Conclusioni

I disturbi del sonno si confermano essere un’importante comorbidità della cefalea in età pediatrica, con una prevalenza del 29,5% nella popolazione presa in esame così come riportato in letteratura (prevalenza del 25-40%). I disturbi del sonno più frequentemente riportati dal gruppo di pazienti esaminati sono stati: restless sleep, difficoltà ad addormentarsi, ritardo di fase del ciclo circadiano e parasonnie. Nel contesto di quest’ultima categoria di disordini del sonno sono stati riferiti in particolare: sonniloquio, sonnambulismo ed incubi. Ciò che è stato rilevato nella popolazione analizzata corrisponde a quanto riportato in letteratura da autori quali Bruni et al. e Miller et al.; solo i disturbi del sonno correlati alla

Emicrania senza aura Terapia Melatonina+ Magnesio 3 18 21 _0.259 Magnesio 6 15 21 Totale 9 33 42 Totale Terapia Melatonina+ Magnesio 6 23 29 _0.440 Magnesio 8 19 27 Totale 14 42 56

Risposta Totale p-value

No Si Dosaggio melatonina 2 mg 1 4 5 0.925 1 mg 7 25 32 Totale 8 29 37

69 respirazione sono stati rilevati con una frequenza poco significativa e ciò può essere imputato al fatto che il suddetto tipo di disturbo del sonno viene riscontrato più frequentemente in pazienti affetti da cefalea secondaria a patologia respiratoria.

La melatonina costituisce il fondamento della terapia dei disturbi del sonno e del ciclo circadiano visto il suo ruolo centrale nella sincronizzazione degli eventi interni all’organismo ed esterni, la capacità di regolare il ciclo circadiano e di facilitare l’addormentamento. Pur mantenendo l’indicazione alla terapia dei disturbi del sonno negli ultimi 10 anni è cresciuto l’interesse per la melatonina in diversi ambiti: neurologico, anestesiologico, oncologico e gastroenterologico. I benefici dimostrati da alcuni studi clinici e gli scarsi effetti avversi correlati a questa molecola rendono la melatonina una potenziale terapia allettante. Negli ultimi anni sono stati condotti molti studi sull’efficacia della melatonina nella profilassi della cefalea, di questi solo due sono stati condotti sulla popolazione pediatrica (Miano et al. nel 2008 e Fallah et al. nel 2018); entrambi hanno messo in luce risultati positivi anche se lo studio di Miano è stato condotto su un limitato campione di pazienti e in assenza di un gruppo di controllo e Fallah et al. hanno dimostrato l’efficacia della melatonina ma l’inferiorità della stessa rispetto all’amitriptilina.

Il nostro studio è stato il primo ad aver preso in considerazione melatonina e magnesio. La risposta clinica in termini di efficacia (riduzione degli episodi di cefalea ≥ 50%) nel gruppo che ha assunto melatonina in associazione al magnesio ammonta al 78% mentre nel gruppo di controllo ammonta al 70,5%. La somministrazione di melatonina ha quindi comportato una risposta percentuale maggiore ma non tale da essere ritenuta statisticamente significativa; questo dato può essere riferibile ai più bassi dosaggi utilizzati nel nostro studio rispetto a quanto riportato in letteratura, infatti gli studi in questo ambito sono difficilmente paragonabili proprio per i diversi dosaggi utilizzati e per la diversa formulazione di melatonina utilizzata (rilascio prolungato o immediato). Nel nostro studio in particolare i pazienti hanno assunto 1mg o 2mg, mentre gli studi in letteratura che hanno avuto esito positivo hanno utilizzato dosi superiori o uguali ai 3mg. Possiamo affermare dai dati da noi raccolti che vi è un risultato analogo sia in caso di somministrazione di 1mg che di 2mg, probabilmente con un ulteriore aumento della dose potremmo assistere ad un risultato statisticamente significativo dal punto di vista clinico. In contrapposizione a queste ipotesi è comunque la recente teoria avanzata da Ebrahimi-Monfared, il quale ha proposto l’assenza di una significativa correlazione tra risposta e dosaggio di melatonina utilizzato e che l'eventuale condizione di resistenza alla melatonina potrebbe essere riferibile alle pregresse terapie effettuate per la prevenzione della cefalea stessa.

70 Si è voluto testare in questo studio l’associazione tra melatonina e magnesio poiché molti dati in letteratura supportano l’efficacia della melatonina nella terapia preventiva della cefalea e il magnesio rappresenta il trattamento di prima scelta nella profilassi della cefalea; abbiamo pertanto voluto verificare se nei soggetti resistenti alla terapia con magnesio, l'associazione con la melatonina avrebbe potuto migliorare la risposta clinica evitando in tal modo il ricorso ai farmaci veri e propri i quali possono presentare un corteo di reazioni avverse più importanti. Il nostro lavoro rappresenta uno studio preliminare in un campo relativamente nuovo e vasto che negli ultimi anni sta testando l’efficacia della melatonina in molteplici campi; pertanto è necessario confermare se a dosi superiori la melatonina è effettivamente in grado di ottenere un miglioramento clinico significativo e se la risposta positiva si manifesta anche nella popolazione cefalalgica senza disturbi del sonno; questo dato sarà importante per valutare se il meccanismo con il quale agisce la melatonina dipende principalmente dalla capacità di indurre il sonno e regolare il ciclo circadiano o dalle altre proprietà di natura antiossidante, antinfiammatoria e analgesica che la melatonina ha recentemente dimostrato di avere. Attualmente i dati in letteratura ricavati dai trials condotti sugli adulti sembrano indicare un significativo ruolo di quest’ultime proprietà.

Sarebbe inoltre interessante valutare in uno studio prospettico i livelli di melatonina endogena nei pazienti che riferiscono una risposta positiva per indagare una eventuale correlazione tra le basse concentrazioni di melatonina endogena e la risposta alla melatonina esogena, già proposta in letteratura ma non ancora confermata, e confrontare infine l’azione della melatonina a rilascio immediato, della forma a rilascio prolungato e degli agonisti melatonergici per indagarne l’eventuale superiorità.

71

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