Sedation and pain relief in neonatal care PERINATOLOGI KURS 2010, KI

1. Sedation and pain relief in neonatal carePERINATOLOGI KURS 2010, KI Marco Bartocci, MD, PhD Neonatal Intensive Care Unit Neonatal Research Unit Karolinska University Hospital Karolinska Institutet Stockholm

2. contents • Physiologic background of supraspinal pain perception • Clinical approach • Pain scales • Pain drugs in NICU

3. Supraspinal pain processing • The pain system is a dynamic interactive system creating an interoceptive view (relating to stimuli arising within the body) of the body integrity (Price, Science 2000) • Pain perception involves multilayered networks of nociception, nerves, neurons and glia, distributed in multiple spinal and supraspinal areas. (Woolf, Science 2000)

4. What is pain? Pain is a subjective sensory and emotional experience that requires the presence of consciousness to permit recognition of a stimulus as unpleasant. Next questions • Is the brain of the newborn ready (mature enough) to process painful stimuli? • When do we become conscious of ourselves? • How can a newborn communicate his/her pain?

5. Development of pain • Sensory receptors in the moth already at 7 wks • Peri-oral cutaneuos 77,5 wks • Palmar cutaneuos 1010,5 wks (Humphrey, 1964) • Abdominal cutaneuos around 15 wks • Spinal reflex arc in response to noxious stimulus from 8 wks (Okado & Kojma 1984) • Neuron for nociception in the dorsal root ganglion from 19 wks (Kostantinidou 1995) • Receptors on the skin from week 20 • Synapses develop around week 20 • Endorfins present at week 20 • Nociceptive connections develop between week 22 and 24 • Thalamic afferents reach the subplate zone 20 wks (Rakic, Kostovich, Hevner 1984) • Thalamic afferents reach the cortical plate (Rakic, Kostovich, Golman 1984) • Myelinisering till brainstem, thalamus at week 30 • Somatosensory evoked potential with distinct constant component 29 wks (Klimach ‘88) • EEG denoting clear shifting wakefulness-sleeping differences 30 wks Clancy 2003 NICU

6. Why pain perception is potentially possible already in early of development • Number of nociceptive nerve fibers in the skin of the neonate is similar to and possibly even greater than the number found in the adult. • Despite the incomplete myelination of pain fibers, pain transmission is preserved. The short distances in the immature brain compensate any slowing of velocity that may be caused by the lack of myelinisation. • There is abundance of pain neurotransmitters in the newborn brain and in the fetal brain. • There are receptive fields of neurons in the somatosensory cortex.

7. Why newborn infants may potentially feel more pain than adults? Pain transmission and neurotransmitters are extremely well developed at birth as well as in the premature, but modulatory and inhibitory circuits are still immature and partially lacking (physiological imbalance excitatory vs. inhibitory fibres) Physiological background: • There is a delay in the maturation of descending inhibitory pathways from supraspinal areas • There is a delayed maturation of interneurons in the “substantia gelatinosa” • There is a deficiency of inhibitory neurotransmitters

8. Development of pain response Lower gestational age may be associated to lower pain thresholds in early development (Anand 1998; Fitzgerald et al. 1988), eventually resulting in greater cortical responses in the more immature preterm neonates following pain stimuli

9. Which cortical areas are involved in pain processing? How nociceptive/painful stimuli arrive at the cortical level in preterm newborn infants?

10. Other areas: Hypothalamus, anterior cyngulate gyrus, amygdala, hyppocampus, nucleus accumbens, cerebellum amygdala basal ganglia (etc.) Inhibitory and facilitatory effects

11. The newborn is not “a little adult” • The structures and mechanisms involved in pain processing during early development are unique and different from those of the adult. • Many of these structures and mechanisms are not maintained beyond specific periods of early development Narsinghani & Anand 2000 Fitzgerald 2005

12. Pain processing in the brainstem Medulla • 5-10 wks  development of medullary nuclei • Formation of the rhombencephalon (hindbrain) • 10 wks  vagal afferents, visceral afferents (nucleus of the solitary tract), general somatic afferent nuclei (trigeminal nuclei)

13. Pain processing in the brainstemMedullary nuclei • Rostral ventromedial medullla (RVM) • Pain modulatory circuitry (especially chronic pain) • Inhibitory and facilitatory effects • Bilateral nociception bladder and colorectal distension (Visceral Sensory Information) (Robbins, Neurosci Lett 2005) • Connections with the Periaqueductal Grey (PAG) and involved in hyperalgesia and allodynia (prostaglandin-PGE2 effect) (Heinrecher, Pain 2004, Robbins 2005) • μ-opioid agonists activate neurons in RVM (despite RVM neurons are quite resistant to the development of μ-opioid tolerance) (Mourgan, Pain 2005)

14. Pain processing in the brainstemMedullary nuclei • Dorsal raphe nucleus (DRN) and nucleus raphe magnus (NRM) • They are crucial in opioid induced analgesia (Fields, Nature Review Neurosci 2004) • They are implicated in stress-induced analgesia (Freitas, Exp Neurol 2005) • Intra-oral sucrose activates neurons in the PAG, DRN and NRM modulating the descending pain pathways (Anseloni, Neurosci 2005; Miyase, Neurosci Lett 2005)

15. Pain processing in the brainstemMedullary nuclei • Nucleus tractus solitarius (NTS) • Especially involved in visceral afferent input • Descending inhibitory and facilitatory loops to the spinal cord • Referred pain and viscerotopic specificity (Hua, Am J Phys 2004) • Autonomic response to visceral stimulation (deLange, Neurosci Lett 2005) • Viscerosomatic hyperalgesia (visceral distension) Involved in the “irritable bowel syndrome” (Anand, J Pediatr 2004)

16. Pain processing in the brainstemMedullary nuclei • Trigeminal nuclear complex • 2 distinct nuclei: • interpolaris/caudalis transition zone (Vi/Vc) • Sensory processing deep tissue, somatovisceral, HPA axis and descending modulation of pain • and subnucleus caudalis • Sensory discriminative aspects of pain (Dubner, J Orof Pain 2004) • Focused on oro-facial and dental pain • Crucial importance in the newborn in NICU as 2 of the most common interventions stimulate the trigeminus (intubation and oral suctioning) (Simons, Arch Ped Adol Med 2003) • Possibly involved in the so called mechanism of “Long Term potentiation (LTP) and may contribute to the “Oral aversion syndrome” noted in ex-prematures.(Smith, 2007; Ljang, Pain 2005)

17. Pain processing in the brainstemPons nuclei • Parabrachialis complex (PBC) • Particularly involved in emotional, autonomic and neuroendocrine features of painful stimulation • Projects to amygdala (emotional affect), hypothalamus and ventrolateral medulla (autonomic adaptation), PAG (emotional behaviour). (Richard, J Comput Neurol 205)

18. Pain processing in the brainstemPons nuclei • Pontine reticular formation • Particularly involved in somatic motor responses, arousal and emotional feature of pain via medial thalamic and prefrontal cortical connection. (Gauriau, Exp Physiol 2002) Pictures of a neonates showing emotional features just before a venipuncture…..

19. Pain processing in the brainstemPons nuclei • Locus ceruleus/sub ceruleus (LC/SC) • Neurons in LC are activated by acute and inflammatory pain • Chronic pain suppresses LC activity to produce hyperalgesia (Imbe, Pain 2004; Freitas Exp Neurol 2005)

20. Pain processing in the brainstemMidbrain • It develops from the mesencephalon between the 9th and the 16th gestational week • It consists of: • Periaqueductal grey (PAG) and Ventral tegmental area • Modulatory system of pain • PAG Stress-induced analgesia, sucrose-mediated analgesia, visceral reaction to pain (Cavum, Brain Res 2004; Anseloni Neurosci 2005) • Opioid and non-opioid mechanisms of endogenous analgesia are located in PAG • Different maturational stages of the opioid receptors in PAG may lead to different effects (Rahman, Brain Res Dev Brain Res 1995)

21. Supraspinal Pain processingThalamus • Relay station conveying sensory, motor and autonomic information. • It is visible at 6 weeks of gestation • Special sensory projection nuclei (lateral geniculate body – visual; medial geniculate body – auditory) • General sensory projections nuclei (especially involved in pain processing) • ventral posterolateral (VPL) - somatosensory • Ventral posteromedial (VPM) • Posterior nuclear group (Po) and the triangular pain processing

22. Supraspinal Pain processingSucortical level • Anterior cyngulate gyrus It develops fully at about 24 weeks of gestation • Intensity, sensory-integrative, affective and cognitive modulation • Habituation (Bingel, Pain 2007)

23. Other subcortical areas • Hypothalamus (16-20 weeks of gestation) • Integration discending/ascending information to pain, stress and emotion • Connection with other subcortical areas • Amygdala (12-16 weeks of gestation) • Stress component. Neuroendocrine responses. • Hippocampus (15-16 weeks of gestation) • Anxiety  hyperalgesia. Chronic and repetitive pain and stress abundant glucocorticoid receptors • Nucleus accumbens (early in gestation) • Suppression of chronic pain. Antinociception via opioid receptors, dopamine D2 receptors, and calcitonin gene-related receptors

24. Supraspinal Pain processingCortex • Primary somatosensory cortex (S1) • Somatotopic mapping with narrow receptive fields • Not yet clear its role in conscious experience of pain • Secondary somatosensory cortex (S2) • Large, bilateral receptive fields • More likely directly involved in the processing of the noxious stimulus.

25. Bartocci et al, Pain 2006

26. CBV Blood Oxygen level Neural response Stimulus CBF CMRO2 Hb O2 Hb H Hb tot Stimulus

27. Bartocci et al, Pain 2006

28. primary somatosensory cortex and parts of the secondary somatosensory cortex, insula, cingulate cortex, thalamus, and the amygdala. E E R R Cortical areas illuminated by NIRS Areas of the preterm brain likely to be illuminated by NIRS Figure 1b Bartocci et al, Pain 2006

29. Near Infrared Spectroscopy - NIRS • Photon 1 is scattered and reaches the detector • Photon 2 is absorbed after a number of scattering events • Photon 3 leaves the head without being detected H. Obrig et al. International Journal of Psychophysiology 2000

30. Venipuncture Tactile stimulus 30 seconds Period: P0Baseline NIRS recording 60 seconds Period: P1Tactile NIRS recording 60 seconds Period: P2Pain NIRS recording 60 seconds

31. Venipuncture [Hb tot] left NIRS mmol/L [Hb tot] right Sat O2 % HR bpm 0 60 s

32. Μmol/L tactile venipuncture 60 sec Bartocci et al Pain 2006

33. A A. Comparison of the cortical [HbO2] increases between the female (black columns) and male (white columns) neonates following venipuncture. B B. Differences in cortical [HbO2] changes following venipuncture on the left or the right hand. Black bars denote [HbO2] increases on the left hemisphere and white bars on the right hemisphere.

34. Cortical activity in the somatosensory cortex during tactile and painful stimulation (venipunture). Bartocci et al, 2006

35. Bartocci et al, Pain 2006

37. Conclusion from our study • Painful and tactile stimuli elicit specific haemodynamic responses in the somatosensory cortex, implying conscious sensory perception in preterm neonates. • Somatosensory cortical activation occurs bilaterally following unilateral stimulation and these changes are more pronounced in male neonates or preterm neonates at lower gestational ages.

38. Mean PMA at time of study (weeks), 35.0 (5.2); range, 25.7– 45.6 The long latencies of the cortical responses in the youngest infants are likely attributable to the low conduction velocities and slow synaptic responses in the nociceptive circuitry Slater et al. The Journal of Neuroscience, 2006

39. [HbO2] puncture [HbH] Effect of squeezing during heel lancing Unpublished data

40. Unpublished data Thanks to Felicia Nordenstam

41. Slater et al, PLoS 2008

42. Neuroimage 2010 Non-noxious touch stimulation Noxious heel lance stimulation 7 infants; born 24–32 weeks 8 infants; born 37–40 weeks mean PCA at time of heel lance 39.2 ± 1.2 weeks

43. Conclusions – 1 • More and more evidence has been gathered about the anatomical and maturational potentials for supraspinal pain processing in newborn infants, particularly in prematures. • Some of the nociceptive pathways or mechanisms may not be maintained beyond specific periods of early development. This fact has to be taken into account both in research and clinical practice.

44. Conclusions – 2 • There is starting evidence indicating that in newborn infants, especially those born extremely premature, supraspinal pain processing may be not accompanied by corresponding detectable behavioural changes. • Procedures with low pain scores based on behavioural assessment tools alone may not be pain free. • Advances in functional neuroimaging and electrophysiology and molecular neuroscience will provide better understanding of pain processing and therefore increase the possibility of a better pain assessment and treatment.

45. Pain assessment Most neonatal intensive care units rely on subjective assessments made by nursing and medical staff to determine whether a baby requires analgesia or sedation and whether this treatment is effective. Staff perceptions vary considerably, resulting in under-treatment or over-treatment of pain (Lago et al., 2005; Walker, 2005).

46. The “first pain” and the “second pain” The most of the procedures may have a double impact to the discomfort of the baby:  acutely during the tissue damaging procedure (‘‘first pain’’)  after the procedure (‘‘second pain’’) Boyle et al. Pain 2006 Newborns at 26 (23–31) weeks and birth weight of 845 (500–1935) grams.

47. Pain Scales

48. Commonly used methods for assessment of pain in newborns

50. FLACC