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 MigraineTension-type headache Age group Men WomenMen Women n387 353387 353 25-345%18%68%93% 35-447%14%63%92% 45-546%12%70%82% 55-647%19%49%74% All ages6%15%63%86%

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

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

7. Migraine prophylactic medication  -blockers: Propranolol, Atenolol 2. 5-HT Blockers: Pizotifen, Methysergide 3. Tricyclics 4. Anti-epileptics: Valproate, Topiramate 5. Calcium channel blockers: Flunarizine 6. Metabolic enhancers: Riboflavin, Nicotinamide 7. ACE Inhibitors: Lisinopril 8. Also: NSAID’s, Magnesium, Feverfew Amine Modulation Channel Modulation Others

8. Prophylactic Agents: Europe v USA Source: IMS MIDAS; 2002 RXs; N2C Migraine Products + top products used for G43 diagnosis code (which includes off-label products). North AmericaG5 EUROPE (France, Germany, Italy, Spain, and UK) 6% Total others (26) !0% Other β-blockers 7% Verapamil 8% Amitriptyline 17% Valproate sodium 12% Topiramate 14% Gabapentin 4% Propranolol 22% Total others (33) 15% Other β-blockers 9% Flunarizine 15% Amitriptyline 10% Valproic acid 1% propranolol 33% Pizotifen 17% Nortriptyline

9. 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

10. Daily dose (adult) mg. StartMax. Propranolol80320 Atenolol50150 Pizotifen0.51.5 Methysergide16 Valproate4001600 Naproxen2501000 Amitriptyline10-25100 Conventional migraine prophylactic drugs

11.  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 trialsMetoprolol > aspirin Propranolol > Nifedipine Neither trial with placebo Flunarizine = Propranolol [Cephalalgia 2001]

12.  Blockers Diener Propranolol since 1964; very cheap 26 drugs now available:- EffectivePerhaps not PropranololAcebutolol MetoprololAlprenolol TimololOxprenolol BisoprololPindolol Nadolol Atenolol ?? Differences due to trial design

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

14. Antidepressants Bendtsen Migraine Widely used – second only to  -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

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

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

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

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

19. Methysergide 5HT 2 A,B&C receptor antagonist (But mianserin, ketanserin and ICI 169369 do not work) Metabolised to Methylergometrine, an agonist at 5HT 1 B receptors. - Greater bioavailability - Longer half-life. Antagonist at 5HT 7 receptors. Increases Neuropeptide Y levels in the hypothalamus – appetite stimulant

20. 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.

21. 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.

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

23. 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 % of patients with >50% reduction in Migraine Frequency TopiramateTopiramate MIGR-001 / MIGR-002

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

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

26. 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

27. ‘Therapeutic gain’ compared to placebo proportion of patients with  50% reduction in attack frequency (verum – placebo) 1 st choice (EBM) well tolerated substances, mechanism: energy metabolism new antiepileptics 42 flunarizine gabapentin 22 topiramate 40 051015202530354045 50 55 20 amitriptyline 40 betablockers 45 valproate therapeutic gain 37 riboflavin (Vit B2) 18 Mg (24 mM) 33 coenzyme Q10 [Sandor 2004]

28. 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

29. Angiotensin :- Converting enzyme inhibitors and receptor antagonists Lisinopril20mg 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] CandesartanTrial of 16mg daily in 57 migraine patients 32-46% had headache reduced by 50% No significant adverse events [Tronvik. JAMA 2003 289 65-9].

30. Tronvik. JAMA 2003 289 65-9

31. Binding of 5-HT 2B receptors

32. 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.

33. 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

34. 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

35. 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]

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

37. 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!

38. Exploding vs Imploding Headaches Burstein Kyoto, Dodick AAN 2006 ExplodingBursting 12% responded Imploding Tightening 92% responded Ocular100% responded ? Related to fine extracranial c-fibres passing through the skull to innervate the dura (in the rat)

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

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

41. USA different from UK! 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. Vertical integration of costs and savings in the USA

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

43. Prophylaxis in real life

44. MIGRAINE PROPHYLACTIC MEDICATION Dose used in trialsCost / 28 days Percent of patiens likely mg £to make a 50% improve- ment compared to placebo Propranolol 240 1.44 34 Atenolol 100 0.95 33 Pizotifen 3 8.28 28 Methysergide 637.68 30 Valproate 1000 7.84 34 Amitriptyline c100 2.41 32 Topiramate 10032.07 31 Revised prices 27 November 2005

45. 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

49. 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.

50. 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.

51. DRUGS ACTING ON SEROTONIN RECEPTORS (Adapted from Saxena) SumatriptanPizotifenMethysergideErgotamine 5HTID AgonistInactivePartial Agonist Agonist 5HT2AInactiveAntagonistAntagonistAgonist 5HT2CInactiveAntagonist AntagonistAgonist 5HT3InactiveInactiveInactive Inactive

52. Select for positive side effects, e.g. anxiety → betablocker insomnia → sedating tricyclic at night (amitriptyline) constipation → magnesium obesity → topiramate comorbid depression → antidepressant in sufficient dosage Sandor 2004

53. Long Q-T interval Upper limit 450msec, less in women

54. Long QT interval Measure from the beginning of Q to the end of T Resting ECG can be normal –need an exercise test Patients may collapse during exercise QT c is corrected for the heart rate >460msec in women; 440msec in men

55. Congenital long Q-T interval 7 identified genes; 300 mutations Mostly related to K + Channels Risk of sudden death, especially during sudden arousal or exercise Prophylactic  -blockers may lower this risk

56. Drugs prolonging the Q-T interval WithdrawnTerfenadine, Astemazole, Cisapride. HazardousAmiodarone, Sotalol. Quinidine Care!Erythromycin, Chlorpromazine, Haloperidol, Tricyclics, Domperidone, Amantadine. www.longqt.org

57. Valproate in Migraine Prevention 16-week double-blind, placebo-controlled trial of valproate; N=171 Study design –4-week placebo run-in –Patients randomized to receive 500, 1000, or 1500 mg/d valproate or placebo for 12 weeks Initial dose, 250 mg/d Titration every 4 d (8 d for 500 mg/d group) of 250 mg/d to maintenance dose 8-week maintenance phase –Efficacy evaluations every 4 weeks Klapper J et al. Cephalagia. 1997;17:103-108.

58. Topiramate in Migraine Prevention MIGR-001 / MIGR-002 / MIGR-003 % of Patients  75% and 95% Responder Rate Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL et al. JAMA. 2004;291(8):965-973