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Migraine Prophylaxis 2009

Migraine Prophylaxis 2009. Dr Richard Peatfield . MD FRCP Princess Margaret Migraine Clinic Charing Cross Hospital London W6 8RF r.peatfield@imperial.ac.uk. Prevalence of headache in the previous year Rasmussen et al J. Clin.Epidemiol. 44 1147 1991

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Migraine Prophylaxis 2009

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  1. Migraine Prophylaxis 2009 Dr Richard Peatfield. MD FRCP Princess Margaret Migraine Clinic Charing Cross Hospital London W6 8RF r.peatfield@imperial.ac.uk

  2. Prevalence of headache in the previous year Rasmussen et al J. Clin.Epidemiol. 44 1147 1991 Migraine Tension-type headache Age groupMen Women Men Women n 387 353 387 353 25-34 5% 18% 68% 93% 35-44 7% 14% 63% 92% 45-54 6% 12% 70% 82% 55-64 7% 19% 49% 74% All ages 6% 15% 63% 86%

  3. Functional impact of migraine by self-reported physician diagnosis of migraine. Lipton et al Headache 41 638 2001

  4. INDICATIONS FOR MIGRAINE PROPHYLAXIS Two attacks monthly. Less frequent attacks proving intractable. Note • Cost benefit. • Abolition of the first hour or so of each headache if successful. • Persistent symptoms after 2 hours, eg:- • Mild Headache • Nausea • Photophobia • Disability Quality of life can be impaired despite ‘effective’ treatment.

  5. Migraine prophylactic medication Amine Modulation b-blockers: Propranolol, Atenolol 5-HT Blockers: Pizotifen, Methysergide Tricyclics Anti-epileptics: Valproate, Topiramate Calcium channel blockers: Flunarizine Metabolic enhancers: Riboflavin, Nicotinamide ACE Inhibitors: Lisinopril Also: NSAID’s, Magnesium, Feverfew Channel Modulation Others

  6. Propranolol Total others 22% (26) !0% Amitriptyline 17% 6% Other β-blockers 7% Verapamil 8% Valproate Gabapentin sodium Topiramate 4% 12% 14% Prophylactic Agents: Europe v USA North America G5 EUROPE(France, Germany, Italy, Spain, and UK) propranolol 33% Amitriptyline 10% Valproic Nortriptyline acid 1% Total others Pizotifen (33) 17% 15% Other Flunarizine β-blockers 15% 9% Source: IMS MIDAS; 2002 RXs; N2C Migraine Products + top products used for G43 diagnosis code (which includes off-label products).

  7. Migraine - Preventive Treatment First choice • betablockers • antiepileptic drugs Second choice • antidepressants • calcium-antagonists • serotonin antagonists Third choice • riboflavin, coenzyme Q10, magnesium “Special cases“ • menstrual migraine: NSAIDs, continuous contraceptive pill, naratriptan, frovatriptan • exercise induced: betablockers, indomethacin Sandor 2004

  8. Conventional migraine prophylactic drugs Daily dose (adult) mg. Start Max. Propranolol 80 320 Atenolol 50 150 Pizotifen 0.5 1.5 Methysergide 1 6 Valproate 400 1600 Naproxen 250 1000 Amitriptyline 10-25 100

  9. b Blockers Diener • Mode of action unknown; no animal models • No proper dose finding studies of propranolol 160=80mg, or 160>80? • Short titration times, never over 12 weeks • Metoprolol second greatest number of trials, again for a short time • Bisoprolol largest, best designed trial 226 patients. • All seem of equal efficacy ~ 50% response rate. • No correlation between plasma levels and efficacy • 16 comparative trials Metoprolol > aspirin • Propranolol > Nifedipine • Neither trial with placebo • Flunarizine = Propranolol [Cephalalgia 2001]

  10. b Blockers Diener Propranolol since 1964; very cheap 26 drugs now available:- Effective Perhaps not Propranolol Acebutolol Metoprolol Alprenolol Timolol Oxprenolol Bisoprolol Pindolol Nadolol Atenolol ?? Differences due to trial design

  11. Propranolol http://www.cochrane.org/reviews/en/ab003225.html

  12. Antidepressants Bendtsen Migraine Widely used – second only to b-blockers. No DBXO trials following IHS guidelines Three small trials of amitriptyline 1973-1987 21-42% reduction in attacks Effect independent of depressive state Trials of fluoxetine- benefit modest if any Tension-type headache Most trials of amitriptyline (1964-1996) show benefit Pfaffenrath’s trial had a tough endpoint Bendtsen’s own trial:- (1996) Amitriptyline effective; Citalopram had no effect Holroyd 2001 144 patients 30% reduction

  13. Antidepressants Discordant results with SSRI’s:- Patients do not care any more Headache continues unaltered Not evidence based!!

  14. Valproate in Migraine Prevention: Efficacy—ITT * * * Mean Reductionin 4-WeekMigraine Frequency(%) *P<.05. ITT=intent to treat. Klapper J and the Divalproex Sodium in Migraine Prophylaxis Study Group. Cephalalgia. 1997;17:103-108. Valproate

  15. Valproate in Migraine Prevention: Overall Responder Rate—ITT * ≥50%ResponderRate (%) *P≤.05 (vs placebo). ITT=intent to treat. Klapper J and the Divalproex Sodium in Migraine Prophylaxis Study Group. Cephalalgia. 1997;17:103-108.

  16. Divalproex in Migraine. Cochrane reviews 2006 http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003226/frame.html

  17. Methysergide • 5HT2A,B&C receptor antagonist • (But mianserin, ketanserin and ICI 169369 do not work) • Metabolised to Methylergometrine, an agonist at 5HT1 B receptors. • Greater bioavailability • Longer half-life. • Antagonist at 5HT7 receptors. • Increases Neuropeptide Y levels in the hypothalamus • – appetite stimulant

  18. Methysergide in Migraine Prophylaxis 60 patients, double blind cross over. 6 mg daily. Placebo Methysergide No attacks 4 16 Over 50% fewer 12 18 Unchanged 44 26 p<0.01 Petersen & Moller: Clin.Pharm.Ther. 1966 7 520.

  19. Methysergide: side effects • Less severe than the publicity! • Pain in the legs (?vasospasm) is less likely if the drug dose is increased slowly ( 0.5mg daily for a few days- etc etc). • Retroperitoneal and cardiac fibrosis. Rare; commoner with larger doses. In one series 11/19 affected patients had received > 8mg/day Seen after 6mg/day or less. Reversible if the drug is stopped. • The risk of retroperitoneal fibrosis is lessened if the drug is stopped for 1 month every 6 months.

  20. Methysergide: fibrotic side effects n cases Continuous use ( ?Dose) 1000 36 Stopping for 1 month annually 300 Nil (Bala Am Ht J 1974 88 640) Worth regular auscultation, and checking a renal ultrasound and echocardiogram annually What to do in the ‘Holidays’? • Topiramate • Prednisolone ( 50mg, reducing by 5mg/day)

  21. % of patients with >50% reduction in Migraine Frequency Topiramate Topiramate in Migraine Prevention Response to Topiramate Therapy (50% Responder Rate) *P<.05; †P<.01; ‡P<.001. Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL. et al. JAMA. 2004;291(8):965-973 MIGR-001 / MIGR-002

  22. Topiramate in Migraine Prevention: Onset of Action Month Cumulative Reduction in Mean Migraine Frequency * † † † † ‡ † † ‡ ‡ ‡ ‡ ‡ *P=.032; †P≤.015; ‡P<.001. Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL. et al. JAMA. 2004;29198):965-973

  23. Topiramate in Migraine. Cochrane reviews 2006 http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003226/frame.html

  24. Topiramate side-effects • 50% get paraesthesiae – carbonic anhydrase inhibition - try K+ • 20% Cognitive – concentration, memory, speech unpredictable ? K+ • 1½% Kidney stones Calcium oxalate • Fatigue • Anorexia; weight loss • Diarrhoea • Taste change • Glaucoma Brandes JAMA 2004 291 965; Silberstein Arch N. 2004 61 490

  25. valproate 45 betablockers 40 amitriptyline 20 flunarizine 42 Mg (24 mM) 18 riboflavin (Vit B2) 37 33 coenzyme Q10 topiramate 40 gabapentin 22 ‘Therapeutic gain’ compared to placeboproportion of patients with 50% reduction in attack frequency (verum – placebo) therapeutic gain 0 5 10 15 20 25 30 35 40 45 55 50 1st choice (EBM) well tolerated substances, mechanism: energy metabolism [Sandor 2004] new antiepileptics

  26. Levetiracetam in Headache Co-sponsored prospective multicentre trial of 1.5G - No benefit. Unpublished. ?? Suppressed (? Dose too low) Young (Philadelphia) Open study 3G 35% >50% reduction in attacks No control series Personality change problems Headache 2004 44 2238 Clin J Pain 2004 20 198 All retrospective

  27. Angiotensin :- Converting enzyme inhibitors and receptor antagonists Lisinopril 20mg is an effective prophylactic 20% improvement above placebo in a DBXO trial in 47 patients [Schrader BMJ 2001 322 19-22]. Fewer headaches in patients on ACE inhibitors [Etminan Am J Med 2002 112 642-6] Candesartan Trial of 16mg daily in 57 migraine patients 32-46% had headache reduced by 50% No significant adverse events [Tronvik. JAMA 2003 289 65-9].

  28. Tronvik. JAMA 2003 289 65-9

  29. Binding of 5-HT2B receptors

  30. Botulinum Toxin Zinc dependent Metalloproteinases Cleaves proteins responsible for exocytosis of transmitter vesicles Acts on sensory afferents too Inhibits release of all neurotransmitters, including SP, CGRP etc, in doses comparable to those used in man. Consensus is that is does work, so long as there are enough separate injection sites – 15-20 per patient. Sites of action are not confined to the neuromuscular junction In published trials most patients are unaware of the treatment used. Some trials are biased; placebo patients less severe.

  31. Type A – Most potent and lasting effect Light Chain cleaves SNAP 25 protein inside membrane - 1 of the 3 proteins in SNARE complex that leads to Ach release Collateral axonal sprouts lead to early recovery, until original terminal recovers

  32. Sensory effects of botulinum toxin In cervical dystonia low doses relieve pain before the motor effects Relja 2006 Suppresses secondary inflammatory pain after formalin injection Release of Substance P, CGRP, etc. Cui Pain 107 125 2004 Less c-fos expression in cervical neurones Gazer~~ Pain 122 315 2006

  33. Botulinum Toxin in Chronic Daily Headache Mathew Headache 45 293 2005. 355 subjects 47% met criteria for analgesic abuse; slightly more in the active group Side effects in 2.3% only (usually neck pain from weakness) Primary end-point (change in the number of headache free days) not met --6.7 cf 5.2.in placebo non-responders Doubtful clinical significance Significant improvement in:- Headache frequency The proportion with >50% decrease of headache days per month Those not on prophylaxis [H 45 315 2005]

  34. Botulinum Toxin NO effect in tension-type headache Possible effect in Migraine High Placebo response rates Greatest potential role in ‘Chronic Migraine’

  35. Blinding Aesthetic change Less Sweating Incidental effect in cosmetic patients In the trials the number of patients guessing correctly fell from 65% to 55% as they improved!

  36. Exploding vs Imploding Headaches Burstein Kyoto, Dodick AAN 2006 Exploding Bursting 12% responded Imploding Tightening 92% responded Ocular 100% responded ? Related to fine extracranial c-fibres passing through the skull to innervate the dura (in the rat)

  37. Differences in Migraine Features for Botulinum Toxin-A Responders and Nonresponders % of study participants % improvement over pre-treatment phase Headache Characteristics Description of Headache Pain N=35 responders N=24 nonresponders Burstein et al., Neurology 2006

  38. Expensive! £129 for a 100 unit ampoule 4 patients at low dose – 25 units per patient Trial used 150-190 units per patient

  39. USA different from UK! Vertical integration of costs and savings in the USA Chronic migraine sufferers are already costing insurers a lot of money by the time they are referred for Botox treatment, and the additional costs are seen as marginal and the potential gains large.

  40. If you don’t have Botox… USA UK Emergency $600 Multiple Opinions Someone Else’s Budget! Analgesics Cost Botox of Scans

  41. Prophylaxis in real life

  42. MIGRAINEPROPHYLACTIC MEDICATION Propranolol 240 1.44 34 Atenolol 100 0.95 33  Pizotifen 3 8.28 28  Methysergide 6 37.68 30  Valproate 1000 7.84 34  Amitriptyline c100 2.41 32 Topiramate100 32.07 31 Dose used in trials Cost / 28 days Percent of patiens likely mg £ to make a 50% improve- ment compared to placebo Revised prices 27 November 2005

  43. Consensus view on migraine prophylaxis Offered :- Patients with 6 or more headache days per month; 4 or more days with some impairment; or 3 or more days with severe impairment. Considered:- Patients with 4 or 5 headache days per month with normal functioning; 3 days with some impairment; or 2 days with severe impairment. Not indicated:- Patients with <4 headache days per month with normal functioning; or no more than 1 day per month regardless of impairment. Lipton Neurology 2007 68 343

  44. Principles of Preventative Pharmacotherapy Goadsby • Clarify Diagnosis:- History is taken, not given. • Explain what it means to the patient. • Assess the burden to the patient. • Establish what the patient expects. • Be clear what the Physician can offer; limited! • Advise on areas where the patient can intervene. • Optimise the treatment of acute attacks. • Plan preventative treatment.

  45. Migraine: Prophylactic trials • Small trials in single centres • Some crossover and some parallel group designs • Variety of endpoints used:- • - Percentage of patients improving in categories • - Overall percentage improvement •  Not a comprehensive metaanalysis:- results from individual selected trials.

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