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Headache Forum Treatment of Migraine Series 1. 2. 3. 4. Preventative therapy Acute therapy Treatment in special populations Advanced treatments for refractory cases Treatment of Migraine Series 1. Preventative Treatment March 2006 Lucy Vieira MD Preventative treatment All patients require acute or abortive therapy, many need preventative also. Goals of preventative treatment: – – reduce frequency, duration or severity of migraine attacks. Potentially reduce the risk of chronic forms of migraine? (Limroth et al.,2007 Headache 47(1):13-21) When do we consider using preventative treatment? Can be considered in any patient where there is significant disability associated with migraine. 1. 2. 3. 4. 5. 6. 7. 8. in the patients' opinion, migraines significantly interfere with their daily routines, despite acute treatment frequent headaches (increased risk of chronic forms if>4-5/month*) contraindication to, failure of, or overuse of acute therapies adverse events with acute therapies the cost of both acute and preventive therapies patient preference the presence of uncommon migraine conditions, including hemiplegic migraine, basilar migraine, migraine with prolonged aura, or migrainous infarction (to prevent neurologic damage) US headache consortium guidelines 2000 *Katsarava Neurology 2004 Goals of Treatment for Prevention of Migraine 1. 2. 3. reduce attack frequency, severity, and duration improve responsiveness to treatment of acute attacks improve function and reduce disability Reasonable goals for your patient Reduce headache frequency by 50% How to use prophylactic agents A. Start low and go slow: try for usual effective dose (or until limited by adverse events). B. Give each treatment an adequate trial: usually minimum of 2-3 months. C. Avoid interfering medications (e.g., overuse of certain acute medications such as ergotamine). D. Use of a long-acting formulation may improve compliance. Patient education is essential for success: A. Maximize compliance: discuss with the patient the rationale for a particular treatment, when and how to use it, and what adverse events are likely. B. Address patient expectations: discuss with the patient the expected benefits of therapy and how long it will take to achieve them. C. Create a formal management plan Evaluation: A headache diary is essential: -considered the “gold standard” in headache evaluation. -should be user-friendly -should measure attack frequency, severity, duration, disability, response to type of treatment, and adverse effects of medication. Re-evaluate therapy. After a period of stability, consider tapering or discontinuing treatment. Danish Headache Clinic Diagnostic Headache Diary Russell MB, Rasmussen BK, Brennum J, Iversen HK, Jensen RA, Olesen J. Presentation of a new instrument: the diagnostic headache diary. Cephalalgia 1992; 12:369– 74. Choosing a prophylactic agent 1. Consider coexisting conditions: The Coexisting diseases present both treatment opportunities and limitations. Select a drug that will treat both disorders. Establish that there are no contraindications for the selected drugs (beta-blockers are contraindicated with asthma) Choosing a prophylactic agent 2. Establish that there are no contraindications for treatment – pregnancy. Do not use or if absolutely necessary use drug with lowest teratogenic potential. 3. Beware of drug interactions 4. Choose a drug based upon highest clinical efficacy and safety. Group 1: Med- high efficacy, good evidence, and var. side effects Amitriptyline Propranolol Timolol Divalproex Topiramate Group 2: Lower efficacy or ltd evidence, mild to moderate side effects Aspirin Flurbiprofen Ketoprofen Mefenamic acid Naproxen sodium Tolfenamic acid Gabapentin Fluoxetine Metoprolol Atenolol,Nadolol Nimodipine Verapamil Group 3: Efficacious on consensus and clinical experience, but no scientific evidence a. mild-to mod. side effects Bupropion Fluvoxamine Paroxetine Sertraline Venlafaxine Mirtazepine Doxepin Imipramine Nortriptyline Protriptyline Trazodone Group 4: Med- high efficacy, good strength of evidence, but with side effect concerns Methysergide Flunarizine* Pizotifen* TR-DHE* Cyproheptadine b. side effect concerns Methylergonovine Phenelzine Vitamin B2 Magnesium Feverfew US headache consortium guidelines and update Silberstein Headache Currents 2006 *N/A in USA Recommended substances (drugs of first choice) for the prophylaxis Substances Betablockers Metoprolol Propranolol Calcium channel blockers Flunarizine Antiepileptic drugs Valproic acid Topiramate Daily dose Level 50–200 mg 40–240 mg A A 5–10 mg A 500–1800 mg 25–100 mg A A Drugs of second choice for migraine prophylaxis (evidence of efficacy, but less effective or more side effects) Substances Daily dose (mg) Level Amitriptyline 50–150 B Naproxen 2 X250–500 B Petasites 2 X 75 B Bisoprolol 5–10 B S. Eversa et al., EFNS guideline on the drug treatment of migraine. European Journal of Neurology 2006, 13: 560–572 Drugs of third choice for migraine prophylaxis (only probable efficacy) Substances Daily dose Level Acetylsalicylic acid Gabapentin Magnesium Tanacetum parthenium Riboflavin Coenzyme Q10 Candesartan Lisinopril Methysergide 300 mg 1200–1600 mg 24 mmol 3 X 6.25 mg 400 mg 300 mg 16 mg 20 mg 4–12 mg C C C C C C C C C S. Eversa et al., EFNS guideline on the drug treatment of migraine. European Journal of Neurology 2006, 13: 560–572 Mechanisms of Action in Migraine Generally uncertain; most were found by accident. Thought to generally raise the threshold of migraine activation: – – – – Inhibit CSD Enhance antinociception Inhibit peripheral and central sensitization Modulate sympathetic, parasympathetic or serotonergic tone. B Blockers 1. inhibit central B receptors interfering with vigilance-enhancing adrenergic pathways 2. interaction with 5HT receptors – increasing 5HT synthesis 3. inhibition of NO production by blocking inducible NOS. 4. inhibition of kainate-induced currents Beta-Blockers Inhibition of B1 medicated mechanisms: inhibition of NE release by blocking presynaptic B receptors. Delayed effects: – – – decr. Tyrosine hydroxylase activity (NE synthesis) Delayed Decr. LC firing Increased serotonin synthesis Low serotonin synthesis/activity The preactivation level of cortical excitability may depend on the state-setting projections from the brainstem (5HT,NA) May reflect low interictal raphe-cortical 5HT activity. Megela and Taylor, J Comp Physiol Psychol1970; Schoenen J, Biomed Pharmacother1996 Figure 2. Whole-brain serotonin synthesis capacity (K-complex, mL/g/min) values before and after prophylactic treatment with propranolol or nadolol in five migraine patients Chugani, D. C. et al. Neurology 1999;53:1473 Antidepressants: elavil has most evidence of efficacy TCAs, SSRI and SNRIs incr synaptic NE or 5HT by inhibiting re-uptake---reduction in B adrenergic receptor density. Long-term treatment decreases 5HT2 receptor binding - actually enhances 5HT neurotransmission. TCAs up regulate GABA-B receptors, down-regulate histamine receptors. Some are 5HT2 receptors antagonists. Also interact with adenosine systems as well as BDNF. Topamax Increase threshold of activation and decrease excitability: – – – – Inhibit VG sodium channels Promote GABA neurotransmission Inhibit Glutamate transmission at AMPA/Kainate receptors Inhibit carbonic anhydrase Serotonin Antagonists: Pizotofen and methysergide metabolites 5HT 2B and 2C antagonists Methysergide – 5HT 1 receptor agonist and also has activity on the 5HT 2 receptor. – – Chronic administration attenuates dural plasma extravasation after electric stimulation of the rat trigeminal ganglion (Moskowitz) Effect on reduction of CGRP release? Theories of migraine pathogenesis Hyperexcitability: Ion channels Reduced serotonin synthesis Energy Metabolism failure CSD Trigeminovascular system activation (defense system??) –CGRP release Activation of certain brainstem nuclei CSD: Cortical spreading depression slowly progressive wave of neuronal and glial depolarization. – – – Decr membrane resistance Incr ECF K+ and neurotransmitters Incr ICF Na+, Ca+ Can be triggered by trauma, K+ or excitatory amino acids, electrical stimulation, energy failure and Na+/K+-ATPase inhibition. FIG. 2. Leao's original illustration of spreading depression Somjen, G. G. J Neurophysiol 94: 2-4 2005; doi:10.1152/classicessays.00031.2005 Copyright ©2005 The American Physiological Society Visual Aura Wave of hyperexcitability (positive phase) Followed by a Wave of cortical depression (negative phase) Ictal and interictal BOLD responses to checkerboard stimulation in human visual cortex 1. INTERICTAL Amplitude of BOLD signal induced remains constant 2. ICTAL Hadjikhani, Nouchine et al. (2001) Proc. Natl. Acad. Sci. USA 98, 4687-4692 Copyright ©2001 by the National Academy of Sciences - ↑ in mean MR signal with ↓ in oscillation (scintillations) - ↓ in mean MR (scotoma) and ↓ in stimulus response Mechanisms of migraine aura revealed by functional MRI in human visual cortex Progression: -3.5 ±1.1mm/min -Does not cross the PO sulcus -Does cross cytoarchitectonic boundaries (V1 to V2) -Does not follow vascular territory PNAS 2001;98:4687-92 Initial cortical hyperemia like in CSD (3-4.5 min.) With an amplified response to visual stimulation Followed by mild hypoperfusion(1-2h) With an attenuated response to visual stimulation Characteristic duration and velocity 3.5 ± 1.1 mm/min Fig. 2. Time-dependent BOLD activity changes from a single region of interest in VI, acquired before and during episodes of either spontaneous(C) or induced (B) visual aura Copyright ©2001 by theNouchine National Academy ofet Sciences Hadjikhani, al. (2001) Proc. Natl. Acad. Sci. USA 98, 4687-4692 Cortical spreading depression in the human brain 1- CSD liberates K+, H+, NO in ECF→ depolarisation of perivascular trigeminal terminals on BVs 2- proinflammatory peptides are released from trigeminal axons →local meningeal inflammatory reaction 3- Activation of the SSN and vasodilatation 4- Perception of pain Iadecola C.Nature Medicine 2002:8(2):110112 FHM 1 AND CSD Mouse knock in model (CACNA1A gene): enhanced susceptibility to CSD through increased Ca influx via increased channel opening and subsequent neurotransmitter release (ie: glutamate) at lower levels of depolarization. In vitro blockage of VGCC results in suppression of KCL induced CSD Neuron 2004:41(5):701-710 Neurosci Lett 2002;334(2):123-126 Mutations found in FHM Ca channel Na/K ATPase Glu Transporter Na channel Neuronal excitability, Glutamate transmission and CSD Preventative agents and CSD Rats were treated either over weeks and months, with one of Topiramate, valproate, propranolol, amitriptyline, or methysergide , vehicle, or Dpropranolol, a clinically ineffective drug. The impact of treatment was determined on the frequency of evoked CSDs after topical potassium application or on the incremental cathodal stimulation threshold to evoke CSD. Ayata et al., 2006. Ann Neurol 2006;59:652–661 Suppression of CSD by chronic administration of migraine prophylactic agents . Dose response Duration Ayata et al., 2006. Ann Neurol 2006;59:652–661 propranolol The need to have long term treatment • suggests that these drugs may lead to long-term modulation of gene expression or their encoded proteins. – Ie: modulation of ion channels, pumps, neurotransmitter receptors, or transporter genes • For example, amitriptyline and methysergide, administered chronically for 2 to 3 weeks, decreased 5-HT2 receptor expression which may reduce the frequency of migraine attacks. • long-term treatment with all five drugs can alter glutamatergic transmission, either directly or indirectly. – chronic valproate treatment: • decr whole-brain glutamate levels after 2 weeks Valproate • alters whole-brain expression of genes including ion channels (eg, decreased aquaporin-4, K channel Kv3.2b, and gap junction protein) • presynaptic Ca-binding proteins (eg, decreased synaptotagmins II and XI), • and neurotransmitter receptors (eg, decreased metabotropic glutamate receptor 3 and 5-HT2C receptor) after 30 days of treatment. GTN model Valproic acid but not propranolol inhibit induced migraine Other models are being sought after for the development of prophylactic agents. Some factors associated with Chronification Obesity Head injury Low socioeconomic status and education Caffeine overuse Poor sleep quality (snoring) Stressful life events Co-morbid pain Bigal et al.,Headache 2002;42:575-581, Scher et al.,Curr Pain HeadacheRep.2002;6:486-91 Scher AI et al.,Pain 2003;106:81-9 Multivariable* risk factors for headache chronicity in patients with episodic migraine Risk factors Odds ratio 95% CI p Value Headache freq 5–9 d 6.2 1.7–26.6 0.005 Headache freq >10 d 20.1 5.7–71.5 0.001 Overuse 19.4 8.7–43.2 0.001 --------------------------------------------------------------------------------------------*Adjusted for all other variables in the model. -30% patients developed CDH without medication overuse Katsarava et al., headache 2004;62(5):788-90 Factors that may play a role in chronification of migraine 1. Central sensitization after repeated bouts of migraine 2. Damage to CNS pain modulation system 3. CNS changes due to medication overuse 4. Abnormal focal neurological activity (CNS pain generators) 5. Persistent activity in a peripheral pain generator (cervical pathology) Can treatment with prophylactics reduce the risk of chronification? *p=.05 **p<.001 Limmroth,V. Headache 2007. Change in headache rate. The mean change in the number of headache days per month from the 4 week baseline period to the last 4 weeks of treatment – by subgroups acc. to mean headache days per subgroup during baseline References • • • • • • Cenk Ayata, MD,1,2 Hongwei Jin, PhD,1 Chiho Kudo, DDS, PhD,1 Turgay Dalkara, MD, PhD,3 and Michael A. Moskowitz, Suppression of Cortical Spreading Depression in Migraine Prophylaxis Ann Neurol 2006;59:652– 661 Volker Limmroth MD, David Biondi DO, Joop Pfeil MSc, Susanne Schwalen MD (2007) Topiramate in Patients With Episodic Migraine: Reducing the Risk for Chronic Forms of Headache. Headache 2007 Jan. 47 (1), 13–21. Katsarava Z, Schneeweiss S, Kurth T Incidence and predictors of chronicity of headache in patients with episodic migraine Neurology 2004;62:788-90 S. Eversa, J. A´ frab, A. Fresea, P. J. Goadsbyc, M. Linded, A. Maye and P. S. Sa´ndorf. EFNS guideline on the drug treatment of migraine. European Journal of Neurology 2006, 13: 560–572 Russell MB, Rasmussen BK, Brennum J, Iversen HK,Jensen RA, Olesen J. Presentation of a new instrument: the diagnostic headache diary. Cephalalgia 1992; 12:369–74. Silberstein S. Current Preventative Therapy: preventative treatment mechanisms. Headache Currents 2006; 3 (5/6): 112-119