization” of investigators studying similar phenomena but previously reporting their findings in their own journals and discussing their data at their own specific meetings. An example of interdisciplinary exchange in this area is the newly formed William T. Grant Foundation Research Consortium on the Developmental Psychobiology of Stress in Children. The goal of this monograph is to update the comprehensive review by Schechter in t!%5.“2 Current theories of pain transmission and inhibition will be reviewed, followed b.y a discussion of the de416

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velopmental considerations that make pain in children unique and different from adult pain. Pain assessment will be discussed in relation to developmental factors that influence measurement of pain in pediatric populations. Because of recent research in the area of infant pain, particularly neonatal pain, a special focus will be given to this special age group. Pain management will be reviewed from the perspective of psychological and pharmacologic treatments, two strategies that are not mutually exclusive. Special attention will be given to the need to abolish the “DPT” (Demerol, Phenergan, Thorazine) method of preprocedural sedation/analgesia. Guidelines for requesting a pediatric anesthesiology consultation will be discussed. Specific pain problems will be addressed throughout the text as they come up, with referral to excellent reviews already published. Finally, some areas of recent research will be presented along with our views on the directions of future research in pediatric pain. We hope to sensitize pediatricians to the problem of pain in children and to increase the pediatric knowledge base so that pediatricians can play a major role in reducing the suffering of the infants, children, and adolescents under their care.

PAIN

TRANSMISSION

AND

INHIBITION

The perception of pain is highly subjective and extremely variable. Individual perceptions are not related just to the amount of tissue damage encountered. Differences in pain perception and tolerance between patients, sexes, age groups, individuals at different cognitive stages, ethnicities, hospitals, and countries make it impossible to develop broadly applicable measurements of pain.338 34 Moreover, communication of subjective experiences is a highly verbal phenomenon placing children at a severe disadvantage in transmitting the extent of their suffering to their caregivers. There is also confusion about the different terms used by caregivers to refer to the presence or absence of a type of pain.” Table 1 is a glossary of terms particularly useful as a basis on which a discussion of pain can be made more universal and more accurate.“” Prevailing attitudes held by many physicians, nurses, and lay personnel about children’s experience of pain and about the possible risk of addiction to narcotics have acted as barriers to the humane treatment of children in pain. Controversy in lay36 and medical literature over whether infants in the perinatal period sense pain or whether they should receive anesthesia or analgesia remains. Some of the commonly held views underlying such practices as operating on an infant without the benefit of anesthesia or analgesia include7: (1) infants have no memory so they will be unaffected by the pain experience; (21 the lack of a well-developed nervous system prevents Cur-r Probl

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TABLE 1. Pain Terms* Pain resulting from a nonnoxious Stimulus Absence of pain on nOXiOUS StiIIIUkitiOn. Pain in an area or region that is anesthetic.

Allodynia Analgesia Anesthesia dolorosa Causalgla central pain Dysesthesia Hyperalgesia Hyperpathia Hypoalgesia Hypoesthesia Neuralgia Neuritis Neumpathy Nociceptor Noxious Pain

Pain threshold Pain tolerance level ‘Fmm

DeJong

RH:

to normal

skin.

Sustained burning pain after a traumatic nerve lesion. Pain associated with a lesion of the central nervous system. An unpleasant abnormal sensation. Increased sensitivity to stimulation. A painful syndrome characterized by overreaction and after-sensation to stimuli. Diminished sensitivity to noxious stimulation. Decreased sensitivity to stimulation. Pain in the distribution of a nerve. Inflammation of a nerve. A disturbance of function or pathological change in a nerve. A receptor preferentially sensitive to a noxious or potentially noxious stimulus. A noxious stimulus is a tissue-damaging stimulus. An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. The least stimulus intensity at which a subject perceives pain The greatest stimulus intensity causing pain that a subject is prepared to tolerate. Defining pain terms. JAM4 1980; 244:143. Used by permission

children from experiencing pain; and (3) the adverse effects of analgesics and anesthetics are too great to take the chance of administering them to children. Biochemical, physiological, and histological evidence is accumulating that dispels these beliefs. Pain is an individual phenomenon, and differences in the combination of psychological, physiological, and biochemical mechanisms underlying pain will influence its expression. Nociception, the perception and response to noxious stimuli involving a complex set of interactions between receptors in a variety of tissues, the spinal cord, and high brain centers including the thalamus, periductal gray area, and cerebral cortex, appears to be present early in the development of the fetus. Neuronal pathways necessary for the transmission of signals to the brain after encountering a noxious stimulus are completed before birth (Fig 1I.l’ The tachykinin and endogenous opioid systems are also functional at birth. Physiologic responses associated with pain, such as fluctuations in heart rate, changes in respiration, palmar sweating and increases in intracranial pressure, can all be seen during the performance of invasive procedures in neonates. The stress response involving the neuroendocrine axis is also very active in neonates.37 418

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22 24 2G 20 32 Y-TT-l-,-l-T-l-,7~l-T-l-l

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20

22

24

26

28 30 32 WEEKS Of GESTQTION

34

36

36

40--

FIG 1. Neurophysiologic (From Anand J Med 1987;

and neuroanatomic developments KJS, Hickey PR: Pain and its effects 317:1321-1347. Used by permission.)

in the fetus during in the human neonate

the third tnmester. and fetus. N Engl

With refinement in electrophysiologic, immunologic, and histologic techniques, much has been learned about the path pain signals take after being released. What follows is a discussion of pain pathways and mechanisms of pain modulation. PAIN

PATH WAYS

Nociceptors, receptors preferentially sensitive to noxious or potentially noxious stimuli, are located not only on the skin but in joints, tooth pulp, bone, and muscle. They are encapsulated and unencapsulated specialized units that detect thermal, chemical, and mechanical stimuli.38 Signals from the nociceptors are carried to the central nervous system (CNS) via several types of fibers: CL-~ (moderately myelinated, fast conducting) carry impulses from pressure/position sense receptors; A-6 (moderately myelinated, fast conducting) fibers carry impulses from high-threshold mechanoreceptors and polymodal peripheral sensory neurons that respond to multiple forms of stimuli, such as cold, pressure, and temperature. C fibers lunmyelinated, slow conducting) carry impulses from cutaneous Cur-r Probl

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and deep, low threshold mechanoreceptors, chemoreceptors, and thermoreceptors. Both a-6 and C fibers specialize in alerting the body of tissue damage. Transmission of sharp spatially distinct pain is attributed to 01-s fibers. C fibers carry dull diffuse pain signals. Only a small number of the sensory fibers of neonates are myelinated, suggesting that they are less able to localize noxious stimuli. If stimulated electrically, only specific sensations are elicited from specific fibers (Table 21.“” ASCENDING

AND

DESCENDING

TRACTS

The majority of sensory neurons from the periphery have their cell bodies located in the dorsal root ganglion. Some afferent input is transmitted through the ventral root,40 thus explaining why pain is not completely relieved after sectioning of the dorsal roots. As the sensory neurons enter the gray matter in the spinal cord from the TABLE

2.

Nociceptor

and

Receptor

Nociceptive Axon

Fiber

Characteristics

Diameter

lj.unJ

and Function* Mvelint

Proprioceptor

A-o

12-20

+++

Meissner’s Pacinian Merkel’s disk dome receptor Ruffini’s corpuscle

A-P A-P A-P

5-12

++ ++ ++

Encapsulated neurite “Free nerve endings”

A-6

“Free nerve endings”

C

++

A-P

1-4

A-6

++ ++

0.5-l

Function Motor-large alpha motor neurons of lamina IX Tap; intermittent Vibration; tickle Pressure, continuous or sustained Tonically active-a skin proprioceptive sensor In0 conscious response) Pain; high threshold mechanical transducer Sharpness, cool, hot, pain, chemosensitive, several types: high threshold, mechanical, cooling, sharp pain, noxious heat Mechanoreceptors, low threshold; polymodal nociceptors responding to noxious heat and T wave damage, cold thermonociceptor, warm receptor, nonnoxious

*Adapted from Strichartz GR: Neuronal physiology and local anesthetic action, in Cousins MJ, Bridenhaugh PO ledsJ: Neuronal Blockade in Clinical Anesthesia and Management of Pain, ed 2. Philadelphia. JB Lippincott, 1988; and Raymond Sk Physiology and anatomy of pain. Presented at the Regional Hnesthesia Update, Harvard Medical School, November 1-4, 1986, Boston, Mass. t+ + t = Heavily myelinated: ++ = moderately myelinated; + = lightly rnyelinated; - = no myelin

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periphery through the dorsal root, they separate into bundles of A and C fibers. Several of the bundles segregate, forming a medical and lateral division of the dorsolateral fasciculus (the Lissauer’s tract). The medial division is composed of small, unmyelinated or thinly myelinated neurons. Heavily myelinated and moderately myelinated fibers form the medial division of the Lissauer tract.41 The dorsal root sensory neurons can bifurcate and synapse within one to six segments above or below their level of entry with neurons in the gray matter of the spinal cord (the tissue resembling an H in the spinal cord). The synaptic connections occur both ipsilaterally and contralaterally on secondary neurons within the gray matter of the cord. The spinal cord gray matter is divided into 9 or 10 laminae,4z’ 43 based on cytoarchitecture, functional properties, and the spatial organization of the neurons (Fig 2, Table 3). Neurons in laminae I-V appear to be intricately involved with nociception.44 Neurons within the laminae synapse with the peripheral sensory neurons and subsequently relay information to the long ascending tracts. A number of synaptic connections from the peripheral afferent sensory fibers are made with several types of secondary cells: interneurons in laminae I, II, and V, and both ipsilateral and contralateral projection neurons (secondary sensory neurons). Lissauer’s tract, the (paleo and neoJ spinothalamic, spinoreticular, spinomesencephalic, ipsilateral spinocervical, spinocervicothalamic, ipsilateral postsynaptic dorsal tract, and possibly other tracts that are formed by axons from the projection neurons represent the pathways into the brain for sensory impulses. The long ascending tracts

Columns

nucleus

posteriomarginalis

substantia

gelatinosa

nucleus leus

(Nuclei)

dorsalis nucleus

)

proprius

-A

(Clarkegs)

4

reticularis

termediolateral termediomediol

nucleus nucleus!

lateral medial

nuclei *A

motor motor

nuclei

7

-

--

TIO FIG 2. Splnal cord nuclei and lamlnae (From Nervous System Philadelphia. FA Davis

Dunkerley Co, 1975,

GB (ed): A Basic ANas p 25 Used by permission

of the ~ufr~fl ) 421

TABLE

3.

Configuration Laminae I

of the Nociceptive

Element

Column Nucleus

Transmits thermal and mechanical impulses, especially intense noxious input. projections to thalamus. Transmits thermal and mechanical impulses; modulation of input occurs from interneurons. Transmits input from A-o, A-R and C fibers. Classified as wide dynamic range neurons. Responds to light touch, visceral distention, inflammatory agents Ibradykinins, histamine, 5-HT, Kf and PGE,J. Projections to thalamus, lateral cervical nucleus. Contain the motor nuclei of the ventral horn

11 and III

NandV

Nuckus

X

Cord*t

Function

posteriomarginalis Imarginal zone) Substantia gelatinosa

IX

in the Spinal

proprius

Medial and lateral nuclei Central canal

motor

Transmits noxious and temperature impulses. Has ipsilateral and contralateral projections.

‘Adapted from Dunkerley GB: A Basic Atlas of the Human Nervous System. Philadelphia, FA Davis Co. 1975; and Yaksh ‘I? Neurologk mechanisms of pain, in Cousins MJ, Brtdenbaogh PO ledsl: Newa/ Blockade in Clinical Anesthesia and Management ofPain. Philadelphia, JB Lippincott, 1989. tSome sonmes say that the substantia gelatinosa is composed of both laminae II and III and others suggest

that lamina

II is its only

constituent.

make monosynaptic or polysynaptic reflex connections with lower motor neurons in the ventral horn of either side and have projections to higher brain centers. In the brain, secondary neurons terminate in several areas including the medulla (medial reticular formation and nucleus raphe magnus) midbrain, periaqueductal gray matter, thalamus, hypothalamus, and the frontal, parietal, and limbic areas of the cortex.38 Processing of pain occurs at a number of different levels. The perception of pain, the emotional interpretation of pain, the motivational response, and the cognitive processing of noxious stimuli occur in the higher brain centers.45 The system would be incomplete without some dynamic mechanism to modulate the afferent pain impulses. Multiple systems involved with modulation appear to exist in the nervous system. A number of putative neurotransmitters affecting nociceptive transmission have been identified (Table 4.) Amino acids (aspartate and glutamate), somatostatin, endogenous opioids (enkephalins, endorphins, and dynorphins),46 tachykinins4’ (substance P, neurokinin A, and neuromedin K), serotonergic,48 noradrenergic,4s and cholinergic and GABA-ergic substances (gamma-aminobutyric acid) have been isolated in the spinal cord after supraspinal stimulation.50 Release of these compounds in a Ca++ dependent fashion from A-s and C afferent neurons has been demonstrated. All are thought to influence 422

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TABLE

4.

Putative

Neumtransmitters*t Receptor

Agent Opioid

Intrinsic to DHlpituitaryi gastrointestinal Intrinsic to DH

Adrenergic

0

Intrinsic to DH/no analgesia Bulbospinal, descending Lat, funiculi

Serotonergic

5-HT

GABA-ergic

1 2

‘From

Bulbospinal, descending lat, funiculi Intrinsic DH Intrinsic DH Intrinsic DH Bulbospinal

Muscarinic

Yaksh T: Neumlogic

fS

tract

Rat vas deferens Intrinsic to DH

01

Naloxone Antagonism

P-Endorphin (met/leu) Enkephalin/morphine

E I(

a2 P

Neumtensin Cholinergic

Endogenous/Exogenous Ligand

Location

(Met/km) enkephalti DADL P-Endorphin&endorphin Dynorphin/ ketocyclazocine SKF 1004i’/ketamine

+ + + (?I

Norepi/methoxamine Norepticlonidine Epinephrine/isopmterenol Semtonitisemtonin GABA/baclofen GABA/muscimol Neumtensin/neumtensin Acetylcholin/oxotremorine

7 ? ? ?

of pain, in Cousins MJ, Bridenbaugh PO ledsl: Neural Blockade ofPain. Philadelphia, JB Lippincott, 1989. Used by permission. tIJADL = D-z-ala-D-5-Ieu-enkephalin; + + + = markedly inhibited; + + = mildly inhibited; + slightly inhibited; - = not inhibited; lat = lateral; norepi = norepinephine; DH = dorsal horn; GABA = gamma-aminobutyric acid. in Clinical

Anesthesia

mechanisms

and Management

pain transmission and to play a role in the modulation of the pain response as excitatory and inhibitory compounds.*’ The best studied of these pain modulating systems involves the endogenous opioids . The specific pharmacological effects‘of opioids include: 21) analgesia, (2) euphoria; 13) dysphoria, (4) respiratory depression, (5) inhibition of gastrointestinal motility; (63 bradycardia/tachycardia, and 17) dependency. Specific opioid receptors with stereospecificity were identified in 1973.228822s The receptors are highly concentrated in a limited number of areas in the CNS: the spinal cord (laminae I-VII), the limbic system, and the respiratory centers of the midbrain. Additionally, these receptors have been found in a number of peripheral areas. Multiple types of opioid receptors are postulated and some have almost been completely characterized. There is cross-reactivity between some of the receptors. This may be secondary to the structural properties of the agonists tested, however. Soon after the discovery of the opioid receptors multiple endogenous opioids were isolated. Enkephalins were the first endogenous C’orr

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to be discovered. Further research led to the identification of P-endorphins and dynorphins. These compounds are synthesized separately in distinct populations of neuronal cell bodies, transported, stored in vesicles, and released by depolarization of the sensory cells. Pro-enkephalin is the precursor of met- and leu-enkephalin. P-endorphin has @lipotropin as a precursor. It is interesting to note that (5lipotropin and adrenocorticotropic hormone (ACTH) are derived from a common pre/prohormone: proopiomelanocortin.51z ” All endogenous opioids produce intense analgesia; however, rapid degradation attenuates their activity quickly. The exact mechanism for endogenous opioid neuromodulation remains to be further elucidated; however, the proposed mechanisms offer exciting possibilities. Several descending pathways involved with the inhibition of peripheral sensory input have been identified. Anatomical structures that have been implicated in these pathways include the cortex, thalamus, periaqueductal gray area (PAG), medullary structures (the nucleus raphe magnus [NRMI and the nucleus reticularis paragigantocellularis [NRPGI, and the dorsolateral funiculus.“” Stimulation of certain areas of the cortex attenuates the afferent transmission of impulses from C fibers to the spinothalamic neurons.54 The corticospinal system has efferent projections from the cerebral cortex to the spinal cord through the thalamus and PAG. Electrical stimulation5” of the PAG area or administration of opioids to this area” inhibits afferent nociceptive impulses. There is a scarcity of direct projections to the spinal cord from the PAG. The NRM and NRPG act as intermediaries, receiving projections from the PAG and then sending projections to the spinal cord through the dorsal lateral funiculus. Stimulation of the NRM and NRPG of the medulla releases neuromodulators, such as serotonin and neurotensin, at the level of the spinal cord. Enkephalins are released by interneurons in response to serotonin and inhibition of the release of substance P, the pain enhancing compound. Noradrenergic inhibitory systems have additionally been postulated as playing a role in pain modulation.“7 opioids

PAIN

THEORY

Over the last century a number of hypotheses have been proposed for the mechanisms of pain. Three of these have gained wider acceptance. The specific theory of pain invoked a hard wire scheme in which painful stimuli are directly received by the brain from the specific pain receptor(s) located on the skin, or in the viscera. The problem here is that no modulation of nociception occurred in this scheme. Subsequently, the pattern theory of pain proposed by Wollard and Sinclair in the 1920s postulated that the spatial and tempo424

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ml impulses from nerves stimulated produced specific patterns recognized and acted upon by the brain.58 Melzack and Wall, id an effort to join form with function and blend several theories of pain into a unifying theory, proposed the gate control theory of pain (Fig ~1.~” It encompasses the complex interactions between pain stimulation, perception, integration, and motivation. It differs dramatically from earlier theories in that it allows for modulation (“gating”) at a number of different levels. Nociceptive impulses enter the dorsal horn where they are processed prior to reaching the level of perception in the brain. Large fibers and small fibers affect gating by inhibiting or enhancing signals, respectively. Descending impulses are also postulated to have an influence on the processing. Neurophysiological, biochemical, and histological investigations continue to try to verify or refine this theory.

It appears that a number of dimensions of pain may be modulated through endogenous and exogenous mechanisms.60J ” An awareness of this complex system should sensitize the reader to the wide range of responses that children have to stimuli. The infant coming

FIG 3. The gate-control theory. Mark II The new model Includes excrtatory (white clrclej and inhrbrtory (black orcle) lrnks from the substantra gelantrnosa (SG) to the transmrssion (T) cells, as well as descendrng rnhrbitory control from braln stem systems. The round knob at the end of the Inhibitory link Implies that its action may be presynaptlc, postsynaptic, or both All connectrons are excitatory, except the inhibitory link from SG to T cell. (From Melzack R: Psychological aspects of parn: lmplrcations for neural blockade. in Cousins MJ. Bndenbaugh PO (eds): Neural Blockade /n C/mica/ Anesthesia and Management of “ain Philadelphra JB Lippincott. 1989 pp 845 ~860 Used by permissron )

into the world has the anatomical and biochemical capacity to process nociceptive impulses and produce physiologic and hormonal stress responses. The next section will focus on the assessment and management of pain in neonates and young infants.

DEVELOPMENTAL

CONSIDERATIONS

According to Wall and Melzack,ti2 there are two salient components of pain perception. There is the sensory component involving the sensory aspects of the nociceptive stimulus. There is also a motivation&affective component that involves the emotional and aversive aspects underlying behaviors aimed at avoiding or reducing the stimulus. Thus, as sensory, cognitive, and emotional systems mature, this process influences the experience of pain in infants and children. As suggested by the studies of Anand,g-10 even .sedated preterms demonstrate evidence of a hormonal stress response to the nociceptive stimuli of surgery and this response can be reduced with opioid analgesia. While nerve conduction may be slower in unmyelinated nerve fibers that are relatively more abundant in neonates, the distances that impulses must travel from the periphery to the dorsal horn of the spinal cord, up to the thalamus, and then to the limbic system and cerebral cortex are thus much shorter in neonates than in children or adults. Thus, the myth that neonates do not experience pain because of poor myelinization is not supported. Considering that the sensory component of pain is transmitted primarily through C fibers and A-2 fibers, both of which are present at birth, there is evidence that nociception is present at birth, if not before. A diffuse motoric withdrawal response is evident in neonates in response to a heel lance, although the extent of this response may be modified by the state of the infant ‘(e.g., sleep, alert) at the time of the heel stick. An argument often used by those who believe pain treatment is unnecessary in infants, and especially neonates, is that young infants and neonates do not remember the pain and thus it has no lasting effect on them. To refute this argument, we will present some evidence on the development of cognition, including memory, and emotions. Specific attention will be paid to critical transition periods in the development of self-regulation in which new abilities in regulatory control (Rothbart and Posner call this “effort”) over initial patterns of reactivity appear.63 These developmental cognitive milestones of the infant serve to guide the caregiver’s response to the infant. For example, the basic reactive components of the emotion of fear are present at birth, although they appear to be activated primarily by intensive aspects of stimuli (e.g., nociceptive stimuli).“4 With growth and development, reactivity to a nociceptive stimulus is 4243

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increasingly regulated by the development of behavioral inhibition and effortful action. Learning increases the range of potential stimuli that automatically activate fear (e.g., the appearance of a needle, rather- than the needle stick itself). Neurologic maturation of the effort system permits increasing regulation of this activation. The rate which these regulatory capacities develop will vary according to the age of the child tdevelopmental age). However, within a given age, there will also be individual differences in maturation rates. The behavioral manifestation of these individual differences has been called “tempemment.” There will likely be both age-dependent and individual differences in children’s ability to control their distress. Thus, children’s experience in relation to a nociceptive stimulus or representation of a nociceptive stimulus may differ, depending on the status of self-regulatory controls for each child when the pain stimulus is experienced. According to McGuire and Turkewitz,“’ withdrawal and approach are two processes operative in the early weeks of life. Withdrawal processes generally involve the expenditure of energy, are controlled by the sympathetic branch of the autonomic nervous system, and are associated with heart rate acceleration, looking or turning away, limb flexion, and distress. This early form of self-regulation orients the infant away from the source of stimulation. On the other hand, tonic approach processes serve to conserve energy, are under parasympathetic control, and include motor quieting, heart rate deceleration, lower respiration and blood pressure, looking and turning toward the stimulus, smiling, and limb extensions. It is believed that approach responses have a lower stimulus threshold than withdrawal responses, and approach and withdrawal responses are seen as acting in opposition to one another. Thus, in neonates, a strong stimulus (e.g., pinprick, loud noise, pressure1 may be experienced as aversive and produce a withdrawal response. The infant’s crying as a manifestation of distress in turn creates an aversive stimulus for the caregiver (i.e., parent) that he OF she attempts to terminate. FOF example, in a study of Frodi et alC6 in which parents of newborn infants were shown a videotape of a smiling or crying infant, feelings of parental distress, increased diastolic blood pressure, and higher skin conductance were associated with the tape of the crying infant but not with the smiling infant tape. Thus, the behaviors of the infant serve to guide regulatory interventions of the caregiver (e.g., soothing the infant by initiating quieting procedures). However, even in the first 2 months of life, differences have been noted in the irritability, soothability, and stimulus threshold (sensitivity to stimuli) of infants. A major biobehavioral shift takes place between 2 and 3 months of life.“7 This period marks the onset of social smiling, a decrease in fussiness, an increase in quiet sleep, and a decrease in activation of Curr

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transitory reflexes. The infant is also increasingly able to develop habituation to a stimulus if repeatedly exposed to that stimulus. Maturational changes in neural control mechanisms and increased visual resolution lead to increased sensitivity to exogenous stimuli (i.e., nociceptive stimuli) during this period. Evidence for neural maturation of cardiac controls is noted by the shift from the dominance of noradrenergic excitatory effects (heart rate acceleration) in the neonatal period to increasing cholinergic control of heart rate, with deceleration observed most clearly only after 2 to 3 months of age.“” Emotionality at birth chiefly involves activation of gross withdrawal and approach responses, including distress and a kind of vegetative pleasure. A withdrawal response constitutes the first component of the emotion of fear. At 2 to 3 months of age, motor quieting, electroencephalogram changes, and overall increasing parasympathetic control indicate increasing maturation of neural inhibitory control mechanisms that can result in a decrease in physiologic and behavioral manifestations of distress to overstimulation. What is developing is an orienting reaction that provides a period of appraisal (similar to that seen prior to an overt fear response in older children) accompanied by some preparation for a response. With increasing age, these appraisal and preparatory periods become more extensive, allowing for increased amounts and complexities of choice and action in response to a nociceptive stimulus. By 7 to 9 months of age, the infant begins to show a sensitivity to signs of imminent pain, leading to behavioral distress (e.g., crying when seeing someone in a white coat approach).“” The wariness of strangers (inhibition of approach responses) that develops during this age period suggests the development of yet another component of fear called “behavioral inhibition.” For example, a hospitalized 8month-old child in pain may become withdrawn rather than fussy and crying. By this age, the capacity for distress previously elicited by overstimulation now can be elicited by both unconditioned (e.g., novelty, a stranger) and conditioned (e.g., a syringe and needle) fear stimuli. This represents a major shift from other-regulation to selfregulation. However, the parents play a critical role at this time in providing security for the infant. The parents’ presence and soothing behaviors during medical procedures can enhance the infant’s own abilities to inhibit the stress response. Infants also show individual variation in the extent to which they display behavioral distress and can be soothed. For example, the need for parental presence during a nociceptive stimulus such as an immunization or phlebotomy may be less salient for an infant who is not easily distressed or has enhanced self-soothing abilities. For the infant who has a less well developed behavioral inhibitory system, distress in the same situation may be more extreme and prolonged. Hence, we see both develop42s

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mental changes in infants’ responses to painful and fearful stimuli and individual variation as well. During the next major developmental milestone, the preschool period from 18 months to 4 years of age, the child’s capacity for internal inhibition matures as verbal self-control develops. Internal inhibition maturation is also associated with maturation of the prefrontal cortex, which Luria7’ suggests may occur as late as 5 to 7 years of age. According to Gray,71 the prefrontal cortex may be the route whereby verbally coded descriptions of threats (e.g., a mother’s threat of a “doctor’s visit” if the child does not behave) can contact the behavioral inhibition system. Thus, a new level of self-regulation emerges. Additionally, dopaminergic projections into the prefrontal cortex have been shown to be important in the experience of “anxietyJ’71 This period of developing language and verbal controls over behavior allows for increasing sources of both fear and self-regulation. At this age, children who lag behind in these maturational developments may demonstrate fewer self-control strategies and create behavioral management problems. Hence, it is not helpful to ask a child to hold still during a medical procedure if he is maturationally incapable of such self-control. It is more appropriate to provide psychological and pharmacologic intervention, in addition to parental support. As children get older, they are instructed how they “should” feel in different situations,72 and they also begin to learn that external expression of emotions should sometimes be suppressed. This voluntary emotional inhibition is called the “socialization of emotions” by Selman7:’ and involves a cognitive understanding of possible dissociations between feeling and action. For example, despite no age differences found in the private experience of suffering during bone marrow aspirations (measured by self-reports of pain and anxiety), overt behavioral displays of distress (crying, physical resistance) were significantly reduced in adolescents compared to children.74 However, adolescents displayed more covert behaviors, such as grimacing and hand clenching,75 compared to the screaming, crying, and physical resistance of children during these medical procedures. The maturation of self-regulation leads to behavioral coping styles in response to painful and fearful stimuli. Children who are “repressors” or “avoiders” tend to internalize distress by becoming withdrawn in pain situations, while “expressers” or “information seekers” tend to display their feelings behaviorally and verbally and perhaps mitigate their distress through these behaviors. For example, information seekers tend to ask questions about a procedure and want to handle and play with the procedure-related equipment and materials, while an avoider might become more anxious if presented with these same materials. For a review on children’s coping

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styles in response to pain, readers are referred to a review by Siegel and Smith.76 The child’s previous pain experiences, familial responses (e.g., “soothing” responses, scolding, etc.) to the child’s behavioral and verbal displays of distress, parental displays of their own pain (“modeling” pain behaviors), and cultural norms will each contribute to children’s experience of and response to pain. In summary, there is evidence for pain (nociception) at birth, but the development of self-regulatory abilities to respond to this experience progresses with age. A diffuse motoric and vocal (cry) pain response occurs at birth; with maturation, this response becomes more focal and effortful. Maturation also brings the development of anticipatory fear in relation to unfamiliarity and to memory of past distress experiences associated with particular stimuli. As learning and verbal abilities mature, the child’s array of self-regulatory procedures becomes more varied and complex. However, the number and types of stimuli capable of producing fear also increase. The rate of maturation of a child’s self-regulatory abilities, interactive with the caregiver’s abilities to sooth the child and perturbation load itself (i.e., the magnitude of aversive stimuli), will determine the impact of an aversive stimulus on the child (e.g., the pain experience) {Fig 4). We believe that this complex model accounts for the variation in response observed in children undergoing the same medical procedure or with the same extent of disease. It also may account for the variability noted in children’s response to the same analgesic dose (corrected for body weight). The reader is referred to a chapter by Barr for further information on the developmental aspects of pain in children .’

PAIN ASSESSMENT Because of developmental differences in children’s experience of and response to an aversive stimulus, assessment of pain in infants, children, and adolescents necessitates an evaluation methodology that accounts for maturation in involved systems. The health status of the child during the pain experience warrants consideration in assessing the existence and magnitude of pain. For example, a sick toddler in respiratory distress might conserve energy by becoming withdrawn rather than crying and flailing during a phlebotomy. The type of pain situation might also influence assessment. As an example, with medical procedurerelated pain, behavioral observation, and, if the child is old enough (i.e., willing to respond on an age-appropriate instrument), a self-rating of pain would suffice for assessment. These evaluations help the clinician determine if a behavior& analgesic regimen was effective. Asking the child to describe the location and qualitative aspects of the pain might be interesting but 430

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FIG 4. Proposed

model

of coping

unnecessary in managing medical procedure-related pain. Since anxiety almost always. accompanies acute pain, assessment of this emotion would permit a more efficient tailoring of treatment to the needs of the patient (e.g., psychological preparation, sedatives, analgesics, etc.). For chronic or persistent pain, unless the etiology and expected time course is known (e.g., postoperative pain), additional factors in the assessment include descriptors of the qualitative aspects (how does it feel?), location (where does it hurt?), time relationships (when does it happen?), provocative factors (what makes it worse?), palliative factors (what makes it better?), and other associated somatic (e.g., nausea) and affective (e.g., depression) symptoms. This task may be more easily accomplished in adults, since the nature of children makes this task more complicated. Not only do developCurr

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431

mental and cognitive factors influence a child’s response (i.e., do they even understand what you are asking and do their words have the same meaning to them as to you?), but motivation also influences their response. For example, Ross and ROSS~~found that responses of children to questions about pain are influenced by how the questions are asked and who does the asking (i.e., why does the “asker” want to know? Will the outcome be influenced by the response?). Adolescents with recurrent pain problems, such as those with sickle cell disease, are particularly vulnerable to problems related to pain assessment, especially adolescents with frequent hospitalizations for pain-related events. The verbal reports of pain are frequently not believed by staff who label analgesic requests by the patient “drug-seeking behavior” rather than indicators of pain. The adolescents become distressed, angry, and mistrustful of staff and thus escalate their pain complaints and behaviors in an attempt to seek relief. This vicious cycle escalates both the patient’s and staffs frustration with each other until the staff members no longer know how they will be able to assess the extent of the patient’s suffering and response to analgesic medication. The patient no longer believes that the staff can provide adequate pain relief and becomes disillusioned with any medications given. Because of changed expectations about the efficacy of the analgesics and the adolescent’s feeling of loss of control, the medications are, in fact, less effective than they otherwise might be. Thus, the adolescent’s poor response to otherwise high doses of analgesics further contributes to the stall’s lack of belief in the patient’s self-reports of pain. While pain assessment is necessary for effective treatment, as in the situation cited previously, pain treatment, if not effective, may influence adequate pain assessment. Additionally, since focusing on the pain can make it worse, repeated assessment in some situations may actually aggravate the pain. For example, the lo-year-old girl’s response to her mother’s inquiry about whether her head was still aching was, “I had forgotton about it until you reminded me. Now it hurts a lot!” Children can display their experience of pain through behaviors, such as facial expression, body movements, and vocalizations (crying, screaming, or more organized verbal responses). As noted, they can also display distress by a withdrawal of interest in the environment. They may become quiet, withdrawn, stop smiling or crying, develop a poor appetite, and show a limited array of body movement. Often, when children become withdrawn and pain is suspected as the reason for withdrawal, the best way to determine if this assumption is correct is to treat the pain and observe whether the child’s behavior changes.78 A variety of assessment tools have been developed to determine the extent and type of pain experienced by children. Evaluation of pain in infants has relied on facial expression,7s body movements,” cry characteristics and duration,‘l stress hor432

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mone responses,g’ lo, 24--26 and cardiovascular reactivity.23’ ” Assessment of pain in infants, particularly neonates, will be described later in this monograph. The development of language permits the potential of self-reports of pain and opens the possibility of a variety of assessment tools to ascertain not only pain intensity but also the emotional and motivational aspects of pain. Some investigators have modeled multidimensional assessment instruments for children after the McGill Pain Questionnaire,83 and have incorporated a variety of techniques including structured interviews, lists of verbal descriptors, interval rating scales, and visual analogue scales3 Projective and visual analogue measures have also been used to evaluate children’s pain, including the use of poker chips,84 co10rs,~~~” drawings,87 and cartoons.” While these latter measures are less verbal-dependent, they may also lack specificity, since it may be difficult to determine whether a color, for example, is selected for its association with the severity, affective, or emotional aspect of the pain experience. Visual analogue scales (VA%) that utilize a measured line (typically 10 cm) anchored at each end by verbal descriptors and/or faces (no pain at one end and maximal pain at the other), comprise another commonly used self-report assessment technique, since they can be used with very young children (5 years of age) through adolescence. Beyer notes that children less than 8 years of age have more difficulty conceptually with a horizontal compared to a vertical VAS.17 The validity and reliability of VAS tools have been studied in children over 5 years of age and range from very good (r = .70) to excellent (r = 99) as children grow older.” Interval rating scales have also been used and include faces,8g’ So pain thermometers,g1 col~rs,~” and words and numbers .75,“- g4 As a validity check on self-ratings of acute pain and anxiety in children and adolescents undergoing bone marrow aspirations, LeBaron and Zeltzer75 found a moderately high correlation between children’s ratings and those of observers during the procedure. Behavioral distress ratings and behavioral checklists have also been developed.74, 75, y5 For more information about assessment tools, readers are referred to reviews of Savedrag” and Barr.” In summary, in the clinical setting, children will require observation for age-appropriate distress behaviors (e.g., crying in the young child, flinching or groaning in the adolescent). A change in behavior toward increasing withdrawal should also be a signal that potentially indicates pain. In school-aged children, a combination of visual analogue scales and interviews with the child about his/her pain will yield additional information. The latter method is particularly useful for learning about the emotional and motivational aspects of the pain experience, as well as the ways in which the child has attempted to cope with the pain. Physiologic and hormonal indices of Burr

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stress are suggestive of pain, especially if they revert to normal levels with pain treatment, but are not specific for pain and do not quantify the pain. More research is needed before assessment in these parameters becomes clinically useful (except perhaps as suggestive of pain in neonates).

pAIN

IN NEONATES

AND YOUNG INFANTS

Pain in infants, even more than pain in older children or adults, has been clinically neglected. Assumptions about the neurological immaturity of the infant’s nervous system, the complexity of infant pain assessment, and concerns about the sensitivity of infants to analgesics have severely limited research and clinical interest in this area, Unanesthetized circumcision stands as the symbol of traditional attitudes in this area. Recently, however, interest has been sparked by sources from within and outside of the medical community. In a series of papers, Anands7-” demonstrated that infants who had undergone surgery with minimal anesthesia (as per traditional practice) undergo a profound hyperglycemia that is indicative of physiologic stress. He found, in addition, that these babies had greater postoperative problems than those whose surgery was accompanied by more adequate anesthesia. Anand’s work yielded a series of editorials in influential medical journals100-103 urging the use of appropriate analgesia in infant surgery and a formal statement by the American Academy of Pediatrics on neonatal anesthesia.16 His work dovetails with a simultaneous increase in what has been termed “environmental neonatolAS more babies are surviving, a greater emphasis is being %Y.“104 placed on quality of life issues, such as the impact of lighting, sound, sleep deprivation, and handling of their morbidity. As a result, pain inflicted in the neonatal intensive care unit is being examined with greater scrutiny. Another source of pressure for change in the approach to pain management came from consumers in the medical community, spearheaded to a considerable extent through the efforts of Jill Lawson. Lawson’s son underwent surgical closure of a patent ductus arteriosus and subsequently died. In her grief, Lawson reviewed the operative records and noticed that the child had had no anesthesia or analgesia during the procedure. In an effort to alter this practice, she began an active campaign consisting of letter writing, testifying, and other activities to alert the public about this practice.lo5 As a result of these forces, the en&ire area of pain management in infancy is receiving far greater scrutiny in clinical practice and in research studies. Studies done on infants undergoing circumcision without anes434

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thesialo6 and heel lancelo reveal that infants respond to these procedures with decreased PoZ, increased heart rate, and increased blood pressure. Studies examining the metabolic consequences of unanesthetized circumcision in infants also reveal increased cortisol levels as compared with anesthetized controls.‘08 Anand has documented a significant stress response mounted by infants on whom surgery was performed with minimal anesthesia (which has been acceptable practice in infants) .s7 The infants respond with increased catecholamines, growth hormone, glucagon, and cortisol, and decreased insulin, yielding hyperglycemia and an increase in total ketones.

ASSESSMENT

Assessment of pain in infancy is far more complex than pain assessment in older children or adults because the most reliable indicator of discomfort, verbal reporting, is unavailable in infants. A number of behavioral and physiologic measures therefore must be used that are not specific for pain but are assumed to be correlated with it. The intercorrelations of these measures are limited, however, and as a result, it is more complicated to evaluate gradations of discomfort in newborns than to identify whether or not pain exists. Much of the work attempting to identify pain in infants has been developed in research settings and has limited clinical applicability at the present time. The work of Grunau and Craig” on newborn facial action has received much attention and stands as a model for infant pain assessment research. These investigators methodically catalogued infant facial actions in response to a painful stimulus during four infant states (quiet/sleep, active/sleep, quiet/awake, active/awake). They found predictable patterns of facial action that were related both to the degree of discomfort of the stimulus (heel rub vs. heel lance) and to the infant state (sleep vs. awake) (Fig 5). IzardloY and Craigll’ have examined facial expression in older infants and toddlers (l-9 months and 2-24 months, respectively) and found similar consistent response patterns. This work has only examined response to an acute pain stimulus and has limited relevance in assessing ongoing pain in infants, such as postoperative pain. Many authors, as previously discussed, have examined the use of physiologic variables as markers of infant distress. In studies of children undergoing heel lance and circumcision, heart rate, respiratory rate, blood pressure, and cortisol levels all increase with the pain stimulus while PO, decreases. Palmar sweating in response to painful stimulilll occurs in the newborn period and has been used to evaluate interventions aimed at pain reduction.‘l” Unfortunately, all Curr

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435

QWET~SLEEP

HEEL LAMCE

Ol3If-T

MEL

AWAKE

LANCE

FIG 5. Facial expression Paln expression permission.)

related to the infant state (asleep/awake). (From Grunau WE, in neonates: Facial actlon and crying. Pain 1987A; 28:395-410.

Craig KD: Used by

of these responses are nonspecific and the majority of work documenting them has been done on healthy newborns undergoing acute pain. For sick newborns, who may be physiologically unstable and who may be restrained, intubated, or paralyzed for medical purposes, such measures used independently have less clinical relevance. The idea that infants have a unique pain cry that is qualitatively different from other infant cries is controversial. Studies examining the acoustic characteristics of infant cries have been contradictory as to whether there are specific cry characteristics associated specifically with pain.l13’ ‘I4 In general, pain cries are found to be higher in pitch, to have a difference in frequency modulation signal suppression and to have different mean relative spectral levels.115’ ‘I6 Although no single behavioral variable correlates directly with pain, scales have been developed that attempt to cluster infant behavioral variables to create a clinically useful format. The Infant Pain Rating Scale was developed to assess the behaviors of 2- to 24month-old children.1’0 The scale focuses on a number of vocal actions that the infant might perform (crying), and both verbal and nonverbal expressions distinct from crying, such as screaming, grimacing, moaning, and whining. The work of Attia and colleagues’17 has created the most clinically usable pain assessment technique for infants to date. Pain assessment techniques are not really necessary 436

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to determine whether pain accompanies circumcision or heelstick-of course it does. We need assessment instruments for subtle discomfort that might not be as obvious (e.g., pain 2 days after abdominal surgery). Attia’s scale uses a mixture of behaviors such as sleep, quality of cry, sucking, and consolability to assess the discomfort a child is experiencing (Table 5). Clearly, infant pain assessment has a long way to go because, unfortunately, no one behavioral or physiologic measure correlates directly with pain. At the present time, nurses tend to rely primarily on fussiness, crying, and grimacing to identify pain in infants’l’ Until more adequate instruments are developed, in a situation in which pain might be reasonably expected (e.g., postoperative pain), use of an assortment of physiologic and behavioral criteria, although imprecise, allows for the more humane care of infants.

TREATMENT Although a number of behavioral and pharmacologic approaches are available for use in neonates, the array of choices and the depth of research supporting their efficacy is more limited than in older children.

Pharmacologic

Approaches

Analgesics are the mainstay of pain treatment in the newborn. Reviewed here will be some of those with particular relevance to newborns-morphine, fentanyl, and lidocaine. Analgesic use, in general, and opioid use, in particular, has been limited in this population because of sparse information available on the pharmacokinetics of these agents in newborns. In particular, there are concerns that newborns are more susceptible to the respiratory suppressant effects of opioids than are older children or adults.11s Recent work for the first time has formally determined the pharmacokinetics of morphine in children. Dahlstrom12’ reported that for children over 1 year of age, the absorption, metabolism, and elimination of morphine is similar to that of adults. For infants under 2 months, however, morphine is handled differently. Its elimination half-life is much longer (6.8 hours in infants vs. 3.9 hours in 10 week olds vs. 2 hours in adults).121 Clearance in newborns is less than half of that in older infants. This combination of longer half-life and lower clearance may explain the prolonged effects of morphine in newborns. Data on preterm infants suggest an even longer half-life and lower clearance than in term infants. As a result of these findings, morphine should continue to be used with caution in young infants and only in a carefully monitored setting.“’ Fentanyl is a s-ynthetic opioid that is 80 to 100 times more potent C‘urr Probl

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TABLE

5.

Measurement

of Postooerative

Pain in Infants*

ci 1. Sleep during preceding hour 2. Facial expression pain 3. Quality

1 Shorl naps min

None

Marked,

constant

of

of cry

Screaming, painful, pitched

high

Longer min

naps

Less marked, intermittent

Calm,

relaxed

Modulated, can be distracted

No

Normal

4. Spontaneous motor activity

Thrashing, incessant agitation

Moderate agitation

5. Excitability and responsiveness to stimulation

Tremulus, clonic movements, Mom reflexes spontaneously

Excessive reactivity

6. Flexion fingers toes

Pronounced, marked constant

Less marked, intermittent

of and

7. Sucking

8. Overall

tone

9. Consolability

10. Sociability (eye contact) in response to voice, smile, face

and

cry

any stimulation

Strong hypertonicity

Moderate hypertonicity

Absent

lO+

Quiet

Intermittent 41, stops c*ng

2

5 - 10

Subtotal

to

Absent or disorganized

None after minutes

2

(3 of with

Quiet after of effort Difficult

Strong, rhythmic, pacifies

Normal

1 min

Quiet within minute

to obtain

1

Easy and prolonged

Total score ‘FIWII Attia J, Amiel-Tison C. Mayer MN. et al: Measurwnent istration using a new clinical scoring system. /\nesthesir~/oLq

438

of postoperative pain and narcotic admin1987; 67:3A, A532. Used hy permission

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than morphine and has achieved widespread use in the operating room. Its characteristics make it popular for newborn surgery and its short half-life makes it attractive for medical diagnostic procedures out of the operating room. Newborn pharmacokinetics and pharmacodynamics have been investigated for fentany1.123’ lz4 The metabolism of local and regional anesthetics in newborns has received only limited investigation. Hepatic microsomal enzymes that metabolize amide-linked anesthetics are immature in early infancy. Anesthetic agents metabolized by these systems (lidocaine, bupivacaine) may, therefore, have a prolonged duration of action. Procaine and chloroprocaine are detoxified by other mechanisms (e.g., red cell cholinesterase) and as a result may be safer in newDespite these theoretical concerns, regional anesthesia is bornsl” safe in neonates if traditional guidelines are followed (i.e., dosing based on weight and time intervals). With the caveats that these drugs must use in a carefully monitored setting and that their actions are prolonged, there is no reason why systemic and local anesthetics should not be used in neonates. This point has been emphasized by the American Academy of Pediatrics16 in the following statement: The Committee on Fetus and Newborn, the Committee on Drugs, the Section on Anesthesiology, and the Section on Surgery believe that local or systemic pharmacologic agents now available permit relatively safe administration of anesthesia or analgesia to neonates undergoing surgical procedures and that such administration is indicated according to the usual guidelines for administration of anesthesia to high-risk, potentially unstable patients. In occasional situations, physiologic instability will be so great that the anesthetic agents must be reduced or. discontinued. However, the decision to withhold such medication should be based on the same medical criteria used for older patients. The decision should not be based solely on the infant’s age or perceived degree of cortical maturity.

BehavioralApproaches A number of behavioral strategies for the management of pain in newborns have been examined. Many of these approaches are intuitive, and their efficacy has only recently received formal investigation. Rocking, soothing, and stroking are almost automatic responses to infants in discomfort. It is not known if the demonstrated efficacy of these techniques results from distraction away from the painful stimulus, increased organization of the infant, stimulation of larger afferents that might interfere with pain transmission, or effects of vestibular stimulation. Pacifiers have been used in an attempt to decrease the discomfort associated with medical procedures in newborns. They have been found to decrease irritability and crying associated with heel sticks and circumcisions. Presumably, pacifiers work by organizing the infant’s response to discomfort, a response Curr

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that had previously been disorganized. Regardless of their mechanism of action, pacifiers offer a noninvasive approach to ameliorating some of the discomfort associated with these procedures.12”S lz7 Restraint of infant movement may have some benefits. By controlling the infant’s disorganized movements, swaddling, like a pacifier, helps to organize the infant. However, only limited formal research has investigated this phenomenon.

MANAGEMENT

OF PAIN FOR SPECIFIC NEWBORN PROBLEMS

Perioperative Pain Management Two aspects of perioperative pain management have received some attention in the literature. One concerns the adequacy of anesthesia/analgesia during surgery and the other the adequacy of postoperative pain management. As previously mentioned, Anand and colleagues”7 --” reported the responses of newborns undergoing surgery for patent ductus arteriosus ligation performed with and without potent anesthesia. In newborns anesthetized with curare and nitrous oxide only, a significant increase was noted in the infants’ elaboration of adrenalin, noradrenalin, glucagon, glucose, aldosterone, and corticosterone. These changes were interpreted as evidence of a significant surgical stress response. In the group that had more potent anesthesia, which included fentanyl in addition to the nitrous oxide and curare, the increases in these hormones and metabolites were not seen. In addition, postoperative morbidity and mortality were reduced in the maximally anesthetized group. Although the exact implications of this surgical stress response are unclear, Anand and others have argued that the results strongly support the need for potent anesthesia and analgesia in newborns undergoing surgery. Postoperative pain management is often not a high priority in the neonatal intensive care unit and, according to Yaster,l” is “almost never done.” Despite this, the same reasons for providing adequate postoperative care in adults apply to newbornsthat is, humanitarian (preventing unnecessary suffering) and medical (decreasing microatelectasis by diminishing hypoventilation secondary to splinting and, in general, providing more physiologic stability). A number of papers published over the past 2 years have examined the safety and efficacy of continuous infusion morphine in newborns for 24 to 48 hours following surgery. At a dose of 15 pg/kg/hour few side effects were encountered; however, continuous infusion requires sophisticated monitoring.“” X3’ Kaplan131 suggests that “selected infants should be electively ventilated following surgery to allow for analgesia to be administered without concern for respiratory depression.”

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Procedure

Pain

Circumcision.-The procedure that most symbolizes a disregard for infant pain is circumcision. During this procedure, the baby is restrained while the foreskin of the penis is clamped, crushed, and removed. Although in some ritual circumcisions, symbolic recognition of the attendant pain of this procedure is acknowledged through the offering of wine to the infant, until recently medical circumcisions did not address this issue. Few strategies to diminish circumcision pain were available, and the implications of the pain associated with this procedure had not been studied carefully. Marshal1,132 in one of the few studies to address the consequences of circumcision pain, identified state control differences in circumcised and uncircumcised babies as well as effects on maternal/infant interaction. Recently, three approaches to ameliorating the discomfort associated with circumcision have been formally studied: dorsal penile nerve block (DPNB), pacifiers, and postprocedure pain relief. The DPNB was first described by Kirya and WertheimlS3 and appears to offer significant benefits to the infant. In a number of studies’06’134J 13’ use of DPNB has been shown to decrease crying, heart rate, serum cortisol, and the fall in 0, saturation associated with circumcision. The procedure is relatively simple and has few associated complications. The additional needlesticks necessary to perform the block are thought to be a relatively trivial source of distress compared to the discomfort associated with the unanesthetized procedure. The consensus of investigators is that DPNB clearly offers a humane and effective alternative to unanesthetized circumcision. At least one study136 has explored the use of a pacifier during circumcision. Although there was no difference in serum cortisol levels between groups using a pacifier and those without a pacifier, the pacifier group cried significantly less. Tree-Trakarn*37 investigated the use of morphine, nerve block, and topical anesthesia in children following circumcision and found that topical lidocaine placed on the wound at the end of the procedure was as effective as the other modalities in eliminating postoperative discomfort. This study was not performed on newborns, however, where absorption and halflife of lidocaine may be altered. In addition, postoperative lidocaine does not diminish the pain that occurs during the procedure. Regardless, postoperative pain management in circumcision should also be considered as part of the humane management of this procedure. With the recent work of Wiswelll”’ and the subsequent response of the American Academy of Pediatricsl”” suggesting that circumcisions may have medical benefit, more investigation should be focused on providing comfort during and after these procedures.

Heel Lance.-Analysis of blood drawn through lancing of the infant’s heel is a major source of laboratory data in newborns. The heel lance procedure must yield enough blood for analysis and, as a msult, the heel often must be squeezed and additional wounds must be inflicted. Despite the commOnplaCe occurrence Of this pI’ocedure and the obvious displeasure it evokes in the infant and often in the cmgver who must perform it, little attention has been given to the amelioration of pain associated with this procedure. ~0 approaches to decreasing the discomfort of this procedure have been investigated. Harpin and Rutte? examined the use of an Autolet, a spring loaded device that when released pierces the skin at a predictable depth (2.4 mm) and is immediately retracted. This device is commonly used by children with diabetes to help them in blood sampling. In the Harpin and Rutter study, infants were far less distressed by the Autolet than by manual heel pricking, as measured by palmar sweating. They were less likely to awaken and more likely to remain quiet during the procedure when the Autolet was used. Nursing statf members were more comfortable and, because of the fixed depth of puncture, the risk of osteomyelitis was diminished. Blood flow and success of the procedure were not affected. In another study, Field and Goldson1Z7 used the pacifier to ameliorate the pain associated with heel lance and found that pacifiers decreased crying and fussiness in the infants but had no effect on other physiologic variables. Lumbar Punctures.Lumbar punctures are commonly performed on newborns for a variety of diagnostic purposes. Because of the conventional wisdom that the needle stick associated with the placement of local anesthesia is as painful as the lumbar puncture itself, these procedures are often performed without anesthesia or analgesia. Porter and associates140 examined this hypothesis by randomly assigning infants to two groups: one receiving I% intradermal lidocaine and the other receiving no anesthesia. They then monitored the heart rate, respiratory rate, transcutaneous oxygen, and CO, levels in the infants 26 minutes before, during, and after the lumbar puncture. Although the details of their work have not been published, they interpret their study to suggest that lidocaine significantly ameliorated the response of infants to the pain of this procedure and increased their physiologic stability without producing adverse side effects. Another study that has implications for lumbar puncture pain was reported by Shreiner and Kleiman.141 They observed 289 lumbar puncture attempts in the neonatal intensive care unit and found that 61 were unsuccessful at obtaining cefebrmpinal fluid and an additional 76 were considered traumatic. This yielded a failure rate of 47%. Their work implies that training in the mechanics of these techniques could be significantly improved. It also further 442

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justifies the need for local anesthetic if lumbar punctures will require multiple attempts. One additional area that offers the possibility of pain reduction during lumbar puncture involves the use of lidocaine-prilocaine (EMLA) cream. This product, not presently available in the United States, will produce total local anesthesia when placed on the skin under a closed dressing 45 minutes prior to the procedure. It has been used successfully for lumbar punctures14’ and venipunctures143 in older children. Although it has not yet been studied in infants, it has potential applicability for neonatal circumcisions, lumbar punctures, venous cannulations, and other potentially painful procedures. Other Procedures.-Although they have not been formally studied, other procedures might benefit by implication from Porter’s work14’ with lumbar punctures. Venous cutdowns, percutaneous line insertions, and chest tubes should be placed with the use of local lidocaine.*” The relative safety of the drug and its proven efficacy in older children strongly suggest that its use would be beneficial to infants as well. However, repeat doses should be timed to prevent toxicity. One can increase the intervals or give less drug. If the latter is chosen, careful assessment of the child’s reaction should be made. Nonemergency intubations in newborns are often performed without the use of sedatives or analgesics, nor are these drugs typically used during ongoing ventilatory management. This is in contrast to practice in older children and adults who are often paralyzed and then given analgesics and sedatives during the period in which they are being ventilated. Awake intubations have been linked to increased anterior fontanel pressure and increased intracranial pressure.144 It would appear that infants would benefit from analgesic/ sedative usage during ventilatory management, but more research is clearly needed in this area. GENERAL APPROACH NE WBOZUV

TO THE

MANAGEMENT

OF PAIN

IN THE

The previous discussion allows for the development of general guidelines for the management of pain in newborns (Table 6). First and foremost, recognition of the fact that infants experience pain is essential to the development of a treatment plan aimed at ameliorating pain. It should be assumed that tissue damage that would hurt an adult or older child hurts an infant. Knowledge of the infant behaviors and physiologic changes that correlate with pain is also essential so that pain can be recognized. In general, noxious procedures and stimuli should be minimized. Blood drawing should be consolidated as much as possible and laboratory tests should have Cur-r

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443

TABLE General 1. 2. 3. 4. 5. 6.

6. Aooruach

to Pain Manacement

Assume that infants experience Be aware of behavior that might Minimize noxious stimuli (painful Use local anesthesia for procedures Use adequate anesthesia during Use behavioral techniques such

in the Infant pain (what will hurt an adult will hurt an infant). signal discomfort. procedures, handling). (e.g., chest tubes, lumbar puncture, circumcisionl. surgery and adequate analgesia postoperatively. as rocking and pacifiers.

justifiable value. Procedures should be performed by individuals who have had formal training and who utilize the most effective techniques available. If possible, local anesthesia should be used for painful procedures and use of a pacifier and other behavioral approaches should be considered. Adequate analgesia and anesthesia should be used during surgery and postoperative analgesia should be offered.

PEDIATRIC ASSESSMENT

PAIN;

PSYCHOLOGICAL

REGARDING

CHOICE

INTERVENTIONS OF INTERVENTION

All children can benefit from some type of support during painful or frightening situations. The decision about how best to help children is based on the type of pain situation (medical procedure, chronic disease pain, recurrent abdominal pain, etc.), the previous experience of the child with that or other pain situations, the child’s social support system, and individual characteristics of the child. Factors related to the type of situation include the duration, intensity, and expected recurrence of the pain period. For example, to help a child undergo an invasive medical procedure, one should carefully address the child’s anxiety in addition to the pain. However, to help a child experiencing chronic pain, factors such as the meaning of the pain and learned pain behaviors become more salient. For management of recurrent pain problems such as recurrent abdominal pain or headaches, diet, family relations, and school problems should also be considered. For more information about these conditions, the reader is referred to articles by Rappaport’4” and McGrath.14’ The child’s previous experience with the same or related pain experiences can have both positive and negative consequences for the child. Previous pain situations that were experienced as distressing may sensitize the child and increase anxiety when the next pain situation is approached. Similarly, if the child views his past experience as a failure of his ability to cope, he will have expectations of failure for future similar situations and may feel overwhelmed by the

belief that he is completely powerless in that type of pain situation. On the other hand, if his previous experience has given him the opportunity to develop coping skills that helped him to feel a sense of mastery over a difficult situation, then he/she may approach future pain situations with confidence. Therefore, it is important to ask the child about his past experiences related to pain: for example, what aspects/parts of the experience bothered him the most and what did he do to get through it? What did he or anyone else do that was most helpful? The child’s social support system is also an important element in understanding how best to help a child who is in pain or about to experience a painful situation. Social support can act as a buffer or mediator in the impact cf environmental stressors upon the child. usually, the child’s primary supports are his parents. If they have been sensitive to his needs and feelings and been able to provide distraction, soothing, and modeling of adaptive behaviors when their child has been in painful and/or fearful situations, their child will trust that these supports will be forthcoming when needed. However, a mismatch between the child’s coping style and support needs and the parents’ abilities to respond appropriately may result in the child’s mistrust of his parents’ or anyone’s abilities to help him in times of distress. In this latter situation, an active effort should be made to help the child directly while also teaching the parents how to help their child. Time devoted to the parents themselves may be necessary to help them to cope with their own anxieties (or appropriate referral can be made as indicated). Finally, the child’s own characteristics warrant consideration in deciding on the best management strategy for helping him to cope with pain. As previously noted, the child’s cognitive/developmental level will play a major role in determining his understanding of the pain experience. Related to developmental status is the meaning that the child ascribes to the pain. In a study of children and adolescents with rheumatoid arthritis, Beales and associates147 report that adolescents with the same amount of joint destruction as younger children reported significantly more pain. They attributed this reported pain difference to the meaning that the adolescents gave to the pain, since they had a better understanding of the serious medical consequences of joint destruction and might have worried more about what the pain might signify. Apart from developmental status, children demonstrate characteristic coping styles in their response to stressful situations. These strategies have cognitive (what children think) and behavioral (what children do) components. Siegel78'148 and Peterson,14’ among others, have described children’s coping styles on a continuum from active (information-seeking) to avoidant (information-avoiding). A number of studies15” 15’ have indicated that children using the more active coping strategy generally Cur-r

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appear to have more beneficial responses during pain situations. Children who ask more questions, who look at and want to touch and play with hospitai preparatory materials, and who show increased physiologic arousal while watching a preparation film are more likely to be cooperative during medical procedures and to report medical procedures or surgery as more tolerable than are children who are avoiders. To learn about children’s characteristic responses to novel/threatening situations, one can observe the child during pain/stress situations and ask parents how their child typically reacts to other new or frightening situations at home. One can then help the child use those coping behaviors that are effective and also teach the child some new skills to permit a wider array of responses from which the child can select.15’

INTERVENTIONS

Given that the type of pain situation, the previous pain experiences of the child, the child’s social support system, and the inherent characteristics of the child are all important factors in determining the psychological methods most likely to be effective in reducing a child’s distress, the next section will provide an overview of common intervention strategies. Preparation.-Preparation is perhaps the most widely used psychological intervention. There are a variety of ways to prepare children for invasive medical procedures or potentially frightening hospital experiences that can add fear to pain. The central core of preparation is the provision of information, including both procedural (what will be done) and sensory (what it may feel like) components. Preparation can be provided by parents, nursing staff, and child life specialists, and often takes the form of descriptions about what will take place and opportunities to handle the equipment or enact the procedure through doll play. Familiarization with the hospital or treatment room and introduction of the child to the medical personnel involved in the procedure are also part of preparation. For a review of preparation procedures, readers are referred to an excellent review by Peterson and Mori.15’ Hypnosis.-A variety of cognitive-behavioral intervention strategies can be used to help children to cope with pain. One method that has been most carefully studied is hypnosis. Hypnosis involves a combination of distraction, time distortion, reframing (putting things in a different perspective), and alterations in sensory experiences. It accomplishes these goats to varying degrees by helping the child to become as intensely involved as possible in a fantasy experience.

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The fantasy may be based on past experiences of the child, on future hopes, or on the recreation of a story that the child knows, or it may simply be a creation of the child’s imagination (likely based on all of the above). For example, during a medical procedure a child might become distracted from a focus on the scary parts of the procedure (e.g., the needle, etc.) with the help of an interesting story about an adventure with his pet dog. His involvement might be enhanced by asking him questions that require some thought and imaginative visualization, e.g., “Where should we go today? It looks as if Spot already knows where he wants to go! Let’s follow him. Oh, look! He’s going to the park. Let’s run so that we can catch up with him.” Imaginative involvement can also be enhanced by piquing the child’s curiosity, e.g., “It looks as if Spot found something . . it looks white and fuzzy . . I wonder what it is? Let’s go closer and take a look.” As the child becomes involved in the fantasy, the time in the treatment room seems to go by faster than if the child focused on the medical procedure during that time. Aspects of the procedure can be reframed, e.g., “Doesn’t it feel good to take such strong, deep breaths so that all the muscles in your body begin to feel stronger and stronger?” Sensory aspects can also be altered: “Notice how the cool cotton begins to make your arm feel sleepy.” The type of imagery theme used may provide some children with a sense of mastery. For example, the winning of a race, scoring of a touchdown, climbing of a mountain, or coming in first in the spelling bee in the fantasy may help the child to feel as if he just accomplished something special and important, unlike the feelings of failure that he might otherwise feel following the medical procedure. Some children like to pretend that they are superhero figures, such as the Incredible Hulk or Sheera, who are possessed with superhuman powers. In addition to medical procedure pain, hypnosis can also be a useful intervention strategy for chronic pain. Children have used fantasy to successfully work through their fears and wishes.153, 154 For example, an adolescent in persistent pain from metastatic nonHodgkin’s lymphoma used imaginative involvement to “build a house,” which he hoped to do as an adult. He reported with a sense of accomplishment that he had “finished it” a few weeks before he died. For more information on the use of hypnosis in the treatment of pain in children, readers are referred to a review by Zeltzer and use of hypnosis is now proLeBaron.‘55 Training in the pediatric vided by workshops given by three major national societies: The Society for Behavioral Pediatrics (241 E. Gravers Lane, Philadelphia, PA 19118, 12151 248-91681, The Society for Clinical and Experimental Hypnosis (128-A Kings Park Avenue Drive, Liverpool, NY 13090, [315] 652-72991, and The American Society of Clinical Hypnosis (2250 E. Devon Ave., Suite 336, Des Plaines, IL 60018, 17081 297-3317).

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Desensitization.Desensitization is another intervention strategy used to help children to cope with frightening medical/surgical procedures. It requires a period of time during which the child can be exposed to and successfully master increasingly feared aspects of the procedure. For example, the child might first imagine the treatment room. Then the child might imagine and then handle, when he is ready, the procedure equipment (i.e., the syringe, alcohol swabs, drapes, tape, etc.). He might then go through the steps involved in the procedure, either in his imagination or with a doll. Some children who have experienced numerous unsuccessful painful procedures develop such extreme conditioned anxiety reactions that they literally require multiple steps in the densensitization process in which they imagine aspects of the medical procedure before they can even look at the equipment. However, for many children an age-appropriate explanation, handling the equipment, “performing” the procedure on a doll or on the nurse, and having the opportunity to ask questions may take place in one session so that the child is rapidly ready to experience being in the treatment room without extreme fear. What typically happens on a pediatric ward is that a child is forcefully restrained for a medical procedure, with little preparation. If other invasive medical procedures are required of that child, a situation may be created in which the child’s resistance becomes unmanageable, disruptive, and distressing to the medical and nursing stalf (to say nothing about its effects on the child). When the situation becomes intolerable to the staff, a psychologist or child psychiatrist may be consulted to “make the child manageable.” However, often the consultant is called about 20 minutes before the next medical procedure to provide intervention. No matter how knowledgeable and skillful the consultant is with behavioral intervention for helping children to cope with pain, he may be able to do no more than to observe the screaming, squirming, restrained child during the procedure and help the child ventilate his feelings following the procedure. For this type of child, the consultant may need a number of sessions to “uncondition” or desensitize the child to the procedure. Such desensitization and teaching of positive coping skills require time. Thus, if multiple painful procedures (e.g., IVs, blood draws, bone marrow aspirations, lumbar punctures, burn debridement, etc.) are expected as part of a child’s medical treatment, as a preventive measure it would be wise and cost-efficient for the medical team to assign someone with intervention knowledge and skills to work with the child on the first day of hospital admission. If no one on the team has these skills or the time, then the appropriate consultant should be called in at that time (i.e., on the first day).

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Positive Reinforcement.-Another intervention strategy that all members of the medical team can perform with little training is positive reinforcement. This strategy involves encouragement with positive statements about the child, tangible rewards (stickers, badges, prizes, etc.), or rewards of time and attention immediately following cooperative behavior. For example, a child might cry but hold still during a blood draw. The child would then be fussed over with encouraging statements for being so brave and strong. On the other hand, uncooperative behaviors should not be punished and the child should never be threatened or made to feel ashamed if he is unable to cooperate. Cooperation achieved in this way will come at a price (i.e., lowered self-esteem, feelings of powerlessness, and future expectations of failure). Positive reinforcement works best if the child is also taught some coping strategies that he can use during painful procedures and if his feelings are understood in addition to his behavior during painful experiences. Other Strategies.-Other cognitive/behavioral strategies include distraction, relaxation, positive self-statements, thought-stopping, modeling, and rehearsal to reinforce learned coping methods. The goal of distraction is to focus the child’s attention on something other than his pain or the feared painful procedure. For example, during the insertion of an IV, the child might be asked to count the stripes on his mother’s blouse or father’s tie. An older child might be asked to count by fives or sixes. As added incentive, the nurse might ask everyone in the child’s room to guess the number that the child might reach by the time the needle is inserted. Of course, the child could “guess” also and the “winner” could be applauded. Reading a story to a younger child, playing games (videogames, cards, or checkers), and telling jokes are other ways to distract children. A child can be taught to achieve relaxation through a variety of methods. It might help a younger child to take deep breaths during a procedure. An older child or adolescent might be taught to sequentially contract and then relax different muscle groups. The purpose of the contraction aspect is to help the child feel the difference between a tense and relaxed muscle. In this manner, the child also learns that he has control over his skeletal musculature and that his body can feel so much better when his muscles are relaxed. He might even be given some relaxation exercises to practice at home. The positive self-statements strategy includes teaching the child a number of simple statements that the child can repeat to himself during times of fear. These statements usually relate to appraisal of the situation (“This is an IV stick. I’ve had this before”), self-efficacy (“I know what to do during an IV stick”), and positive expectations (“I know that the IV stick will go quickly and it won’t bother me”).

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Positive self-statements are often coupled with thought-stopping.156 In this strategy, the child is told that whenever he starts thinking about the feared procedure (e.g., an IV stick), he should stop whatever he is doing and say “stop!: He should follow this by repeating the three or four positive self-statements that he learned. This procedure can be repeated until the child feels that he has achieved some mastery over his fears. These statements can be repeated during the actual medical procedure as well. Modeling involves some type of actual demonstration that displays positive coping behavior. Children often learn to model their parents’ behaviors during distressing situations. Depending on the parents’ own abilities to cope, children may learn either adaptive or maladaptive behaviors. Therefore, one form of modeling is to teach parents positive coping behaviors that they can demonstrate to their child. The most common use of modeling is to have the child view a videotape of another child undergoing the same medical procedure. The child can then watch the behaviors of the child in the videotape, and it is most helpful when the child in the tape also expresses his thoughts and feelings during the procedure (with a voice overlay). After teaching the child a variety of coping strategies that best suit the needs and characteristics of the child, it is beneficial to provide him the opportunity to practice these techniques. Such rehearsal not only reinforces these positive behaviors but also gives the child the reassurance that he knows what to do during medical procedures or other pain situations. This knowledge can lead to positive expectations, reduced fear, and feelings of self-efficacy. For more information about psychological interventions, readers are referred to the three pediatric pain textbooks’-3 mentioned earlier and to a review of the management of pain associated with medical procedures by Zeltzer and associates.4 PHARMACOLOGIC

TREATMENT

OF PAIN

The pharmacologic management of pain is challenging. Children with pain are subject to the same vagaries as adults with pain. Pain is a highly individual phenomenon that is altered by the location and amount of tissue damage, and is influenced by the overlay of cultural, ethnic, cognitive, and time factors.157 For many years there has been a reluctance to develop dynamic innovative strategies, anchored in fundamental principles of pain transmission, neuroanatomy, and pharmacology, for the pediatric patient with pain. A number of barriers have prevented the advancement of effective pain management .34 Pain in adults is associated with a strong emotional response believed to he not present in the neonate and infant. In a 450

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survey of neonatal intensive care units, demonstrated that the same reluctance by staff to adequately treat pain in adults exists for neonates. He found the amount of analgesia ordered for infants was not given or was not given in the amounts ordered.15’ A number of other studies have shown similar results.17,18 Pain can result from tissue manipulation, trauma, or threat of tissue damage. Multiple endogenous compounds (serotonin, histasubstance P, and prostaglandins) mine, K+, Hf, Ca++, bradykinin, are released by painful stimuli. They sensitize the peripheral chemoreceptors and mechanoreceptors that induce a reduction in the pain threshold of the nociceptors (Fig 6).15s’“’ A patient’s response to pain can be modulated by a number of internal and external factors. Figure 7 represents a schematic of the pain pathway and depicts many of the endogenous substances that mediate pain. Modulation of pain impulses is influenced by the endogenous, opioid, noradrenergic, serotonergic and GABA-ergic systems. Management strategies involving pharmacologic interventions and psychological preparation that will effect changes in pain transmission, perception, and integration are available. Investigations into the use of

Efferent Sympathetic

Smooth

Muscle

FIG 6. Local ttssue factors and peripheral pain receptors. The physical stimuli of “trauma,” the chemical environment (H+), algesic substances (serotonin [SHT], bradykinrn [5K],) and microcirculatory changes may all modify peripheral receptor activity. Efferent sympathetic activity may increase the sensitivity of receptors by means of noradrenaline (NA) (norepinephrine) release. Substance P may be the peripheral pain transmitter. Points of potential blockade of nociception are shown as “blocker.” Other potential sites involve BK, 5-HT, NA, and SP. (From Phillips GD, Cousins MJ; Neurological mechanisms of pain and the relationship of pain, anxrety, and sleep, In Cousrns MJ, Phillips GD (eds): Acute Pain Management London, Churchill Livingstone. 1986. Used by permission.) Curr

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methods

s&staKc GAeA Wctrical

of pain

dicf

P olwgonirts stim.UENS

)

ontiiamiwr somtonb-antagonists +d cycio-orygmaw inhibitors substance P antagonists local cmnthettcs

@iCOCOftkOidS

FIG 7. Various techniques that may provide paln relief in surgical patients and thereby eventually modify the endocrine metabolic response. At present no information IS avallable from antagonlsm of peripheral mediators of pain. while neural blockade with local anesthetics inhlbits a malor part of the stress response. Pain relief with epidural/intrathecal opiates IS less efficient in reducing the stress response despite sufficient pain relief. The effect of stimulation of descending inhibitory pathways on the stress response is unknown. Admlnistration of systemic opiates In usual low doses has no consistent influence on the stress response. (From Kehlet H: Modification of Responses to Surgery by Neural Blockade: Clinical Implications, in Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain. Philadelphia, JB Lipplncott, 1989, pp 14% 188. Used by permission.)

antagonists to peripheral mediators such as antihistamines, glucocorticoids, cycle-oxygenase inhibitors,‘“l substance P-antagonists and serotonin-antagonists have not been well studied, GENEHAL

APPtiOACH

The child or adolescent in pain who is admitted to the emergency room should first be evaluated for airway patency, presence of breathing, and cardiovascular stability. The ABCs of resuscitation must be followed to stabilize the patient. A detailed, concise history and physical examination with emphasis on cardiopulmonary function, neurologic status, recent ingestions, allergies, and past anesthetic history should be completed without delay. Definitive diagnostic tests and therapeutic interventions should be initiated as

soon as possible. While the pain that may have brought the patient to medical attention initially has its utility, once the child is in the care of medical personnel, its purpose is questionable. Often the emphasis on possibly masking a patient’s symptoms or the possible development of respiratory depression, hypotension, aspiration, constipation, and urinary retention has resulted in a continued lack of a coherent approach to pain management in the pediatric patient. This has led, as an aftermath, to unnecessary suffering. The burn patient need not continue to writhe in pain and the victim with multiple fractures needs relief. While efficacious pain control can be challenging to the physician, a balance between patient suffering, diagnostic integrity, and patient safety can be achieved. Instituting pain relief and alleviating anxiety early can aid in the rapid restoration of normal function. The choice of methods to treat pain and stress will depend on several factors”‘: 1. The patient’s clinical condition including cardiovascular and neurologic status. 2. The patient’s diagnosis, if indeed one has been established. 3. The clinician’s skill and knowledge of regional anesthetic/ analgesic technique. 4. The clinician’s knowledge of pharmacology of anesthetics (general and local) and analgesics (opioid and nonopioid). 5. The practitioner’s knowledge of methods of delivery for anesthetics and analgesics. 6. The type or source of the patient’s pain. Many painful procedures or conditions lend themselves to adjunctive therapy with pharmacologic agents. No single agent will be appropriate for all children or all situations. The drug regimen should be tailored to the route of drug administration. Rectal medicines are not well suited for children 5 years and older or for alleged rape victims. The choice of agents (e.g., morphine vs. fentanyl), like the choice of techniques (e.g., regional anesthesia vs. general anesthesia) depends on factors already described. Familiarity with a particular drug or delivery system should not preclude the use of another more appropriate agent or method that may complement the treatment objectives more readily. The degree of pain and treatment goals should dictate the agent(s) administered. Mild pain can be adequately addressed with nonsteroidal anti-inflammatory drugs, whereas moderate to severe pain requires interventions with local anesthetics, opioids, or general anesthesia. Adjunctive agents, such as antidepressants, anxiolytics, anticonvulsants, and stimulants, can enhance pain relief and greatly diminish the frequency and severity of analgesic and anesthetic side

effects.” Psychologic treatment should always be incorporated into the overall management plan. Many of the agents listed below have adverse side-effects and should only be administered in the presence of persons trained in resuscitation.

USEFUL AGENTS FOR ANALGESIA, ANESTHESZA, AND SEDATION Opioids

A variety of opioid agonists are commonly used for analgesia. The pharmacokinetic and pharmacodynamic properties of the opioid agonists morphine, meperidine, Dilaudid, fentanyl, methadone, sufentan& and alfentanil should be familiar to physicians treating patients in pain. Fentanyl, sufentanil, alfentanil, and midazolam are commonly used in an operating room setting for children and infants. However, it should be noted that alfentanil has not yet received FDA approval for use in children under twelve years of age. The choice of agent should depend on the clinical setting and the treatment objectives and will be facilitated by knowledge of the pharmacologic characteristics of the drug available for use. Opioids have several sites of action in the brain and in the spinal cord. Multiple receptors mediating the actions of the opioids have been discovered or postulated. Many side effects have been noted from the use of opioids. All opioids have a dose-dependent depressive effect on ventilation, apparently affecting this action at the pontine and medullary ventilatory control centers. At equianalgesic doses all opioids have similar degrees of respiratory depression. They induce a decrease in tidal volume, respiratory rate, and thus minute ventilation. Opioids lead to a reduced compensatory response to hypoxia and hypercapnia.16’ Other side effects depend on the specific agent used, the dose, and the rate at which it is given. As an example, the rapid injection of fentanyl causes chest wall rigidity to a much greater extent than does morphine given at the same rate. Other side effects include increased intracranial pressure from CO, retention, hypotension Tom histamine release, and urinary retention. Side effects can be effectively eliminated with agonists, antagonists, stimulants, laxatives, and antipruritics. There is a great interpatient variability in response to morphine. Therefore, the dose should be determined by the patient’s response, i.e., administer the amount required to make the patient comfortable.163 Morphine has been the most commonly utilized opioid agonist. It remains the gold standard by which the newer agents are measured. As of yet, alfentanil has no approved pediatric dose, and there is no approved dose of Fentanyl and Sufentanil for children under 2 years. 464

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Morphine.-Morphine produces sedation and analgesia. It is more effective in relieving dull continuous pain than sharp intermittent pain. It is rapidly absorbed and peaks within 15 to 20 minutes of intravenous administration. Intramuscular administration and oral absorption are not reliable, consequently, the appearance of the analgesic effect is erratic with these routes. The respiratory depressant effect of morphine can be biphasic, with an early initial depressant effect, then a delayed response up to 24 hours after injection. Morphine does not cross the blood-brain barrier easily except in neonates, secondary to its unionized fraction at physiologic pH and its lipid solubility.‘“4 FentanyL-Numerous other agonists recently synthesized have a variety of biophysical properties, making them preferable for use in an emergency room setting. Fentanyl, a synthetic opioid that is more potent than morphine, has a high lipid solubility and readily crosses the blood-brain barrier. However, because of its increased lipid solubility, when it is given intrathecally it does not have the rostral spread exhibited by morphine, thus limiting its CNS effects at low concentrations. Fentanyl has a very short duration of action. This is a reflection of its rapid redistribution from the blood into other tissue sites such as fat and muscle. A great deal of nonspecific binding of fentanyl occurs .165 This drug must be titrated carefully, and it should be noted it does not work well for pain resulting from orthopedic procedures. If a constant infusion is being used to deliver fentanyl to the patient, the infusion port should be as close to the patient as possible. Fentanyl suppresses the stress response from acute injury. It has been shown to decrease the morbidity of major surgery when given in combination with an inhalational agent vs. the inhalational agent alone.166 It is very effective for acute pain relief, especially when given in combination with an anxiolytic agent. However, significant respiratory depression can occur, especially when it is used in conjunction with midazolarn4 Fentanyl can be given via multiple different routes167”68; however, intravenous administration is the most efficacious. The initial dose should be 1 to 5 lig/kg followed by 1 to 3 pg/kg/hr. Repeat doses with small aliquots of this drug may be necessary depending on the patient’s individual requirements. is a new synthetic opioid that is a less AlfentaniZ.-Alfentanil’64 potent derivative of fentanyl. When compared to fentanyl it has a shorter duration and shorter onset of action. The large unionized fraction of alfentanil at physiologic pH, its small volume of distribution, and the rapid redistribution account for its rapid onset of action and short duration of action. Acute pain can be well controlled Curr

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with small doses of alfentanil. It can be used as an alternative to ketamine and has as an advantage the ability to be directly antagonized with naloxone. However, it does produce respiratory depression that is not delayed as in the case of morphine. Other side effects that have been noted include bradycardia, systemic vasodilation, chest wall rigidity, and nausea.“j4 The myocardial depression and histamine release seen with other opioids is not seen with alfentanil. Small incremental doses of alfentanil, 3 to 5 p.g/kg i.v., can control acute pain. Continuous infusions of alfentanil maintain plasma levels and tend to give more constant pain relief. Larger recommended doses of 15 to 20 kg/kg i.v. also accomplish this goal but are associated with significant respiratory depression. SufentaniZ.-Sufentanil is a potent opioid agonist that binds to mu receptors and has 10 times the analgesic activity of fentanyl. This agent has been used as a sedative for premeditation, 2.5 pg/kg nasally1”7; but because of its increased potency and potential for chest wall rigidity, it should not be used in conjunction with nitrous oxide. Sufentanil should be used with great care and in the presence of someone experienced with airway management. Only intravenous use of Sufentanil has been approved by the FDA. Other Agents.Demerol, Dilaudid, and methadone each have different biochemical characteristics that lend themselves to various clinical settings. It should be noted that the long half-life of methadone makes it an ideal agent for chronic pain treatment and for patients who will have prolonged hospital stays and will need pain treatment that can be initiated in the hospital. Methadone, because of its ideal pharmacokinetics, will lessen the number of intramuscular injections a patient needs. However, intramuscular injections should rarely be used for pain treatment in children, since they themselves produce pain and fear and thus complicate pain management. Methadone can also be given orally and intravenously. Although Demerol (meperidine) has been a popular drug (often given intramuscularly for postoperative pain), most pediatric pain experts believe that it has little place in pediatric pain care unless it is given intravenously and the patient is monitored closely. Barbiturates Barbiturates do not relieve pain but are useful for their sedative/ hypnotic effects. They are classified as long, intermediate, short, and ultrashort acting. They all suppress the CNS at the reticular activating system in a nonspecific manner to provide sedation. As derivatives of barbituric acid, the barbiturates are chemically altered in a number of ways to change their hypnotic potency, rapidity of action, and duration of effect. As a group of compounds, they act on both 456

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presynaptic and postsynaptic neurons. They alter the release of neurotransmitters such as acetylcholine from presynaptic neurons and they prolong the binding of GABA at its receptors on the postsynaptic neurons. All barbiturates are water soluble, but are extremely alkaline and produce pain or irritation upon injection. The distribution of the barbiturates throughout the body is dependent on their lipid solubility. After the initial dose, barbiturates are rapidly redistributed from the highly perfused areas of the body to muscle and fat. The rapid redistribution into the other tissues accounts for the short sedative effect of these drugs. The liver is responsible for the metabolism of the barbiturates. Hepatic failure can markedly prolong their elimination. The barbiturates can produce apnea, coma, thrombophlebitis, paradoxical excitement, and dependence. In some cases, especially when pain is already present, the barbiturates lower the pain threshold, therefore they should not replace analgesics. It is prudent to give opioid agents, inhalational gases, or local anesthetics concomitantly with the barbiturates for the relief of pain. Methohexital is a commonly used ultrashort-acting barbiturate. It is given rectally to provide sedation for minor painless procedures and for helping small children separate from their parents prior to the performance of a procedure. When 25 to 30 mg/kg are given rectally, it induces sleep in 6 to 10 min.‘“8 Rectal sloughing, ulceration, and edema have been reportedly associated with higher concentrations (10%) of methohexital.“” A lower concentration (1.0% ) has been found to be as effective and to have similar pharmacokinetics; however, a larger volume must then be given to the patient.16’ Continuous intravenous infusion has been proven quick and effective in providing sedation.17’ Benzodiazepines Benzodiazepines are anxiolytics that produce antegrade amnesia, muscle relaxation, sedation, tolerance, and anticonvulsant activity.17’ They typically have a wide therapeutic index and produce little respiratory depression and hemodynamic alteration. The parent compound, 1,4-benzodiazepine, is substituted with a number of different adducts to produce the variety of different benzodiazepines; diazepam; lorazepam, and midazolam. Diazepam and midazolam have been administered intravenously, intramuscularly, orally, rectally, and intrathecally.““’ 17’ Diazepam, when injected intravenously, is very painful due to the carrier compound propylene glycol.J It has variable absorption when given rectally or intramuscularly. The benzodiazepines act centrally, possibly in the mammillary bodies,“J to produce anxiolytic activity, and in the spinal cord to produce muscle relaxation. Curr

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Midqolam.Midazolam (Versed), the newest benzodiazepine marketed, is a short-acting water soluble agent that is extensively metabolized by the liver and excreted in the urine.171 The metabolites of midazolam have little CNS activity, unlike those of diazepam. As is typical in all benzodiazepines, midazolam works at two different receptors, the benzodiazepine receptor and the glycine receptor. Binding at the glycine receptor is responsible for the anxiolytic effects of benzodiazepines. Binding at the benzodiazepine receptor enhances the binding of GABA at its own receptor through a coupling mechanism. GABA has sedative and anticonvulsant activity and benzodiazepines facilitate this activity. The binding of a benzodiazepine drug produces hyperpolarization of the nerve cell membranes and inhibits impulse transmission, culminating in sedation.17’ Onset of sedation after intramuscular and intravenous administration are 15 and 3 to 5 minutes, respectively. The peak sedation occurs at 30 to 60 minutes for intramuscular and 10 minutes for intravenous midazolam. Midazolam is used for short procedures to render the patient amnesic and cooperative. It has synergistic effects with opioids and should be carefully titrated to elicit the desired response and avoid any untoward reaction. If intravenous access has been established, the drug can be given as a continuous infusion to more precisely control and limit variability in drug plasma concentrations and to decrease recovery time after the procedure.176’ 177 There is little change in intracranial pressure with midazolam and it may be protective against cerebral ischemia. Cerebral blood flow and cerebral oxygen consumption are reduced after intravenous administration of midazolam. The hemodynamic perturbations caused by midazolam include reduction in blood pressure (diastolic greater than the systolic), a decrease in systemic vascular resistance, decreased filling pressures, and direct depression of myocardial contractility.171 A compensatory response to the decrease in blood pressure is an increase in heart rate. Midazolam inhibits the stress response by reducing the amount of circulating catecholamines.177 Respiratory depression is a significant side effect of midazolam administration. Apnea is dose related and dependent on the rate of administration.“l Other side effects of this drug include nausea, vomiting, pain on injection (this is much less frequent when compared to diazepam), and hallucinations. Flumazenil, a specific benzodiazepine antagonist that inhibits the central effects of midazolam and other benzodiazipine side effects mediated by the benzodiazepine receptor, awaits FDA approval. Ketamine Ketamine (Ketalar, Ketaject)1”4,‘7n has been a mainstay of physicians treating acute pain for many years. A dissociative anesthetic 4st!l

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agent, ketamine is structurally similar to phencyclidine (PCP) and has anesthetic, analgesic, and antegrade amnestic properties that make it a very popular drug for outpatient pediatric and emergency room use. Although administration of ketamine can cause nystagmus (vertical), myoclonic movements, copious secretions, and catalepsy, ketamine appears to be a safe, rapidly acting agent with minimal respiratory effects. It can be given intramuscularly, intravenously, orally, rectally, or nasally. It is frequently used in burn patients for wound care, in pediatric cardiac patients undergoing cardiac catheterization, and as a premedication for children prior to surgery. Ketamine’s high solubility in lipids is the principal reason for its rapid uptake by the brain. It has a rapid onset of action, but because of redistribution into highly perfused tissues such as the brain, lungs, liver, kidneys, and heart, a short duration of action is notable.17’ In addition, ketamine increases cerebral blood flow, thus delivering more drug to the CNS. The drug has limited protein binding, thus a reduced duration of action. Ketamine is metabolized by the P-450 microsomal enzyme system in the liver to an active metabolite, norketamine, and then several inactive forms of the compound that are excreted into the urine. Clearance of ketamine is dependent on hepatic blood flow and thus may be influenced by drugs like cimetidine that reduce hepatic blood flow and also inhibit the P-450 system.164 Diazepam appears to inhibit the hepatic breakdown of ketamine, leading to a prolonged half-life of the drug.“’ The elimination half-life of ketamine is 1 to 3 hours.164,178 In children, after an intramuscular injection of ketamine, the absorption is more rapid and a higher concentration of norketamine is created.l’* In the CNS, ketamine is thought to produce a dissociation between the thalamoneocortical and limbic systems.18’ Changes seen on EEG with this drug are quite profound; alpha wave activity is reduced and beta, delta, and theta wave activities are enhanced. Both auditory and visual evoke potentials are depressed by ketamine. Cerebral blood flowIS and intracranial pressure have been found to be increased by ketamine; thus, this drug is contraindicated in patients at risk for increased intracranial pressure. However, direct injection of ketamine into cerebral vessels does not dilate them as would be expected.la4 Ketamine appears to have local anesthetic properties, blocking nerve action potentials and eliciting sensory and motor blockade.“’ The direct effect on vascular resistance could be dose dependent as is the case for lidocaine.186 As mentioned previously, ketamine produces vivid dreams, hallucinations, and dissociation on emergence. Preprocedun? or postprocedure administration of a benzodiazepine reduces the incidence of these unpleasant experiences. When midazolam and diazCurr

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epam given as a bolus or as an infusion in conjunction with ketamine were compared, midazolam was superior to diazepam in reducing the psychic phenomena associated with ketamine.17” Ketamine does not appear to lower the seizure threshold.164 Additionally, ketamine has multiple’effects on the cardiovascular system. The direct effect on the myocardium by ketamine is depressant. However, the cardiovascular stimulation seen with this drug is associated with an increase in plasma catecholamine concentration. In adults, ketamine produces an increase in heart rate, cardiac output, blood pressure (systolic greater than diastolic), cardiac work, systemic vascular resistance, and stroke volume (early after its administration). However, many of these parameters return to normal preketamine levels. In premeditated infants breathing spontaneously or whose ventilation is controlled, ketamine has minimal effect on the pulmonary or systemic circulation.‘n8 The degree of respiratory depression associated with the opioids is not experienced with ketamine; however, episodes of apnea have been experienced. Bronchodilation following ketamine injection makes it an ideal drug for use in asthmatics. However, copious secretions encountered with ketamine administration can lead to laryngospasm and coughing. This can be prevented by pretreatment with an anticholinergic agent such as glycopyrrolate or atropine. Glycopyrrolate is a better choice as an antisialagogue since it does not cross the blood-brain barrier to the same extent as atropine, thus reducing its contribution to the possible delirium.lti4

Chloral Hydrate Chloral hydrate is a halogenated hydrocarbon with sedative properties and minimal analgesic property. It has been a mainstay of pediatricians for years. Chloral hydrate has a half-life of several minutes; however, its active metabolite trichloroethanol has a half-life of 4 to 14 hours. Chloral hydrate can be given orally or rectally, yet its absorption is variable. When given orally it should be diluted with a pleasant tasting diluent. The exact mechanism of action has not been fully delineated. This compound is rapidly metabolized by the liver to trichloroethanol and to the inactive agent trichloroacetic acid. Urinary excretion is the route of elimination from the body. Toxic effects of chloral hydrate include respiratory depression, hypotension, vomiting, hepatic failure, areflexia, jaundice, gastrointestinal hemorrhage, and esophageal stricture. Delirium, physical dependence, lack of reversibility, and arrhythmogenicity all contribute to the disadvantages of this drug. No significant respiratory depression is seen with low doses of this drug.

460

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ZNHALATZONAL Nitrous

ANESTHETICS

Oxide

Nitrous oxide is a potent analgesic agent that has been effectively used in settings outside of the operating room for a number of years. It can provide analgesia, sedation, and reduced anxiety in nonhypoxic concentrations. Nitrous oxide is especially useful for orthopedic procedures, wound care, bone marrow biopsies, and vaginal examinations. Administration of the inhalant should be supplemented with 50% to 70% oxygen to guard against delivering a hypoxic mixture of gas to the patient. Premixed tanks containing a 50 : 50 mixture of oxygen and nitrous oxide are available commercially (Entonox).4 When using nitrous oxide, the patient’s heart rate, blood pressure, respiration, and oxygen saturation should be monitored closely, and scavenging system, pop-off valve, and full resuscitative equipment should be available. Normally the patient can hold the mask and breathe the mixture. Supplemental sedation can be given to reduce the concentration of nitrous oxide needed. Patients can continue to communicate while having painful or anxiety-provoking procedures performed. Patients with full stomachs, pneumothoraces, small bowel obstruction, chronic lung disease, a history of nausea or vomiting, depressed mental status, or recent drug ingestion are not candidates for inhalational agents. More potent inhalational agents, such as enflurane, halothane, and isoflurane, are not to be used except under the supervision of an experienced anesthesiologist or anesthetist. ADJUNCTZVE

AGENTS

Nonsteroidal

Anti-inflammatory

Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are grouped with salicylates and acetaminophen as nonopioid analgesicsl’” and are generally used for mild to moderate pain. Only oral preparations are commercially available; however, parenteral agents have been utilized in clinical trials. The NSAIDs block the enzymatic conversion of arachidonic acid by cycle-oxygenase and lipoxygenase to prostaglandins and leukotrienes, respectively. Since both the prostaglandins and leukotrienes act at the peripheral nociceptors to lower the pain threshold and produce hyperalgesia,ls5 blocking their production reduces the amplification of the pain stimuli. There is additional evidence that the NSAIDs act centrally to inhibit prostaglandin synthesis and may enhance the effect of the opioids. Only a select number of NSAIDs inhibit both cycle-oxygenase and lipoxygenase, such as ketoprofen, meclofenamate, and benoxaprofen. Most of the NSAIDs inhibit cycle-oxygenase only, and thus are not as effective as Ihe dual inhibiting agents. Cum

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The use of these agents in treating acute pain is limited, since they do not directly block the action of prostaglandins or leukotrienes, but act to inhibit synthesis and release from endogenous stores. This results in a lag time between action and effect. It has been suggested that these agents be given preoperatively or prior to the initiation of a planned p’ainful procedure.185 However, because of the platelet dysfunction associated with these agents, prophylactic administration of these compounds should be performed with great care. Other adverse effects associated with NSAIDs include liver toxicity, water retention, hyperkalemia, increased blood pressure, renal dysfunction, and gastrointestinal hemorrhage. Stimulants Stimulants such as dextroamphetamine can provide several beneficial effects. They increase the analgesic effect of opioids, decrease the respiratory depression associated with opioids, minimize the opioid-induced nausea, and provide a modicum of euphoria while decreasing the level of sedation occasioned by opioids.lgO When given in the morning the patient’s wake/sleep cycle is minimally disturbed. Patients with chronic pain, such as sickle cell anemia, hemophilia, and cancer, are often treated with opioids and commonly complain of being too sedated. The addition of 5 to 10 mg or 0.1 to 0.2 mg/kg PO of dextroamphetamine will alleviate this problem. Anticonvulsants Anticonvulsants such as carbamazepine, phenytoin, and clonazepam have been useful in treating pain of a neuropathic origin, such as trigeminal neuralgia. The exact mechanism of action is unknown; however, the anticonvulsants are thought to act by inhibiting peripheral nerve impulses and suppressing their excitability. In addition they may interfere with GABA metabolism.1s1 Antidepressants Agents such as amitriptylene and imipramine appear to be useful in the treatment of chronic pain syndromes. They not only relieve depression associated with the disease but they also have a direct analgesic action mediated by the blockage of the re-uptake of serotonin and norepinephrine. They to enhance the efficacy of opioids. REGIONAL AND LOCAL BLOCKADE Neural blockade with local anesthetics given intrathecally, epidurally, or locally for pain has a myriad of favorable effects. These benefits include a reduction in the hormonal stress response, which is three to five times greater in neonates when compared to adults, 462

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and a reduction in the number of postoperative complications seen in infants .16’ Neural blockade with local anesthetics has been enormously useful in some situations in providing acute and long-term analgesia. Its duration can be extended with the use of indwelling catheters placed near the nerves blocked. Used alone or in conjunction with intravenous agents, regional anesthesia can result in a more comfortable patient. The purpose of this section is to inform the reader about the diverse variety of local and regional anesthetic techniques available, which are not just the province of the anesthesiologists. It has come to our attention that these methods are typically found in anesthesiology but not in pediatric texts. Thus, pediatricians rarely think of these methods and therefore rarely use them in children’s pain management. These analgesic methods provide a good example of how the anesthesiology consultant can be of help in pediatric care outside of the operating room. For the motivated and interested pediatrician, a close working relationship with an anesthesiology colleague can provide the opportunity for the pediatrician to learn how to perform some of these techniques. Local anesthetics block nerve impulse propagation by altering sodium channel function on the nerve cell membrane.lg2 By their actions local anesthetics do not alter the resting membrane potential or the threshold potential of the nerve cell. They are thought to inhibit the propagation of the action potential by interfering with the Na+ conductance through channels in the nerve cell membrane. Local anesthetics are classified as esters or amides based on their chemical composition. Procaine, tetracaine, and chloroprocaine are esters; prilocaine, lidocaine, mepivacaine, bupivacaine, and etidocaine are amides. Esters are rapidly degraded by plasma pseudocholinesterases; liver enzymes have only a minor role. The amount of esterase activity in the plasma will vary with age, nutritional state, and clinical condition. Esterase activity increases during the first year of life and is reduced by significant hepatocellular disease.lg3 The allergic potential of the esters is increased by the elaboration of para-aminobenzoic acid (PABA) as a degradation product. PABA is allergenic in a small number of individuals. The amides undergo biotransformation, N-dealkylation, and hydroxylation by hepatic microsomal enzymes. By-products of amide metabolism are excreted ‘in the urine. It is important to note that prilocaine degradation products can cause methemoglobinemia in younger children; thus, its use is limited. There are very rare reports of allergic reactions directly attributable to the metabolism of amide agents. The systemic absorption, tissue deposition, metabolism, and drug excretion of local anesthetics is determined by a number of factors .lS4 A large vascular supply and high blood flow in the vicinity of C’urr

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the deposition will lead to greater systemic absorption and an increased potential for toxic side effects (intercostal nerve block + caudal + epidural space + brachial plexus + femoral nerve and sciatic nerve sites + subcutaneous tissue). Addition of vasoconstrictors, such as epinephrine, to the local anesthetic impedes vascular absorption. However, it is important to note that local anesthetics with vasoconstrictors added to the solution should not be used on tissues where end arterials supply the blood (e.g., dorsal penile block). Local anesthetics are commercially available in the form of salt solutions. The salts are composed of positively charged (cation) and uncharged (base) molecules. The ratio of the charged to uncharged species is dependent upon the pH of the solution. Increasing the pH of the solution shifts the equilibrium toward the uncharged free base species. The amount of uncharged form that is present will determine the onset of anesthesia, since this is the form that traverses the nerve cell membrane. The addition of bicarbonate to local anesthetic solutions to decrease the time of onset of anesthesia has gained popularity recently. The lipid solubility of a local anesthetic directly correlates with its anesthetic potency. Plasma protein binding correlates with drug lipid solubility and limits the availability of active drug. However, membrane proteins binding the drug will retard its diifusion away from the membrane and therefore lead to a prolonged duration of action. Albumin is one of the major plasma proteins binding local anesthetics. It has a low affinity for local anesthetics, but a high capacity to bind them. Orosomucoid or alpha-1-glycoprotein appears to be another major plasma protein that binds local anesthetics. Alpha-l-glycoprotein has a high affinity, but low capacity for local anesthetics. Competitive binding from protein-bound drugs such as pentobarbital, phenobarbital, or biological degradation products, like bilirubin, can displace local anesthetics from their binding sites and result in toxic levels of the anesthetics. Neonates have lower concentrations of plasma proteins; thus, more free drug may be available when local anesthetics are used in this group.lg5 In addition, the amount of myelination of the neural fibers could have a role in the duration of blockade. The higher hepatic blood flow, greater cardiac output, and increased volume of distribution at steady state may offset the factors such as an increased terminal elimination half-life and lower plasma protein content that would predispose the child to a higher systemic concentration of agent. The systemic side effects of local anesthetics are confined mainly to the cardiovascular system and the CNS.lg6 Cardiovascular side effects from toxic levels of local anesthetics include hypotension from vasodilation, decreased myocardial contractility, decreased cardiac output, and conduction abnormalities. Central nervous system ef464

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fects are related to the potency of the drug. The greatest side effects are seen with bupivacaine and tetracaine, the most potent drugs. A progression from lightheadedness, with minor auditory and visual disturbances, to convulsions is seen with toxic doses. The CNS side effects appear to be secondary to the progressive neural blockade of the central neural impulse transmission. As with any other class of drugs, careful selection and administration will limit the number of untoward events related to the use of local anesthetics. Although there are a number of differences between adults and children in the manner in which local anesthetics are processed, this does not preclude the safe use of these agents for postoperative relief in children.

Management Regional anesthesia for postoperative pain relief has enjoyed a resurgence in the last several years.‘Y7 Application of regional anesthetic techniques has moved from the realm of the operating room to utilization in other areas of the hospital. This is exemplified by the use of epidural catheters and caudal anesthesia for the management of pain in intensive care units. For example, children with extensive burns, meningococcal purpura fulminans, and Kawasaki’s disease need frequent, painful bandage changes for skin care. EpidUral catheters placed for the management of their pain have met with great success.1s8 Selection of appropriate patients, drugs, and types of regional blocks must be made carefully. This will be based on the patient’s age, disease or site of surgical operation, clinical status, past anesthetic experience and skill of the person performing the block, duration of postoperative pain relief desired, and accessibility of equipment and personnel available to assist in monitoring the patient in the recovery room and on the floor. Contraindications to regional nerve blocks are listed in Table 7. A list of the types of regional techniques that are useful for children can be found in Table 8. Choice of the local anesthetics will depend on the duration of blockade required and the toxicity of the agent (Table 9).

Monitoring Monitoring the patient’s vital signs should precede any type of regional technique. This should include heart rate, respiratory rate, temperature, blood pressure, and pulse oximetry, if available. It is helpful for a pediatric unit to own at least one pulse oximeter, since this method of monitoring oxygenation will permit the most effective analgesia. Resuscitation equipment should be examined and readily available in case of untoward events. Intravenous access should be established to provide sedation, hydration, and a route for resuscitaCurr

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TABLE

7.

Contraindications

to Regional

Anesthesia

Absolute

Relative

No parental consent Infection at the site of needle

insertion

Absence of seizure control Sensitivity to local anesthetic agents Hypovolemiasevere Difficult airwaydepends on assessed risk, i.e., is the airway manageable by any means such as masking Coagulopathy Anatomical abnormalities at site of injection; i.e., fistula Presence of degenerative neumlogic disease-confusion over exacerbation of disease should be avoided Absence of adequate monitoring devices 01 personnel to attend patient

tive drugs. Knowledge of bony and vascular landmarks is mandatory for the safe and effective performance of these techniques.

Techniques7’

*s’J200

The use of a local anesthetic to infiltrate the skin can provide relief of pain from surgical incisions, wound debridements, and instrumentation of orifices. Toxicity is not usually a problem if one adheres to the safe limits in the amount of drug infiltrated. Bupivacaine is generally used at our institution because of its long duration. The amount used is usually 1 ml/kg of 0.25% bupivacaine or 0.5 TABLE

8.

Regional

Anesthetic

‘Techniaues

Technique

Indication

Local infiltration Brachial plexus block Selective ulnar or radial Wrist/digital Intercostal Caudal IlioinguinalAliohypogastric Femoral/lateral femoral block Ankle block Bier block Epidural

Incisional pain, wound care Upper extremity fracture Fracture, incisional pain Fracture, incisional repair Thoracotomy, rib fracture Inguinal hernia, orthopedic pmblems Inguinal hernia Orthopedic problems, lacerations, femoral fracture Post orthopedic repair, fracture Extremity fractures, wound care Incisional pain, thoracic or abdominal; wound care from burns, exfoliation, or amputation

466

nerve

blocks

nerve cutaneous

block nerve

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TABLE Local

9. Anesthetic

Drua

Dosages

for Pediatric

Twe Tetracaine Chloroprocaine Procaine Lidocaine Bupivacaine Mepivacaine Etidocaine

Patients* No Epinephrine

Epinephrine

Ester Ester Ester Amide Amide Amide Amide

(1.5 mgkgl 110 mg/kg) mgkg) mg/kgi (7 mgkg) (3-4 mgfkgJ (7-10 12.5-3

‘AdvantaBes.-Selectively actiwbupivacaine has mom sensory blockade than motor blockade, tetracaine has mom motor blockade than sensory blockade; multiple delivery mutes; patient can remain awake and vocalizes-verbal contact with patient is best monitor for presence of any untoward reactions; no respiratory depression. Disadvantages.-Not reversible; side effects depend on drug and its physiocochemical characteristics-esters have allergic potential due to PABA derivative; neumtoxicity/cardiotoxicity; contraindicated in patients with neumdegenerative disease/infection at site of injection/coagulopathy lepidural or subarachnoid injectionl. Adapted from references 197 and 199.

ml/kg of 0.5% bupivacaine.’ This is based on an upper limit of dosing of 2.5 to 3.0 mg/kg. Lidocaine in solution or as jelly is very useful. The solution can be given for nerve blocks, gingivostomatitis, and wound care. The jelly, which comes as a 2% concentration, is used in conjunction with urethral instrumentation. The amount used should be based on the patient’s weight and the maximum recommended dose for lidocaine. A reduction in the amount of drug used in premature infants or children with hyperbilirubinemia is prudent, since more free drug may be available in the systems of these children. Tetracaine in combination with adrenalin and cocaine (TAC) has been used topically for laceration repair or cleansing an abrasion. TAC is a combination of 0.5% tetracaine, 1 :ZOO,OOOadrenalin, and 11.8% cocaine all dissolved to 5 ml with normal saline. The toxicity of the solution is related to its components. Cocaine is a ,CNS stimulant with chronotropic properties. Adrenalin also increases the heart rate and causes vasoconstriction. The toxicity of the local anesthetics has been previously discussed. A brachial plexus block is recommended for emergency procedures involving the upper extremity and for postoperative pain relief. A Bier block, which involves injecting local anesthetic into the veins of an extravasated limb to provide neural blockade, is useful for distal extremity procedures. While prilocaine is an agent commonly used for this block in adults, it is not recommended for use in children because of its ability to be metabolized to methemoglobin as a byproduct. Wrist and digital nerve blocks require minimum *A 1% solution pivacaine contains cwkg

will

he: the

Curr

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contains 2.5 m#w maximum August

lOmg/cc of material. ‘Therefore, of solution Since the maximum

a 0.25% dose

solution is 2.5 rntikg,

of bu1

dose.

1990

467

amounts of anesthetic agents and are useful for hand/finger procedures. Pain resulting from thoracotomies, rib fractures, pleurocentesis, chest tube placement, and upper abdominal surgical procedures can be alleviated with intercostal blocks. A significant improvement in pulmonary function (arterial oxygenation and the ratio of force expired volume in 1 second to hnctional residual capacity) after trauma or surgery, is seen with intercostal blocks when compared to parenteral opioids. Early ambulation can also be achieved with this technique. As an alternative to the individual rib blocks, an intrapleural catheter can be placed. Caudal blocks are used for urological and anorectal procedures, and sacral/lower extremity procedures or persistent pain (e.g., tumors). They can be performed as a single injection of local anesthetic or a catheter can be inserted into this space, permitting continuous neural blockade. The catheter can be placed anywhere along the vertebral column and fed up or down to a desired level. Use of continuous infusion or intermittent boluses of local anesthetic or opioids will depend on the type of pain and type of monitoring available. Caudal or lumbar epidural opioids used separately include morphine (0.08 to 0.1 mg/kg every 10 to 24 hours), hydromorphone (0.02 mg/kg every 8 to 16 hours), and fentanyl (0.6 to 1 pg/kg every 4-6 hours). Fentanyl with its higher lipid solubility may be ideal for blocking segmental areas. Respiratory depression is always a consideration, so the patient’s respiratory status should be monitored. Blockade can be substantially prolonged when opioids and local anesthetic are used in combination. This method of pain relief should be considered an option for children with prolonged (actual or expected) sacral or bilateral lower extremity pain (e.g., tumor, orthopedic injury, severe burn, etc.). For blocking a single extremity, femoral nerve and lateral femoral cutaneous blocks can be performed. They are particularly useful for children with fractures of the midshaft or lower third of the femur, and for muscle biopsies. Topical application of local anesthetic, ring blocks, or a dorsal penile block provides postoperative analgesia for circumcisions or hypospadias repair. Most pediatricians can easily learn these techniques with help of an anesthesia colleague. Doses for the anesthetic range from 1 to 5 ml of 0.25% bupivacaine. Vasoconstricting solutions should never be used since they can result in significant tissue ischemia.

TRANSCU’IANEOLIS

ELECTRICAL

Transcutaneous electrical peripheral nerve stimulators 468

NERVE

STIMULATION

nerve stimulation (TENS) units are small that appear to have some efficacy in the Cum

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treatment of acute and chronic painzol The goal is to stimulate large nerve fibers by the unit to suppress the firing of small pain fibers. The units are inconspicuous and can be adjusted to provide optimal pain relief. They are quite safe and require little maintenance. Patients with pacemakers should not use these units. For patients with focal pains, TENS units can be tried prior to the initiation of pharmacologic agents.

PATIENT-CONTROLLED

ANALGESIA

Administration of analgesics can and has occurred through multiple routes: oral, intramuscular, epidural, intrathecal, rectal, and transdermal. Each route has its advantages and disadvantages. Recently, patient-controlled analgesia (PCAI devices have been used in the pediatric patient population for postoperative pain relief. Although these devices have been available since the 1960s,“02 microprocessing technologv has recently allowed for the development of portable, reliable, user-friendly units. The efficacy of PCA devices stems from their ability to maintain a constant blood concentration of analgesic, allow the patient to individualize analgesic administration according to need, and to provide around-the-clock dosing (Fig the pain/analgesia cycle.“04 I)).zo:i These devices help to interrupt Conventional PRN therapy fails in an abysmal manner to address the individual analgesic requirements of patients. Reasons for this in-

FIG 8. Comparison of tntramuscular rrqectron vs. PCA for parn control. Theoretical relatronshtp between analgesic drug concentratron, dosrng Interval, and clinical response for PCA (dashed I/ne) and Intramuscular oprord (solid i/nej. Arrows pornting downward represent admrnistratron of patrent-controlled or intramuscular oprord doses (From Ferrante FM, Orav EJ, Rocco AG, et al A statistical model for parn in patient controlled analgesra and conventronal Intramuscular opiord regrmens Anesth Am/g 1988: 67 457-461 Used by permrssron ) Cur-r Probl

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dude a lack of knowledge about pharmacokinetic prineipIes governing drug distribution, utilization, and metabolism; the rehtctance of hospital personnel to administer the correct amount of anaI@c ordered in a timely fashion; and a Iimited understanding of the phenomenon of addictionP4 Children retiving intramuscular injections are reIuctant to ask for pain medication and are subject to overdosing ar underdosing once they receive their medication. Patients not able to communicate their discomfort must wait for a sympathetic perceptive soul to rescue them from their suffering. Continuous drug infusion devices eliminate many of these prohIerns. h-r a number of studies, PCA has been found to be effective in children,zQ5 shurten patients’ hospital stay,z06 lead to earlier patient mobilization, and decrease overall opioid use. All of these advantages in combination wouId probabIy resuIt in a reduction in haspitat costs. The newer devices in use have the options of the continuous administration of Iow Ievels of analgesia as well as the ability to deIiver small boluses as needed. The cost of the devices may be prohibitive and their use requires some sophistication on the part of the patient. However, reports of PCA use in patients as young as 8 years of age can be found (Charles Berde, personal communication). Strict guidelines for monitoring, patient selection, drug administration, and lockout periods should be instituted prior to starting a PCA program. Personnel should be availabIe at all times to address any problems or to adjust the rate of infusion. After an initial loading, dose of 0.05 to 0-1 mg/kg of morphine ondemand bolusing can begin at 0.01 to 0.03 mg/kg with a lock-out period of 10 to 1.5 minutes. The basal infusion rate is started at 0.01 mg/ kg&r during, the evening hours and with one third to one half the hourly demand bolus rate during the day. Patients typically wean themselues from PCA.

CHRONZC PAZN Ry convention, chronic pain is that which lasts beyond the normal time for recovery. Its effect on the patient is often exaggerated and poses a difficuIt diagnostic and management challenge tbr the physician. Medical and/or surgical therapies that deal with chronic pain as if it were an organic disturbance isolated from environmental and psychoIogical factors are usually unsuccessful. Regardless. of the initiaI medical/anatomic reason for the pain, chronic or recurrent pain typica& involves altered patferns of healing, abnormal pain transmission pathways, or chronic ischemia. Common problems in pediatrics associated with chronic pain are sickle cell anemia, arthritis, headaches, hemophilia, chronic bowel disease, recurrent abdominal pain syndrome, cancer, and trauma leading to reflex sympathetic 47a

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dystrophy or causatgia. Somatic pain can lead to chronic pain syndromes and abnormal behavior. Alternatively, psychological distress can exacerbate known disease-initiated pain. Pediatric chronic pain, unlike chronic pain problems in adults, typically is related to persistent (e.g., postoperative pain, inflammatory bowel disease) or recurrent Ie.g., sickle cell disease) pain. Modalities for treatment of chronic pain include, individually or in combination, depending on the type of pain problem, psychological counseling, physical therapy aimed at regaining function, nerve blocks, medications {including antidepressants given to alter the pain threshold and not necessarily for depression per se, NSAIDs, muscle relaxants, etc.), TEN,S, and limited surgical intervention. A multidisciplinary approach to the problems of the pediatric patient with true chronic pain appears to offer the best opportunity for success. Ideally, a team of consultants would work with the patient to tailor an individualized treatment plan. The team should include a pediatrician, ,anesthesiologist, psychologist, nurse specialist, physical therapist, neurologist, and surgeon and/or oncologist working together to ensure that the most comprehensive and rational approach is instituted.

PHARMACOLOGIC

TREATMENT

SUMMARY

A critical evaluation and integrated approach to the treatment of pediatric pain has only recently begun, and education about the physiological, behavioral, and biochemical differences related to pain in the pediatric population is now instituted in some medical schools and pediatric training programs. Children deserve special consideration in pain management since they may not be able to verbalize their discomfort, may not be capable of comprehending the need for painful procedures, and may not have learned strategies to cope with them. Many of the local and regional techniques discussed earlier can easily be performed by an interested pediatrician. In addition, several pain management centers involved with acute and chronic pain have been established throughout the country.“” These Enters, our centers (UCLA and University of Connecticut), and the local pediatric anesthesiologist, can be utilized as resources. The control of pain alleviates suffering and reduces stress, and decreases morbidity, mortality, and the likelihood of developing a chronic pain syndrome. THE DPT COCKTAIL The DPT “cocktail” is also known as the cardiac catheterization cocktail, 1.ytic cocktail, CM3, MPC, and Demerol compound. It was Cum

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developed by Smith and colleagues in 19.58 to provide sedation and analgesia during cardiac catheterizations.“07 Since that time, the scope of its usage has broadened appreciably and it is now the most commonly used preparation for premeditation in children prior to painful procedures (e.g., debridement, fracture reduction, abscess drainage, bone marrow aspiration, endoscopy, etc.). In addition, it is frequently used to provide sedation in painless procedures that require the child’s compliance, such as computed tomography (CT) scans and magnetic resonance imaging. Over the past few years, questions about its safety and efficacy have arisen. We review available data on the DPI cocktail in an attempt to help the clinician evaluate the appropriateness of this drug combination for present day pediatric practice. The DPT cocktail has three ingredients: meperidine, a synthetic opioid, and two phenothiazine derivatives, promethazine and chlorpromazine. Theoretically, the meperidine provides analgesia and some sedation while the phenothiazines deepen and lengthen the sedation and provide antiemetic benefits.“‘” However, this fixed combination also has potential problems. Sedation may be lengthened to an excessive amount (average of 7 hours),20s possibly by alteration of meperidine metabolism. Chlorpromazine and promethazine both increase the respiratory depression associated with meperidine. The hypotension produced by chlorpromazine is also magnified by this combination. In addition, while meperidine provides analgesia, promethazine has been, in fact, found to be antianalgesic.zlo The solution is administered as a deep intramuscular injection. Various ratios among the drugs have been developed but the most commonly used appears to be 25 mg of meperidine, 6.25 mg of promethazine, and 6.25 mg of chlorpromazine in 1 cc of the mixture. It is then administered at a dose of 0.1 ml/kg of body weight21’ Studies that have examined the efficacy of the DFT cocktail for specific procedures reveal a relatively high failure rate. For example, failure rates of 14% to 28%“” ‘I2 have been reported for CT scans and 7% for cardiac catheterizations.213 Figueroa-Colon in a randomized study of the success of various premeditation regimens for endoscopy found that 83% of children in the DPT group required supplemental diazepam to complete the procedure.‘14 In contrast, Terndrup and colleaguesz15 recently reported the results of a large retrospective study of DIYT usage in the emergency department. They found that efficacy (as defined by patients who did not require a second injection to perform the procedure) was excellent, approximately 98%. However, their clinical impression was that the failure was much higher and that their methodology was not sensitive enough to identify it. Numerous side effects have been associated with the DPT cocktail. The most significant are respirator?/ depression and arrest. This oc472

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curred in 3% of Nahata’s study population,216 4% of Mitchell’s,‘17 and 0.6% of Smith’s.‘07 Hypotension, agitation, and prolonged lethargy were additional problems. Seizures have been reported in adults in whom the DR has been administered.‘l’ In addition, the DPT cocktail is administered through intramuscular injection. Not only is the injection itself painful, but recently, a soft tissue pseudotumor has been reported at the site of a DPT injection given prior to magnetic resonance imaging.‘l’ Other problems are potentially associated with the DPT cocktail. Because it involves mixing three drugs into a single solution, the potential for error is compounded. In addition, in one report DPT was interpreted as diphtheria-pertussistetanus instead of Demerol-Phenergan-Thorazine, a rather unsuccessful substitution.2Z0 Finally, the term “cocktail” is misleading and can lead to oral rather than intramuscular administration.2z1 In all, although the studies vary, the DPT cocktail appears to have a complication rate of approximately 13% .‘17 A number of pharmacologic and psychological alternatives to the DPT exist at the present time and more may be available in the near future. Some of these alternatives require the presence of an anesthesiologist, such as the use of general anesthesia for painful procedures. Another approach is the pairing of an opioid with a benzodiazepine. The short-acting benzodiazepine, midazolam, has been used independentlyz”” or paired with fentanyl, a short-acting opioid. These can be administered intravenously, or an oral benzodiazepine can be given while an intravenous opioid is given during the procedures.“‘” Brzustowiczzz4 has reported the use of oral meperidine, diazepam, and atropine for premeditation prior to surgery. Toxicity of opioids and benzodiazepines used in combination can be avoided by careful monitoring. However, toxicity of opioids is reversible with naloxone and that of the benzodiazepines is reversible with Flumazenil,‘“” a benzodiazepine antagonist that will eventually be commercially available. The DPT cocktail has been used for over 30 years to provide analgesia and sedation during pediatric procedures. Although many believe it has been adequate for these purposes, it appears that its longevity has resulted more from a lack of interest in developing alternatives rather than from the benefits of the combination itself. As a combination, it makes limited pharmacologic sense because it contains two phenothiazines. Its efficacy is variable and it is associated with a high incidence of side effects. Lethargy is often prolonged following its administration, thus limiting its usefulness in outpatient settings. It requires an intramuscular injection and is complicated to compound. Although the effects of meperidine are reversible, the effects of the phenothiaxines are not. Alternatives are available to the I)fyI‘ cocktail at the present time. Some require the prcscncc of an Curr

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anesthesiologist, but most do not. Research is badly needed to identify safe and effective oral or intravenous agents to ameliorate painful procedures in children. FUTURE

DIREX’I’IONS

This monograph is intended to provide an overview of the salient issues related to pain in infants, children, and adolescents. New events are highlighted, such as the developing interest in neonatal and infant pain. Similarly, relatively older issues, such as the psychological and pharmacologic treatment of pain, are reviewed. Particular aspects of pharmacologic treatment, such as local and regional anesthesia, are included in some detail to inform pediatricians about their potential usefulness and availability. We encourage pediatricians to consult their anesthesiology colleagues for help in managing a variety of pain problems. Often, the anesthesiologist is reiegated to the operating room. It is our contention that professionals in these two disciplines can learn from each other. In addition to reviewing the developmental nature of pain, and the assessment and treatment of pain, this monograph is intended to heighten readers’ awareness of suffering in children. Although much has been learned about pediatric pain during the past 5 to 7 years, the largest stumbling block to reducing the suffering of our child patients seems to be failure to apply what has been learned. Also, the cost of pediatric pain needs to be evaluated, in terms of increased hospital stay, increased medical morbidity, and reduced functional status. Research in pediatric pain is still in its infancy. There are crucial issues yet to be worked out. One of the most important is how to individualize the treatment of pain. We need to understand more about children% physiological, hormonal, and behavioral responses to nociceptive stimuli, especially from a developmental perspective. How does neural organization mediate the pain experience? Specifically, how does maturation of affective and cognitive systems influence the affective, sensory, and motivational aspects of pain? Studies relating to infant temperament have suggested individual differences in children’s pain threshold, magnitude of physiologic response, and recovery. It is likely that these differences are genetically driven and biologically mediated. However, transactional studies of the child and his/her primary caregiver indicate that the environment also influences the child’s responses and self-regulatory abilities. For example, infants who grow up without a secure, trusting relationship with their primary caregiver may respond diierently to painful hospital situations than a securely attached child, especially in terms of duration of distress in relation to each nociceptive event. As 474

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children mature, their behaviors are shaped to some extent not only by their parents but also by their siblings, community, and the cultural group to which they belong- Thus, the way in which familial, community, and cultural factors influence pain perception and behavioral responses to pain warrants investigation. Additionally, differences in receptor availabilities and binding capacities may likewise be responsible for the variance seen in children’s responses to different analgesic agents. Research might focus on the development of drugs with specific pain receptor-binding properties, such as clonidine tan alpha-2 agent), since these drugs would be expected to have fewer side effects. Also, new uses for older drugs might be considered, such as the preoperative use of NSAIDs, especially if newer agents could be developed that do not affect platelet function. Better drug delivery systems need to be developed to make analgesia administration more tolerable to the child and more easily given by medical staff (i.e., without the need for intramuscular OF intravenous “injections”). In this regard, transdermal medications warrant study (e.g., transdermal fentanyl). The drug delivery system of the future might be computerized so that a patient is connected to a “pain sensor” that is able to discriminate different components of pain (anxiety, sensory, depressive, etc.). In turn, the “pain sensor” would be connected to a delivery pump that would deliver the appropriate type-specific medication (e.g., midazolam to reduce catecholamines if anxiety is a large component, an opioid for sensory predominance, etc.). We also need to learn more about children’s natural coping styles and how parents and health care providers can enhance their effectiveness. In this regard, laboratory pain paradigms would be useful in learning about the development of “pain tolerance” and “pain sensitivity.“226, 227 The impact of pain on the functioning of other biologic systems would give further fuel to the developing field of psychoneuroimmunology. Does pain impact disease status? Finally, we also need to know more about pain in nonclinical populations. Why do some children with recurrent abdominal pain present themselves for medical attention, while others apparently experience these symptoms without their physician’s knowledge? What is the spectrum of headache pain? Is severity the salient factor deserving medical attention or are there other more important factors that need to be addressed? This is a crucial question since lack of attention to these “other” factors might explain “treatment failures.’ It is our hope that readers will notice their patients’ behaviors a little more closely, think about the extent of their private suffering, and become more willing to offer aggressive and knowledgeable pediatric pain management. Cm-r

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ACKNOWL.EDGMENT

We wish to thank Maria Gonzalez, Lynn Weber, Saundra Collins, and Virginia E. Williams II for assistance in preparing this manuscript. This effort was supported in part by the W.T. Grant Foundation Faculty Scholars Award (L.Z.), and a Research Career Development Award (1 K04CA1268-03) to L.Z. REFERENCES

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