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

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

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 Types Approved Triptan Brand Formulation 1992 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 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

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

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 Free 24hrs 67 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