5/16/13 Disclosures Triptans for Kids Amy A. Gelfand, MD GelfandA@neuropeds.ucsf.edu Departments of Neurology and Pediatrics UCSF Child Neurology and Headache Center I receive grant funding from: NIH/NINDS UCSF CTSI And honoraria from Journal Watch Neurology Some off-label uses of medications will be discussed 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 Akerman et al, Nature Reviews Neuroscience, 2011 Afridi et al Brain 2005 Migraine Diagnostic Criteria in Pediatrics A. At least 5 attacks B. Duration 1-72 hours C. At least two of: Pounding quality Moderate or severe intensity Unilateral or bilateral location Movement sensitivity D. At least one of: (can be inferred from behavior) Photophobia and phonophobia Nausea and/or vomiting E. Not attributable to another disorder Disability from Migraine Disability from headache can be measured using PedMIDAS Areas of disability: -Missed school 1 -Impaired performance in school 1 -Impaired ability to participate in sports and other extra-curricular activities Impact on Quality of Life Impact on other family members (parents, sibs) 1 Arruda, Neurology, 2012 ICHD-II, Cephalalgia, 2004 2
5/16/13 Question #1 You re seeing a 15 year old girl who has migraine attacks twice a month. The pain during her attacks is severe and associated with photophobia and phonophobia, but not nausea or vomiting. Naproxen (Aleve) helps a bit but she is still not able to get out of bed during an attack. Would you: A) Refer her to Neurology for treatment recommendations B) Curbside Neurology regarding which triptan would be appropriate in her age group and what dose C) Prescribe a triptan yourself D) Prescribe another class of medication Expectations of efficacy for acute migraine agents No universally agreed upon primary end point for acute migraine trials Ideal: Pain-free within two hours every time you take it, with no recurrence over the next 24 hours, and no side effects. Practical: Pain-relief by two hours 50% of the time you take it, with usually no recurrence over the next 24 hours, and no intolerable side effects. Overview of Pediatric Acute Migraine Treatment Triptans Non-pharmacologic measures: Quiet, dark environment Encourage PO fluid intake Encourage sleep Positive Trial(s) in children and/or adolescents: 1) Sumatriptan (Imitrex) 2) Almotriptan (Axert)* 3) Rizatriptan (Maxalt)* 4) Zolmitriptan (Zomig) Pharmacologic measures: 1) Non-specific analgesics: Studied down to Age 4 Acetaminophen NSAIDs: Naproxen, Ibuprofen, Ketorolac 2) Dopamine receptor antagonists: e.g. prochlorperazine 3) Dihydroergotamine (DHE): IM, IV, NS 4) Opioids 5) Barbiturate containing compounds (i.e. Fioricet) 6) Triptans No positive trials (yet) in children or adolescents: 5) Naratriptan(Amerge): pharmacokinetics studied 6) Eletriptan (Relpax): one negative trial (placebo 57%) 7) Frovatriptan (Frova): not studied (except 15 yo in menstrual migraine) *FDA labeled for acute migraine in pediatric patients 3
5/16/13 Triptans: Mechanism of Action When to consider a triptan 5HT 1B/1D/1F agonists Child has moderate or severe pain with migraine attacks NSAIDs or acetaminophen inadequately treat the pain When not to consider a triptan History of stroke or myocardial infarction Uncontrolled hypertension Hemiplegic or basilar-type migraine Pregnancy (relative contra-indication) In someone with triptan overuse medication overuse headache; a risk when using triptans 10 triptan days/month for 3 months How should I counsel the patient to use a triptan? 1) Treat early, when pain is still mild Act when Mild 1 study: -Early/mild group: 53% 2-hr pain free rate vs 37.5% of mod/severe. -But still better late than never: placebo 17.5% 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 interactions are there? 1) Avoid other 5HT 1B/1D agonists within the same 24 hour period: other triptans, dihydroergotamine (DHE) 2) Risk of serotonin syndrome from concurrent SSRI/ SNRI use is quite low, if any: Based upon their pharmacology, the involvement of triptans in contributing to a serotonin syndrome, either alone or in combination with other medications, seems Evans et al Headache 2008 implausible. What about side effects of triptans? Few Can have sensations of tightening in chest or throat CNS side effects (i.e. somnolence, asthenia) are more likely from unmasking of symptoms that are part of the attack that come after pain passes 1 If these effects were drug-effects, they should occur equally among those who respond and those who don t More common among triptan responders than nonresponders Equally likely among responders in placebo and triptan groups 1 Goadsby Cephalalgia 2007 Question #2 You would like to try a triptan to treat the 15 year old patient from Question #1. Which one would you choose? A) Sumatriptan PO B) Sumatriptan NS C) Frovatriptan PO D) Zolmitriptan NS E) Rizatriptan MLT Sumatriptan In clinical use in the U.S. since early 1990s OTC (sort of) in the UK since 2006 4 forms: Tablets Nasal spray (NS) Subcutaneous injection (SC) Rectal suppository (PR) Pediatric studies: PO: one negative trial, but SC: Open-label use suggests efficacy 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 Ages studied Dose Used Pain Relief 6-9 years 1 20 mg 86% at 2 hours 12-17 years 2 5-20 mg 66% at 2 hours 8-17 years 3 10-20 mg 64% at 2 hours 2004 Practice Parameter from American Academy of Neurology and Child Neurology Society: Sumatriptan nasal spray is effective and should be considered for the acute treatment of migraine in adolescents 4 1 Ueberall, Neurology, 1999 2 Winner, Pediatrics, 2000 3 Ahonen, Neurology, 2004 4 Lewis, Neurology, 2004 Almotriptan FDA-labeled for treatment of acute migraine in adolescents 12-17 years old Available as a tablet: 6.25 mg and 12.5 mg Randomized, double-blind, placebo-controlled, parallel-group trial in 12-17 year olds: 2h pain relief in 72-73% vs. 55%, p<0.001 1 Also an open-label adolescent study suggested benefit (pain relief 62% at 2 hrs) 2 1 Linder, Headache, 2008 2 Berenson, Headache, 2010 Rizatriptan Ages studied Rizatriptan studies Study design Treatment arms Primary endpoint FDA-labeled for treatment of acute migraine in ages 6-17 years Labeled dosing: <40 kg: 5 mg MLT 40 kg: 10 mg MLT Tic-tacs 6-17 yrs 1 Double-blind placebocontrolled crossover 6-17 yrs 2 RCT, parallelgroup 12-17 yrs 3 Long-term open label use 5 or 10 mg MLT vs. placebo 5 or 10 mg MLT vs. placebo 5 or 10 mg MLT 2h pain relief: 74% vs. 36%, p<0.001 2h pain free: 31% vs. 22%, OR 1.6(95% CI1.1-2.3), p=0.03 2h pain free 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 Available as a tab, NS, or ZMT (orange melt) Nasal spray formulation: better absorption than sumatriptan NS, but only available in one (adult) dose so generally appropriate just for those > 40 kg. Positive trials: Ages studied Study Design 6-18 yrs 1 Double-blind placebocontrolled crossover Treatment arms 2.5 mg PO Zomig vs. placebo Endpoint 2h pain relief: 62% (64% in those <13) vs. 28%, p<0.05 12-17 yrs 2 Double-blind placebocontrolled crossover 5 mg NS vs. placebo 2h pain free: 39% vs 19%, p<0.01; Negative trial: A second oral trial was negative, placebo response rate very high (58%) 1 Evers, Neurology, 2006 2 Lewis, Pediatrics, 2007 Question #3 Your 15 year-old migraine patient responds within 2 hours to rizatriptan 10 mg MLT and has no side effects. However, about half the time the headache comes back the next morning. What do you tell her? A) There s no way to decrease the likelihood of recurrent headache B) Take a second dose of rizatriptan before bed C) Take naproxen with the rizatriptan Triptans combined with NSAIDS In adults, efficacy of 85 mg sumatriptan/500 mg naproxen (pain relief at 2 hours and sustained pain relief 2-24 hrs) is greater than that of either agent alone 1 Adolescents 12-17 (n=622) treated over 12,000 attacks open-label without any serious adverse events, providing safety data for this combination in adolescents 2 Likely an NSAID/triptan class effect, so could substitute FDA-labeled triptans for the sumatriptan 1 Brandes, JAMA, 2007 2 McDonald, Headache, 2011 7
5/16/13 Question #4 You re seeing a 7 year old whose migraine attacks are associated with significant nausea and vomiting. Prochlorperazine (Compazine) PR causes a dystonic reaction and does not relieve the headache. Which triptan might you consider for her? Summary Points Triptans have been studied in pediatric patients, and two are now FDA-labeled for use in pediatrics. For those who can tolerate oral medications during an attack: almotriptan (12-17) and rizatriptan (6-17) are both on label; sumatriptan is generic so generally covered. A) Sumatriptan PO B) Almotriptan PO C) Zolmitriptan NS D) Rizatriptan MLT For those who can t tolerate the oral route: sumatriptan NS is studied down to age 6, with zolmitriptan NS having better absorption so preferable for those >40 kg. Sumatriptan SC or PR also options. Whenever possible, combining the triptan with an NSAID is likely to be helpful. Helpful References Gelfand AA, Goadsby PJ, Treatment of Pediatric Migraine in the Emergency Room, Pediatric Neurology, 47 (2012) 233-241. Need slides? GelfandA@neuropeds.ucsf.edu Ho TW et al, Efficacy and tolerability of rizatriptan in pediatric migraineurs: Results from a randomized, double-blind, placebo-controlled trial using a novel enrichment design. Cephalalgia 2012: 32: 750-65. Ahonen K et al, A randomized trial of rizatriptan in migraine attacks in children, Neurology 2006; 67: 1135-40. Linder SL et al, Efficacy and tolerability of almotriptan in adolescents. A randomized, double-blind, placebocontrolled trial. Headache 2008; 48: 1326-36. 8