1/31/2018

1

Pediatric Pain and the Developing Brain

Jessica K. Goeller, DO

Assistant Professor, Anesthesiology, UNMC

Director, Acute Pain Service

Children’s Hospital and Medical Center, Omaha NE

2

Disclosures

• Consultant/Speakers Bureaus—No disclosures

• Research Funding—No disclosures

• Stock ownership/Corporate boards-employment—No

disclosures

• Off-label uses: almost all medications used in the pediatric population are ‘off label’. I will be discussing many medications

not-FDA approved for use in pediatrics or for the purpose it is

described.

Objectives

• Describe the history of pain perception in neonates

• Examine the impact of pain on the developing brain as well as

the long-term sequelae of frequent pain exposure

• Discuss the current literature as it pertains to pediatric pain and the effects on the developing brain

Do neonates feel pain?

History of Pain Perception

• What is the definition of pain?1

– ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage’

– ‘always subjective, each individual learns the application of the word through experiences related to injury in early life’

– 19th century America: ‘…the very young lack the mental capacity to suffer’

• Consciousness

– Noun: Awareness of the mind of itself and the world; perception of one’s surroundings; state of being awake and aware.

1International Association for the Study of Pain (IASP) Committee on Taxonomy (1997)

1/31/2018

2

Pain and Consciousness

• Impressions stored in the mind are obtained from the five

senses (Aristotle)

• Evolution and pain

• Typical pain behaviors

• Evoked by stimuli that threaten their integrity or survival

• Recognize/respond to pain in others with compassionate tending behaviors

Evolution and Consciousness

• Do neonates and animals experience pain?

• Is consciousness developed or inherent

• Conscious experiences of different lifeforms

• CNS evolution to progressively increased complexity from

earlier life forms to the human

• Genetic and social evolution

– New Yorker vs Neanderthal

When can a human being first feel pain?

1. During birth (any gestational age)

2. Infancy ( 1 – 12 month old)

3. Third trimester fetus ( > 26 weeks)

4. Preterm neonate (24-36 weeks gestational age)

5. Term neonate ( > 37 weeks at birth)

6. Once able to verbalize discomfort

Consciousness in the term neonate

• Awareness, perception, discrimination at birth

• Active regulation of behavioral states to maintain optimal level of stimulation

• Dynamic interactive process of the neonate and its caregiver and environment

• Numerous studies support extraordinary capacity for infant memory

– Positive effect� memory retrieval

– Negative effect � memory storage but impeded retrieval

• Important implications for memories of early painful experiences

Consciousness in the preterm neonate

• When does consciousness develop?

• Neuronal activation at birth

• All preterm infants (24-36 weeks gestation) will actively

approach and favor developmentally supportive experiences and avoid disruptive ones

• Support energy conservation, organization of sleep-wake

cycles, and achievement of age-related developmental

milestones

Consciousness in the fetus

• Fetal sentience

• Political, medical, legal, philosophical studies

• Consciousness associated with shifting patterns of activity of the

cerebral cortex

• Impossible to obtain unequivocal evidence

1/31/2018

3

Does a neonate with congenital defects experience pain?

Do neonates experience pain?

Until 1985, the nervous system of the neonate was widely considered to

be underdeveloped for pain sensation. Owens, M. and Todt, E. (1984) Pain in infancy: neonatal reaction to a

heel lance, Pain, 20 (1), 77–86.

Surgical procedures would be performed with paralytic and no analgesic. Cote, C., Lerman, J. and Todres, D. (2009) A Practice of Anaesthesia for Infants and Children, 4th edn. Saunders Elsevier, Philadelphia, PA.

1985, Anand, et al. observation of pain-induced responses and death due

to endocrine shock during neonatal surgery, emphasizing the importance of anaesthesia. Anand, K., Brown, M., Causon, R. et al. (1985) Can the human neonate mount an endocrine

and metabolic response to surgery? Journal of Pediatric Surgery, 20 (1), 41–48.

14

When do neonates experience pain? Nociception

• Reflex movement in response to a noxious stimulus, without

cortical involvement or conscious pain perception.

• Nociception involves peripheral sensory receptors whose afferent fibers synapse in the spinal cord on interneurons, which

synapse on motor neurons that also reside in the spinal cord.

• These motor neurons trigger muscle contraction, causing limb

flexion away from a stimulus

Lee SJ, Ralston HJP, Drey EA, Partridge JC, Rosen MA. Fetal Pain: A Systematic Multidisciplinary Review of the Evidence. JAMA. 2005;294(8):947

Pain Perception

• Cortical recognition of the stimulus as unpleasant.

• Peripheral sensory receptor afferents synapse on spinal cord neurons, the axons of which project to the thalamus, which sends afferents to the cerebral cortex, activating any number of cortical regions.

• Sensory receptors and spinal cord synapses required for nociception develop earlier than the thalamocortical pathways required for conscious perception of pain.

Lee SJ, Ralston HJP, Drey EA, Partridge JC, Rosen MA. Fetal Pain: A Systematic Multidisciplinary Review of the Evidence. JAMA. 2005;294(8):947–954.

How was pediatric pain treated?

• Pain was undertreated, or not treated at all

• Pediatric patients were a conundrum as they aren’t ‘little adults’

and pharmacokinetics and pharmacodynamics vary greatly during development

• Medications trialed and approved by FDA for adults, off label

use for children

– Limited studies on most medications

18

1/31/2018

4

What types of clinical interactions cause discomfort?

1. Physical therapy

2. Repositioning during cares

3. Vital signs

4. Lab draws

5. Intravenous access

6. Monitoring cords laying over nerves

Development: Fetal Pain Pathways

1/31/2018 20

Development: Fetal Pain Pathways

From the periphery to the thalamus:

•6 weeks: dorsal horn cells in spinal cord have synapses with

developing sensory neurons (8-10 weeks, Substance P in dorsal horn)

•11 weeks: sensory neurons in skin (12 weeks, myelination spinal

cord)

•15 weeks: sensory neurons in trunk

•20 weeks: remaining cutaneous and mucosal surfaces

Term fetuses have the same or higher density of nociceptive nerve

endings in the skin

Development: Fetal Pain Pathways

The Subplate Zone (11 weeks, peak 22-34 weeks, gone at 6 mo)

•Zone in cortex where afferent thalamic fibers gather during cortical target area selection

•Synaptic activity facilitates and refines connections between thalamus (crucial for pain experience) and cortex � key areas in experience of pain in adults

•Third trimester: direct thalamocortical fibers

Judaš, M., Kostović, I., Sedmak, G., & Vukšić, M. (2015).

The relevance of human fetal subplate zone for developmental neuropathology of neuronal migration disorders and cortical dysplasia.

CNS neuroscience & therapeutics, 21 2, 74-82.

Development: Fetal Pain Pathways

Thalamocortical fibers

•23-30 weeks: direct fibers emerge

•24-32 weeks: frontal, somatosensory, visual and auditory cortex, deep cortical plate

1/31/2018

5

Brain Development

• Cerebral cortex: 8-10 weeks

– Few axonal/dendritic connections

– Second trimester maturation and differentiation

– Subplate zone 15 weeks

– Dendritic arborization/synaptogenesis 19-20 weeks

– Cortex isolated organ until thalamocortical connections established

• Nociceptive fibers from the thalamus penetrate primary

somatosensory cortex 24-26 weeks

Brain Development

EEG

23 week preemie

30 weeks

Behavioral

10 weeks: skin sensitivity � hyperexcitability possible

Endocrinology

Stress response � stress hormones

Not under anesthesia

Fetal transfusion via hepatic vein vs umbilical cord

1/31/2018 26

Development: Fetal Pain Pathways

Cortex

•20 weeks: full complement of cells

•13 weeks: fold on each side of brain

– 15 weeks: insular cortex �region for external stimulus experience

•26-28 weeks: cortical maturation

•Subcortical vs cortical fetal processing of pain

Pain Fibers

1/31/2018 28

Validated Neonatal Pain Scales

Neonatal Pain Scales

•Premature Infant Pain Profile

•Neonatal Infant Pain Scale

•NPASS (Neonatal Pain, Agitation, & Sedation Scale)

•Neonatal Facial Coding Scale

Validated Neonatal Pain Scales

Neonatal Infant Pain Scale

NPASS (Neonatal Pain,

Agitation, & Sedation Scale)

1/31/2018

6

Pain Assessment Challenges

Pain receptors activated by:

• Contact of foreign bodies with the conjunctiva

• Massage or gentle touch on injured skin/mucosa

• Pressure above an injured organ (bone/bowel)

• Strong pressure/scratch on intact skin/mucosa

• Sprain of joints or muscle stretching

• Excessive heat/cold

• Excessive noise (>120 DB)

1/31/2018 31

Difficulties with pain assessment

• Assessment, calculations, recording of 3-10 parameters in real time

• RN performing procedures vs. those observing pain vs. video analysis

• Concurrent validity questioned, since there is no gold standard for pain

• Dissociation between physiological vs. behavioral parametersMost pain scales developed on healthy babies vs. critically ill patients

• Pain measures validated only in the 30-60 secs following acute pain

Don’t include type of the stimulus or the body region where it occurs

• Should we assess pain in newborn infants using a scoring system or just a detection method?

1/31/2018 32

What are the short- and long-term consequences of pain in the neonate?

1/31/2018 33

Preterm Neonatal Data

11% live births (8% USA)

15% very preterm (2% of all USA births)

50% neurodevelopmental problems

Weeks – months in NICU during delicate and critical phase of very rapid brain development and programming of stress systems

NICU: 2-14 invasive procedures per day

Short- and long-term effects of pain-related stress and

associated treatments on brain maturation and

neurodevelopmental outcomes

1/31/2018 34

Preterm Neonatal Data

Advances perinatal care

•increased the survival of preterm neonates in neonatal intensive

care units (NICUs) worldwide

– Viability

•physiological instability and underlying diseases of these infants

necessitate various invasive procedures

– endotracheal intubation, heelsticks, insertion of indwelling venous and arterial catheters, nasal/tracheal/gastric suctioning

1/31/2018 35

Pain and the immature nervous system

• Prolonged NICU care during period of rapid neuronal

proliferation and cell differentiation

• Exogenous/endogenous insults can lead to detrimental effects on neuronal migration and cortical development

• Repetitive pain-related stress has been associated with long-

term consequences on somatosensory processing, sensitivity to

pain, and response to pain (altered central sensitization).

1/31/2018

7

Pain and the immature nervous system

• Hyposensitivity to thermal (unmyelinated C-fibers and A-delta

fibers) but not mechanical (A-beta sensory) stimuli at 12 months vs FT infants

– Greater if surgery as neonate

• Increased somatization at 4-5y

– Greater catastrophizing

1/31/2018 37

Neonatal Pain and Brain Development

• Reduction in gray and white matter volumes in infancy,

childhood and adolescence

• Greater exposure to stressful procedures (heel lance/IV start, intubation/extubation) associated in reduced brain size in

frontal/parietal regions

1/31/2018 38

Current Literature

Animal models

•Pain vs inflammation

•Outcomes

Validated assessment models

Neurodevelopmental outcomes

Multimodal analgesia

Pharmacological vs non-pharmacological treatment outcomes

1/31/2018 39

Mechanism and outcomes

• Repeated painful stimuli � chronic pain

• Allodynia: pain out of proportion to stimulus

• Hyperalgesia: increased sensitivity to noxious stimulus

1/31/2018 40

Consequences of early exposure to pain

1/31/2018 41

• Neurodevelopmental outcomes

– Altered neural development

– Neuroapoptosis

– Stress response

– Psychometric

– Behavioral

• Emotional development

• Social development

• Pain response

– Acute pain

– Post-surgical pain

– Chronic pain

Prevention and treatment

• Avoiding painful procedures/physical handling

• Pacifier, sucrose, kangaroo care, massage, sensorial saturation

• Topical anesthetic cream or gel

• Acetaminophen or NSAIDS

• Slow IV infusion of opioids

• Local anesthetics: subcutaneous infiltration, regional, neuraxial

• Deep sedation/analgesia vs general anesthesia

1/31/2018 42

1/31/2018

8

Non-pharmacological approaches

• Non-nutritive sucking

• Presence of parents at bedside

• Breast feeding

• Swaddling/facilitated tucking

• Skin-to-skin contact or kangaroo care

• Therapeutic touch

• Osteopathic manipulations

• Sucrose therapy

Pharmacological Options

• Opiates

– Morphine

– Fentanyl

– Methadone

• Acetaminophen

• NSAIDs

• NMDA

• Alpha agonists

1/31/2018 44

Impact of Current Cultural Concerns

Opiate use

•Inadequate treatment/prevention � JCAHO � administrative

concerns � overtreatment

– Opiate epidemic

– Clinical judgement vs patient/parent/caregiver satisfaction

•Long term exposure, escalating doses, conversion, weaning

•Future expectations

– Parents, patients, providers, political

•Balance vs extremes

1/31/2018 45

Pain Management in Neonates

• Acute pain: avoid invasive procedures, sucrose, pacifier,

local/topical anesthesia

• Postoperative pain: short-term opioid infusions (24-48 hrs), positioning, remove drains, use adjuvant therapy

• Inflammatory pain: anti-inflammatory agents, consider opioids if

severe or extensive

• Visceral pain: Ditropan for bladder pain/spasms, consider

caudal/epidural analgesia, specific therapies for condition

• Neuropathic pain: relieve nerve compression?

• Limited studies in neonates/infants

1/31/2018 46

1/31/2018 47

Questions?

48