Neonatal Pain Management: Integrating the science, evidence, and art of therapeutics with early development

Transcription

1 Disclosures: Dr. Anand has no financial relationships with any commercial, pharmaceutical, or medical device companies related to this presentation; there are no conflicts of interest to disclose. As senior editor for the book Pain in Neonates & Infants, he receives royalty payments from Elsevier Science Publishers and from Up-To- Date, Inc. He is not associated with any Pro-Life or Pro-Choice groups and he receives no financial benefits from the organizations promoting these viewpoints. Neonatal Pain Management: Integrating the science, evidence, and art of therapeutics with early development K. J. S. Anand, MBBS, D.Phil., FCCM. Professor of Pediatrics and Anesthesiology Division Chief, Palliative & Critical Care Medicine Stanford University School of Medicine, Palo Alto, CA.

2 Learning Objectives To review the development of pain and consciousness in the human fetus and neonate To describe epidemiology of acute pain and analgesia during neonatal intensive care To survey the established and novel approaches for pain assessment in the neonate To review the scientific evidence for commonly used analgesic approaches in newborns

3 Do newborns consciously experience pain?

4 Self-awareness Newborns root more to external stimuli as compared to self-stimulation à they can differentiate the touch from self vs. non-self (P Rochat 2003) Photograph Courtesy: Bjorn Westrup, MD, PhD

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7 Are neonates more sensitive to pain? Accentuated stress responses (Anand et al, 1985; Anand & Aynsley-Green, 1988; McIntosh et al, 1994) Lower thresholds for the dorsal cutaneous flexor reflex (Andrews & Fitzgerald, 1994 & 1999; Koch et al, 2008) Delayed maturation of diffuse noxious inhibition (Fitzgerald & Koltzenberg, 1986; Marti et al, 1990; Fitzgerald et al, 1998; Ren et al, 1997) Altered function of inhibitory neurotransmitters: GABA, glycine (Wang et al., 1994; Obrietan & van den Pol, 1995) Prolonged windup and hyperalgesia (Fitzgerald et al, 1988; Andrews & Fitzgerald, 1999; Taddio et al, 2002; Taddio et al, 2009) Increased evoked responses in cortical EEG (Norman et al, 2008; Slater et al, 2010; Maimon et al, 2013)

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10 Epidemiology of Acute Pain in Infants Porter & Anand, babies: 7,672 procedures 53 procedures/baby, 87% were heelsticks Pain relief for 3% procedures Simons, Anand, et al., babies for 14 days in NICU Total 19,674 procedures, 31% repeats Procedures/baby/day: 14.3±4.0 60% neonates received some analgesia (continuous, episodic) Carbajal, Anand, et al., 2008 All ICUs in Paris = 430 babies Total 72,515 procedures: 52,779 painful, 19,736 stressful 115 procedures/baby; 16/day Pain relief for 20% procedures Roofthooft, Anand, et al., babies for 14 days in NICU Total 21,076 procedures Higher number in newborns <29wk Procedures/baby/day: 11.4±5.7 37% neonates received some form of analgesia

11 Epidemiology of Acute Pain in Infants

12 Epidemiology of Acute Pain in Infants

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15 Clinical Assessment of Pain Standardized & validated pain assessment methods: for acute vs. prolonged pain Assess contextual factors, behavioral / physiological signs Every 4 6 hrs, after each painful or therapeutic intervention RCT of parental input: greater satisfaction with role attainment, no change in Parent Stress (Franck, et al. Pediatrics 68: , 2011) Pain assessment by MD/NNP vs. RNà 4-fold odds of postop analgesia (Taylor, et al. Pediatrics 118: , 2006 ) Neonatal Pain Scales Premature Infant Pain Profile Neonatal Infant Pain Scale NPASS (Neonatal Pain, Agitation, & Sedation Scale) Neonatal Facial Coding Scale Infant Pain Scales (1-12 mo.) Faces, Legs, Activity, Crying Consolability Scale (FLACC) COMFORT / COMFORTneo Modified Behavioral Pain Scale Toddler/Child Pain Scales The Oucher (J. Beyer, et al.) Baker-Wong Faces Scale (+ many other scales)

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24 Difficulties with pain assessment Ø Assessment, calculations, recording of 3-10 parameters in real time Ø RN performing procedures vs. those observing pain vs. video analysis Ø Concurrent validity questioned, since there is no gold standard for pain Ø Dissociation between physiological vs. behavioral parameters Ø Most pain scales developed on healthy babies vs. critically ill patients Ø Pain measures validated only in the secs following acute pain Ø Don t include type of the stimulus or the body region where it occurs

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28 Non-pharmacologic Treatments Non-nutritive sucking Reduces pain in heel lance, circumcision, immunizations Effective in preterm infants Swaddling/facilitated tucking Stimulates proprioceptive, tactile, thermal systems Effective in preterm infants Skin-to-skin contact or kangaroo care Therapeutic touch Osteopathic manipulations Support sleep-wake cycles Presence of parents at bedside (Franck et al. Pediatrics 2011; 128: ) Breast feeding Less crying, HR changes, pain scores Greater or similar efficacy as sucrose Oral breast milk less effective than oral glucose or sucrose therapy Sucrose therapy Role of endogenous opioids Naloxone blunts response Dose: grams Given 2 min pre-procedure

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32 Efficacy of sweet solutions for infants 1-12 mo. (Harrison et al. Archives of Disease in Childhood 2010; 95(6):406-13) 695 studies à 42 RCTs with 3,963 patients Sucrose or glucose decreased crying in all RCTs Reductions in PIPP /other scores, HR/HRV responses Sucrose effective against acute heelstick pain, but not ROP exams 57 studies including 4730 infants, reduced HR, crying time, etc. Stevens B, et al. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database of Systematic Reviews 2013 Jan 31; 1: Long-term effects of repeated doses of sucrose in the 1 st week of life? Johnston CC, Filion F, Snider L, et al.. Pediatrics. 2002; 110:523-8 Sucrose increases ATP use and oxidative stress in preterm neonates? Asmerom Y, et al. Journal of Pediatrics 2013; 163(1): Sucrose may be ineffective: EEG, EMG studies in preterm neonates? Slater R, et al. Lancet 2010; 376 (9748):

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40 Acetaminophen Most widely used oral agent analgesic and antipyretic use; minimal side effects (Cuzzolin et al. Curr Drug Metab 2013, 14(2):178-85) Ibuprofen more effective antipyretic than Acetaminophen at 2, 4, 6 hrs (9 RCTs, n=1078) (Perrott et al. JAMA Peds 2004, 158:521-6) Ibuprofen (4-10 mg/kg) vs. Acetaminophen (7-15 mg/kg): similar efficacy for treating moderate to severe pain (3 RCTs) No differences in safety or side effects (17 RCTs, n=1820) Doses (mg/kg/day): (24-30 wks GA), (31-36 wks GA), (37-42 wks GA), (1-3 mo) (Cuzzolin et al., 2013) Newborns protected from hepatic or renal toxicity (Porta et al, 2012)

41 Acetaminophen increased pain associated with: Heel lance (PIPP score, Bernese Pain Scale) Assisted vaginal delivery (EDIN score) ROP exam (PIPP score) IV Acetaminophen reduced morphine requirements after thoracic or abdominal surgery over 48 hours postoperatively (mean diff. 157 µg/kg)

42 IV Acetaminophen Used widely in UK, within dosing guidelines for preterms <32 wks 60%, wks 90%, 36 wks-i yr 80% (Wilson-Smith & Morton, 2009) Dosing: 20 mg/kg load, 10 mg/kg Q6hrs (Allegaert et al, Paed Anaes 2013) Reduced pain scores from 30 min to 6hrs PK 2-compartment model: Vd cc 52 L/70kg, Vd pc 23 L/70kg, Cl 5 L/70kg/hr, increased by weight + PMA, reduced 40% by bilirubinemia, LFTs stable (Palmer et al, 2008; Allegaert et al, 2011) No changes in HR, SBP, DBP, but MAP decreased more in newborns hypotensive at baseline (Allegaert et al, 2010, 2011) Reduced postop opioids 66% in infants (49% newborns 0-10 days; 73% infants days) (Ceelie et al, JAMA 2013, 309:149-54) No differences in pain scores or adverse effects

43 IV Acetaminophen Used widely in UK, within dosing guidelines for preterms <32 wks 60%, wks 90%, 36 wks-i yr 80% (Wilson-Smith & Morton, 2009) Dosing: 20 mg/kg load, 10 mg/kg Q6hrs (Allegaert et al, Paed Anaes 2013) Reduced pain scores from 30 min to 6hrs PK 2-compartment model: Vd cc 52 L/70kg, Vd pc 23 L/70kg, Cl 5 L/70kg/hr, increased by weight + PMA, reduced 40% by bilirubinemia, LFTs stable (Palmer et al, 2008; Allegaert et al, 2011) No changes in HR, SBP, DBP, but MAP decreased more in newborns hypotensive at baseline (Allegaert et al, 2010, 2011) Reduced postop opioids 66% in infants (49% newborns 0-10 days; 73% infants days) (Ceelie et al, JAMA 2013, 309:149-54) No differences in pain scores or adverse effects

44 Morphine Slow onset of action, ceiling effect, acute pain? Longer duration due to lower lipid solubility Metabolized in liver to active compounds: M6G: Potent analgesic, T 1/2 > MSO 4. M3G: MSO4 antagonist, may cause seizures Start infusions at 5-7 µg/kg/h in term neonates, 15 µg/kg/h in 1-12 mo., 25 µg/kg/h in kids 1-4 yrs; adjusted based on pain scores, adjuvants, side effects (Taylor et al. Paed Anaesth 2013; 23(1):40-4) Histamine release: hypotension, bronchospasm Greater effects on GI motility, biliary spasm Less risk of tolerance and opioid withdrawal than fentanyl (Franck LS et al. Am J Crit Care. 1998; 7: 364-9; Geiduschek JM et al. Crit Care Med. 1997; 25: )

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50 Blinded RCT of Fentanyl vs. Placebo N=131 Higher EDIN (p=.003) PIPP scores (p<.05) in placebo group Higher incidence of PIPP scores >12 (OR 5.14, p=0.000) Fentanyl side effects: Prolonged 1 st ventilation course (152 vs. 110 hours, p=0.019) More infants ventilated at 1 week (42% vs. 25%, p=0.042) but no differences in total ventilation (10 vs. 7 days, p=0.211) Delayed meconeum passage (55 vs hours, p=0.027)

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53 Fentanyl, other routes Transdermal or intranasal route with limited IV access Intranasal route is safe and effective dose µg/kg (Mudd S. J Pediatr Health Care. 2011; 25(5): ) Transdermal patches at 12.5, 25, 50, 100 µg/hr Partially occluded patch? (Mitchell. J Opioid Manag. 2010; 6(4):290-4) High skin permeability, increased skin blood flow Slow increase in plasma concentrations, hours Gradual tail-off after the patch is removed Management of chronic or prolonged pain, particularly if opioid tolerant (Zernikow, et al. J Pain. 2007;8(3): )

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56 Methadone May be more effective than morphine, fewer side effects Mechanisms include: specific µ-opioid effects, desensitization of δ- opioid receptors, antagonism of NMDA receptors Slow onset (20 min); oral bioavailability 75-85% Effects can be monitored by pupillary size (Heil et al. Drug Alcohol Depend. 2012;126:268-71) 3-compartment linear disposition, PK parameters similar in neonates, children, adults (Ward, et al. Pediatric Anesthesia 2014; 24: ) Metabolites: EDDP, EMDP (similar clearance as methadone) Management of chronic or prolonged pain, palliative care (Zernikow et al. Paediatr Drugs. 2009;11(2):129-51) Unique side effects and potential for toxicity in neonates

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61 Dexmedetomidine Analgesia, anxiolysis, & sedation, but tolerance does occur Stimulates α 2A - and α 2C -adrenergic receptors, indirect effects via opioid and γ-aminobutyric acid receptors 8-fold greater specificity than Clonidine Infusions 0.2 µg/kg/hr, maximum rates µg/kg/hr Analgesic plasma levels are µg/l (adult pts) Sedative plasma levels are mcg/l (pediatric pts) No significant changes in BP, HR, SaO 2 Dex during surgery reduces postop pain and analgesic use (11 RCTs, n=434 vs. 440; Dex vs. placebo or opioids) (Schnabel et al. Paediatr Anaesth. 2013;23(2):170-9)

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64 Dose finding studies in wks (n=18), wks (n=24) Loading doses of: 0.05, or 0.1, or 0.2 mcg/kg IV, followed by Continuous infusions of: 0.05, or 0.1, or 0.2 mcg/kg/hour For NPASS scores >3, 10% reqd. Midazolam (Gr. I/II: 0/4), 40% reqd. analgesia with Fentanyl (Gr. I/II: 3/14), or Morphine (Gr. II: 3), or both drugs (Gr. II: 2) PK: lower clearance (0.3 vs. 0.9L/kg/hr), longer elimination t½β (7.6 vs. 3.2 hrs), greater AUC (2049 vs. 357) in Gr I vs. II 3 (7%) patients showed 4 AE s: hypotension/hypoventilation in Group I; hypertension, agitation in Group II patients

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66 Ketamine IV anesthetic agent; procedural pain Produces Dissociative anesthesia A cataleptic state, nystagmus, patients may appear awake but are non-communicative Intense sedation, analgesia and amnesia; increases muscle tone, increases secretions Maintains hemodynamic stability, respiratory drive, causes bronchodilation Usual doses: mg/kg IV; 2-4 mg/kg IM; 5-8 mg/kg orally Meta-analysis postop pain (Dahmani et al. Paed Anaes 2011;21(6):636-52) IV Ketamine reduced pain intensity and non-opioid analgesics required, but had no opioid-sparing effects Caudal/tonsillar ketamine reduced analgesia, prolonged block

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70 Ketamine and neurodegenerative mechanisms (Anand et al., Anesthesiology, 2004, 2005, 2007 Bhutta, et al. Acta Pædiatrica, 2007) Differences between human and rodent brains High doses/concentrations of Ketamine used Prolonged duration of anesthetic exposure Anesthesia given in the absence of pain Nutritional and metabolic needs Use of continuous monitoring

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72 Pain Management in Infants: brief summary 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?; drug therapies have not been studied in newborns or infants