TriptansEfficacy and tolerability

Steven RyanEssex University

Migraine and Headaches• Migraine

– 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• 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

Available TypesApproved Triptan Brand Formulation1992 Sumatriptan Imitrex, Imigran Injections

1995 Sumatriptan Imitrex, Imigran Tablets

1997 Sumatriptan Imitrex, Imigran Nasal spray

1997 Zolmitriptan Zomig Tablets

1998 Naratriptan Amerge, Naramig Tablets

1998 Rizatriptan Maxalt, Maxalt-MLT Tablets

2001 Zolmitriptan Zomig-ZMT Dissolvable tablets

2001 Almotriptan Axert Tablets

2001 Frovatriptan Frova Tablets

2002 Eletriptan Relpax Tablets

2003 Zolmitriptan Zomig Nasal spray

(Adapted from Cologno et al 2012)

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

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

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

• 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

Cost effectiveness of Triptans in 2003 (US)

Triptan $ 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 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 timeThird 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

• 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

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 61

Free 24hrs 67 66

Recur. 24hrs 11 24

Recur 48 hrs 15 26

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) 565-569

• • 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

• Johnston MM & Rapoport AM (2010) ”Triptans for the Management of Migraine’ Drugs 70 (12); 1505-1616

• 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 47:1152-1168

• NHS Corby Clinical Commissioning group (2012) http://www.neneccg.nhs.uk/resources/uploads/files/Triptan%20comparison.pdf