Pro p h y l a c t i c dru g tre a t m e n t of mi g r a i n e in chi l d r e n an d ad o l e s c e n t s : an up d a t e
Jáno s Tajti1, Délia Szok1, Anett Csáti1, László Vécsei1,2*
1Dep a r t m e n t of Neu r ol o g y , Fac ulty of Medicin e, Unive r si ty of Szeg e d , Szeg e d , Hu n g a r y
2MTA – SZTE Neu r o s c i e n c e Res e a r c h Gro u p , Sze g e d , Hu n g a r y
1Dep a r t m e n t of Neu r ol o g y , Unive r si ty of Sze g e d , Sem m e l w e i s u. 6, H- 672 5 , Szeg e d , Hu n g a r y
2Neu r o s ci e n c e Res e a r c h Grou p of the Hu n g a r i a n Acad e m y of Scie n c e s and Unive r si ty of Szeg e d (MTA – SZTE Ne u r o s ci e n c e Rese a r c h Grou p ), Se m m e l w e i s u. 6, H- 672 5 Szeg e d , Hun g a r y
*Corr e s p o n d i n g aut h o r . E- mail: vecs ei.la s zlo@ m e d . u - szeg e d . h u , Tel.:
+ 3 6- 62- 545 3 4 8 , Fax: + 3 6- 62- 545 5 9 7
Abs t r a c t
Migr ai n e as a hig hly disa blin g pain con di tio n influe n c e s the daily activitie s of tho s e affect e d , inclu din g child r e n an d adole s c e n t s .
The pat h o m e c h a n i s m of mig r ai n e is not fully und e r s t o o d , and th e differ e n t typ e s of pro p h yl a c ti c anti mi g r a i n e dru g s th a t ar e ap plie d ar e not sp ecific for mig r ai n e . Ther e is a ne e d for prev e n t iv e tre a t m e n t in the eve n t of freq u e n t mig r ai n e att a c k s , an imp ai r m e n t of th e qu ality of life, sev e r e acco m p a n y i n g or au r a symp t o m s , an d th e failu r e of acu t e dru g tre a t m e n t . The followin g ph a r m a c o l o g i c a l class e s ar e reco m m e n d e d : anti d e p r e s s a n t s , antie pil e p t i c s , antihis t a m i n e s , bet a- ad r e n e r g i c rec e p t o r block e r s an d calciu m ion cha n n e l an t a g o n i s t s , besid e s ona b o t u li n u m toxin A an d nut r a c e u t i c a l s (but t e r b u r ) .
The mos t urg e n t goal as con c e r n s ph a r m a c e u t i c a l innov a tio n is th e develo p m e n t of pat h o m e c h a n i s m - bas e d an ti mi g r a i n e dr u g s an d per s o n a liz e d the r a p y tailor e d to th e child r e n an d adole s c e n t s .
Key w o r d s : an ti d e p r e s s a n t s , an ti e p il e p ti c s , anti hi s t a m i n e s , bet a- ad r e n e r g i c rec e p t o r block e r s , butt e r b u r , calciu m ion ch a n n e l an t a g o n i s t s , effica cy, mig r ai n e , ona b o t u li n u m toxin A, pedi a t r i c, pro p h yl a c ti c, safe ty, the r a p y , toler a b ility
Intr o d u c t i o n
Migr ai n e is a hig hly deva s t a t i n g neu r o v a s c u l a r prim a r y hea d a c h e diso r d e r th at can affec t subje c t s fro m child h o o d onw a r d s [1, 2].
The He a d a c h e Clas sific a tio n Com mi t t e e of th e Inte r n a t i o n a l Hea d a c h e Socie ty (IHS) [3] has clas sifie d mig r ai n e into sub ty p e s : mig r ai n e with o u t au r a , mig r ai n e with au r a , chr o n i c mig r ai n e , com plic a ti o n s of mig r a i n e , pro b a b l e mig r ai n e and episo dic synd r o m e s tha t may be asso ci a t e d with mig r ai n e . The ea rlie r na m e of this last sub ty p e was child h o o d perio dic syn d r o m e s th a t ar e com m o n ly pr e c u r s o r s of mig r ai n e [3]. Episo dic syn d r o m e s tha t may be asso ci a t e d with mig r ai n e ar e furt h e r sub divid e d : rec u r r e n t gas t r o i n t e s t i n a l dist u r b a n c e : cyclic vomitin g syn d r o m e an d ab d o mi n a l mig r ai n e , benig n par oxy s m a l ver tig o an d benig n par o xy s m a l torticollis [3]. In youn g patie n t s , mig r ai n e may occu r with or with o u t au r a and th e r e may be an incr e a s e d risk of the dev elo p m e n t of eith e r of th es e diso r d e r s [3]. A rec e n t ret r o s p e c t iv e stu dy de m o n s t r a t e d tha t the prev al e n c e of episo dic syn d r o m e s th a t may be asso ci a t e d with mig r ai n e was 5.6% [4]. The mos t freq u e n t typ es of mig r ai n e ar e mig r ai n e witho u t au r a an d mig r ai n e with au r a. The typic al clinic al feat u r e s ar e a dur a t io n of 4- 72 hou r s , a unilat e r a l localiz a tio n , a puls a ti n g qu ality an d mod e r a t e to seve r e inte n s i t y, wor s e n i n g in res p o n s e to rou tin e physic al activity, and usu ally com bi n e d with nau s e a , vomitin g , an d/o r phot o p h o b i a an d pho n o p h o b i a as conco m i t a n t symp t o m s of th e he a d a c h e [3]. In the even t the occu r r e n c e of mig r ai n e au r a , visu al, sen s o r y or oth e r cen t r a l nerv o u s syst e m symp t o m s dev elo p gr a d u a lly and tem p o r a r ily, usu ally pr e c e d i n g the hea d a c h e ph a s e [3]. Chro ni c mig r ai n e , one of the dev a s t a t i n g sub ty p e s of mig r ai n e , has a consid e r a b l e influ e n c e on the quality of life, eve n in youn g patie n t s [5, 6]. By definitio n, chro ni c mig r ai n e is the per si s t e n c e of hea d a c h e for at leas t 15 days per mo n t h (mig r ai n e qu ality on at leas t 8 days) and for at leas t 3 con s e c u t iv e mon t h s [3].
In pedi a t r i c mig r ai n e patie n t s , th e du r a ti o n of th e mig r ai n e att a c k may be sho r t e r , the locatio n of the pain is often bilat e r a l, an d abd o m i n a l pain, nau s e a an d vomitin g are mor e freq u e n t [7]. The diag n o s i s of mig r ai n e in
child r e n and adole s c e n t s is th e r e f o r e rat h e r difficult, and th e IHS diag n o s t i c crite r i a ar e bro a d e r th a n in ad ult s [7, 8].
The impo r t a n c e of mig r ai n e in child h o o d is reflec t e d by th e fact th at a majo rity of the hea d a c h e cas e s obs e r v e d in the pedi a t r i c em e r g e n c y dep a r t m e n t involve mig r ai n e [9]. Epid e m i olo gi c al dat a have rev e a l e d tha t 40% of hea d a c h e s ar e pri m a r y hea d a c h e s , 75% of the s e cas e s bein g mig r ai n e [9]. Clinical stu di e s hav e de m o n s t r a t e d th a t the pr ev al e n c e of mig r ai n e incr e a s e s with ag e, [1, 10] 3% or less in tho s e up to 7 year s old, 11% amo n g 11 - yea r – olds, an d 23- 28% in adole s c e n t s (13- 18 yea r s old) [1, 10]. In a larg e coho r t , of child r e n the prev al e n c e of mig r ai n e prov e d to be 10.1 %, an d th a t of mig r ai n e with au r a 1.6% [11]. The pr ev al e n c e of mig r ai n e dep e n d s on the ag e an d th e gen d e r . The sex ratio of mig r ai n e patie n t s is 1:1 (boys:girls) in child h o o d , the ratio sub s e q u e n t l y incr e a s i n g with the pro g r e s s i o n of ag e to 1:3 (male s:f e m a l e s ) [11]. The me a n ag e of ons e t of mig r ai n e is 7.2 year s in boys an d 10.9 yea r s in girls [1].
The pat h o m e c h a n i s m of mig r ai n e has not bee n clea rly elucid a t e d , but activ a tio n an d sen si tiz a ti o n of th e trig e m i n o v a s c u l a r syste m an d distin c t neu r o p e p t i d e s ar e de e p ly involve d [12- 15] (Figu r e 1).
In con s e q u e n c e of the lack of knowl e d g e the pr e ci s e pat h o g e n e s i s of the initia tio n an d the rec u r r e n c e of mig r a i n e att a c k s , specific anti mi g r a i n e pro p h yl a c t i c tre a t m e n t is not availa bl e [16- 19]. In ever y d a y pedia t r i c clinic al pr a c ti c e , the reco m m e n d e d dru g s for th e prev e n t i o n of mig r ai n e hea d a c h e att a c k s ar e antid e p r e s s a n t s (amit ri p t ylin e (AMI) an d nort r i p t ylin e (NOR)), antie p il e p ti c s (valp r o a t e s , VALPs; topir a m a t e , TOP;
leveti r a c e t a m , LEV; zonis a m i d e , ZON; an d gab a p e n t i n , GBP), anti his t a m i n e s (cypr o h e p t a d i n e , CYP), bet a- ad r e n e r g i c rec e p t o r block e r s (pro p r a n o l o l, PROP) an d calciu m ion cha n n e l ant a g o n i s t s (flun a r i zi n e , FLUN) [7, 20]. Ona b o t u li n u m toxin A (OBOT- A) has rec e n t ly bee n applie d for the allevia tio n of chro ni c mig r a i n e in child r e n an d adole s c e n t s [21- 23], an d butt e r b u r may be me n tio n e d as a nut r a c e u t i c a l .
This revie w discu s s e s th e dr u g s cur r e n t ly use d in the prev e n t iv e the r a p y of mig r ai n e in child r e n an d adole s c e n t s .
Pro p h y l a c t i c dru g tre a t m e n t in pe d i a t r i c mi g r a i n e
The indic a ti o n s of pro p h yl a c ti c mig r ai n e th e r a p y inclu d e a hig h freq u e n c y of mig r ai n e att a c k s , an imp air m e n t of the qu ality of life an d of the reg u l a r i t y of sch o ol att e n d a n c e , the ineffec tiv e, not toler a t e d , con t r ai n d i c a t e d or over u s e d acu t e man a g e m e n t of hea d a c h e att a c k s , or the pr es e n c e of com pl e x an d seve r e acco m p a n y i n g symp t o m s or long unco mf o r t a b l e au r a symp t o m s [1, 7, 16, 17]. The fund a m e n t a l aims of anti mi g r a i n e tre a t m e n t ar e a dec r e a s e of the att a c k freq u e n c y by at leas t 50% within 3 mon t h s an d a dimin u t io n of the du r a t i o n and inte n s i ty of the hea d pain [1, 17]. Altho u g h aro u n d one- thir d of adole s c e n t s nee d pro p h yl a c t i c anti mi g r a i n e the r a p y , only 10- 19% ar e offer e d it [24]. For this sp eci al pop ul a tio n , the par e n t s or oth e r family me m b e r s sho ul d be ed u c a t e d as to the effec t s an d possi bl e adv e r s e even t s (AEs) of the dru g s and th e dru g titr a tio n an d dosin g sch e d u l e [25]. Avoida n c e of th e side- effec t s of th e dr u g s dem a n d s slow titr a tio n (4- 12 week s ) and the tre a t m e n t perio d is sug g e s t e d to be at leas t 6- 8 week s [25]. In gen e r a l, it is very impo r t a n t th a t the ph a r m a c o l o g i c a l tre a t m e n t of youn g mig r ai n e patie n t s sho ul d be acco m p a n i e d by psyc h olo g ic a l sup p o r t for.
Anti d e p r e s s a n t s
Amitri p t yli n e
AMI, a tricyclic an tid e p r e s s a n t , has a multipl e mod e of actio n , which inclu d e s the block a d e of nor e p i n e p h r i n e an d ser o t o n i n reu p t a k e , tog e t h e r with antic h o lin e r g i c , hist a m i n e r g i c an d ga m m a - amin o b u t y r i c acid (GABA)-er gic effect s [26, 27]. AMI influe n c e s the antin o cic e p t iv e func tio n via activ a tio n of the ad e n o s i n e A1 rec e p t o r and en h a n c e s neu r o n a l sen si tivity to sub s t a n c e P (SP) [19].
In the pro p h yl a c t i c tre a t m e n t of pedi a t r i c mig r ai n e , AMI is one of th e mos t widely use d ph a r m a c o n s des pi t e th e perfo r m a n c e of only a low nu m b e r of ran d o m i z e d clinic al trials. A rec e n t lar g e aca d e m i c hospit al stu d y rev e al e d th a t AMI was the mos t com m o n pr ev e n t iv e medic a t i o n
pre s c r i b e d to pedi a t r i c patie n t s with mig r ai n e eith e r with or with o u t au r a [28]. In a stu d y wh e r e low- dos e AMI or PROP was add e d to non p h a r m a c o l o g i c al th e r a p e u t i c me a s u r e s (e.g. rela ti n g to slee p hygie n e , diet e ti c and lifestyle reco m m e n d a t i o n s , or sun expo s u r e ) , it was con clu d e d tha t th e bot h two dru g s wer e eq u a lly effec tiv e in red u ci n g th e freq u e n c y of pedi a t r i c mig r ai n e [29]. A dou bl e- blind place b o- con t r olle d multic e n t e r com p a r a t iv e effec tiv e n e s s stu d y of AMI an d TOP is ong oin g (Child h o o d an d Adoles c e n t Migr ai n e Prev e n ti o n Stu dy, CHAMP), with the aim of a 50% red u c t io n in mig r a i n e freq u e n c y in child r e n and adol e s c e n t s as prim a r y outc o m e [30]. The first res ul t s ar e plan n e d to be pu blis h e d in 201 6 . A pro s p e c t i v e trial has led to th e findin g th a t sup pl e m e n t a r y vita mi n D the r a p y in ad ditio n to AMI signific a n tly red u c e s the nu m b e r of mig r ai n e att a c k s in pedi a t r i c mig r a i n e patie n t s [31]. A ran d o m i z e d clinic al trial focusin g on the effect s of cog nitiv e beh a vio r a l the r a p y (CBT) plus AMI vers u s hea d a c h e edu c a t io n plus AMI in chro ni c mig r ai n e pedi a t r i c patie n t s prov e d tha t the red u c ti o n in the nu m b e r of hea d a c h e days was sup e r i o r in th e CBT plus AMI gro u p [32].
The reco m m e n d e d dos e of AMI is 10- 150 mg qhs (“eve r y nigh t at bed ti m e ”) (at mos t 1 mg/k g / d a y ) [7]. The rea s o n for the bed ti m e dosin g is the som n ol e n c e th a t occu r s as one of the most com m o n side- effect s of the dru g [25, 33]. Oth e r freq u e n t AEs ar e dizzin e s s , con s ti p a t i o n , an incr e a s e d app e t i t e an d a weig h t gain [7]. AMI is pr ef e r r e d in view of its rela tiv ely favor a b l e side effect profile and dosin g regi m e [33]. The reco m m e n d a t i o n levels of mig r ai n e pro p h yl a c t i c dru g s ar e bas e d on th e rep o r t s of the Scie n tific Task For c e of the Euro p e a n Fed e r a t i o n of Neu r o lo gi c a l Socie ti e s an d the Quality Sta n d a r d Sub c o m m i t t e e of the Americ a n Acad e m y of Neu r ol o g y an d the Americ a n He a d a c h e Society [34, 35]. The reco m m e n d a t i o n level of AMI: Class IV, Level U [25] (Table 1.).
Nor tri p t yli n e
In actu a l medic al pr a c ti c e inst e a d of AMI may be repla c e d by NOR, which has a lowe r sed a t iv e effect, but men ti o n mu s t be mad e of its significa n t
pote n t i al car di a c side effec t (ar r h y t h m i a ) [7, 25]. The reco m m e n d e d dos e of NOR is 10- 75 mg qhs [7].
Anti e p i l e p t i c s
Valpro a t e s
The VALPs con sis t of valp r oic acid, sodiu m valp r o a t e an d som e com bi n a t i o n of the s e dru g s . They str o n g ly block the perip h e r a l an d cen t r a l trig e m i n o v a s c u l a r res p o n s e s an d nocic e p t iv e tr a n s m i s s i o n , exer t a gr e a t influe n c e on th e cor tic al neu r o n a l hyp e r e x ci t a b ility an d sup p r e s s cor tic al spr e a d i n g dep r e s s i o n via th e GABA-A rec e p t o r [36, 37].
A pro s p e c t i v e ran d o m i z e d clinical trial in whic h PROP an d sodiu m valp r o a t e wer e com p a r e d as con c e r n s th eir efficacy in prev e n tiv e mig r ai n e tr e a t m e n t in child r e n an d adole s c e n t s foun d no significa n t differ e n c e bet w e e n the s e two dr u g s in mea n hea d a c h e dur a ti o n per week , in hea d a c h e sev e ri ty, or in th e com pl e t e ces s a t io n of he a d a c h e att a c k s . The me a n hea d a c h e freq u e n c y per mon t h was lowe r in the PROP gro u p tha n in th e sodiu m valp r o a t e gro u p . As reg a r d s th e side- effec t s , the r e was no signific a n t differ e n c e bet w e e n the two dr u g s [38]. Dose s of 15- 20 mg/k g / d a y ap p e a r to be effec tiv e. The com m o n AEs of VALPs ar e som n o l e n c e , a skin ras h , a weig h t gain, tr e m o r , dro w si n e s s , hair loss, an d he m a t o l o g i c al or liver ab n o r m a l i ti e s [39, 40]. Due to th eir ter a t o g e n i ci ty , VALPs can n o t be reco m m e n d e d for fem al e s of rep r o d u c t i v e ag e [19]. A rec e n t met a- an alysis focu sin g on th e ph a r m a c o l o g i c al prev e n t iv e tre a t m e n t of pedi a t r i c mig r ai n e indic a t e d th a t VALPs wer e foun d ineffec tiv e in red u c i n g the nu m b e r of hea d a c h e s per mon t h [41]. The reco m m e n d a t i o n level of VALPs: Clas s IV, Level U [25].
Topira m a t e
As conc e r n s mig r ai n e , TOP influe n c e s the pain tra n s m i s s i o n in the trig e m i n o c e r v i c a l com pl ex and the thir d- ord e r neu r o n s in the ven t r o p o s t e r o m e d i a l th al a m u s [37].
A pros p e c t iv e clinical stu dy conclu d e d th a t a low pro p h yl a c ti c dos e (< 2 mg/k g / d a y ) of TOP is effectiv e in red u ci n g the mea n freq u e n c y , du r a ti o n and inte n si ty of pedi a t r i c mig r ai n e [42].
A ran d o m i z e d com p a r a t i v e clinical trial de m o n s t r a t e d th a t TOP an d PROP tre a t m e n t displ ay e d the sam e efficie n cy in red u c i n g the hea d a c h e freq u e n c y and the sev e ri ty an d dur a ti o n of mig r ai n e att a c k s in child h o o d [43].
In a furt h e r clinical stu dy, TOP prov e d effec tiv e (the mon t h ly freq u e n c y , sev e r i ty and dur a ti o n of mig r ai n e hea d a c h e wer e all decr e a s e d ) an d safe for the pro p h yl axis of mig r a i n e in child r e n [44]. A ret r o s p e c t i v e com p a r a t iv e trial reve al e d tha t the effect s of FLU N an d TOP did not differ significa n t ly as conc e r n s the tot al nu m b e r of hea d a c h e days per mo n t h in pre a d o l e s c e n t an d adole s c e n t mig r ai n e patie n t gro u p s with or with o u t au r a [45].
A rec e n t revie w con clu d e d tha t TOP is effec tiv e in dec r e a s i n g the freq u e n c y of he a d a c h e s in pedi a t r i c mig r a i n e pati e n t s [46]. A > 50%
red u c ti o n in mig r ai n e rat e was att ai n e d in 83- 95% of th e patie n t s . The reco m m e n d e d dose of TOP is 1- 10 mg/k g/ d a y , with a gen e r a l dose of 50 mg bid (twice per day) [7]. TOP is well toler a t e d ; its com m o n AEs ar e nu m b n e s s , a weig h t loss, a cog ni tiv e imp air m e n t (affec ti n g th e ver b al flue n cy, conc e n t r a t i o n an d wor kin g me m o r y), fatig u e , na u s e a and som n o l e n c e [47]. The reco m m e n d a t i o n level of TOP: Class IV, Level U [25].
Leve tira c e t a m
LEV is a pyrolid o n e deriv a tiv e with an antie p il e p ti c effect. It has a novel and ap p a r e n t l y uniq u e mec h a n i s m of actio n , whic h may be ass o ci a t e d with its bin din g to syn a p t i c vesicle pro t ei n SV2A, th e r ef o r e influe n ci n g the neu r o t r a n s m i t t e r rele a s e [48].
An ea rly sm all ret r o s p e c t i v e stu d y, on the efficacy of LEV in pedi a t r i c mig r ai n e point e d to its ben efici al effect (in 10 of 19 child r e n and adol es c e n t s , LEV elimin a t e d the mig r a i n e hea d a c h e ) [49]. An open label stu d y led to th e conclu sio n tha t LEV red u c e d th e freq u e n c y of mig r a i n e : a
mor e tha n 50% dec r e a s e in the freq u e n c y of mo n t h ly hea d a c h e s an d was achiev e d (in 18 of 20 patie n t s ) , an d th e Pedia t r i c Mig r ai n e Disability Asses s m e n t Test (Ped MIDAS) rev e al e d a significa n t decr e a s e in disa bility as com p a r e d with the bas eli n e in pedi a t r i c mig r a i n e u r s [50]. The reco m m e n d e d daily dos e of LEV is 500- 150 0 mg bid [7, 20]. Its safety profile app e a r s acc e p t a b l e , but its com m o n AEs inclu d e som n ol e n c e , fatig u e , irrit a b ility and dizzin e s s [7, 20, 25]. The reco m m e n d a t i o n level of LEV: Clas s IV, Level U [25].
Zonisa m i d e
ZON is a synt h e t i c 1,2- ben zis ox a z ol e- 3- me t h a n e s u l f o n a m i d e , which acts by inhibiti n g the voltag e- sen si tiv e sodiu m and red u ci n g th e volta g e- sen si tiv e T-typ e calciu m cha n n e l s [51].
A very small ret r o s p e c t iv e stu dy sug g e s t e d th a t ZON had the cap a b ility to red u c e th e hea d a c h e freq u e n c y in refr a c t o r y pedi a t r i c he a d a c h e patie n t s (8 of 12 patie n t s res p o n d e d favor a b ly) [52]. The reco m m e n d e d dos e of ZON is 100- 600 mg per day [7, 20]. Its com m o n AEs ar e dizzin e s s , nau s e a , irrit a b ility an d som n ol e n c e [7, 20]. The reco m m e n d a t i o n level of ZON: Class IV, Level U [25].
Gaba p e n t i n
GBP is str u c t u r a lly rela t e d to GABA, but with o u t any dire c t effect s on GABA or any of its rec e p t o r s [53]. Ther e hav e bee n only very rar e clinic al stu di e s of GBP in pedi a t r i c mig r ai n e . Belm a n et al. rep o r t e d dat a on 18 mig r ai n e child r e n tre a t e d with GBP, 80% of who m att ai n e d a mor e th a n 50% red u c t i o n in mig r ai n e freq u e n c y [20, 54]. The reco m m e n d e d dos e of GBP is 300- 120 0 mg thr e e time s daily (tid) [20]. The com m o n AEs of GBP ar e sed a ti o n , ataxi a, fatig u e and perip h e r a l ed e m a [20]. The reco m m e n d a t i o n level of GBP: Class IV, Level U [25].
Anti h i s t a m i n e s
Cypro h e p t a d i n e
CYP exer t s antihis t a m i n e r g i c , antis e r o t o n i n e r g i c an d antic h olin e r g i c actio n s , and has the ability to block (com p e t i tiv ely an d reve r si b ly ant a g o n i z e) th e hist a m i n e an d ser o t o n i n rec e p t o r s [55]. The 5- hyd r oxy t r y p t a m i n e 1B an d 1D rec e p t o r s tak e par t in th e activa tio n of the trig e m i n o v a s c u l a r syst e m via cer e b r o v a s c u l a r vasoco n s t r i c ti o n and inhibitio n of th e rele a s e of vaso a c tiv e neu r o p e t i d e s , e.g. calcito ni n gen e- rela t e d pep ti d e (CGRP), SP an d pituit a r y ad e n yl a t e cyclas e- activ a ti n g polyp e p t i d e (PACAP) [2, 18, 56, 57].
In a dou bl e- blind cont r o ll e d stu d y in which patie n t s ag e d 16 to 53 yea r s (me a n 28.6) rec eiv e d CYP as pro p h yl a c ti c tr e a t m e n t of mig r a i n e , the me a n hea d a c h e freq u e n c y dec r e a s e d fro m 8.4 to 3.7 per mon t h , with an over all positiv e res p o n s e rat e of 83% [58]. A rec e n t ret r o s p e c t iv e clinical stu d y led to th e findin g th a t CYP was effec tiv e in ab d o m i n a l mig r a i n e an d in cyclic vomitin g syn d r o m e (amo n g th e func tio n a l gas t r o i n t e s t i n a l diso r d e r s ) , the res p o n d e r rat e provin g to be high: in ab d o m i n a l mig r ai n e 13 of 18 pedi a t r i c pati e n t s (72%) an d in cyclic vomitin g synd r o m e 6 of 8 patie n t s (75%) exhibit e d a clinic al imp r o v e m e n t [59]. CYP is availa bl e as table t s an d liquid sus p e n s i o n s , with reco m m e n d e d dos e s of 0.25- 1.5 mg/k g / d a y [20]. The mos t com m o n sid e- effect s of CYP ar e slee p i n e s s , a weig h t gain and an incr e a s e d app e ti t e [7, 33, 59]. An inves ti g a t i o n by a lar g e aca d e m i c child r e n’ s hos pit al of the pre s c r i p ti o n pat t e r n s in pati e n t s ag e d 2- 17 yea r s de m o n s t r a t e d , th at th e one of the most com m o n by pre s c r i b e d medic a t i o n s for pedi a t r i c mig r ai n e pro p h yl axis was CYP [28].
The reco m m e n d a t i o n level of CYP: Clas s IV, Level U [25].
B e t a - adr e n e r g i c re c e p t o r blo c k e r s
Propra n olol
PROP, a non s el e c t iv e bet a- ad r e n e r g i c rec e p t o r block e r th a t inhibit s the thir d- ord e r trig e m i n o v a s c u l a r nocic e p t iv e neu r o n s in th e ven t r o p o s t e r o m e d i a l nucl e u s of th e th al a m u s [19, 60], has a long histo r y
of use in mig r a i n e pro p h yl axis in child r e n [61]. The res ul t s em e r g i n g fro m clinic al trials hav e bee n conflictin g [1, 25].
In rec e n t stu di e s , PROP has bee n wid ely use d as a com p a r a t i v e ph a r m a c o n .
In a pro s p e c t iv e ra n d o m i z e d trial which com p a r e d the pro p h yl a c ti c an ti- mig r ai n e effect s of PROP an VALP in child r e n (ag e d 5- 15 yea r s) with mig r ai n e witho u t au r a, VALP was foun d to be sup e r i o r to PROP only in red u ci n g the me a n he a d a c h e freq u e n c y per mo n t h [38]. Low- dos e PROP and low- dos e AMI prov e d equ ally effec tiv e in red u c i n g th e freq u e n c y of sev e r e mig r ai n e att a c k s in pedi a t r i c mig r a i n e u r s (me a n ag e 12.5 4 yea r s), but it was not e w o r t h y th at PROP had few e r side- effect s [29]. A ra n d o m i z e d clinic al com p a r a t i v e trial rela tin g to child h o o d mig r a i n e pro p h yl a xis rev e al e d th a t TOP an d PROP display e d the sam e efficacy in red u ci n g the freq u e n c y , seve ri ty an d du r a ti o n of mig r ai n e att a c k s [43]. In con t r a s t , ano t h e r pa r all el single- blin d e d ran d o m i z e d clinical trial involvin g 5- 15- yea r- old mig r ai n e u r s reve al e d tha t TOP was mor e effectiv e tha n PROP in red u c i n g the mo n t h ly freq u e n c y , seve r i ty an d du r a t i o n of hea d a c h e an d in the Ped MI DAS sco r e . Both dru g s exer t e d tr a n s i e n t an d mild side- effec t s [62]. A rec e n t comp a r a t i v e ra n d o m i z e d cont r oll e d trial tha t focu s e d on the effec t s of PROP as com p a r e d with pr e g a b a li n in pedi a t r i c mig r ai n e led to the res u lt tha t pre g a b a li n red u c e d th e hea d a c h e freq u e n c y consid e r a b l y mo r e effectiv ely tha n did PROP [63].
The reco m m e n d e d dos e of PROP is 2- 4 mg/k g/ d a y . The mos t com m o n side- effec t s ar e hypo t e n s i o n , dep r e s s i o n an d dizzin e s s [7, 20]. The unfav o r a b l e AEs of PROP hav e limite d its wid e- ran g i n g use in youn g mig r ai n e u r s [25]. The reco m m e n d a t i o n level of PROP: Clas s II, Level U [25].
Calci u m io n ch a n n e l an t a g o n i s t s
Fluna ri zi n e
FLUN is a non s el e c t iv e calciu m ion ent r y block e r tha t mainly act s via T- type ion ch a n n e l s [64]. Its exact mec h a n i s m of actio n in mig r ai n e is still
unk n o w n , but it may involve smo o t h mus cl e inhibitio n in the vasc ul a t u r e and effec t s on neu r o n a l activa tio n via 5- hyd r oxy t r y p t a m i n e ant a g o n i s m [65].
A clas sic al dou bl e- blin d, plac e b o- cont r o ll e d , cros s o v e r stu dy reve al e d th a t FLUN was effectiv e in the pro p h yl axi s of child h o o d mig r ai n e [66].
A single- cen t e r ret r o s p e c t iv e obs e r v a t i o n a l stu dy whic h evalu a t e d the effec t s of FLUN in vario u s sub ty p e s of child h o o d mig r ai n e , i.e. mig r ai n e with o u t au r a , mig r ai n e with au r a , spo r a d i c an d familial he mi pl e g i c mig r ai n e , foun d tha t FLUN was mo r e effectiv e in th e he mi pl e g i c mig r a i n e gro u p [67].
With th e focu s on dis a bility an d the qu ality of life of pedi a t r i c mig r ai n e u r s , FLUN tr e a t m e n t significa n tly decr e a s e d th e Ped M IDAS scor e , but in the sa m e stu d y, FLUN was inferio r to TOP an d PROP in th e Ped MI DAS syst e m [68].
The reco m m e n d e d dos e of FLU N is 5- 10 mg qhs [7, 20]. The com m o n AEs of FLUN ar e sed a ti o n , a weig h t gain, fatig u e an d gas t r o i n t e s t i n a l disco mf o r t [7, 20, 25].
The reco m m e n d a t i o n level of FLU N: Clas s I, Level B [25].
Ona b o t u l i n u m toxi n A
One of the lates t the r a p e u t i c re gi m e s for adult mig r ai n e patie n t s is OBOT- A injectio n tr e a t m e n t , which was ap p r o v e d by the US Foo d an d Dru g Adminis t r a t i o n in 201 0 [69, 70].
Botulin u m neu r o t o xin- A is a purifie d neu r o t o xi n compl ex pro d u c e d by th e an a e r o b i c bact e r i u m Clostridi u m botulin u m [71, 72]. The main mec h a n i s m of actio n of bot ulin u m toxin involves the tar g e t i n g of the neu r o m u s c u l a r junctio n s by me a n s of a spe cific cleav a g e of the solu bl e N - ethyl m al ei m i d e- sen sitiv e facto r (NSF)- att a c h m e n t pro t ei n rec e p t o r com pl ex (SNARE)- like syn a p t o s o m a l- ass o ci a t e d pro t ei n of 25 kDa (SNAP- 25) [71, 72]. The final outco m e of this multis t a g e proc e s s is the br e a k i n g of pain neu r o t r a n s m i s s i o n , inclu din g the inhibitio n of the rele a s e of mig r ai n e- rela t e d neu r o p e p t i d e s (e.g. CGRP and SP) an d glut a m a t e [71- 74].
The prev al e n c e of chro n ic mig r a i n e amo n g pedi a t r i c mig r ai n e u r s is aro u n d 3% [23]. A ret r o s p e c t iv e cas e seri e s stu dy of th e us e of OBOT- A for the tre a t m e n t of refr a c t o r y pedi a t r i c chr o n i c daily hea d a c h e , inclu din g chr o n ic mig r a i n e , reve al e d th at 4 of 10 patie n t s rep o r t e d a dec r e a s e in hea d a c h e inte n s i ty an d 2 of the m dec r e a s e in he a d a c h e freq u e n c y , and th e s e 4 res p o n d e r pati e n t s achi ev e d a favor a b l e imp r ov e m e n t of the qu ality of life [21]. A ret r o s p e c t i v e review of the dat a on 45 pedi a t r i c chr o n ic daily he a d a c h e patie n t s who par ti ci p a t e d in 252 OBOT- A injectio n s (aver a g e dos e 188. 5 + 32 units) con clu d e d th a t th e mon t h ly hea d a c h e freq u e n c y was dec r e a s e d and the Ped MI DAS scor e sho w e d an imp r ov e m e n t [23]. A rec e n t small cas e seri e s stu d y of chro ni c mig r ai n e u r s (ag e d 13- 17 yea r s) sho w e d a goo d res p o n d e r rat e (7 of 10 patie n t s ) . The nu m b e r of he a d a c h e days per mo n t h dec r e a s e d from 19.2 to 10.1 [22]. The reco m m e n d e d dos e of OBOT- A is 100 units. The com m o n AEs of OBOT- A ar e red n e s s or tem p o r a r y pain at th e injectio n site, ptosis and blur r e d vision [25]. The reco m m e n d a t i o n level of OBOT- A: Class IV, Level U [25].
Nu t r a c e u t i c a l s (H e r b a l pro d u c t s ) Petasi t e s hyb ri d u s (but t e r b u r )
Extr a c t s of the root s of Petasi t e s hyb ri d u s exe r t an anti- infla m m a t o r y effec t via the inhibitio n of leuko t r i e n e pro d u c t i o n , an d influe n c e intr a c e ll ul a r calciu m acc u m u l a t i o n thr o u g h the L-typ e volta g e- gat e d calciu m ion cha n n e l s [75].
A multic e n t e r pros p e c t iv e ope n- lab el stu d y with a but t e r b u r root extr a c t for mig r ai n e prev e n t i o n (50- 150 mg for 4 mo n t h s ) , which involve d 108 child r e n an d adole s c e n t s (ag e d 6- 17 yea r s ) res ul t e d in 77% of all pati e n t s rep o r t i n g a 63% dec r e a s e in freq u e n c y of mig r ai n e att a c k s [76]. A pro s p e c t iv e , ran d o m i z e d , par tly dou bl e- blin d, plac e b o- con t r olle d , par all el- gro u p trial was set up to exa mi n e the pro p h yl a c ti c anti mi g r a i n e effect s of butt e r b u r root extr a c t an d mu sic the r a p y in prim a r y scho ol child r e n [77].
The evalu a ti o n of this stu d y rev e al e d th a t bot h the but t e r b u r extr a c t and mu sic th e r a p y wer e sup e r i o r to plac e b o in red u ci n g th e freq u e n c y of
hea d a c h e att a c k s in th e follow- up perio d [77]. The reco m m e n d e d dos a g e of butt e r b u r is 50- 150 mg pe r day. The main AE of but t e r b u r extr a c t is bu r pi n g . The reco m m e n d a t i o n level of Peta sit e s : Clas s II, Level U [25].
Co n c l u s i o n
The pat h o m e c h a n i s m of mig r ai n e is not fully und e r s t o o d , and per s o n a liz e d the r a p y tailor e d to th e patie n t is th e r e f o r e not availa bl e for pedi a t r i c mig r ai n e . A furt h e r difficulty is the fact th at th e late s t the r a p e u t i c guid elin e s wer e pu blis h e d mor e th a n ten yea r s ago. This review has surv ey e d the late s t liter a t u r e dat a rela ti n g to the pro p h yl a c t ic dru g s use d in the daily clinical pr a c ti c e in child r e n an d adol es c e n t s with mig r ai n e . For th e nea r futu r e , basic exp e r i m e n t a l an d hu m a n hea d a c h e res e a r c h is nee d e d , suc h as innov a tiv e ph a r m a c e u t i c a l inves t m e n t s with fully hu m a n i z e d mon o clo n a l antib o d i e s ag ai n s t CGRP an d CGRP rec e p t o r s . Ran d o m iz e d clinical trials ar e still nec e s s a r y as reg a r d s cur r e n t l y use d pro p h yl a c ti c anti mi g r a i n e dru g s an d new com p o u n d s desig n e d for the tre a t m e n t of youn g mig r ai n e u r s . Over all, new the r a p e u t i c guid elin e s ar e clea rly re q u i r e d in this field.
Co nf l i c t of int e r e s t
The aut h o r s decl a r e tha t th ey hav e no conflict of inte r e s t an d have rec eiv e d no pay m e n t in the pr e p a r a t i o n of thei r ma n u s c r i p t .
Ack n o w l e d g m e n t s
This work was sup p o r t e d by projec t TÁMOP- 4.2. 6. 3 . 1 , by the Hu n g a r i a n Brain Res e a r c h Pro g r a m (NAP, Gra n t No. KTIA_13_NAP- A-III/9. an d KTIA_13_NAP- A-II/17.) an d by EUROH EADPAI N (FP7- Healt h 201 3- Innov a tio n ; Gra n t No. 602 6 3 3 ) an d by th e MTA-SZTE Neu r o s c i e n c e Res e a r c h Grou p of the Hu n g a r i a n Acad e m y of Scie n c e s an d the Unive r si ty of Szeg e d .
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Tabl e
Tabl e 1 Pro p h y l a c t i c dru g s re c o m m e n d e d in pe d i a t r i c mi g r a i n e
Dru g s Re c o m m e n d e
d daily do s a g e
Co m m o n adv er s e ev e n t s
Re c o m m e n d ati o n lev e l Anti d e p r e s s a n t s
Amitrip tylin e 10- 150 mg qhs dizzin e s s , cons ti p a t i o n ,
incr e a s e d ap p e ti t e , weig h t gain
Clas s IV Level U
Nor t r i p t ylin e 10- 75 mg qhs car di a c (ar r h y t h m i a )
no dat a Anti e p i l e p t i c s
Valpr o a t e s 15- 20
mg/k g / d a y
som n ol e n c e , skin ras h , weig h t gain, tr e m o r , dro w si n e s s , hair loss,
hem a t o l o g i c a l or liver ab n o r m a l i ti e s
Clas s IV Level U
Topir a m a t e 1- 10 mg/k g / d a y nu m b n e s s , weig h t loss, cog nitiv e imp ai r m e n t , fatig u e , nau s e a , som n ol e n c e
Clas s IV Level U
Leveti r a c e t a m 500- 150 0 mg bid
som n ol e n c e ,
fatig u e , irrit a b ility, dizzin e s s
Clas s IV Level U
Zonis a m i d e 100- 600
mg/ d a y
dizzin e s s , nau s e a , irrit a b ility,
som n ol e n c e
Clas s IV Level U Gab a p e n t i n 300- 120 0 mg
tid
sed a ti o n , ataxia, fatig u e , perip h e r a l ed e m a
Clas s IV Level U Anti h i s t a m i n e s
Cypr o h e p t a d i n e 0.2 5- 1.5 mg/k g / d a y
slee p i n e s s , weig h t gain, incr e a s e d ap p e ti t e
Clas s IV Level U B e t a - adr e n e r g i c re c e p t o r blo c k e r s
Pro p r a n o l ol 2- 4 mg/k g/ d a y hypo t e n s i o n , dep r e s s i o n , dizzin e s s
Clas s II Level U Calci u m io n ch a n n e l an t a g o n i s t s
Flu n a r i zi n e 5- 10 mg qhs sed a ti o n , weig h t gain, fatig u e , gas t r o i n t e s t i n a l disco mf o r t
Clas s I Level B
Ona b o t u l i n u m toxi n A
100 unit s red n e s s or
te m p o r a r y pain at
Clas s IV Level U
th e injectio n site, pto sis, blur r e d vision
Nu t r a c e u t i c a l s (h e r b a l pro d u c t s ) Pet a si t e s
hyb ri d u s (but t e r b u r )
50- 150 mg/d ay bur p i n g Clas s II
Level U Abbr evi a ti o n s : qhs: eve ry nig h t at bed ti m e ; bid: twic e daily; tid: thr e e time s daily
Modifie d fro m Ref. [7, 20, 25].
Fig u r e le g e n d s
Fig u r e 1 Sc h e m e of th e act iv a t i o n of th e tri g e m i n o v a s c u l a r sy s t e m
The put a t iv e mec h a n i s m of activ a tio n of the sen si tiz a ti o n of the trig e m i n o v a s c u l a r syst e m is the followin g . The proc e s s of cor tic al spr e a d i n g dep r e s s i o n (CSD), a slowly pro p a g a t i n g wav e of neu r o n a l and glial dep ol a r iz a t i o n , activ a t e s trig e m i n a l nocic e p t o r s . Activatio n of me ni n g e a l affer e n t s lead s to th e rele a s e of CGRP, SP, and PACAP via the peri p h e r a l br a n c h of the trig e m i n a l pse u d o u n i p o l a r neu r o n s . The rele a s e d sub s t a n c e s may pro m o t e neu r o g e n i c infla m m a t i o n in th e cer e b r a l dur a mat e r an d lea d to activ a tio n an d sen sitiz a tio n of peri p h e r a l me ni n g e a l nerv e ter mi n a l s , the nocic e p t o r s . The con s e q u e n c e s of peri p h e r a l sen sitiz a tio n inclu d e th e cen t r a l sen sitiz a tio n of the seco n d- ord e r neu r o n s in the trig e m i n o c e r v i c a l com pl ex (TCC) as well as tha t of the thir d- ord e r neu r o n s in th e th al a m u s .
Modifie d fro m Ref. [2, 78].
Abbr evi a ti o n s : CGRP: calcito ni n gen e- rela t e d pep ti d e ; CSD: cortic al spr e a d i n g dep r e s s i o n ; PACAP: pituit a r y ad e n yl a t e cyclas e- activ a ti n g polyp e p t i d e ; SP: sub s t a n c e P; TCC: trig e m i n o c e r v i c a l com pl ex; TRIG:
trig e m i n a l gan g lio n .
