i triptani

I TRIPTANI
NELLA TERAPIA DELLE CEFALEE
Luigi Alberto Pini
TRIPTANI
FORMULAZIONI DISPONIBILI E DOSAGGI
MASSIMI CONSIGLIATI
ALMOTRIPTAN
12.5 mg cp
25
NM e 2
N
ELETRIPTAN
S
O
O
40 mg cp 80; 20 mg cp 80
N
H
Me
O
RIZATRIPTAN
N
O
S
5-10 mg cp
10 mg RPD
N
H
20
20
NMe 2
SUMATRIPTAN
50-100 mg per os
6 mg f s.c.
25 mg supp
20 mg spray nasale
NMe 2
Me NHSO 2
N
H
300
12
50
40
O
NH
O
N
H
ZOLMITRIPTAN
2.5 mg cp
2.5 mg rapimelt
7.5
7.5
NM e 2
N
N
N
N
H
FROVATRIPTAN
2,5 mg
Mechanism of Action of
TRIPTANs
Pre-clinical studies have suggested that one mechanism of antimigraine
action of the 'triptan' 5-HT1B/1D receptor agonists may be through inhibition
of central nociceptive transmission in the trigeminal dorsal horn.
anatomical studies show that 5-HT 1B/D receptors are located in the trigeminal
ganglia and in the trigeminal nucleus caudalis in the region of termination of
dural afferent fibers. These data strongly support a central role of 5-HT 1B/D
receptors in anti-migraine therapy, in addition to any peripheral effects.
It has also been shown that 5-HT1D receptors have a more restricted
trigeminal distribution than 5-HT1B receptors The results of this
study support the hypothesis that brain penetrant 5-HT 1B/D
receptor agonists have central anti-nociceptive effects in the
trigeminal nucleus caudalis
Cumberbatch et al 1998, European Journal of Pharmacology 3621998.43–46
Evidence suggests that in man there are no 5-HT 1D
receptors on the meningeal vasculature and that these
receptors are found specifically on trigeminal
perivascular afferent fibers. Additionally, 5-HT1D
receptors are located in the trigeminal ganglion and on
pre-synaptic elements within the nucleus caudalis but
have a restricted distribution elsewhere in the brain
compared to 5-HT1B receptors. This suggests that brain
penetrant 5-HT1D selective receptor agonists may be
centrally antinociceptive without vasoconstrictor activity
and with reduced central side effects
Cumberbatch et al 1998, European Journal of Pharmacology 3621998.43–46
. Schematic
picture of sumatriptan binding to 5-HT1D receptor
Triptani
affinità verso i recettori 5-HT1B
(pKi - scala log)
Frovatriptan
8,6
Almotriptan
8,0
Eletriptan
8,0
Naratriptan
8,7
Rizatriptan
6,9
Sumatriptan
7,8
Zolmitriptan
8,3
McHarg AD, 41st Annual Scientific Meeting AASH, 1999
Triptani
affinità verso i recettori 5-HT1D
(pKi - scala log)
Zolmitriptan
Eletriptan
9,2
8,9
Sumatriptan
Frovatriptan
8,5
8,4
Naratriptan
8,3
Almotriptan
Rizatriptan
8,0
7,9
McHarg AD, 41st Annual Scientific Meeting AASH, 1999
Triptani
potenza funzionale sui recettori 5-HT1B
pEC50 - scala log
Frovatriptan
8,17
Eletriptan
7,71
Zolmitriptan
7,60
Naratriptan
7,55
5-HT
7,40
Almotriptan
7,16
Rizatriptan
7,11
Sumatriptan
6,99
McHarg AD, 41st Annual Scientific Meeting AASH, 1999
TRIPTANI
meccanismo d’azione
• inibizione dell’infiammazione neurogena tramite
l’attivazione dei recettori 5-HT1D
• riduzione dell’ipereccitabilità delle cellule dei
nuclei trigeminali tramite i recettori 5-HT1B/1D
del midollo allungato
• regressione della dilatazione dei vasi meningei,
durali, o piali tramite la attivazione dei recettori
5-HT1B
Longmore J, Cephalalgia 1997; Ferrari MD, Lancet 1998
TRIPTANI: MECCANISMO D’AZIONE
TRIPTANI
CARATTERISTICHE GENERALI
 Prima scelta per attacchi invalidanti.
 Efficaci sul dolore e sintomi di accompagnamento.
 Recidive nel 25-40%.
 Efficacia di una seconda dose sulla recidiva.
 Gli studi hanno confermato l’efficacia e sicurezza in soggetti di
età compresa tra 14 e 18 anni; non disponibili dati ufficiali su
popolazione di età superiore ai 65 anni.
Long-Term Safety of Daily
Triptans
Robbins, 2002
CONCLUSION: In this study, there were no adverse
consequences discovered from the utilization of
frequent triptans, over a prolonged period of time.
118 patients (primarily with migraine and CDH) had
‘self-selected’ triptans as the only beneficial therapy
for their daily headaches. These patients had been
refractory to the usual chronic daily headache and
migraine preventives.
Eventi avversi correlati ai Triptani
Frovatriptan
Rizatriptan
Zolmitriptan
Almotriptan
%
39/357 50/362
p=NS
3/304
10/299
p<0.05
13/327
18/329
p=NS
Savi et al 2011, J Headache Pain 12:219–226
Tullo et al2010, Neurol Sci 31 (Suppl 1):S51–S54
Bartolini et al2011,J Headache Pain 12:361–368
• Assessing
the risk of stroke in persons with migraine is
complicated by the intricate relationship between these
two conditions.
•Migraine is an independent risk factor for stroke both
during, and remote from, the migraine attack. Women of
childbearing age and those with aura are at greatest risk of
migraine-related stroke.
• Additional risk of stroke in migraineurs occurs in those
using oral contraceptive pills and who smoke cigarettes.
CNS Drugs 2005; 19 (8): 683-692
•
Hereditary conditions, including CADASIL , MELAS and
hereditary haemorrhagic telangiectasia, appear to predispose
to both migraine and stroke.
• Purported mechanisms for migraine-associated stroke include
involvement of the vasculature (including vasospasm, arterial
dissection and small vessel arteriopathy), hypercoagulability
(elevated von Willebrand Factor, platelet activation) and
elevated risk of cardioembolism (patent foramen ovale, atrial
septal aneurysm)
• Triptans and ergotamines, used to treat acute
migraine attacks, appear to be safe in low-risk
populations. These medications should be
avoided in persons with haemiplegic migraine,
basilar migraine, vascular risk factor and prior
cerebral or cardiac ischaemia.
CNS Drugs 2005; 19 (8): 683-692
Tollerabilità
Frovatriptan use in migraineurs with or at high risk
of coronary artery disease.
In questo studio esplorativo di emicranici con, o
ad alto rischio di, malattia coronarica, frovatriptan
2.5 mg è stato ben tollerato e, durante il
monitoraggio, non è risultato associato a
incremento di anomalie cardiovascolari.
Elkind AH. Headache 2004;44:403-10
Frovatriptan
azione cerebroselettiva
Sumatriptan
% massima risposta a 5-HT
Frovatriptan
200
200
150
150
100
100
50
50
0
-10
-9
-8
-7
-6
-5
-Log
arteria cerebrale
-4
-3
0
-10
-9
-8
-7
-6
-5
-4
-3
-Log
arteria coronaria
Parsons AA, J Cardiovasc Pharmacology 1998
Headache 2010;50:256-263
Headache 2010;50:256-263
• Conclusion: Triptan use is lower in those
with vs without CV risk, suggesting that
doctors and/or patients fear using
triptans in individuals at risk to CVD.
• Furthermore, triptan use in those with
established CVD increases with
headache-related disability, suggesting
that patients and providers balance risks
and benefits. Additional and analytical
data are needed on the safety of triptans
in the setting of CVD risk.
• This study has not assessed adequacy
Headache 2010;50:256-263
of care.
• Conclusions.—Use of triptans is not
associated with increased risk of any
ischemic events, including myocardial
infarction and stroke, or mortality.
Consistent with previous studies,
migraineurs in general have an elevated
risk of stroke, but not myocardial
infarction, compared with nonmigraineurs.
Headache 2004;44:642-651
• We report a case of myocardial infarction
associated with the use of sumatriptan and review
the literature regarding similar cases.
• A 54-year-old woman with a history of migraine
without aura, mild arterial hypertension,
depression, and no history of coronary artery
disease was admitted to our hospital for acute
myocardial infarction, 30 minutes after using 6 mg
of subcutaneous sumatriptan. Coronary
angiography performed several days later revealed
a normal coronary arterial system.
• Although at discharge the patient was advised to
permanently avoid triptans, she continued the use
of oral sumatriptan at low dosage (25-50 mg)
without any problems.
• Recommendations.—With only Class IV
evidence available in the literature and available
through the FDA registration of adverse events,
inadequate data are available to determine the
risk of serotonin syndrome with the addition of a
triptan to SSRIs/SNRIs or with triptan
monotherapy.
• The currently available evidence does not
support limiting the use of triptans with SSRIs
or SNRIs, or the use of triptan monotherapy, due
to concerns for serotonin syndrome (Level U).
• However, given the seriousness of serotonin
syndrome, caution is certainly warranted and
clinicians should be vigilant to serotonin toxicity
symptoms and signs to insure prompt treatment.
Health care providers should report potential
cases to MedWatch and consider submitting them
Headache 2010; 50: 1089-99
for publication.
• Conclusions: In general practice,triptan
treatment in migraine does not increase
the risk of stroke, MI, cardiovascular
death, IHD, or mortality. Triptans are
prescribed to those less at risk of these
events.
NEUROLOGY 2004;62:563–568
CONCLUSIONI
I triptani sono farmaci con un buon indice
terapeutico
Triptani sono ancora i farmaci di prima scelta
per cefalea a grappolo ed emicrania di forte
intensità
I
I triptani possono essere associati alla
trasformazione verso le forme croniche
TRiPTANS
CHRONIC USE
Neurology Today: 2002 - Volume 2 - Issue 10 - pp 1,24–
25
Triptans Play A Larger Role in Medication Overuse
Headache, Study Finds
Henkel, Gretchen
Investigating the pharmacologic features of MOH, a group of
neurologists at the University Hospital in Essen, Germany,
determined that the mean duration until onset of MOH was 1.7
years for triptan users, 2.7 years for those taking ergots, and
4.8 years for patients taking analgesics. In some patients taking
triptans, as few as 10 doses per month caused MOH
(Neurology 2002;59: 1011–1014).
Triptan overuse in the Dutch general population:
A nationwide pharmaco-epidemiology database
analysis in 6.7 million people
Cephalalgia June 2011 31: 943-952
Triptans were used by 85,172 (1.3%) people; of these, 8,844 (10.4%;
95% CI 10.2-10.6) were overusers by International Headache Society and
2,787 (3.3%; 95% CI 3.2-3.4) were overusers by stringent criteria. The
triptan-specific odds ratios for the rate of International Headache Society
overuse compared with sumatriptan were: 0.26 (95% CI 0.19-0.36) for
frovatriptan; 0.34 (95% CI 0.32-0.37) for rizatriptan; 0.76 95% CI 0.680.85) for naratriptan; 0.86 (95% CI 0.72-1.02) for eletriptan; 0.97 (95% CI
0.88-1.06) for zolmitriptan; and 1.49 (95% CI 1.31-1.72) for almotriptan.
Costs for overuse were 29.7 million euros; for the International Headache
Society criteria this was 46% of total costs and for stringent criteria it was
23%.
DISCUSSION:
In the Dutch general population, 1.3% used a triptan in 2005, of which
10.3% were overusers and accounted for half of the total costs of triptans.
Users of frovatriptan, rizatriptan and naratriptan had a lower level of
overuse.
Triptan-induced latent sensitization: a possible basis for
medication overuse headache.
De Felice M, et al. Ann Neurol. 2010 Mar;67(3):325-37
Sustained or repeated administration of triptans to rats elicited time-dependent and
reversible cutaneous tactile allodynia that was maintained throughout and transiently
after drug delivery. Triptan administration increased labeling for CGRP in identified
trigeminal dural afferents that persisted long after discontinuation of triptan exposure.
Two weeks after triptan exposure, when sensory thresholds returned to baseline levels,
rats showed enhanced cutaneous allodynia and increased CGRP in the blood following
challenge with a nitric oxide donor. Triptan treatment thus induces a state of latent
sensitization characterized by persistent pronociceptive neural adaptations in dural
afferents and enhanced responses to an established trigger of migraine headache in
humans.
INTERPRETATION:
Triptans represent the treatment of choice for moderate and severe migraine
headaches. However, triptan overuse can lead to an increased frequency of
migraine headache. Overuse of these medications could induce neural adaptations
that result in a state of latent sensitization, which might increase sensitivity to migraine
triggers. The latent sensitization could provide a mechanistic basis for the
transformation of migraine to medication overuse headache.
Pathophysiology of medication overuse headache: insights
and hypotheses from preclinical studies.
Meng ID, Dodick D, Ossipov MH, Porreca F. Cephalalgia. 2011 May;31(7):851-60.
Gathering evidence indicates that migraine patients are more susceptible to
development of MOH, and that prolonged use of these medications increases
the prognosis for development of chronic migraine, leading to the suggestion
that similar underlying mechanisms may drive both migraine headache and
MOH. In this review, we examine the link between several mechanisms that
have been linked to migraine headache and a potential role in MOH. For
example, cortical spreading depression (CSD), associated with migraine
development, is increased in frequency with prolonged use of topiramate or
paracetamol.
CONCLUSIONS:
Increased CGRP levels in the blood have been linked to migraine and
elevated CGRP can be casued by prolonged sumatriptan exposure. Possible
mechanisms that may be common to both migraine and MOH include
increased endogenous facilitation of pain and/or diminished diminished
endogenous pain inhibition. Neuroanatomical pathways mediating these
effects are examined.
Medication-overuse headache.
Tepper SJ. Continuum (Minneap Minn). 2012 Aug;18(4):807-22
MOH development is linked to baseline frequency of headache
days per month, acute medication class ingested, frequency of
acute medications ingested, and other risk factors. Using less
effective or nonspecific medication for severe migraine results in
inadequate treatment response, with redosing and attack
prolongation, frequently leading to chronification. Use of any
barbiturates or opioids increases the transformation likelihood.
Patients with MOH can usually be effectively treated. The first
step is 100% wean, followed by establishing preventive
medications such as onabotulinumtoxinA or daily prophylaxis
and providing acute treatment for severe migraine 2 or fewer
days per week. Slow wean or quick termination of rebound
medications can be accomplished for most patients on an
outpatient basis, but some more difficult problems may need
referral for multidisciplinary day hospital or inpatient treatments.
Frovatriptan vs. Altri triptani
Eventi avversi correlati al farmaco in studio
Frovatriptan
Altri triptani
p<0.05
55/988
78/990
Cortelli et al 2011, Neurol Sci 32 (Suppl 1):S95–S98