1. MIGRAINE IN PRIMARY CARE ADVISORS Vienna, 25 October 2002, 2-6 pm Individualising migraine care: The clinical relevance of providing different modes of administration of antimigraine drugs

2. Introduction and objectives Dr Andrew Dowson Kings’ Headache Service, London

3. Programme Dr Andrew Dowson: Introduction and objectives Dr Trevor Rees: Modes of administration of available antimigraine drugs: a review of their strengths and weaknesses Dr Bruce Charlesworth: The clinical profile of the conventional tablet, orally dispersible tablet and nasal spray formulations of zolmitriptan (Zomig ® ) Break

4. Programme What factors should be considered in the choice of formulation to be used for antimigraine therapies? Dr Andrew Dowson: Selection of initial therapy Dr Sue Lipscombe: Follow-up care: monitoring treatment and selection of therapy General discussion

5. Objectives of today’s meeting Review available formulations of antimigraine drugs –Emphasis on the triptans Review the clinical profile of the Zomig formulations Agree on concepts of individualisation of care for migraine

6. Objectives of today’s meeting Review the factors that should be evaluated in choosing the appropriate formulation for each patient Develop recommendations for the prescription of different triptan formulations in primary care

7. Outputs from the project Article to be published in a learned journal MIPCA newsletter (‘popular’ GP version) Slide set for educational purposes

8. Modes of administration of available antimigraine drugs: a review of their strengths and weaknesses Dr Trevor Rees Hawthorns Surgery, Sutton Coldfield

9. Overview Available drugs and formulations in the UK Review of clinical profile of different triptan formulations –Relative strengths and weaknesses

10. Available drugs and formulations in the UK OTC acute medications Simple analgesics/NSAIDs and combination medications (e.g. Solpadeine) –Conventional tablets –Dispersible tablets

11. Available drugs and formulations in the UK Prescribed acute medications NSAIDs –Conventional tablets Analgesic-anti-emetic combinations –Tablets / dispersible tablets Analgesic-isometheptene combinations (Midrid) –Capsules Analgesic-codeine combinations (Migraleve) –Tablets

12. Available drugs and formulations in the UK Prescribed acute medications Triptans –Conventional tablets (all) –Orally dispersible tablets (Zomig, Maxalt) –Nasal sprays (Imigran, Zomig) –Subcutaneous injection (Imigran) Ergotamine –Conventional tablets (Cafergot / Migril)

13. Available drugs and formulations in the UK Prescribed prophylactic medications Beta-blockers –Conventional tablets, sustained-release capsules, oral solutions Serotonin antagonists Anticonvulsants Antidepressants –All conventional tablets

14. Clinical profiles of the different triptan formulations

15. Conventional tablets Generally well absorbed from the intestine Effective therapy –  60% of patients with headache relief after 2 hours Onset of action within 30-60 min Generally well tolerated Differences between the triptans are generally small and of uncertain clinical significance Sheftell FD, Fox AW. Cephalalgia 2000;20(Suppl2):14-24 Dowson AJ, Cady RK. Rapid Reference to Migraine, 2002

16. Conventional tablets: Efficacy 0 10 20 30 40 50 60 70 80 90 Sum 100 Sum 50 Nara 2.5 Zolm 2.5 Riz 10Almo 12.5 Ele 40 Patients (%) Proportion of patients with headache relief after 2 hours (maximum published values) Dowson AJ, Cady RK. Rapid Reference to Migraine, 2002

17. Orally dispersible tablets Generally well absorbed from the intestine Effective therapy –  60% of patients with headache relief after 2 hours Onset of action within 30-60 min Generally well tolerated Similar clinical profile to conventional tablet formulations Sheftell FD, Fox AW. Cephalalgia 2000;20(Suppl2):14-24 Dowson AJ et al. Cephalalgia 2001;21:419-20

18. ODT tablets: Efficacy 0 10 20 30 40 50 60 70 80 90 ZolmitriptanRizatriptan Tablet ODT Patients (%) Proportion of patients with headache relief after 2 hours (maximum published values) Sheftell FD, Fox AW. Cephalalgia 2000;20(Suppl2):14-24 Dowson AJ et al. Cephalalgia 2001;21:419-20

19. Nasal sprays Well absorbed from the nasal mucosa, but some also absorbed from the intestine Effective therapy –Up to 70% of patients with headache relief after 2 hours Rapid onset of action: within 15 min Generally well tolerated, with some reports of taste disturbances May have superior clinical profile to oral formulations Sheftell FD, Fox AW. Cephalalgia 2000;20(Suppl2):14-24 Purdy A et al. Cephalalgia 2001;21:418-9

20. Nasal sprays: Efficacy 0 10 20 30 40 50 60 70 80 ZolmitriptanSumatriptan Nasal spray Oral Patients (%) Proportion of patients with headache relief after 2 hours (maximum published values) Sheftell FD, Fox AW. Cephalalgia 2000;20(Suppl2):14-24 Purdy A et al. Cephalalgia 2001;21:418-9

21. Sumatriptan subcutaneous injections Very rapid absorption Most effective therapy –>80% of patients with headache relief after 2 hours Very rapid onset of action: within 10 min Has superior efficacy profile to all other formulations Has more associated side effects than all other formulations Sheftell FD, Fox AW. Cephalalgia 2000;20(Suppl2):14-24

22. Subcutaneous sumatriptan: Efficacy 0 10 20 30 40 50 60 70 80 90 Subcut 6 mgNasal spray 20 mg Oral 100 mg Patients (%) Proportion of patients with headache relief after 2 hours (maximum published values) Sheftell FD, Fox AW. Cephalalgia 2000;20(Suppl2):14-24

23. Strengths and weaknesses of different triptan formulations

24. Strengths Familiarity/comfort Most drugs well absorbed from intestine Clinical studies show that triptan tablets provide effective migraine relief Well tolerated Relative cost Weaknesses Need water for use Gastric stasis associated with migraine May not be effective for some patients/ attacks Slower onset of action (30-60 min) Conventional tablets

25. Strengths Innovative migraine treatment Flexible use: No need for water Generally well absorbed from intestine Clinical studies show that ODT triptans are effective for migraine As well tolerated as conventional tablets Relative cost Weaknesses Not familiar Gastric stasis associated with migraine May be no more effective than conventional tablets May not be effective for some patients/ attacks Slower onset of action Not absorbed from mouth Orally dispersible tablets (ODT)

26. Strengths Innovative migraine treatment Flexible use: No need for water Good nasal absorption Rapid onset of action (  15 min) May be more effective than tablet formulations As well tolerated as conventional tablets Weaknesses Not familiar Some absorption may occur in the stomach May not be effective for some patients/ attacks Some reports of taste disturbances Nasal sprays

27. Strengths Innovative migraine treatment Flexible use: No need for water Fastest onset of action (  10 min) More effective than all other formulations Non-needle injectors on horizon Weaknesses Fear of injections More side effects than with other formulations Some side effects may be disturbing to the patient and restrict use Relative expense Subcutaneous injection

28. Conclusions All triptan drugs and formulations are effective and well tolerated acute treatments for migraine Triptans are the ‘gold standard’ treatment Different triptan formulations have their own strengths and weaknesses The choice of triptan formulation may not be obvious from the outset Guidance to help the physician choose an appropriate formulation for each patient would be welcome

29. What factors should be considered in the choice of formulation to be used for antimigraine therapies?

30. Selection of initial therapy Dr Andrew Dowson Kings’ Headache Service, London

31. New MIPCA guidelines for migraine management Individualising care processes: Initial consultation and treatment

32.  Detailed history, patient education and buy-in  Diagnostic screening and differential diagnosis  Assess illness severity  Attack frequency and duration  Pain severity  Impact (MIDAS or HIT questionnaires)  Non-headache symptoms  Patient history and preferences Intermittent mild-to-moderate migraine (+/- aura) Intermittent moderate-to severe migraine (+/- aura) Aspirin/NSAID (large dose) Aspirin/paracetamol plus anti-emetic Oral triptan Nasal spray/subcutaneous triptan Initial consultation Initial treatment Rescue Behavioural/complementary therapies Copyright MIPCA 2002, all rights reserved Dowson AJ et al. Curr Med Res Opin 2002;18: in press.

33.  Detailed history, patient education and buy-in  Diagnostic screening and differential diagnosis  Assess illness severity  Attack frequency and duration  Pain severity  Impact (MIDAS or HIT questionnaires)  Non-headache symptoms  Patient history and preferences Intermittent mild-to-moderate migraine (+/- aura) Intermittent moderate-to severe migraine (+/- aura) Aspirin/NSAID (large dose) Aspirin/paracetamol plus anti-emetic Oral triptan Nasal spray/subcutaneous triptan Initial consultation Initial treatment Rescue Behavioural/complementary therapies Copyright MIPCA 2002, all rights reserved Dowson AJ et al. Curr Med Res Opin 2002;18: in press.

34. Assess illness severity Attack frequency and duration Pain severity Impact on daily living –MIDAS/HIT questionnaires Non-headache symptoms Patient factors –History, preference and other illnesses Matchar DB et al. Neurology 2000; www.aan.com.www.aan.com Bedell AW et al. Primary Care Network 2000.

36. Assessment of severity Mild-to-moderate migraineModerate-to-severe migraine Headaches mild-to- moderate in intensity Headaches moderate or severe in intensity Non-headache symptoms not severe in intensity Significant non-headache symptoms, possibly severe Impact not significant: MIDAS Grade I or II HIT Grade 1 or 2 Significant impact: MIDAS Grade III or IV HIT Grade 3 or 4 Matchar DB et al. Neurology 2000; www.aan.com.www.aan.com Bedell AW et al. Primary Care Network 2000.

37. Selection of initial therapy Evidence-based medicine (Duke database) suggests: Behavioural therapy recommended for all Acute therapy recommended for all Prophylactic therapy recommended for certain patients Complementary therapies may be useful as adjunctive therapy Headache Consortium. Neurology 2000; www.aan.com.www.aan.com Bedell AW et al. Primary Care Network 2000.

38. Goals of therapy Acute medications: to rapidly relieve the headache and other symptoms, and permit the return to normal activities (within 2 hours?) Prophylactic medications: to reduce headache frequency by >50% Matchar DB et al. Neurology 2000; www.aan.com.www.aan.com Bedell AW et al. Primary Care Network 2000. Ramadan NM etal. Neurology 2000; www.aan.com.www.aan.com

39. Strategy for providing initial acute therapy in individualised care Migraine diagnosis Severity assessment Mild to moderate migraineModerate to severe migraine Initial therapy Rescue If unsuccessful Migraine attack Dowson AJ et al. Curr Med Res Opin 2002;18: in press Stratified care Staged care

40. Recommended initial acute treatments Mild-to-moderate migraine Aspirin or NSAIDs (high doses) Aspirin/paracetamol plus anti-emetics Paracetamol plus isometheptene –Use if possible before headache starts Rescue medications –Oral triptans –Use for any headache severity Matchar DB et al. Neurology 2000; www.aan.com.www.aan.com

41. Recommended initial acute treatments Moderate-to-severe migraine Oral triptans (tablet/ODT) –Use after the headache starts, if possible when it is mild in intensity Rescue medications –Nasal spray or subcutaneous triptans –Symptom control Matchar DB et al. Neurology 2000; www.aan.com.www.aan.com

42. Who should receive a triptan as initial therapy? Patients with moderate-to-severe migraine Patients with any severity migraine who have failed on other acute medications Matchar DB et al. Neurology 2000; www.aan.com.www.aan.com

43. What formulation of triptan should be used as initial therapy? Is a conventional tablet always the best choice? Would ODT formulations be more appropriate? Should any patients receive nasal spray or subcutaneous formulations from the outset?

44. Circumstances where ODT or non-oral formulations may be appropriate ODT / nasal –Unpredictable attacks –Need for greater convenience –Patient preference Nasal / subcutaneous –Severe / fast onset attacks –Need for rapid response –Severe nausea –Vomiting –Patient preference Dowson AJ et al. Curr Med Res Opin 2002;18: in press

45. What formulation of triptan should be used as rescue therapy? Second dose of initial medication? Alternative oral triptan? ODT formulation? Nasal spray? Subcutaneous injection?

46. Factors affecting the choice of rescue medication Impact Work / lifestyle pressures Severity of attack Length of attack Vomiting / severe nausea Patient preference

47. Patient preference factors: What do patients experience? Headache relief too slow Inadequate overall relief Inconsistency of response Headache returns after initial relief Too many side effects Lipton RB, Stewart WF. Headache 1999;39(Suppl2):20-6

48. What do patients want? How do they express their preferences? Greater speed of action Enhanced overall effectiveness Restored ability to function Fewer side effects Satisfaction with therapy Greater convenience Dowson AJ, manuscript in preparation

49. Strategy for providing prophylactic medications in individualised care Prophylactic medications should be provided: –For patients with frequent, high-impact migraine attacks (  4/month?) –Where acute medications are ineffective or precluded by safety concerns –For patients who overuse acute medications and/or have CDH –For patients with the rare migraine variants However: acute medications should also be provided for breakthrough attacks Ramadan NM et al. Neurology 2000; www.aan.com.www.aan.com Bedell AW et al. Primary Care Network 2000. Dowson AJ et al. MIPCA 2000.

50. Recommended initial prophylactic treatments First-line medications: –Beta-blockers (propranolol, metoprolol, timolol, nadolol) –Anticonvulsants* (sodium valproate) –Antidepressants* (amitriptyline) Second-line medications –Serotonin antagonists (pizotifen, methysergide, cyproheptadine) * Not licensed for migraine in the UK Ramadan NM et al. Neurology 2000; www.aan.com.www.aan.com

51. Factors influencing the choice of initial prophylactic medication Side effects mean that certain patients are not able to take specific drugs –Beta-blockers may not be suitable for sportspeople Weight gain experienced with many drugs may limit compliance in a largely female population Anticonvulsants and antidepressants may be used for patients with concurrent conditions Anticonvulsants and antidepressants are also effective if CDH is suspected

52. Conclusions The choice of initial drug can be individualised for each patient’s needs Oral triptans are suitable acute medications for most patients ODT, nasal spray and subcutaneous triptans are suitable initial medications for certain patients and/or as rescue medication

53. Follow-up care: monitoring treatment and selection of therapy Dr Sue Lipscombe Park Crescent New Surgery, Brighton

54. New MIPCA guidelines for migraine management Follow-up treatment

55. Aspirin/NSAID (large dose) Aspirin/paracetamol plus anti-emetic Oral triptan Initial treatment Follow-up treatment Oral triptan Alternative oral triptan Nasal spray/subcutaneous triptan Rescue If unsuccessful Consider prophylaxis + acute treatment for breakthrough migraine attacks Frequent headache (i.e.  4 attacks per month) Consider referral Chronic daily Headache (CDH)? Migraine If unsuccessful Initial treatment Copyright MIPCA 2002, all rights reserved If management unsuccessful Dowson AJ et al. Curr Med Res Opin 2002;18: in press.

56. Aspirin/NSAID (large dose) Aspirin/paracetamol plus anti-emetic Oral triptan Initial treatment Follow-up treatment Oral triptan Alternative oral triptan Nasal spray/subcutaneous triptan Rescue If unsuccessful Consider prophylaxis + acute treatment for breakthrough migraine attacks Frequent headache (i.e.  4 attacks per month) Consider referral Chronic daily Headache (CDH)? Migraine If unsuccessful Copyright MIPCA 2002, all rights reserved If management unsuccessful Dowson AJ et al. Curr Med Res Opin 2002;18: in press.

57. Recommended follow-up procedures Instigate proactive long-term follow-up procedures Monitor the outcome of therapy –Headache diaries –Impact questionnaires (MIDAS/HIT) Make appropriate treatment decisions Dowson AJ et al. Curr Med Res Opin 2002;18: in press

58. Who are the diaries for? The patient The doctor Both

59. What is the diary for? Recording data –Triggers, patterns, results of medication, frequency of medication taken To make the patient feel the doctor is interested To help the doctor make lifestyle and medication suggestions

60. Headache diaries Beneficial for the prospective management of migraine Two types of diary can be used –Patient-held long-term diary for continual use, containing basic information on patterns of headache –Short-term diary used over a specific timescale for intense monitoring The two diaries can be used in tandem Data from the diaries can be used to individualise follow-up treatment decisions

61. Follow-up treatment decisions Acute medications –Patients effectively treated should continue with the original therapy Analgesic-based medications Triptans –Patients who fail on original therapy should be offered other therapies, based on clinical issues and patient preference Analgesic-based medications  oral triptan Triptan  alternative triptan Dowson AJ, Cady RC. Rapid Reference to Migraine 2002.

62. Individual treatment for individual attacks Doctor and patients may be able to identify different severities and types of attacks The patient may choose to have a range of treatments to hand to treat each attack with the medication they feel most appropriate If this is the case, then several prescriptions may be necessary

63. Switching between triptans If one oral triptan fails, an alternative oral triptan may be effective –ODT triptan may be suitable for patients who cannot predict their attacks easily and/or require greater convenience of use Patients needing rapid onset of action and greater convenience of use may benefit from nasal spray and injection formulations

64. Switching between triptans Patients needing greater overall relief and/or experiencing significant impact may benefit from nasal spray or subcutaneous formulations Patients reporting bothersome side effects may require a triptan with a better tolerability profile ODT, nasal spray and subcutaneous formulations may also be suitable as rescue medications

65. Follow-up treatment decisions Prophylactic medications –Initial dose can be titrated up as necessary to achieve an effective dose –Medication needs to be provided for an adequate time period (up to 3 months) –If effective, treatment can continue for 6 months, after which it may be stopped –If ineffective, another prophylactic medication may be tried –Monitor closely for side effects and patients’ subjective impressions Dowson AJ et al. Curr Med Res Opn 2002;18: in press

66. Follow-up treatment decisions Specialist referral –Migraine patients refractory to repeated acute and prophylactic medications –Patients who have developed CDH during treatment –Patients suspected of having sinister headaches, rare migraine variants, cluster headache and other refractory non- migraine headaches –Patient request

67. Specialist referrals Worrying migraine – are they TIAs or hemiplegic migraine? Worrying times – pregnancy, breast feeding, menopause For specialist treatment only, e.g. methysergide, botox, off-licence drugs. For special investigations – CT, MRI

68. Conclusions Follow-up should be available for migraine patients –Headache diaries –Impact questionnaires Acute and prophylactic medications can be changed to maximise therapeutic effect and patient satisfaction The different triptan formulations provide flexible therapy that can be targeted to each patient’s needs and desires