Transcript 1. Triptans - efficacy and tolerability

Triptans
Efficacy and tolerability
Steven Ryan
Essex University
Migraine and Headaches
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Migraine
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thought to affect 43% of women and
18% of men in their lifetime (US)
This is thought to cost the US economy
$20 billion in working hours lost
annually (2002)
Only 50% of patients receive the correct
diagnosis and only 23% of those use
triptans
21% of people suffering with headaches
manage them with opioids or
barbiturates
Migraine is ranked by WHO as the 19th
most debilitating disease
Headaches
– Thought to affect 10 million people in
the UK (1:4 women 1:12 men)
– Can be classified as cluster headaches,
tension headaches, secondary
headaches
Triptans
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Triptans are selective serotonin (5-HT1B/1D)
receptor agonists
“abortive migraine drugs” that are not painkillers
Proposed Mechanism
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The exact mechanism of action is still not fully
understood
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Selective vasoconstrictor of the cranial vasculature
that were thought to distend (Graham and Wolff
1938)
It is believed that compression of the common
carotid artery reduces pain in migraine attacks.
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Inhibit abnormal activation of peripheral
nociceptors
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Effects on the neurons in the trigeminal nucleus
caudalis
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Sumatriptan is a hydrophilic drug and cannot pass the
blood-brain barrier, zolmitriptan and rizatripton are
lyphophilic drugs which can potentially pass through
the brain blood barrier but sumatriptan is still more
effective
Available Types
Approved
Triptan
Brand
Formulation
1992
1995
1997
1997
1998
1998
2001
2001
2001
2002
2003
Sumatriptan
Sumatriptan
Sumatriptan
Zolmitriptan
Naratriptan
Rizatriptan
Zolmitriptan
Almotriptan
Frovatriptan
Eletriptan
Zolmitriptan
Imitrex, Imigran
Imitrex, Imigran
Imitrex, Imigran
Zomig
Amerge, Naramig
Maxalt, Maxalt-MLT
Zomig-ZMT
Axert
Frova
Relpax
Zomig
Injections
Tablets
Nasal spray
Tablets
Tablets
Tablets
Dissolvable tablets
Tablets
Tablets
Tablets
Nasal spray
(Adapted from Cologno et al 2012)
End-points and terminology
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30 minutes – pain relief and pain free
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1 hour – pain relief and pain free
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2 hour – pain relief and pain free
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Recurrence – 24/48 hours
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Adverse events – Relative risks RR
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NNT – Numbers needed to treat.
eg 5:1, for every 5 patients there was a treatment benefit for 1
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Recurrence is limited - in order to have recurrence a drug has to remove the pain
Pascual J et al 2007 – Systematic
Review
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Reviewed studies only using oral triptans
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Inclusion criteria
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Double-blinded RCTs
Placebo arm
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Detailed and repeatable literature search
procedure provided
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Hand search of reference lists
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225 studies were refined to 35.
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Studies showed that 6 out of seven triptans
were superior to placebo after 2 hours
(except naratriptan)
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Sumatriptan 50 almotriptan 12.5 and
frivotriptan 2.5 were no different than
placebo at 1 hour
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Almotriptan was the only triptan to have an
effect after 1 hour.
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The forms of triptan that proved most
effective (sumatriptan 100, almotriptan 12.5)
had the highest volume of adverse effects
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Adverse effects include nausea, vomiting,
dizzyness, vertigo, parasthesia
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Review funded by GSK Spain and all authors
are funded to lecture by pharmaceutical
company
Pascual et al..
• Review not clear on
specific effects of each
type of triptan
• Provides a table but
neglects to explain the
table with a legend or
adequate headings
• Not explained in text
either
• ….GO TO PASCUAL PAPER
Adelman JU & Belsey J (2003)
• Sumatriptan 50 mg
– 602 patients -24% pain free
– 5.4 NNT
• Sumatriptan 100 mg
– 1837 patients - 30% pain free
– 4.7 NNT
• Rizatriptan 10 mg
– 2073 patients – 40% pain free
– 3.2 NNT
• Naratriptan 2.5 mg
– 213 patients – 20% pain free
– 8.2 NNT
• Almotriptan 12.5 mg
– 730 patients 36% pain free
– 4.7 NNT
• Frovatriptan 2.5 mg
– 1611 patients – 11% pain free
– 11.3 NNT
• Zolmitriptan 2.5mg
– 727 patients – 29% pain free
– 5.1 NNT
• Zolmitriptan 5 mg
– 936 patients – 31% pain free
– 4.2 NNT
– WITHIN 2 Hours
Cost effectiveness of Triptans in 2003
(US)
Triptan
$ per dose
$ per package
$ for painfree
patient
Cost to NHS for
1 dose (2013)
Almotriptan
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61
48
3.32
Zolmitriptan
13
80
78
58p
Frovatriptan
14
129
162
2.78
Sumatriptan 50 mg 14
134
75
28p
Sumatriptan100mg 14
134
70
36p
Rizatriptan
15
91
48
4.46
Zolmitriiptan 5mg
15
47
65
2.78
Naratriptan
17
155
141
56p
Adapted from Adelman JU & Belsey J (2003)
First column: price in dollars for one tablet/dose (2003)
Second Column: Available packages at the time
Third Column: Price for effective treatment based on NNT (calculated from previous slide)
Fourth column: Cost based on two commissioning groups 2012
Johnston MM & Rapoport AM (2010)
Review of Literature
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Review looking at more recent research
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No detail given about literature searching
No detail about specific effects
Sumatriptan
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100 mg had a 5:1 NNT for a painfree response in 2 hours.
recurrence at 24 hours was the same as placebo
High instance of adverse events
25 mg had a 7.5:1 NNT pain free at 2 hours and 3.5:1 for any significant improvement
Nasal spray is better tolerated with less adverse events.
Higher doses of sumatriptan are more effective but can cause higher risk of adverse events
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Zolmitriptan has a 50% higher half life than sulmatriptan but not as effective
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Eletriptan has a NNT of 7:1 at 2 hours and 5:1 at 4 hours
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Rizatriptan designed to be faster acting
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Naratriptan is slower acting, less effective but more tolerable
Frovatriptan and menstrual migraine
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50% of women with migraine associate it
with the menstrual cycle
Menstrual migraines are reported as being
more severe, disabling, and longer lasting
than other migraine.
Frovatriptan designed as a preventative
migraine medication with a long lasting
effect and a low risk of adverse events.
The pooled results of 3 RCTs assessed 346
women with migraine
(187 classified as menstrual)
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Frovatriptan found to be no different to three
other triptans (almotriptan, rizatriptan and
zolmatriptan) for immediate effect but had a
lower rate of recurrence after 24 hours
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Lower adverse events are found in
Frovatription
Frova %
Others %
Relief 2hrs
37
43
Free 2hrs
23
30
Relief 4hrs
60
55
Free 4hrs
52
61
Relief 24hrs
66
61
Free 24hrs
67
66
Recur. 24hrs
11
24
Recur 48 hrs
15
26
References
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Ahn AH and Basbaum AI (2005) ‘Where do triptans act in the treatment of migraine?” Pain 115(1-2): 1–4.
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Adelman A & Belsey J (2003) ‘Meta-analysis of Oral Triptan Therapy for Migraine: Number Needed to Treat and
Relative Cost to Achieve Relief Within 2 Hours’ Journal of Managed Care Pharmacology (9)1: 45-52
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Allais Vincenzo Tullo Stefano Omboni Chiara Benedetto Grazia Sances Dario Zava Michel D. Ferrari Gennaro
Bussone (2012) Efficacy of frovatriptan versus other triptans in the acute treatment of menstrual migraine: pooled
analysis of three double-blind, randomized, crossover, multicenter studies Neuroscience 33(1) 565-569
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Cologno D Mazzeo A Lecce B Mundi C Petretta V Casucci G d’Onofrio F (2012) ‘Triptans: over the migraine’
Neuroscience 33(1) 193-198
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Johnston MM & Rapoport AM (2010) ”Triptans for the Management of Migraine’ Drugs 70 (12); 1505-1616
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National Health Service (2013) Headaches
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Pascual J Mateos V Roig Sanchez-del-Rio M Jimenez D (2007) ‘Marketed Oral Triptans in the Acute Treatment of
Migraine: A Systematic Review on Efficacy and Tolerability’ Headache 47:1152-1168
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NHS Corby Clinical Commissioning group (2012)
http://www.neneccg.nhs.uk/resources/uploads/files/Triptan%20comparison.pdf