1. Efficacy and tolerability Steven Ryan Essex University
Triptans
Efficacy and tolerability
Steven Ryan
Essex University

2. Migraine and Headaches
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

3. Triptans
Triptans are selective serotonin (5-HT1B/1D) receptor agonists
“abortive migraine drugs” that are not painkillers
Proposed Mechanism
The exact mechanism of action is still not fully understood
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.
Inhibit abnormal activation of peripheral nociceptors
Effects on the neurons in the trigeminal nucleus caudalis
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

4. Available Types Approved Triptan Brand Formulation
Sumatriptan Imitrex, Imigran Injections
Sumatriptan Imitrex, Imigran Tablets
Sumatriptan Imitrex, Imigran Nasal spray
Zolmitriptan Zomig Tablets
Naratriptan Amerge, Naramig Tablets
Rizatriptan Maxalt, Maxalt-MLT Tablets
Zolmitriptan Zomig-ZMT Dissolvable tablets
Almotriptan Axert Tablets
Frovatriptan Frova Tablets
Eletriptan Relpax Tablets
Zolmitriptan Zomig Nasal spray
(Adapted from Cologno et al 2012)

5. End-points and terminology
30 minutes – pain relief and pain free
1 hour – pain relief and pain free
2 hour – pain relief and pain free
Recurrence – 24/48 hours
Adverse events – Relative risks RR
NNT – Numbers needed to treat. eg 5:1, for every 5 patients there was a treatment benefit for 1
Recurrence is limited - in order to have recurrence a drug has to remove the pain

6. Pascual J et al 2007 – Systematic Review
Reviewed studies only using oral triptans
Inclusion criteria
Double-blinded RCTs
Placebo arm
Detailed and repeatable literature search procedure provided
Hand search of reference lists
225 studies were refined to 35.
Studies showed that 6 out of seven triptans were superior to placebo after 2 hours (except naratriptan)
Sumatriptan 50 almotriptan 12.5 and frivotriptan 2.5 were no different than placebo at 1 hour
Almotriptan was the only triptan to have an effect after 1 hour.
The forms of triptan that proved most effective (sumatriptan 100, almotriptan 12.5) had the highest volume of adverse effects
Adverse effects include nausea, vomiting, dizzyness, vertigo, parasthesia
Review funded by GSK Spain and all authors are funded to lecture by pharmaceutical company

7. 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

8. Adelman JU & Belsey J (2003) Sumatriptan 50 mg Sumatriptan 100 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
Zolmitriptan 2.5mg
727 patients – 29% pain free
5.1 NNT
Zolmitriptan 5 mg
936 patients – 31% pain free
4.2 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
WITHIN 2 Hours

9. Cost effectiveness of Triptans in 2003 (US)
$ per dose
$ per package
$ for painfree patient
Cost to NHS for 1 dose (2013)
Almotriptan 10 61 48
3.32
Zolmitriptan 13 80 78
58p
Frovatriptan 14
129
162
2.78
Sumatriptan 50 mg
134 75
28p
Sumatriptan100mg 70
36p
Rizatriptan 15 91
4.46
Zolmitriiptan 5mg 47 65
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

10. Johnston MM & Rapoport AM (2010) Review of Literature
Review looking at more recent research
No detail given about literature searching
No detail about specific effects
Sumatriptan
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
Zolmitriptan has a 50% higher half life than sulmatriptan but not as effective
Eletriptan has a NNT of 7:1 at 2 hours and 5:1 at 4 hours
Rizatriptan designed to be faster acting
Naratriptan is slower acting, less effective but more tolerable

11. Frovatriptan and menstrual migraine
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)
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
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
Free 24hrs 67
Recur. 24hrs 11 24
Recur 48 hrs 15 26

12. References
Ahn AH and Basbaum AI (2005) ‘Where do triptans act in the treatment of migraine?” Pain 115(1-2): 1–4.
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
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)
Cologno D Mazzeo A Lecce B Mundi C Petretta V Casucci G d’Onofrio F (2012) ‘Triptans: over the migraine’ Neuroscience 33(1)
Johnston MM & Rapoport AM (2010) ”Triptans for the Management of Migraine’ Drugs 70 (12);
National Health Service (2013) Headaches
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:
NHS Corby Clinical Commissioning group (2012)