1/31/2014 Judy Lane, MD The Head Pain Center HOW TO SELECT MIGRAINE HOW TO SELECT MIGRAINE PREVENTIVES Financial Disclosure  Consulting Fees/Honoraria from Allergan and Impax  Speakers Bureau for Nautilus 1 1/31/2014 Learning Objectives  Describe three possible therapeutic mechanisms of oral preventive agents  Cite rational medication combinations for migraine prevention  Summarize current thoughts about lessening tachyphylaxis from preventive medications Introduction  First ( and only) preventive introduced specifically for migraine: Methysergide, 1962  Underutilized (20% use but 38% are appropriate), doesn’t include nutraceuticals and off‐label use  Mostly off‐label use Mostly off label use  ? Reduce transformation 2 1/31/2014 When to Use a Preventive  3+ Headache episodes per month  Dysfunction interfering with quality of life  Acute medications inadequate  Patient preference  Should every patient receive natural preventives? Principles of Preventive Medications  Start low, go slow  Adequate trial: 2‐3 months  Consider co‐morbidity  Avoid MOH  Monitor for drugs that may interfere  Rational polypharmacy: for co‐morbidity, up to 6 months before maximal improvement 3 1/31/2014 Possible Therapeutic Mechanisms  Stabilize excitable CNS  Enhance antinociceptive pathways  Inhibit peripheral and central activation  Inhibit cortical spreading depression Dr…, What is your Favorite Preventive? 4 1/31/2014 Preventives FDA Approved  Methysergide  Propranolol  Timolol  Divalproex sodium, DR and ER  Topiramate  Botulinum A (chronic migraine) Efficacy based on Clinical Trials Level A Level B  Metoprolol  Amitriptyline  Propranolol  Venlafaxine  Topiramate  Atenolol  Sodium valproate  Nadolol  Divalproex sodium  Magnesium  Petasites  Riboflavin  Feverfew 5 1/31/2014 Efficacy based on Clinical Trials Level C Other  Coenzyme‐ Q 10  Lisinopril  Nortriptyline  Candesartan  Gabapentin  Memantine  Estrogen  Verapamil  Nicardipine  Nimodipine  Cyproheptadine Useful Information  Family history: response to medications  What has worked in the past?  Were prior trials done in state of MOH?  Time of day most vulnerable  Are migraines nocturnal?  What does the patient want to try? Alternatives vs prescriptions. 6 1/31/2014 Clinical Pearls  Optimize dosing : time of day, dividing  Follow with headache calendar Monotherapy based on Co‐ morbidity  Anxiety/Depression/Bipolar  Sleep disorders  Fibromyalgia  Epilepsy  Stroke/Cardiovascular 7 1/31/2014 Monotherapy  Simplified  Cheaper  Minimal side effects  Less drug interaction Consider Rational Combinations  Refractory migraine  Strong family history  Early age of onset/ disease modifying?  Disability  Tachyphylaxis  Goal of “ Alternatives only” 8 1/31/2014 Two Studies of Combination Therapy  #1. 52 RM compared beta blocker alone x 2 months, then VPA alone x 2 months, then combination  Combo: > ½ with 50% fewer headache days  #2. 58 patients failed both beta blocker and topiramate alone. alone  Combo: 60% > 50% less frequent with combo, 17% didn’t tolerate Rational combinations  Topiramate  Topiramate  SSRI ( first‐line therapy for depression in 2007)  CCB  Memantine  Magnesium 9 1/31/2014 “This triptan is magic!” Think about an SSRI Think about a daily long‐ acting triptan Migraine with Aura  Topiramate  Calcium channel blockers  Magnesium (glutamate blocker)  Lamontrigine  ? Memantine (glutamate implicated in CSD)  Avoid BBs: case reports of prolonged aura and possible ischemic stroke 10 1/31/2014 Hemiplegic Migraine  CCBs ( associated with calcium channel     mutations) Magnesium Riboflavin Aspirin @ low dose Coenzyme Q Headache Worsened by Triptan Use  Vasospasm?  Think about a CCB 11 1/31/2014 Topiramate Use: The Big Gun  Start low, go slow  When to divide the dose  Tingling reversed with potassium rich foods  BC issue  SSRIs good in combination  Interferes with folate/serotonin synthesis  Memantine good in combination Topiramate: Cognitive  Cognitive side effects: verbal fluency,     psychomotor speed, working memory, h d k processing speed More sx at doses > 96mg (15% and 24%) Higher frequency with psychiatric history Perhaps due to simultaneous effects on multiple channels; GABAergic‐> attention and vigilance, Antiglutamatergic‐> memory and learning Weeks to normalize (Martin; Ojemann) 12 1/31/2014 Botulinum Toxin A  Time to effect first series: 4 weeks  Commit to at least 2 series’  10 % did not respond until third series  12 week intervals  Doesn’t always work during MOH  Polypharmacy DHE is the Only Effective Medication  Methergine  Methysergide  TCA 13 1/31/2014 Methergine/Methysergide  Informed consent  Fibrosis: retroperitoneal, pleuropulmonary,      cardiac valve thickening Dosing Use of DHE abortively Use of holiday fh ld Imaging Blood studies New Information/Duloxetine       Wm. Young: Prospective study 22 completers Nondepressed individuals Episodic migraine Mean dose 110 mg 52% had 50% or greater decrease in headache days  Recommended higher dose: ie, 120 mg rather than 60mg 14 1/31/2014 Memantine Preventively  Bigal, Rapoport et al  Refractory migraine or transformed migraine  Antagonist at NMDA receptors, blocks excessive activity but not normal function  28 patients, 3 months, not placebo controlled  Endpoints: days with headache reduced(22‐>16), d ith days with severe pain reduced (7.8 ‐>3.2), less i d d ( 8 ) l disability at 3 months ( 36.6 vs 54.9)  37% side effects (most mild), 5.5% terminated  Add‐on utility, especially for topiramate Use of Oral Contraceptives  Particular importance in MRM who require      contraception Comorbid endometriosis , dysmenorrheaas, polycystic ovarian syndrome Continuous vs cycling off monthly Review other risk factors 1/3, 1/3, 1/3 Monitor for new aura or worsening 15 1/31/2014 Pregnancy  Early = all or none, SAB, embryo toxicity  Teratogenesis 31 days‐> 10 weeks after last menses  Later use: growth retardation, effects on maternal uterine contraction, drug withdrawal  Most Category B or C g y  Magnesium: category B, riboflavin: category A  CCBs and Propranolol : category C  Amitriptyline: category C or D Pediatrics/Adolescence  Petodolex  Botulinum toxin  Topiramate  SSRIs 16 1/31/2014 Tachyphylaxis: Mechanisms  Pharmacokinetics/Pharmacodynamics/Cross      Tolerance/Behavioral tolerance Placebo effects Natural change in disease Disease progression: genetic, TBI,obesity, MOH, sleep disorder, work stress p , Inadequate recall Drug delivery/ Poor adherence Ways to Deal with Tachyphylaxis  1‐8% per literature  Increase medication dose  Drug holiday  Rational combinations/Treat multiple migraine mechanisms  Retry, especially if prior MOH ll f  Behavioral/environmental treatments 17 1/31/2014 Common Meds that Exacerbate Migraine  Zolpidem( 7‐19%)  Eszopiclone( 13‐21%)  Hycosamine (< 1%)  Nifedipine (10‐23%)  Omeprozole ( 7%)  Ranitidine (3%)  Buproprion ( 25‐30)  Milnacipran(18%) Length of Preventive Treatment  Wober: 64 patients discontinued meds used up to 6 months: 75% relapsed  Repeating same preventive less successful  Pascual: 80 patients discontinued topiramate: after 6 months, 50% worse topiramate after 6 months 50% worse  Recommended at least 1 year on preventive meds 18 1/31/2014 Summary Be creative Be creative Treat co‐morbidity Decrease dose over time Don’t discontinue too quickly one med at a time quickly, one med at a time, one month interval 19