1. INCREASED INCIDENCE OF REBOUND HEADACHES FROM THE DISCONTINUED USE OF THE ANTI-MIGRAINE MEDICATION, MAXALT ® Sherry Neff Department of Biological Sciences, York College of Pennsylvania Project Summary Rebound headaches, which affect 5% of the population, are caused by the discontinued use of many medications that relieve headaches through vasoconstriction. Triptans are the newest class of anti-migraine medications which also function by inducing vasoconstriction of the extracerebral blood vessels. Although the triptan, Maxalt ®, is a commonly prescribed anti- migraine medication, little is known about its potential to cause rebound headaches. The goal of this proposal is to determine whether a 10mg or 20mg dose of Maxalt ® will increase the incidence of rebound headaches if discontinued after three, six, or twelve months of daily use. For six weeks following the cessation of Maxalt ®, the frequency, severity, and symptoms of headaches will be monitored. Based on data from other vasoconstrictors, we expect to see an increase in headache frequency and severity as a function of dose and time of treatment. This will increase our understanding of possible side effects from the daily use and discontinuation of Maxalt ®. Introduction Rebound headaches affect 5% of the population. They are caused by the discontinued use of many over-the-counter or prescription headache medications after frequent, prolonged use. Migraines are caused by vasodilation of the blood vessels around the brain. The medications that have the most potential for causing rebound headaches are ergotamines and caffeine-containing products which both alleviate pain by inducing vasoconstriction. The newest class of anti-migraine medications are serotonin 5-HT1B/1D receptor agonists called triptans. They relieve migraines by binding to serotonin receptors in the brain which reduces neurogenic inflammation and induces vasoconstriction of the extracerebral blood vessels. The first triptan introduced was Imitrex ® (sumatriptan), followed by second generation triptans which include Maxalt ® (rizatriptan), Zomig ® (zolmitriptan), and Amerge ® (naratriptan). Although triptans are commonly prescribed and also cause vasoconstriction, little is known about their potential for causing rebound headaches. Review of Literature  Since migraines are caused by vasodilation, the standard treatment for migraines is through medications that induce vasoconstriction (Ferrari 1998).  Ergotamines and caffeine-containing products such as Excedrin ®, Fiorinal ®, and Fioricet ®, which cause vasoconstriction, are common medications used to treat migraines (Moore and Noble 1997).  Using compound analgesics that contain caffeine more than 3 times a day for more than 3 times a week puts someone at risk for developing rebound headaches (Lipton et al. 1998).  Rebound headaches have developed in patients taking as little as 0.5 – 1 mg of ergotamine 3 times a week (Young 1997).  Triptans, a new class of anti-migraine medications, are a refinement of ergotamines and also induce vasoconstriction of extracerebral blood vessels (Fenuik et al. 1991).  The first triptan introduced was Imitrex ® (sumatriptan), followed by 2 nd generation triptans which include Maxalt ® (rizatriptan), Zomig ® (zolmitriptan), and Amerge ® (naratriptan) (Crawford et al. 2001).  It is unclear whether this new class of anti- migraine medications also has the potential to cause rebound headaches. Objective To determine if Maxalt (10mg or 20mg) can cause rebound headaches when discontinued after daily use for three, six, or twelve months Patients  150 men and women  75 patients – Maxalt ® 10mg (3, 6, or 12 months)  75 patients – Maxalt ® 20mg (3, 6, or 12 months)  Ages 20-45  Primary diagnosis of migraine without aura Expected Results  High number of patients will experience rebound headaches resulting from the discontinuation of Maxalt ®  Increase in frequency of headaches - As dose of treatment increases - As time of treatment increases  Increase in severity of headaches - As dose of treatment increases - As time of treatment increases Future Studies  Determine if there is a difference between the 1 st generation and 2 nd generation triptans and their potential for causing rebound headaches  Determine if there is a difference between men and women and their risk for developing rebound headaches Monitored for 6 weeks following treatment  Frequency of headaches  Severity of headaches on a scale (1-5)  Symptoms of headaches such as nausea, photosensitivity, holocephalic, unilateral, frontally located Acknowledgements Dr. Ronald Kaltreider Literature Cited Crawford, A.W., Cutler, N.R., Jhee, S.S., et al. 2001. Pharmacokinetics and pharmodynamics of the triptan antimigraine agents: a comparitive review. Clinical Pharmacokinetics 40:189-205. Fenuik, W., Humphrey, P.P.A, Perren, M.J., et al. 1991.Rational for the use of 5-HT1-like receptor agonists in the treatment of migraine. Journal of Neurology 238:57- 61. Ferrari, Michael D. 1998. The Lancet 351:1043-1051. Lipton, R.B., Stewart, W.F., Ryan, R.E., et al. 1998. Efficacy and safety of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain. Archives of Neurology 55:210-217. Moore, Kenneth L. and Noble, Sara L. 1997. Acute therapy and drug-rebound headache. American Family Physician 56:2039-2052. Young, W.B. 1997. Appropriate use of ergotamine tartrate and dihydroergotamine in the treatment of migraine: current perspective. Headache 37:42-45. Removal of vasoconstrictor Relief of headache Use of medication that causes vasoconstriction, such as Maxalt ® HEADACHE Vasodilation monitored monthly months 3612 or Experimental Design Maxalt ® rebound headache Homeostasis was disrupted, therefore blood vessels overcompensate and dilate too much (10mg or 20mg) Scheme 1: Proposed Model of Maxalt ® Induced Rebound Headaches daily use