1. MIGRAINE IN PRIMARY CARE ADVISORS Guildford, 1 May 2003, 2-6 pm Understanding the evidence in evaluating acute migraine medications in clinical practice

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

3. Programme Dr Andrew Dowson: Introduction and objectives Discussion: Comparing acute medications: clinical trials experience Comparing acute medications: experience from clinical practice Practical advice for general use in the clinic Dr Andrew Dowson: Conclusions

4. Objectives Review clinical trial evidence for the clinical profiles of triptans and other acute medications for migraine Compare these data with the situation in primary care Provide the practising clinician with rational methods of evaluating clinical trial data –Publications –Detail aids –Integrating clinical trial data into the real world setting

5. Outputs MIPCA newsletter for GPs –How to evaluate detail aids and trial data Slide set for educational use Article on understanding the evidence for GPs –Critical review of the evidence

6. Comparing acute medications: clinical trials experience

7. Overview Clinical trial endpoints Post hoc endpoints Clinical trial data on the triptans and other acute medications Misunderstandings and pitfalls Understanding the evidence

8. Clinical trial endpoints

9. Primary endpoint for clinical trials Headache relief: Improvement from severe or moderate headache to mild or no headache at 2 hours –‘Glaxo’ endpoint Improvement from severe or moderate to no headache at 2 hours –‘IHS’ recommended endpoint Pilgrim AJ. Eur Neurol 1991;31:295-9. IHS Clinical Trials Subcommittee. Cephalalgia 2000;20:765–86.

10. Efficacy outcome Pain-free (‘IHS’) Pain relief (‘Glaxo’) 3 Severe 2 Moderate 1 Mild 0 None Pilgrim AJ. Eur Neurol. 1991;31:295-299.

11. Secondary endpoints for clinical trials Headache relief at other time points Headache free at various time points ‘Meaningful’ relief Return to normal functioning Relief of nausea, vomiting and photophobia / phonophobia Sustained pain relief Headache recurrence Adverse events Pilgrim AJ. Eur Neurol 1991;31:295-9.

12. Discussion: perspective on endpoints In general, pain relief parallels that reported for other symptoms –Headache relief as a proxy for migraine relief? Stopwatch endpoints are used in pain studies, but not in migraine studies If the patient treats the headache when mild, non-headache symptoms may not have developed –Potential problems with IHS diagnostic criteria Adverse events vs safety –Tolerability (AEs) variable between patients –Drug-related AEs – tolerability vs safety –Side effects cloud use of drugs Patients may not differentiate migraine from other headaches –Spectrum study indicates migraine may present with symptoms of TTH

13. Discussion: study design Data need to be accurate –Demonstrating reliability, power and validity Large study size increases power and clinical relevance of the results Placebo responses may be different in different settings –Hospital vs primary care Manipulation of patient populations may be used to obtain desired effects –Relative numbers of patients and centres Different study designs may lead to differences in results –cf ‘Glaxo’ type sumatriptan studies with those used in comparators with domperamol and tolfenamic acid

14. Post hoc endpoints

15. Meta-analyses Therapeutic gain (TG) Number needed to treat (NNT) Number needed to harm (NNH) Ad hoc analyses –e.g. nausea Goadsby PJ. Can J Neurol Sci 1999;26(Suppl 3):S20-6.

16. Efficacy: Therapeutic Gain (TG) Therapeutic gain = Proportion of patients benefiting on treatment Proportion of patients benefiting on placebo — Goadsby PJ. Can J Neurol Sci. 1999;26(Suppl 3):S20-S26.

17. Efficacy: Number Needed to Treat (NNT) Number Needed to Treat = Proportion of patients benefiting on treatment Proportion of patients benefiting on placebo — 100 Goadsby PJ. Can J Neurol Sci. 1999;26(Suppl 3):S20-S26.

18. Tolerability: Number Needed to Harm (NNH) Number Needed to Harm = Proportion of patients with adverse events on treatment Proportion of patients with adverse events on placebo — 100 Goadsby PJ. Can J Neurol Sci.1999;26(Suppl 3):S20-S26.

19. Dr Shaun Kilminster s.kilminster@talk21.com GCPL P harmacology : R oyal S urrey C ounty H ospital Pain clinic : R oyal S urrey C ounty H ospital L awrencian C linical: 1) Short Pain Inventory 2) objective marker of pain S ociety of P harmaceutical Medicine. Chairman Insights into endpoints

20. Headache measures vary in accuracy Accuracy = Reliability x Power x Validity –Outcome measures need to exhibit these features Importance on coefficient of variance

21. Face analogue scale 0 1234 Five-point scale favoured in most therapy areas cf migraine 4-point scales

22. Visual analogue & Likerts NONE EXTREME PAIN Difficult to deduce clinical significance from changes observed Need for simple, intuitive measures

23. NNT based upon % of patients achieving a criterion e.g. % of patients with 50% reduction in pain or no pain

24. Placebo response & NNT NNT varies with the placebo response Problematic in areas where a variable placebo rate is likely, e.g. migraine

25. Discussion: post hoc endpoints Post hoc endpoints (TG, NNT, NNH) may not provide clinically relevant information Placebo response affects NNT High therapeutic response → little effect Low therapeutic response → significant effect

26. Discussion: 7 points for the critical appraisal of clinical trial data and detail aids What to look out for At least 50 patients per treatment group Patient numbers equal in active and placebo arms NNT must have 95% confidence interval Drop-outs from trial ≤ 10% Drop-outs from trial must be same in active and placebo arms Outcome measures use Likert, not visual analogue scales Speed of onset, duration of analgesia and normal coping / functioning well are needed for clinical relevance.

27. Clinical trial data on the triptans and other acute medications

28. Quality of clinical evidence Grade A: Consistent evidence from multiple, well-designed, randomised clinical trials, systematic meta-analyses Grade B: Poorer quality clinical trial evidence; non-systematic meta- analyses Grade C: Opinion and practice in the absence of objective evidence Matchar DB et al. Neurology 2000;54.

29. Comparing the oral triptans: headache relief (Grade A) 0 10 20 30 40 50 60 70 80 90 Suma 100 mg Suma 50 mg Zolmi 2.5 mg Riza 10 mg Ele 40 mg Almo 12.5 mg Nara 2.5 mg Frova 2.5 mg Lowest Highest Patients (%) Dowson AJ et al. Curr Med Res Opin 2002;18:414-39

30. Comparing the ODT and oral triptans: headache relief (Grade A) 0 10 20 30 40 50 60 70 80 90 Zolmi 2.5 mg oral Zolmi 2.5 mg ODT Riza 10 mg oral Riza 10 mg ODT Lowest Highest Patients (%) Dowson AJ et al. Curr Med Res Opin 2002;18:414-39

31. Comparing the non-oral triptans: headache relief (Grade A) 0 10 20 30 40 50 60 70 80 90 Suma 6 mg SCSuma 20 mg NSZolmi 5 mg NS Lowest Highest Patients (%) Dowson AJ et al. Curr Med Res Opin 2002;18:414-39

32. Head-to-head comparator trials with oral triptans (Grade A) Zolmitriptan versus sumatriptan 0 10 20 30 40 50 60 70 Zolmi 2.5 mg n = 500 Zolmi 5 mg n = 514 Suma 50 mg n = 508 Headache response at 2 h (% patients) Gruffydd-Jones K et al. Eur J Neurol 2001;8:237-45. NS

33. Head-to-head comparator trials with oral triptans (Grade A) Rizatriptan versus sumatriptan (n = 1,268) Headache response at 1 h (% patients) 0 5 10 15 20 25 30 35 40 Riza 10 mgSuma 100 mg ** ** p=0.01 Tfelt-Hansen P et al. Headache 2000;40:748-55.

34. Head-to-head comparator trials with oral triptans (Grade A) Rizatriptan versus naratriptan (n = 522) Pain free at 2 h (% patients) 0 5 10 15 20 25 30 35 40 45 50 Riza 10 mgNara 2.5 mg *** *** p<0.001 Bomhof M et al. Eur Neurol 1999;42:173-9.

35. Head-to-head comparator trials with oral triptans (Grade A) Almotriptan versus sumatriptan Headache relief at 2 h (% patients) 0 10 20 30 40 50 60 70 Almo 12.5 mg n = 591 Suma 50 mg n = 582 NS Spierings EL et al. Arch Neurol 2001;58:944-50.

36. Head-to-head comparator trials with oral triptans (Grade A) Eletriptan versus sumatriptan Headache relief at 2 h (% patients) 0 10 20 30 40 50 60 70 80 Ele 40 mgSuma 100 mgEle 40 mgSuma 100 mg NS *** *** p<0.001 a. (n = 692)b. (n = 2.113) a.Goadsby PJ et al. Neurology 2000;54:156-63. b.Mathew NT et al. Headache 2003;43:214-22.

37. Perspective on eletriptan comparator studies Sumatriptan encapsulated in these studies –But marketed as film-coated tablet Studies show that sumatriptan absorption is compromised on encapsulation 1 Because of this, ABPI does not allow Pfizer to use these comparative data in its UK detail aids 1. Fuseau E et al. Clin Ther 2001;23:242-51.

38. Head-to-head comparator trials with oral triptans (Grade A) Triptans versus ergotamine plus caffeine 0 10 20 30 40 50 60 70 Suma 100 mgErg 2 mgEle 40 mgErg 2mg Headache relief at 2 h (% patients) *** a. (n = 580)b. (n = 733) *** p<0.001 a.Study Group. Eur Neurol 1991;31:314-22. b.Diener HC et al. Eur Neurol 2002;47:99-107.

39. Perspective on triptan-Cafergot comparator studies Oral ergotamine formulations have poor bioavailability and suboptimal efficacy Parenteral formulations of ergotamine are superior to oral –Rectal –Injection Matchar DB et al. Neurology 2000;54.

40. Head-to-head comparator trials with oral triptans (Grade A) Triptans versus aspirin plus metoclopramide Headache relief at 2 h (% patients) 0 10 20 30 40 50 60 Suma 100 mgA+M 900+10 mg Zolmi 2.5 mgA+M 900+10 mg NS a. (n = 358)b. (n = 666) a.Study Group. Eur Neurol 1992;32:177-84. b.Geraud G et al. Eur Neurol 2002;47:88-98.

41. Conclusions from Grade A clinical data - 1 All oral triptans are effective and well tolerated –Naratriptan and frovatriptan seem to be less effective than the other triptans –Sumatriptan, zolmitriptan, rizatriptan, almotriptan and eletriptan have similar efficacy profiles Differences are numerically small and of uncertain clinical significance Subcutaneous and nasal spray formulations are more effective and faster-acting than the oral formulations

42. Conclusions from Grade A clinical data - 2 Conventional clinical trial endpoints: Do not effectively distinguish triptans from some other acute medications –e.g. Aspirin plus metoclopramide Use artificial criteria that may not be applicable in clinical practice –Should / will patients wait till the headache is moderate to severe before treating?

43. Caveats from Grade A evidence Suppressing of data –Only positive studies published Manipulation of formulations –Encapsulation issues in eletriptan studies Dose-response effects –Naratriptan and frovatriptan not used at doses equivalent to other triptans –Some patients take up to 4 naratriptan tablets per attack to achieve a satisfactory response Suboptimal dosing schedules Suboptimal endpoints Diagnosis issues (migraine or CDH?) Idiosyncratic responses –Different results with rizatriptan in eastern and western Europe

44. Post hoc comparisons between the triptans (Grade B) Meta-analyses Tfelt-Hansen et al Belsey Ferrari et al Economic analyses (Williams et al)

45. Comparing the triptans: Therapeutic gain (Grade B) 0 10 20 30 40 50 60 Suma 6 mg SC Suma 50 mg po Zolmi 2.5 mg po Riza 10 mg po Almo 12.5 mg po Ele 40 mg po Nara 2.5 mg po Frova 2.5 mg po Tfelt-Hansen P et al. Drugs 2000;60:1259-87. Patients (%)

46. Efficacy: Therapeutic Gain for pain- free 2 hours post-dose (Grade B) Belsey JD. J Clin Res. 2001;4:105-27.

47. Efficacy: Number Needed to Treat for pain-free response (Grade B) Belsey JD. J Clin Res. 2001;4:105-27.

48. Tolerability: Number Needed to Harm for any adverse event (Grade B) Belsey JD. J Clin Res.2001;4:105-27.

49. Integrating efficacy and tolerability data (Grade B) Sumatriptan 100 mg Rizatriptan 10 mg Eletriptan 80 mg Zolmitriptan 5 mg Zolmitriptan 2.5 mg Almotriptan 12.5 mg Sumatriptan 50 mg Tolerability (Therapeutic penalty) Eletriptan 40 mg + Rizatriptan 5 mg Naratriptan 2.5 mg Eletriptan 20 mg Efficacy (Therapeutic gain) Belsey JD. J Clin Res. 2001;4:105-27.

50. Headache relief at 2 hours (Grade B) 40 50 60 70 80 25501002.55 51020408012.5 Headache relief at 2 h (%) Suma Zolmi Nara Riza Ele Almo Ferrari MD, et al. Lancet. 2001;358:1668-75.

51. Pain-free at 2 hours (Grade B) 0 10 20 30 40 50 25501002.55 51020408012.5 Pain-free at 2 h (%) Ferrari MD, et al. Lancet. 2001;358:1668-75. Suma Zolmi Nara Riza Ele Almo

52. Sustained pain-free (Grade B) 0 5 10 15 20 25 30 25501002.55 51020408012.5 Sustained pain-free (%) Ferrari MD, et al. Lancet. 2001;358:1668-75. Suma Zolmi Nara Riza Ele Almo

53. Incidence of any adverse event: Placebo subtracted data (Grade B) -20 -10 0 10 20 30 40 25501002.55 51020408012.5 Any adverse event (%) - Placebo Suma Zolmi Nara Riza Ele Almo Ferrari MD, et al. Lancet. 2001;358:1668-75.

54. 24-Hour Consistency Drug Studied vs Sustained Across Sumatriptan 2-Hour Pain Pain-FreeMigraine 100 mg Relief (1 pill only)AttacksTolerability Suma 50 mg===/-= Suma 25 mg-=/--+ Zolmi 2.5 mg==== Zolmi 5 mg==== Nara 2.5 mg---++ Riza 5 mg==== Riza 10 mg++++= Ele 20 mg---= Ele 40 mg=/+=/+== Ele 80 mg+(+)+=- Almo 12.5 mg=++++ Overall comparison (Grade B) Based on the results of the present meta-analysis and the direct comparator trials. = indicates no difference when compared with sumatriptan. + indicates better when compared with sumatriptan. - indicates inferior when compared with sumatriptan Ferrari MD, et al. Lancet. 2001;358:1668-75.

55. Cost-effectiveness analysis 0 20 40 60 80 100 120 140 160 180 Almo 12.5 mgRiza 10 mgSuma 50 mgSuma 100 mg Cost-effectiveness ratio ($US) Cost-effectiveness ratio per attack for sustained pain relief and no adverse events Williams P, Reeder CE. Am J Manag Care 2003; in press. Williams P, Reeder CE. Clin Ther 2003; in press.

56. Overview of meta-analyses of the oral triptans (Grade B) All oral triptans were effective and well tolerated –More similarities than differences between the drugs Rizatriptan 10 mg exhibited the best efficacy Naratriptan 2.5 mg and almotriptan 12.5 mg exhibited the best tolerability

57. Discussion: perspective on the meta- analyses The different meta-analyses do not provide consistent data –Selection of studies, patient populations and endpoints differ –Bandolier could not repeat results from Ferrari et al meta-analysis Timing of dosing important Power and timing of endpoints important –Data dredging? ‘Economy with the truth’?

58. Acute treatments in clinical practice versus clinical trials

59. Overview Efficacy in clinical practice Early treatment Dose optimisation Sensitivity of endpoints

60. Efficacy in clinical practice In general, triptans seem to be more effective in clinical practice than in clinical trials –Different populations of patients Greater proportion of women CDH patients may be included in trials –Country differences –Primary care versus secondary care Need for long-term naturalistic studies conducted with prescription formulations and doses

61. Sumatriptan in clinical practice 0 10 20 30 40 50 60 70 80 90 Suma 25 mg n = 285 Suma 50 mg n = 2,053 Suma 100 mg n = 1,522 4-h response (% Attacks) Dowson AJ et al. IJCP 1999;Suppl 105:25-33. No. of patients = 338

62. Zolmitriptan in clinical practice 0 10 20 30 40 50 60 70 80 90 Zolmi 2.5 mgZolmi 5 mg Pain-free Headache relief 2-h response (% Attacks) Tepper SJ et al. Curr Med Res Opin 1999;15:254-71. No. of patients = 2,499

63. Rizatriptan in clinical practice 0 10 20 30 40 50 60 70 80 Riza 10 mg tabRiza 10 mg MLT Usual therapy Symptom-free Headache relief 2-h response (% Attacks) Jamieson D et al. Headache 2003;43:223-30. No. of patients = 3,953

64. Early treatment: Optimising timing of dosing Recent evidence indicates that triptans work optimally if taken when the headache is mild early in the attack –Sumatriptan –Zolmitriptan –Rizatriptan –Almotriptan Clinical and cost-effectiveness data

67. Zolmitriptan: Pain-free response at 2 hours treating mild headache 43 18 n=136n=141 Pain-free response (% patients) *** *** p<0.0001 versus placebo n=no. of patients evaluated 0 20 40 60 Zolmitriptan 2.5 mgPlacebo

69. Dose optimisation Patients may require lower or higher than recommended doses to achieve an optimal response –Sumatriptan –Zolmitriptan –Naratriptan / frovatriptan Marketed doses may not be comparable due to dose-response effects

70. Patient selection of optimal dose: Sumatriptan 0 10 20 30 40 50 60 70 Suma 25 mgSuma 50 mgSuma 100 mg Patient preference after treating 6 attacks (n = 338) Patients (%) Dowson AJ et al. IJCP 1999;Suppl 105:25-33.

71. Patient selection of optimal dose: Zolmitriptan Patient choice of 2.5 mg and 5 mg doses (n = 2,499) 0 10 20 30 40 50 60 70 Zolmi 2.5 mgZolmi 5 mg Attacks (%) Tepper SJ et al. Curr Med Res Opin 1999;15:254-71.

72. Sensitivity of endpoints For regulatory purposes, clinical trial endpoints are designed to show significant differences between active drug and placebo –They may be relatively insensitive in distinguishing between two active drugs They are probably not appropriate for use in clinical practice, where more sensitive endpoints may be required

73. Alternative endpoints Patient preference Impact questionnaires Cost effectiveness Qualitative endpoints

74. Patient preference Global measure of efficacy and tolerability In studies, patients consistently prefer oral triptans over non-triptan acute medications Patients also prefer individual oral triptans over other oral triptans –But responses may be idiosyncratic

76. Sumatriptan versus ‘usual’ non- triptan therapies 0 10 20 30 40 50 60 70 80 Sumatriptan 50 mgNon-triptanNo preference Kwong WJ et al. Cephalalgia 2001;21:411. Patients (%) No. of patients = 402

77. ‘Triptans’ versus ‘usual’ non-triptan therapies 0 10 20 30 40 50 60 TriptansNon-triptansBothNo preference Patients (%) Robbins L. Cephalalgia 2001;21:406. No. of patients = 663

78. Sumatriptan 50 mg versus zolmitriptan 2.5 mg tablets Patients (%) 0 5 10 15 20 25 30 35 40 45 50 Suma 50 mgZolmi 2.5 mgNo preference Pascual J et al. Cephalalgia 2001;21:680-4. No. of patients = 94

79. Sumatriptan 50 mg tablets versus rizatriptan 10 mg ODT Patients (%) 0 10 20 30 40 50 60 Suma 50 mgRiza 10 mg ** ** p<0.01 Loder E et al. Headache 2001;41:745-53. No. of patients = 374

80. Zomitriptan ODT versus sumatriptan tablet * * p<0.05 versus sumatriptan tablet 60.1 39.9 0 10 20 30 40 50 60 70 Patients (%) Zolmitriptan 2.5 mg ODT Sumatriptan 50 mg tablet

81. Zolmitriptan ODT versus rizatriptan ODT Source: CIMA Patient Preference Study 2001 (West Pharmaceutical Services) Respondents (%) Prefer Zomig Rapimelt Prefer Rizatriptan MLT No preference 27% 3% 70% 0% 20% 40% 60% 80%

82. Overall reasons for preference Rapid relief Effective relief

83. Discussion: patient preference May not be sensitive to subtleties of pain Some lapsed consulters said they preferred OTC drugs to triptans

84. Impact questionnaires MIDAS HIT Only MIDAS has so far shown sensitivity to change SPI

85. Efficacy of zolmitriptan 2.5 mg tablet assessed with MIDAS 0 5 10 15 20 25 30 35 40 BaselineAfter treatment MIDAS score Torres G et al. Poster at 53rd AAN, 2001. No. of patients = 1,972

86. Change in MIDAS following primary care interventions 0 2 4 6 8 10 12 14 16 Baseline6-mo care MIDAS score Main A et al. Curr Med Res Opin 2002;18:471-8. * * p<0.05 No. of patients = 19

87. Short Pain Inventory © Developed by Dr Shaun Kilminster A 17-item self rating questionnaire ‘measuring the whole pain disturbance’ Potential new endpoint for headache studies

88. SPI © subscales Pain severity Social interaction Anxiety Anger Sadness Sedation T OTAL P AIN D ISTURBANCE 17 items T OTAL M OOD D ISTURBANCE 14 items

89. SPI © subscales that correlate directly with level of headache severity Mood changes Social interaction Sedation Sadness Anger Anxiety Total mood disturbance (TMD)

90. SPI © : correlation of Total Mood Disturbance and Headache Pain (n = 75)

91. SPI © : Conclusions How the patient feels about their headache impacts on mood and vice versa SPI is a reliable, valid and discriminatory measure of headache severity SPI has high potential utility in headache research –Likely to be a highly-sensitive endpoint for clinical trials –Naturalistic studies in clinical practice underway

92. Cost-effectiveness Compared to placebo and non-triptan acute medications, triptans: –Improve quality of life –Increase workplace productivity –Reduce healthcare costs

93. Rizatriptan versus usual therapies: improvements in QOL 0 2 4 6 8 10 12 14 16 Work funct EnergySymptoms Rizatriptan 10 mg Usual medications Social funct Feelings Gerth WC et al. Clin Drug Invest 2001;21:853-60. 24-h Migraine-Specific QOL Questionnaire (n = 265) * * ** *** ** * p≤0.05 ** p<0.01 *** p<0.001

94. Workplace productivity loss following treatment of migraine with sumatriptan or placebo 0 10 20 30 40 50 60 70 80 Sumatriptan 6 mg sc (n = 76) Placebo (n = 40) Time/day (min) *** *** p<0.001 Schulman EA et al. Mayo Clin Proc 2000;75:782-9.

95. Cost-effectiveness analysis in Canada Sumatriptan tablets versus ergotamine plus caffeine tablets Economic benefit in favour of sumatripan –$98 saved per attack aborted –Cost-utility ratio = $29,366 per QALY Evans KW et al. Pharmacoeconomics 1997;12:565-77.

96. Qualitative endpoints Michele Peters University of Surrey, Guildford

97. Qualitative research Objective: to increase the understanding of patients and physicians Processes through interviews –Decision trees –Working through attacks –Patient-doctor behaviour and its evolution over time –Explaining the variations in patient responses

98. Qualitative research in clinical trials programmes MRC advises the use of qualitative research in clinical trials Phase I (modelling, not preclinical) Pre- classic Phase II, III and IV clinical trials Study of behaviours: –Doctor-nurse –Doctor-patient MRC. A framework for development and evaluation of RCTs for complex interventions to improve health; 2000.

99. What can qualitative research investigate? Why does an intervention have therapeutic benefit? –Testing underlying assumptions –Effect of inappropriate beliefs –Active and non-active elements of intervention –Groups of patients likely or not likely to respond Mitigates against no effect results MRC. A framework for development and evaluation of RCTs for complex interventions to improve health; 2000.

100. Qualitative research: methodology Group interviews (focus groups) Individual in-depth interviews Observational research Organisational case studies Quantitative surveys may also be used MRC. A framework for development and evaluation of RCTs for complex interventions to improve health; 2000.

101. Qualitative endpoints Pilot studies with small numbers of people can increase understanding of issues Interviews can give insight into validity of likely trial results –Patient compliance –Importance of placebo response Cf: –Interviews are qualitative –Factor analysis is quantitative

102. Qualitative endpoints New way of analysing headache issues Investigating patient feelings Studies needed on how to deliver care –PCT clinics –GPs with a special interest in headache (GPWSIH) 1 1. Department of Health. www.doh.gov.uk/pricare/gp- specialinterests/headache.pdf

103. Summary Clinical trials may not reflect clinical practice due to different: –Populations of patients –Treatment modalities used –Timings of treatment –Primary versus secondary care sites Clinical trial endpoints often do not differentiate between treatments

104. Future needs Qualitative research to set the agenda –Patient-doctor behaviour –Doctor-nurse behaviour Study the whole range of management options –Pharmacological and non-pharmacological Conduct naturalistic studies Develop more sensitive endpoints Develop an objective test for pain –Blood test?