Background In the past decades, the mortality of preterm infants has decreased thank to more accurate care during their stay in the Neonatal Intensive Care unit (NICU). Though, the management of these babies still arises many questions, as the implication of the use of opioids in very preterm infants is still controversial. Opioids are the first-line analgesic treatment in preterm infants, though their effect on long term development would require further investigation. Furthermore, infants born preterm undergo several other stressful situations, such as mother separation and handling procedures, which might have implications on neurological development on the baby and response to painful and stressful situations later in life. In particular we investigated how pain and opiates might influence pain threshold in developmental age and adulthood. Very few clinical studies have been performed to verify these hypotheses, and therefore the use of murine model acquire a great importance not only in research field, but also to be transmitted to the clinical practice. Design and Methods 38 studies were selected to take part to our meta-analysis. Studies evaluating the effect of pain, opiates treatment, as well as opiate treatment prior to a painful event were analyzed. Within those, 30 studies (79%) evaluated the impact of pain only, 13 studies (34%) evaluated the impact of opiates only, and 10 studies evaluated the effect of opiates prior to painful stimuli (pre-emptive). 34 studies (89%) were conducted on rats, whether just 4 studies (11%) were performed on mice. The first outcome to our study was the study of the three factors (pain, opiates treatment and pre-emptive treatment) on pain threshold. Results According to our results, pain has a significant incidence on the development of pain threshold (Z = 3,24 and P = 0,001). A similar correlation was found also in pre-emptive morphine group (Z= 3.79 and P = 0.001). The use of morphine alone did not show any statistically significant result (Z = 0.47), though a main trend might be present. Conclusions Preterm children experiencing NICU stay undergo several and repeated painful procedures, as well as maternal separation. These painful and stressful stimuli seem to determine a long-term effect on pain perception in later life, suggesting that they might affect neuronal development in the first weeks of extrauterine life. The use of opioids as pre-emptive therapy seems to reduce the long-term hyperalgesia associated to pain exposition in early life. The use of morphine as main source of analgesic is therefore justified, as there is no evidence of long-lasting effect on pain sensitivity. Nonetheless morphine should carefully administered in preterm, to provide a safe and beneficial use.
Background Negli ultimi anni la mortalità dei prematuri ha visto una riduzione della sua incidenza, e questo grazie ad un miglior trattamento della prematurità e delle sue complicanze nelle unità di terapia intensiva neonatale. Nonostante questo, ci sono ancora parecchi quesiti che dovrebbero essere indagati in modo più approfondito nella gestione dei prematuri. L’uso di oppiacei come analgesici è un aspetto ancora controverso. Nonostante la terapia con morfina e oppiacei sia la terapia di prima scelta nel trattamento analgesico dei neonati, gli effetti sullo sviluppo del sistema nervoso non sono ancora noti. Inoltre, i bambini nati prematuri che necessitano di ricovero presso la terapia intensiva neonatale, subiscono l’effetto di ulteriori fenomeni traumatici, come la separazione materna, che serberebbero svolgere un ruolo importante nella risposta alle situazioni stressogene nel corso dello sviluppo e della vita adulta. Con particolare riferimento a queste prime ipotesi, la nostra meta-analisi si è concentrata sullo studio dell’influenza del dolore e della terapia analgesica nello sviluppo della soglia dolorosa. Data la scarsità degli studi clinici condotti rispetto al nostro quesito, abbiamo deciso di prendere in considerazione quanto svolto negli ultimi decenni sul modello animale e svolgere una revisione della letteratura esistente in modo da poter avere a disposizione uno strumento di conoscenza per il miglioramento della gestione clinica del neonato. Tipologia di studio e Metodi di ricerca Attraverso l’analisi di diversi database, 38 studi sono stati selezioni in base alle caratteristiche definite dai ricercatori. Gli studi che prendevano in considerazione gli effetti del dolore e della terapia con oppiacei, in singolo o precedente uno stimolo doloroso, sono stati poi soggetti della nostra analisi statistica. Di questi 38 studi, 30 prendevano in considerazione il fattore dolore, 13 l’utilizzo di oppiacei in singolo e 10 l’utilizzo di oppiacei precedenti l’esposizione allo stimolo doloroso. Di questi studi, 34 sono stati condotti su ratti e solo 4 invece su topi. L’outcome che abbiamo deciso di analizzare è stato l’effetto di queste tre variabili sullo sviluppo della soglia del dolore. Risultati Prendendo in considerazione i risultati ottenuti, il dolore appare come un fattore determinante lo sviluppo della soglia dolorosa. Evidenze simili sono state riscontrate anche negli studi sulla terapia analgesica preventiva. Al contrario, non ci sono state evidenze statisticamente significative rispetto all’esposizione alla terapia oppiacea considerata come variabile singola, anche se un trend generale può essere osservato. Conclusioni I bambini nati prematuri sono sottoposto ad un elevato numero di procedure dolorose durante il ricovero presso le unità di terapia intensiva. Questi eventi sembrerebbero avere un effetto a lungo termine sulla percezione del dolore durante lo sviluppo e in età adulta, suggerendo un effetto diretto sulla plasticità sinaptica osservabile nel periodo post-natale precoce. L’utilizzo di oppiacei e morfina come strumenti per contrastare il dolore sembrerebbero ridurre l’iperalgesia determinata dall’esposizione alla noxa patogena nei primi giorni di vita. Per questo motivo la terapia con oppiacei sembrerebbe avere un razionale giustificato, in quanto non vi è evidenza di effetti a lungo termine sulla sensibilità dolorifica derivanti da queste molecole. Tuttavia, l’utilizzo di morfina deve sempre essere studiato in modo ottimale nei bambini prematuri, in modo da poter somministrare delle dosi ottimali in modo sicuro.
The Impact of Pain, Pre-Emptive Morphine, and Morphine on the Development of Pain Threshold in Preterm Infants: A Meta-Analysis. Understanding the Complexity of Neonatal Development through The Animal Model
BOTTAZZOLI, MARTINA
2019/2020
Abstract
Background In the past decades, the mortality of preterm infants has decreased thank to more accurate care during their stay in the Neonatal Intensive Care unit (NICU). Though, the management of these babies still arises many questions, as the implication of the use of opioids in very preterm infants is still controversial. Opioids are the first-line analgesic treatment in preterm infants, though their effect on long term development would require further investigation. Furthermore, infants born preterm undergo several other stressful situations, such as mother separation and handling procedures, which might have implications on neurological development on the baby and response to painful and stressful situations later in life. In particular we investigated how pain and opiates might influence pain threshold in developmental age and adulthood. Very few clinical studies have been performed to verify these hypotheses, and therefore the use of murine model acquire a great importance not only in research field, but also to be transmitted to the clinical practice. Design and Methods 38 studies were selected to take part to our meta-analysis. Studies evaluating the effect of pain, opiates treatment, as well as opiate treatment prior to a painful event were analyzed. Within those, 30 studies (79%) evaluated the impact of pain only, 13 studies (34%) evaluated the impact of opiates only, and 10 studies evaluated the effect of opiates prior to painful stimuli (pre-emptive). 34 studies (89%) were conducted on rats, whether just 4 studies (11%) were performed on mice. The first outcome to our study was the study of the three factors (pain, opiates treatment and pre-emptive treatment) on pain threshold. Results According to our results, pain has a significant incidence on the development of pain threshold (Z = 3,24 and P = 0,001). A similar correlation was found also in pre-emptive morphine group (Z= 3.79 and P = 0.001). The use of morphine alone did not show any statistically significant result (Z = 0.47), though a main trend might be present. Conclusions Preterm children experiencing NICU stay undergo several and repeated painful procedures, as well as maternal separation. These painful and stressful stimuli seem to determine a long-term effect on pain perception in later life, suggesting that they might affect neuronal development in the first weeks of extrauterine life. The use of opioids as pre-emptive therapy seems to reduce the long-term hyperalgesia associated to pain exposition in early life. The use of morphine as main source of analgesic is therefore justified, as there is no evidence of long-lasting effect on pain sensitivity. Nonetheless morphine should carefully administered in preterm, to provide a safe and beneficial use.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/12885