Knelpunten in het management van acute pijn bij kinderen

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18 nederlands tijdschrift voor anesthesiologie mei '10 | exposure and the working mechanism of analgesics, tissue needs to be collected for histological, molecular and biochemical analysis. Obviously this is not possible in human neonates. An additional problem in clinical studies is the correct comparison between experimental and control groups, e.g. the experimental group of preterm born children can only be compared to a healthy control group of children with a different age, i.e. term born children. Animal experimental studies on the other hand, do allow the comparison between a neonatal pain group and a non-pain group of the same age. Additionally, dose finding and safety testing of analgesics can be more easily carried out in an animal model. To this end, the neonatal rat is used, which developmental stage in the first week of life corresponds to a human foetus in the third pregnancy trimester or to a preterm born child in the NICU. Several clinically relevant animal models for neonatal surgery, which show long-term changes in pain sensitivity, have been developed during the past few decades. Incision of the hind paw skin of a neonatal rat aged 3 days old (P3) or P6, for instance, has been shown to result in hyperalgesia following repeated incision of the ipsilateral paw, performed two weeks later [17]. Experimental modelling of repetitive noxious routine interventions in the NICU faced many difficulties or lacked clinical relevance. Figure 1. Experimental rat model to mimic repetitive pain exposure in preterm born children in the NICU and its long-term consequences on pain sensitivity. Neonatal rat pups were noxiously stimulated with a needle prick 4x/day during the first week of life (A). Control animals received a fourfold daily tactile stimulus (B). When the rats reached the adult age of eight weeks, they were injected with a noxious substance, causing painful inflammation, in the ipsilateral hind paw (C) and 24h later, their pain sensitivity towards mechanical stimuli was tested with a set of calibrated von Frey filaments with increasing stiffness (D). Research conducted at the Pain Management and Research Centre (Maastricht, the Netherlands). Noxious inflammatory substances, such as complete Freund’s adjuvant (CFA), an inflammatory booster, or carrageenan (CAR), a polysaccharide, were used via a single intraplantar injection to induce pain in neonatal rats of several days old (P0-P3) [18-22]. As a consequence, these animals showed long-term changes in pain sensitivity, e.g. hypoalgesia to tactile and thermal stimulation from the young adult age of P34 up to at least P120 (adult) [9]. In contrast, when these adult rats received an ipsilateral (neonatal CAR or CFA exposed) re-inflammation of the paw with CFA, they showed a higher degree of mechanical allodynia and thermal hyperalgesia [19, 20]. The findings of the single-injection neonatal inflammation models already showed some similarity with the clinical situation of long-term pain sensitivity changes after neonatal pain exposure. However, the nature of the neonatal pain stimulus used, has a low clinical relevance since injecting these inflammatory substances does not occur in neonates in the NICU. Moreover, a single injection with a high dose of CFA [18, 20, 21] results in chronic inflammation, lasting for at least 8 weeks after injection, and a low dose of CFA or CAR [19, 22] results in a local inflammation lasting for about 24 hours. Next, researchers tried to develop animal models which mimicked the situation of neonatal pain exposure in the NICU more closely. To this end, neonatal rat pups were repetitively (daily from P0-P14) injected with formalin, a milder inflammatory agent, into all four paws, resulting in longterm increased pain sensitivity [23, 24]. The main limitation of using formalin is the fact that it causes fixation of tissue, since it is a derivative of the tissue preservative formaldehyde. This could change the morphology of peripheral nerve endings. The use of needle pricks as a neonatal pain stimulus was considered as a good model for repetitive pain stimulation as it occurs in the NICU [25]. These researchers only found minor effects on long-term sensitivity to thermal stimulation [25]. The nature of the neonatal stimulus used here, is highly clinically relevant since skin breaking procedures are prevalent in the NICU. Unfortunately the researchers
mei '10 nederlands tijdschrift voor anesthesiologie 19 | did not include an adult painful stimulus, which could have shown the long-term pain sensitivity to noxious stimuli after neonatal pain exposure. Therefore, the neonatal needle prick animal model is used in combination with an adult painful inflammatory pain stimulus to model neonatal repetitive pain exposure and its impacts on pain sensitivity later in life at the Pain Management and Research Centre (Maastricht, the Netherlands). To this end, neonatal rats are noxiously stimulated during the first week of life with a needle prick into the plantar surface of the hind paw (Fig. 1A). Control animals receive only a tactile non-noxious stimulus (Fig. 1B). Pain sensitivity later in life is tested eight weeks later, literature by injecting CFA into the ipsilateral hind paw (Fig. 1C). The sensitivity for mechanical stimulation is tested with calibrated von Frey filaments eliciting paw withdrawal 24 hours after CFA injection (Fig. 1D). 4. Conclusion Repetitive pain exposure occurs frequently in neonates admitted to the NICU and has been shown in both clinical and animal experimental studies to result in long-term changes in pain sensitivity. Adequate analgesic management for this early-life pain exposure is still under investigation. Clinically relevant animal models are of vital importance to overcome the limitations of clinical research into neonatal analgesia. Currently, we have validated the neonatal needle prick model in combination with an adult painful inflammatory pain stimulus. Now this model serves as a clinically relevant tool mimicking the repetitive noxious stimulation in the NICU, and allows us to investigate the three main research questions in neonatal pain research: 1. Investigating molecular and structural changes in the pain network; 2. Testing the efficacy of different analgesic drugs on the long-term pain sensitivity effects and 3. The PK and PD characteristics of the various analgesic drugs used. 1. Simons S.H., van Dijk M., Anand K.S., Roofthooft D., van Lingen R.A., Tibboel D. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med. 2003 Nov;157(11):1058-64. 2. Beggs S., Torsney C., Drew L.J., Fitzgerald M. The postnatal reorganization of primary afferent input and dorsal horn cell receptive fields in the rat spinal cord is an activitydependent process. Eur J Neurosci. 2002 Oct;16(7):1249-58. 3. Peters J.W., Schouw R., Anand K.J., van Dijk M., Duivenvoorden H.J., Tibboel D. Does neonatal surgery lead to increased pain sensitivity in later childhood? Pain. 2005 Apr;114(3):444- 54. 4. Taddio A., Katz J., Ilersich A.L., Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet. 1997 Mar 1;349(9052):599-603. 5. Hermann C., Hohmeister J., Demirakca S., Zohsel K., Flor H. Long-term alteration of pain sensitivity in schoolaged children with early pain experiences. Pain. 2006 Dec 5;125(3):278-85. 6. Carbajal R., Rousset A., Danan C., Coquery S., Nolent P., Ducrocq S., et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. Jama. 2008 Jul 2;300(1):60-70. 7. Anand K.J. Effects of perinatal pain and stress. Prog Brain Res. 2000;122:117-29. 8. Anand K.J. Consensus statement for the prevention and management of pain in the newborn. Arch Pediatr Adolesc Med. 2001 Feb;155(2):173-80. 9. Anand K.J. Pain assessment in preterm neonates. Pediatrics. 2007 Mar;119(3):605-7. 10. Anand K.J., Hall R.W., Desai N., Shephard B., Bergqvist L.L., Young T.E., et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet. 2004 May 22;363(9422):1673-82. 11. Simons S.H., van Dijk M., van Lingen R.A., Roofthooft D., Duivenvoorden H.J., Jongeneel N., et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA. 2003 Nov 12;290(18):2419-27. 12. Bellu R., de Waal K.A., Zanini R. Opioids for neonates receiving mechanical ventilation. Cochrane Database Syst Rev. 2008(1):CD004212. 13. Anderson B.J., Holford N.H., Woollard G.A., Chan P.L. Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children. Br J Clin Pharmacol. 1998 Sep;46(3):237-43. 14. James L.P., Simpson P.M., Farrar H.C., Kearns G.L., Wasserman G.S., Blumer J.L., et al. Cytokines and toxicity in acetaminophen overdose. J Clin Pharmacol. 2005 Oct;45(10):1165-71. 15. James L.P., Wilson J.T., Simar R., Farrar H.C., Kearns G.L., Simpson P.M., et al. Evaluation of occult acetaminophen hepatotoxicity in hospitalized children receiving acetaminophen. Pediatric Pharmacology Research Unit Network. Clin Pediatr (Phila). 2001 May;40(5):243-8. 16. Wilson-Smith E.M., Morton N.S. Survey of i.v. paracetamol (acetaminophen) use in neonates and infants under 1 year of age by UK anesthetists. Paediatr Anaesth. 2009 Apr;19(4):329- 37. 17. Walker S.M., Tochiki K.K., Fitzgerald M. Hindpaw incision in early life increases the hyperalgesic response to repeat surgical injury: critical period and dependence on initial afferent activity. Pain. 2009 Dec 15;147(1-3):99- 106. 18. Hohmann A.G., Neely M.H., Pina J., Nackley A.G. Neonatal chronic hind paw inflammation alters sensitization to intradermal capsaicin in adult rats: a behavioral and immunocytochemical study. J Pain. 2005 Dec;6(12):798- 808. 19. Ren K., Anseloni V., Zou S.P., Wade E.B., Novikova S.I., Ennis M., et al. Characterization of basal and re-inflammation-associated longterm alteration in pain responsivity following short-lasting neonatal local inflammatory insult. Pain. 2004 Aug;110(3):588-96. 20. Ruda M.A., Ling Q.D., Hohmann A.G., Peng Y.B., Tachibana T. Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science. 2000 Jul 28;289(5479):628-31. 21. Walker S.M., Meredith-Middleton J., Cooke-Yarborough C., Fitzgerald M. Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn. Pain. 2003 Sep;105(1- 2):185-95. 22. Lidow M.S., Song Z.M., Ren K. Longterm effects of short-lasting early local inflammatory insult. Neuroreport. 2001 Feb 12;12(2):399-403. 23. Bhutta A.T., Rovnaghi C., Simpson P.M., Gossett J.M., Scalzo F.M., Anand K.J. Interactions of inflammatory pain and morphine in infant rats: long-term behavioral effects. Physiol Behav. 2001 May;73(1-2):51-8. 24. Walker C.D., Xu Z., Rochford J., Johnston C.C. Naturally occurring variations in maternal care modulate the effects of repeated neonatal pain on behavioral sensitivity to thermal pain in the adult offspring. Pain. 2008 Nov 15;140(1):167-76. 25. 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