Knelpunten in het management van acute pijn bij kinderen

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16 nederlands tijdschrift voor anesthesiologie mei '10 | 1 Pain Management and Research Center, Pain management in neonates: Animal models and contactinformation L. Knaepen Tel.: +31 43 388 4114 their clinical relevance Fax: +31 43 367 1096 Email l.knaepen@maastrichtuniversity.nl L. Knaepen 1 E.A.J. Joosten 1 J. Patijn 1 D. Tibboel 2 Department of Anesthesiology, Academic Hospital Maastricht, Maastricht, The Netherlands 2 Department of Pediatric Surgery, Erasmus- MC/Sophia Children’s Hospital, Rotterdam, The Netherlands summary It has been suggested that neonatal pain exposure has a long-term impact on pain sensitivity later in life. Newborns are often exposed to noxious stimuli in the neonatal intensive care unit (NICU). The impact of this pain exposure is increasing due to high preterm birth rates and medical advances which decrease the gestational age at which preterm born neonates survive. Besides major surgery, neonates undergo many noxious stimuli for monitoring of their health status in the NICU for which analgesia is often inadequately administered. Clinically relevant animal models are of vital importance to overcome the limitations of clinical research into neonatal analgesia. This article describes these models and its importance.
mei '10 nederlands tijdschrift voor anesthesiologie 17 | 1. Neonatal pain exposure and its long-term consequences Newborns are often exposed to noxious stimuli in the neonatal intensive care unit (NICU). The impact of this pain exposure is increasing due to high preterm birth rates and medical advances which decrease the gestational age at which preterm born neonates survive. Besides major surgery, neonates undergo many noxious stimuli for monitoring of their health status in the NICU for which analgesia is often inadequately administered. In a Dutch NICU, neonates received up to 14 daily repetitive noxious routine procedures, such as heel pricks, injections and intubations [1]. It has been suggested that neonatal pain exposure has a long-term impact on pain sensitivity later in life. Sensory neuronal circuits within the CNS are still undergoing development after birth and this development is activity-dependent, i.e. the formation and extension of the pain network is based on the amount of nociceptive stimuli neonates receive [2]. Excessive noxious stimulation of the pain network via either major surgery or repetitive pain exposure in the NICU may result in different pain response later in life. For instance, children who had experienced neonatal surgery, showed an increased need of intra- and post-operative analgesia following surgery in the same dermatome later in life[3]. Also, neonatal circumcision increased the pain response to a future pain stimulus, i.e. routine vaccination, three months later [4]. Not only neonatal surgery, but also a history of NICU-stay has been linked with longterm changes in pain sensitivity. Preterm and full-term school-aged (9-11 years) children previously exposed to painful NICU procedures were found to be less sensitive to acute heat stimulation than children which were not exposed to NICU interventions, which reflects a decreased baseline pain sensitivity [5]. In contrast, when exposed to a prolonged noxious thermal stimulus, the ex-NICU children showed lower pain thresholds than control children [5]. In conclusion, clinical evidence is accumulating on the impact of early life pain exposure and its long-term consequences on pain sensitivity. 2. Analgesia in newborns and infants: An evidence based approach Pain and anxiety have been recognized as significant problems in hospitalized children. Especially in the very young and under specific conditions (postoperative; critically ill children), there is a lack of evidence-based selection and dosing of analgesics, while longterm consequences of prolonged use of these drugs are unknown. Eighty percent of drugs are used off-label and/or unlicensed. This has raised public awareness in both the USA and EU (Best Pharmaceuticals for Children Act in 2002, NIH/FDA meeting 2004, European law dedicated to Medicines and Children, 2007). The European Medicines Agency (EMEA) has identified a number of analgesics and sedatives as research focus for pain and anxiety in line with the recently released Medicines for Children Research Network (MCRN) and the ERA-NET PRIOMEDCHILD (2008). These priorities include morphine and paracetamol in the newborn, peri-operative paracetamol and midazolam. The EPIPAIN study (Epidemiology of Procedural Pain in neonates) revealed that each neonate was found to experience a median of 115 procedures during a study period of 14 days while the majority (79,2%) of these procedures was not accompanied by analgesia [6]. It is thought that adequate analgesic therapy for neonates receiving intensive care may be beneficial with respect to shortterm and perhaps long-term outcomes [7-9]. However, two studies on shortterm effects of opioids in premature neonates showed minimal to no effects on the behavioural pain scores and slightly reduced stress hormone levels following continuous morphine treatment in ventilated newborns [10, 11]. None of the studies provided enough evidence to recommend continuous morphine as a standard of care for preterm ventilated newborns. A recent Cochrane review [12] came to the same conclusion. Nowadays paracetamol is the most common used analgesic and antipyretic drug in children and even prescribed in neonates to treat mild to moderate pain or combined with opioids. Paracetamol is less potent than opioids and with probably less side effects, although hepatotoxicity is described [13-16]. Limited studies are published on the use of intravenous paracetamol in preterm neonates, especially those under the gestational age of 28 weeks. To provide evidence for the most effective and safe drug for newborns and infants, studies are needed on the effects and safety of paracetamol and morphine in young infants. As evidence for morphine in neonates is subject to debate, studies on (opioid saving properties of ) paracetamol are needed. In particular, in post-operative conditions and after prolonged use in critically ill children. Within these studies, emphasis should be put upon the characterization of the optimal dose based on body weight, post-menstrual and post-natal age. Therefore the influence of age on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of these drugs should be investigated. Advanced statistical techniques such as non-linear mixed effects modelling are applied. Using these modelling techniques, infrequently obtained samples and observations in the real life clinical situation can be utilized to analyze population PK (drug concentrations) and PD (efficacy and safety endpoints) as well as determinants of variability in drug response. Ultimately this results in rational individualized dosing regimens for neonates and infants. 3. The development of experimental neonatal pain animal models Three important research questions arise from the abovementioned clinical evidence for long-term changes in pain sensitivity after early-life pain exposure in the NICU and use of analgesia in neonates and infants: 1. What are the underlying mechanisms of long-term consequences of repetitive neonatal pain exposure? 2. Which analgesic drugs are effective for pain management in neonates and infants and can they affect the long-term pain sensitivity changes? 3. PK and PD parameter characteristics of analgesic drugs in neonates and infants? Due to several important limitations in clinical research, experimental neonatal pain models have been developed. To study the underlying mechanisms of the long-term changes in pain sensitivity following neonatal pain
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