5/16/13 Disclosures I receive grant funding from: Triptans for Kids NIH/NINDS UCSF CTSI And honoraria from Journal Watch Neurology Amy A. Gelfand, MD Some off-label uses of medications will be discussed GelfandA@neuropeds.ucsf.edu Departments of Neurology and Pediatrics UCSF Child Neurology and Headache Center One-year period-prevalence for migraine by age and sex Victor et al, Cephalalgia, 2010 1
5/16/13 PET activation in dorsolateral pons (locus ceruleus); contralateral to pain Afridi et al Brain 2005 Akerman et al, Nature Reviews Neuroscience, 2011 Migraine Diagnostic Disability from Migraine Criteria in Pediatrics A. At least 5 attacks • Disability from headache can be measured using B. Duration 1 -72 hours PedMIDAS C. At least two of: • Pounding quality • Areas of disability: • Moderate or severe intensity -Missed school 1 • Unilateral or bilateral location • Movement sensitivity -Impaired performance in school 1 -Impaired ability to participate in sports and D. At least one of: (can be inferred from other extra-curricular activities behavior) • Photophobia and phonophobia • Impact on Quality of Life • Nausea and/or vomiting • Impact on other family members (parents, sibs) E. Not attributable to another disorder 1 Arruda, Neurology , 2012 ICHD-II, Cephalalgia , 2004 2
5/16/13 Expectations of efficacy Question #1 for acute migraine agents You’re seeing a 15 year old girl who has migraine No universally agreed upon primary end point for attacks twice a month. The pain during her attacks acute migraine trials is severe and associated with photophobia and phonophobia, but not nausea or vomiting. Naproxen (Aleve) helps a bit but she is still not able Ideal: to get out of bed during an attack. Would you: Pain-free within two hours every time you take it, with no recurrence over the next 24 hours, and no side effects. A) Refer her to Neurology for treatment recommendations Practical: B) Curbside Neurology regarding which triptan would Pain-relief by two hours ≥ 50% of the time you take be appropriate in her age group and what dose it, with usually no recurrence over the next 24 hours, C) Prescribe a triptan yourself and no intolerable side effects. D) Prescribe another class of medication Overview of Pediatric Acute Triptans Migraine Treatment Positive Trial(s) in children and/or adolescents: Non-pharmacologic measures: 1) Sumatriptan (Imitrex) Quiet, dark environment 2) Almotriptan (Axert)* Encourage PO fluid intake 3) Rizatriptan (Maxalt)* Encourage sleep 4) Zolmitriptan (Zomig) Pharmacologic measures: No positive trials (yet) in children or adolescents: 1) Non-specific analgesics: Studied down to Age 4 5) Naratriptan(Amerge): pharmacokinetics studied •Acetaminophen •NSAIDs: Naproxen, Ibuprofen, Ketorolac 6) Eletriptan (Relpax): one negative trial (placebo 57%) 2) Dopamine receptor antagonists: e.g. prochlorperazine 7) Frovatriptan (Frova): not studied (except ≥ 15 yo in 3) Dihydroergotamine (DHE): IM, IV, NS menstrual migraine) 4) Opioids 5) Barbiturate containing compounds (i.e. Fioricet) 6) Triptans *FDA labeled for acute migraine in pediatric patients 3
5/16/13 When to consider a triptan Triptans: Mechanism of Action 5HT 1B/1D/1F agonists Child has moderate or severe pain with migraine attacks NSAIDs or acetaminophen inadequately treat the pain How should I counsel the When not to consider a triptan patient to use a triptan? History of stroke or myocardial infarction Uncontrolled hypertension 1) Treat early, when pain is still mild Hemiplegic or basilar-type migraine Pregnancy (relative contra-indication) “ Act when Mild ” 1 study: -Early/mild group: 53% 2-hr pain free rate vs 37.5% of In someone with triptan overuse medication mod/severe. overuse headache; a risk when using triptans ≥ 10 -But still better late than never: placebo 17.5% triptan days/month for ≥ 3 months 2) Just take one dose…ignore the label 3) Limit use to 2 days per week (on average) to avoid medication overuse headache 1 Goadsby et al Cephalalgia 2008 4
5/16/13 What medication What about side effects of triptans? interactions are there? 1) Avoid other 5HT 1B/1D agonists within the same 24 Few hour period: other triptans, dihydroergotamine (DHE) Can have sensations of tightening in chest or throat 2) Risk of serotonin syndrome from concurrent SSRI/ CNS “side effects” (i.e. somnolence, asthenia) are SNRI use is quite low, if any: more likely from unmasking of symptoms that are “Based upon their part of the attack that come after pain passes 1 pharmacology, If these effects were drug-effects, they should occur the involvement of equally among those who respond and those who don’t triptans in contributing More common among triptan responders than non- to a serotonin syndrome, responders either alone or in Equally likely among “responders” in placebo and combination with other triptan groups medications, seems Evans et al Headache 2008 implausible.” 1 Goadsby Cephalalgia 2007 Sumatriptan Question #2 In clinical use in the U.S. since early 1990s You would like to try a triptan to treat the 15 year OTC (sort of) in the UK since 2006 old patient from Question #1. Which one would 4 forms: you choose? Tablets Nasal spray (NS) A) Sumatriptan PO Subcutaneous injection (SC) B) Sumatriptan NS Rectal suppository (PR) C) Frovatriptan PO Pediatric studies: D) Zolmitriptan NS PO: one negative trial, but… SC: Open-label use suggests efficacy E) Rizatriptan MLT NS: 3 positive double-blind, placebo-controlled trials Labeled for use in 12-17 year-olds in the UK, now generic so unlikely to ever get labeled in U.S. 5
5/16/13 Sumatriptan NS Almotriptan FDA-labeled for treatment of acute migraine in Ages studied Dose Used Pain Relief adolescents 12-17 years old 6-9 years 1 20 mg 86% at 2 hours 12-17 years 2 5-20 mg 66% at 2 hours Available as a tablet: 6.25 mg and 12.5 mg 8-17 years 3 10-20 mg 64% at 2 hours Randomized, double-blind, placebo-controlled, parallel-group trial in 12-17 year olds: 2h pain •2004 Practice Parameter from American Academy of relief in 72-73% vs. 55%, p<0.001 1 Neurology and Child Neurology Society: “Sumatriptan nasal spray is effective and should be Also an open-label adolescent study suggested considered for the acute treatment of migraine in benefit (pain relief 62% at 2 hrs) 2 adolescents” 4 1 Ueberall, Neurology, 1999 2 Winner, Pediatrics , 2000 3 Ahonen, Neurology , 2004 1 Linder, Headache , 2008 4 Lewis, Neurology , 2004 2 Berenson, Headache , 2010 Rizatriptan studies Rizatriptan Ages Study design Treatment Primary studied arms endpoint FDA-labeled for treatment of acute migraine in 6-17 yrs 1 Double-blind 5 or 10 mg 2h pain relief: ages 6-17 years placebo- MLT vs. 74% vs. 36%, controlled placebo p <0.001 crossover Labeled dosing: 6-17 yrs 2 RCT, parallel- 5 or 10 mg 2h pain free: <40 kg: 5 mg MLT group MLT vs. 31% vs. 22%, ≥ 40 kg: 10 mg MLT placebo OR 1.6(95% CI1.1-2.3), p =0.03 Tic-tacs… 12-17 yrs 3 Long-term 5 or 10 mg 2h pain free open label use MLT attacks: 46% 2h pain relief attacks: 65% 1 Ahonen, Neurology, 2006 2 Ho, Cephalalgia , 2012 3 Hewitt, Headache , 2013 6
5/16/13 Zolmitriptan Zolmitriptan Positive trials: Available as a tab, NS, or ZMT (orange melt) Ages Study Design Treatment Endpoint studied arms Nasal spray formulation: better absorption than 6-18 yrs 1 Double-blind 2.5 mg PO 2h pain relief: sumatriptan NS, but only available in one (adult) placebo- Zomig vs. 62% (64% in controlled placebo those <13) vs. dose so generally appropriate just for those > 40 crossover 28%, p <0.05 kg. 12-17 yrs 2 Double-blind 5 mg NS vs. 2h pain free: placebo- placebo 39% vs 19%, controlled p <0.01; crossover Negative trial: A second oral trial was negative, placebo response rate very high (58%) 1 Evers, Neurology , 2006 2 Lewis, Pediatrics , 2007 Triptans combined with Question #3 NSAIDS Your 15 year-old migraine patient responds within In adults, efficacy of 85 mg sumatriptan/500 mg 2 hours to rizatriptan 10 mg MLT and has no side naproxen (pain relief at 2 hours and sustained pain effects. However, about half the time the relief 2-24 hrs) is greater than that of either agent headache comes back the next morning. What do alone 1 you tell her? Adolescents 12-17 (n=622) treated over 12,000 attacks open-label without any serious adverse A) There’s no way to decrease the likelihood of events, providing safety data for this combination recurrent headache in adolescents 2 B) Take a second dose of rizatriptan before bed C) Take naproxen with the rizatriptan Likely an NSAID/triptan class effect, so could substitute FDA-labeled triptans for the sumatriptan 1 Brandes, JAMA , 2007 2 McDonald, Headache , 2011 7
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