Pain management in neonates N. Ambalavanan MD Oct 1999.

Pain management in neonatesPain management in neonates

N. Ambalavanan MD

Oct 1999

Common Common mismisconceptions (“myths”)conceptions (“myths”)

Myth 1: The neuronal and endocrine systems of the newborn infant are not developed to the stage that allows for transmission of painful stimuli

(i.e. that they can’t feel pain) Myth 2: Newborn infants cannot “remember” pain

and, therefore, there can be no sequelae of pain Myth 3: Pain cannot be assessed in the newborn

infant Myth 4: Newborn infants are easily comforted without

analgesics

(Adapted from the CPS statement on neonatal pain)

Outline of this talkOutline of this talk

Rationale : why do it?DefinitionsProblems with neonatal pain managementPain assessmentPain alleviation

Rationale: why do it?Rationale: why do it?

Neonates and infants can perceive pain...…which can have adverse short-term

consequences……and adverse long term consequences……which may be attenuated by analgesia

Rationale: why do it ? (contd.)Rationale: why do it ? (contd.)

Perception of pain:– Neonates and infants perceive pain on behavioral,

physiological, and biochemical measures (KJS Anand et al: PCNA 1989; 36:795-822 & NEJM 1987; 317: 1321-1329; Craig KD et al: Pain 1993; 53: 287-299 & Pain 1987;28:395-410)

– Even the fetus in utero mounts a hormonal (cortisol and -endorphin) response to needling (Giannakoulopoulos X et al. Lancet 1994; 344: 77-81)

Parental perception of pain:– Vivid memories of parental stress (even 3 years post-NICU)

related to neonatal appearance and behavior, and the pain and procedures endured.


Adverse short-term consequences:– Stress hormone level inversely correlated with

severity of illness. Catecholamine levels higher in non-survivors, who have a lower fall in norepinephrine levels with sedation. (Barker DP et al. Arch Dis Child Fetal Neonatal Ed. 1996; 75:F187-190)

– Exposure of preterm neonates to repetitive pain and stress leads to clinical instability and complications. (KJS Anand. Crit Care Med 1993; 21: S358-359)


Adverse long-term consequences:– Circumcision increases pain response to subsequent

vaccination (Taddio A et al: Lancet 1997;349: 599-603) – Permanent structural and functional changes may occur in

infants exposed to multiple painful and stressful events (Porter FL et al: J Dev Behav Pediatr 1999;20:253-61)

– ELBW children noted to have altered pain sensitivity unrelated to temperament or parental style (Grunau RV et al: Pain 1994; 58: 341-346)

– Neonatal pain and stress may program the brain’s response to future stimuli (Winberg J. Acta Pediatr 1998; 87:723-5)

Basis for long-term effectsBasis for long-term effects

Development of HPA responses to stress is modified by

sensory experiences during the neonatal period (Levine S et al. Physiol Behav 1967;2:55-64 & Science 1962; 135:795-796; and Ader R et al. Physiol Behav 1969;4:303-305)

Mechanisms for these changes probably due to plasticity in neonatal limbic structures and related to expression of corticosteroid, vasopressin receptor systems regulating

HPA. (Francis D et al. Ann NY Acad Sci 1996;794:136-152)

Neonatal handling, maternal separation, infections, pain/stress etc can lead to permanent changes in endocrine, behavior, and immune systems. (Anand KJ: Biol Neonate 1998;73:1-9)


Analgesia works!– Anesthesia improves clinical outcomes in surgical

neonates (Anand KJS et al. Lancet 1987;1:243-248)

– EMLA pre-circumcision attenuated altered pain response to subsequent vaccination (Taddio A et al: Lancet 1997;349: 599-603)

– Morphine analgesia given by continuous low-dose infusion reduced the risk of poor neurologic outcome (death/ IVH III or IV / PVL) from 24% in placebo group and 32% in midazolam group to 4% in the morphine group. (The NOPAIN pilot study. Anand KJS et al. Arch Pediatr Adol Med 1999; 153; 331-338) (Previous studies showed no effect: small n?)

Some definitions...Some definitions...

Stress: A mentally or emotionally disruptive condition occurring in response to adverse external influences and capable of affecting physical health, or a stimulus which leads to such a condition

Stress Response: The physiologic response, including motor, visceral, humoral, and behavioral responses of the neonate to stress

More definitions…More definitions…

Pain: An unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage (International Association for the study of Pain: IASP)

Discomfort: Something that would ordinarily be considered to disturb one's comfort or cause annoyance

Neonatal pain management: problemsNeonatal pain management: problems

Confusion regarding Stress vs. Pain– Pain is always stressful– Stress is not always due to pain or associated with pain

Pain assessment– pain is subjective in its assessment– no “gold standard” for evaluation of neonatal pain– Indications for, and monitoring of, analgesia therefore

uncertain

Neonatal pain management: problems Neonatal pain management: problems

Analgesia in the newborn period– Pharmacodynamics and pharmacokinetics vary,

depending on the agent, gestational age, postnatal age, underlying disease process, and many other factors

Focus on evidence-based medicine– Lack of sufficient data on value of analgesia regarding

important short-term and long-term outcomes, and reduction of costs in both full-term and preterm infants

– Absence of evidence is not evidence of absence!

Pain assessment methodsPain assessment methods

Behavioral assessment– Subjective - crying, agitation etc– Semi-objective - scoring systems such as NIPS,

PIPP (also includes HR, SpO2) , NFCS etc

Physiologic variables– HR, BP, SpO2, intracranial pressure etc

Biochemical assessment– Cortisol, catecholamines, -endorphin etc

Pain assessment: which method to use?Pain assessment: which method to use?

Often a lack of significant correlation between physiologic, biochemical, and behavioral indicators of pain - there is no “gold standard”

Behavioral indicators often used as they are:– easier to measure – baseline better established– non-invasive (esp. for repeated measurements)– more “honest signal” of pain

Behavioral assessmentBehavioral assessment

Sedation score: (Jacqz-Aigrain et al, Lancet 344:646-650, 1994)

– Facial expression- calm and relaxed (0) or pronounced (1)

– sucking-absent (0) or strong and rhythmic (1)

– spontaneous motor activity – normal(0) or agitated (1)

– excitability, responsiveness to stimulation- normal (0) or tremulous, clonic movements (1)

– excessive flexion of fingers and toes- absent (0) or present & constant (1)

Scores of 0 or 1 suggest satisfactory sedation Primarily a score for sedation in intubated neonates. Simple, rapid, and construct validity established

Behavioral assessment (contd.)Behavioral assessment (contd.)

Neonatal Infant Pain Scale (NIPS) (Lawrence et al, Neonatal netw.12:59-66, 1993)

– Face: relaxed (0) or grimace (1) ; Cry: no (0), whimper (1), vigorous (2);

Breathing patterns: relaxed (0) or change in breathing (1) ; Arms: relaxed/restrained (0) or flexed/extended (1); Legs: relaxed/restrained (0) or

flexed/extended (1); State of arousal: sleeping/awake (0) or fussy (1) Scoring in one-minute intervals; x2 before time/ procedure, x 5 during

time/procedure, and x3 after time/procedure. Total scores for each minute range from 0-7

Response to acute painful stimuli in non-intubated babies. Full validation done, but score is time-consuming, and items such as

breathing patterns and cry difficult to interpret in intubated neonates


Premature Infant Pain Profile (PIPP)(Stevens B et al. Clin J Pain12: 13-22, 1996).

– Gestational age: >36 wks (0), 32-35.6 (1), 28-31.6 (2), < 28 wks (3)

– Behavioral state: active/awake, eyes open, facial movements (0), quiet/awake, eyes open, no facial movements(1), active/sleep, eyes closed, facial movements (2), quiet/sleep, eyes closed, no facial movements

– Heart rate: 0-4 bpm increase (0), 5-14 (1), 15-24(2), >25 increase (3)

– O2 saturation: 0-2.4% decrease (0), 2.4-4.9% (1), 5-7.4% (2), >7.5% decrease (3)

– Brow bulge: None, 0-9% of time (0), Minimum, 10-39% (1), Moderate (40-69%), Maximum (>70%)

– Eye squeeze: None, 0-9% of time (0), Minimum, 10-39% (1), Moderate (40-69%), Maximum (>70%)

– Nasolabial furrow: None, 0-9% of time (0), Minimum, 10-39% (1), Moderate (40-69%), Maximum (>70%)


Premature Infant Pain Profile (PIPP) (contd.)– Observe baseline HR, SpO2 in 15 s before event. Scoring in 30 s after

event.– Scores for 7 indicators summed for total pain score. Max score dependent

on GA: youngest up to 21, larger up to 18.– Scores of <6 indicate minimal or no pain, >12 moderate to severe pain.

Validated research tool, cumbersome and time-consuming for clinical purposes. Use in intubated neonates is questionable:

1. baseline obtained while infant is under chronic stress

2. if pre-intubation baseline is used, O2 saturation not an indicator of pain but rather of disease process

3. items such as nasolabial furrow difficult to discern


Neonatal Facial Coding System (NFCS)(Grunau RVE, Craig KD: Pain expression in neonates. Pain 28: 395-410, 1987)

• Eight items:– Brow bulge; Eye squeeze; Nasolabial furrow; Open lips; Stretch mouth

(vertical or horizontal); Lip purse; Taut tongue; Chin quiver

– Each present feature scores one, total score eight (modified NFCS in Guinsburg et al. J Pediatr 132: 954-959, 1998)

• Some facial actions (lip purse, tongue protusion, chin quiver) occur in non-pain situations. Other facial actions (Horizontal or vertical mouth stretch, taut tongue) are present less than 50% of the time in pain situations

• Difficult to assess face in intubated neonates

Other behavioral scalesOther behavioral scales

• Modified post-operative comfort score (Attia J et al. Intensive Care Med [abstract]13: 459, 1987)

• Pokela’s behavioral pain score (Pokela ML: Pediatrics 93: 379-383, 1994)

• Behavioral state score (adapted from Bruck et al. Biol Neonate 4: 32, 1962 byOrsini et al. J Pediatr 129: 140-145, 1996)

• Infant Body Coding System (IBCS) (Craig KD et al. Pain 52: 287-300, 1993)

• Modified Behavioral Pain Scale (MBPS): developed from CHEOPS by Taddio et al. (Taddio et al. J Pain Symptom Manage 10:456-463, 1995)

Physiologic assessment Physiologic assessment

Physiologic indicators (FT= full term; PT= preterm)• Heart rate : usually increased (FT, PT)• SpO2: usually decreased (FT, PT)• Vagal tone: decreased (FT)• Resp rate: increased (FT)• ICP: increased (PT)• Variability in HR and RR: increased (PT)

Cannot be unequivocally interpreted as pain as they are more clearly associated with stress (Stevens B et al. Clin J Pain 12: 13-22, 1996)

Biochemical indicatorsBiochemical indicators

Catecholamines (Epinephrine, Norepinephrine)

Cortisol (blood, saliva, or urine can be used)

-EndorphinGrowth hormone, glucose, and lactate have

also been studied

Pain managementPain management

Systematic approach to prevent pain required, rather than “as needed” basis

Risks and benefits of pain management techniques must be considered and individualized

Prevention of :– Acute pain (surgery, procedure)– Pain due disease process/ postsurgical/ postprocedure– Minimize stress due to noxious stimuli

Pain alleviation : basicsPain alleviation : basics

Prevention – Control stress (limit noxious stimuli)

– Limit painful procedures (only if necessary; use non-invasive monitoring whenever possible; art lines or CV lines rather than repeated punctures)

– Skilled caregivers with appropriate techniques (venipuncture less painful than heel lancing)

– Swaddling, non-nutritive sucking, positioning for minor procedures(Prevention and management of stress and/or pain in the newborn infant. CPS statement)

Prevention of acute painPrevention of acute pain

Anesthesia – General– Regional (epidural, nerve blocks etc)

– Local (lidocaine, EMLA etc)• Lidocaine (DPNB) or EMLA effective for circumcision• EMLA not effective for heel lancing• EMLA does not cause methemoglobinemia with single

applications at > 26 wks GA

– Opioids (Morphine/Fentanyl)

Post-op / disease related pain Post-op / disease related pain

Regional blocks (e.g. intercostal block for thoracotomy, caudal block for hernia)

Systemic analgesics:– Opioids : best to titrate dose to effect– Acetaminophen: orally or rectally is safe but

efficacy not well studied– Natural sweeteners: Sucrose or Glucose

effective for pain relief during minor procedures

Minimization of stressMinimization of stress

Non-pharmacological: – Avoid excessive noise, light. Comfort measures

such as swaddling, positioning, non-nutritive sucking.

Pharmacological: – Sedatives (benzodiazepines, barbiturates,

phenothiazines, chloral hydrate)

Analgesics: opioidsAnalgesics: opioids

Morphine or Fentanyl most often used. Avoid Demerol (Meperidine)

Requires frequent and thorough assessment of adequacy of pain relief and possible side effects– Adverse effects include respiratory depression and

glottic/chest wall rigidity (due to fentanyl/alfentanil rapid infusions: give slowly. If they occur, give muscle relaxants/ narcan)

– Avoid use > 5 days. Wean 20% per day if > 5 days. Wean by 10% per day if withdrawal symptoms.

– Continuous infusion (vs. bolus) decreases apnea, but higher total dose may be required for analgesia.

Sedatives: benzodiazepinesSedatives: benzodiazepines

Benzodiazepines are NOT analgesics. They have sedative-hypnotic, amnesic, anxiolytic, muscle relaxant, and anti-epileptic properties.

Midazolam (Versed) has a short half-life and is approved by the FDA for neonatal use. Although shown to be an effective sedative, it can cause abnormal movements and adverse hemodynamic effects (unknown if due to benzyl alcohol).

Insufficient data on lorazepam (Ativan). Diazepam not recommended due to long half-life.

Other sedativesOther sedatives

Chloral hydrate: Trichloroethanol (TCE) is the active metabolite. TCE and its metabolite TCA accumulate with repeated doses and can cause CNS / CVS depression and hyperbilirubinemia. Single doses are safe in neonates.

Phenobarbital / phenothiazines: evidence of benefit is lacking. Half-life may be very long.

Some final thoughts...Some final thoughts...

Neonatal pain relief by itself may be an adequate and distinct objective or outcome, in the absence of other benefits or adverse effects

If opioids are safe and effective and have equivalent or better long term outcomes, it may be ethical to tolerate a small increase in short-term side effects (e.g. bowel dysmotility or prolongation of ventilation) for improved pain relief

Pain management in neonates N. Ambalavanan MD Oct 1999.

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