Advertisement

CNS Drugs

, Volume 21, Issue 1, pp 73–82 | Cite as

Use of the Sustained Pain-Free Plus No Adverse Events Endpoint in Clinical Trials of Triptans in Acute Migraine

  • David W. Dodick
  • Giorgio Sandrini
  • Paul Williams
Original Research Article

Abstract

Objective: To assess the relationship between the sustained pain free (SPF) and adverse event (AE) rates associated with six oral serotonin 5-HT1B/1D receptor agonists (triptans) used for the treatment of acute migraine, employing data from a previous meta-analysis (that included almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan, but not frovatriptan) in order to provide a rationale for the use of the rate of patients who are SPF plus no AE (SNAE) as an endpoint in trials of medications for acute migraine.

Background: The attributes of drug treatment for acute migraine that are most important to people who experience them are complete pain relief, lack of recurrence, rapid onset and lack of AEs. The endpoints used to assess therapy for acute migraine do not always address these elements.

Methods: The relationship between SPF and AE rates was explored using nonparametric regression techniques, and the box-plot method was used to identify outliers. The estimated SNAE rate for each triptan was calculated with and without assuming independence between efficacy and tolerability.

Results: At the level of the individual agent, there was a significant relationship between the efficacy and tolerability of each triptan, with the exception of almotriptan 12.5mg, which had an AE rate approximately 30% lower than would be expected, and eletriptan 20mg, which had an AE rate approximately 20% higher than would be expected, on the basis of their efficacy. Almotriptan 12.5mg and eletriptan 20mg had the highest and lowest base-case values for SNAE, respectively, and both qualified statistically as outliers to the distribution of SNAE values obtained with the other triptans. The probability that each triptan was superior to the reference agent (sumatriptan 100mg) in terms of SNAE was calculated across all possible values (at the level of the individual patient) for the relationship between efficacy and tolerability. Again, almotriptan 12.5mg and eletriptan 20mg had the highest and lowest values for their SNAE rates, respectively, and almotriptan 12.5mg qualified statistically as an outlier from the distribution of the probabilities obtained for the other triptans.

Conclusion: This analysis determined that higher SPF rates were strongly associated with higher AE rates, with the notable exception of almotriptan 12.5mg, which had a lower than expected AE rate, resulting in the highest SNAE rate of the included triptans and doses. SNAE is a useful measure that can be used to discriminate between therapies and this endpoint incorporates the attributes that are most relevant to patient satisfaction with treatment. We recommend calculation of the SNAE rate at the level of the individual patient in future clinical trials of medication for the treatment of acute migraine to facilitate selection of a treatment for acute migraine that offers the best chance for effective management.

Keywords

Migraine Sumatriptan Zolmitriptan Rizatriptan Triptan 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

No sources of funding were used to assist in the preparation of this study.

Dr Dodick has worked as a consultant for and received honoraria from Allergan, Medtronic, Neuralleve, Valeant, GlaxoSmithKline, Merck & Co., Ortho-McNeil and Pfizer. At the time that this paper was written, Dr Williams was an employee of PAREXEL MMS, whose clients include Ortho-McNeil and Almirall. Dr Sandrini has no conflicts of interest that are directly relevant to the content of this study.

References

  1. 1.
    Lipton RB, Stewart WF, Von Korff M. The burden of migraine: a review of cost to society. Pharmacoeconomics 1994; 6(3): 215–21PubMedCrossRefGoogle Scholar
  2. 2.
    Dahlöf CG, Solomon GD. The burden of migraine to the individual sufferer: a review. Eur J Neurol 1998; 5(6): 525–33PubMedCrossRefGoogle Scholar
  3. 3.
    Solomon GD, Skobieranda FG, Genzen JR. Quality of life assessment among migraine patients treated with sumatriptan. Headache 1995; 35: 449–54PubMedCrossRefGoogle Scholar
  4. 4.
    Cohen JA, Beall D, Beck A, et al. Sumatriptan treatment for migraine in a health maintenance organization: economic, humanistic, and clinical outcomes. Clin Ther 1999; 21(1): 190–204PubMedCrossRefGoogle Scholar
  5. 5.
    Lofland JH, Johnson NE, Batenhorst AS, et al. Changes in resource use and outcomes for patients with migraine treated with sumatriptan: a managed care perspective. Arch Intern Med 1999; 159(8): 857–63PubMedCrossRefGoogle Scholar
  6. 6.
    Lipton RB, Scher AI, Kolodner K, et al. Migraine in the United States: epidemiology and patterns of health care use. Neurology 2002; 58(6): 885–94PubMedCrossRefGoogle Scholar
  7. 7.
    Gibbs TS, Fleischer AB, Feldman SR, et al. Health care utilization in patients with migraine: demographics and patterns of care in the ambulatory setting. Headache 2003; 43(4): 330–5PubMedCrossRefGoogle Scholar
  8. 8.
    Goadsby PJ. The pharmacology of headache. Prog Neurobiol 2000; 62: 509–25PubMedCrossRefGoogle Scholar
  9. 9.
    Goadsby PJ, Lipton RB, Ferrari MD. Migraine: current understanding and treatment. N Engl J Med 2002; 346(4): 257–70PubMedCrossRefGoogle Scholar
  10. 10.
    Lipton RB, Stewart WF. Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache 1999; 39Suppl. 2: S20–6CrossRefGoogle Scholar
  11. 11.
    Gallagher RM, Kunkel R. Migraine medication attributes important for patient compliance: concerns about side effects may delay treatment. Headache 2003; 43(1): 36–44PubMedCrossRefGoogle Scholar
  12. 12.
    Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol 2004; 55(1): 19–26PubMedCrossRefGoogle Scholar
  13. 13.
    Silberstein SD. Migraine symptoms: results of a survey of self-reported migraineurs. Headache 1995; 35(7): 387–96PubMedCrossRefGoogle Scholar
  14. 14.
    Caro G, Caro JJ, O’Brien JA, et al. Migraine therapy: development and testing of a patient preference questionnaire. Headache 1998; 38(8): 602–7PubMedCrossRefGoogle Scholar
  15. 15.
    Lipton RB, Hamelsky SW, Dayno JM. What do patients with migraine want from acute migraine treatment? Headache 2002; 42Suppl. 1: S3–9CrossRefGoogle Scholar
  16. 16.
    Davies GM, Santanello N, Lipton R. Determinants of patient satisfaction with migraine therapy. Cephalalgia 2000; 20(6): 554–60PubMedCrossRefGoogle Scholar
  17. 17.
    Santanello NC, Davies G, Allen C, et al. Determinants of migraine-specific quality of life. Cephalalgia 2002; 22(8): 680–5PubMedCrossRefGoogle Scholar
  18. 18.
    Loder E, Brandes JL, Silberstein S, et al. Preference comparison of rizatriptan odt 10-mg and sumatriptan 50-mg tablet in migraine. Headache 2001; 41(8): 745–53PubMedCrossRefGoogle Scholar
  19. 19.
    Pilgrim AJ. Methodology of clinical trials of sumatriptan in migraine and cluster headache. Eur Neurol 1991; 31(5): 295–9PubMedCrossRefGoogle Scholar
  20. 20.
    Tfelt-Hansen P, Block G, Dahlöf C, et al. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 2000; 20(9): 765–86PubMedCrossRefGoogle Scholar
  21. 21.
    Ferrari MD, Goadsby PJ, Roon Kl, et al. Triptans (serotonin, 5-HT1b/1d agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633–58PubMedCrossRefGoogle Scholar
  22. 22.
    Williams P, Reeder CE. Cost-effectiveness of almotriptan and rizatriptan in the treatment of acute migraine. Clin Ther 2003; 25(11): 2903–19PubMedCrossRefGoogle Scholar
  23. 23.
    Williams P, Reeder CE. A comparison of the cost-effectiveness of almotriptan and sumatriptan in the treatment of acute migraine using a composite efficacy/tolerability end point. J Manag Care Pharm 2004; 10(3): 259–65PubMedGoogle Scholar
  24. 24.
    Sandrini G, Dahlof CG, Mathew N, et al. Focus on trial endpoints of clinical relevance and the use of almotriptan for the acute treatment of migraine. Int J Clin Pract 2005; 59(11): 1356–65PubMedCrossRefGoogle Scholar
  25. 25.
    US Geological Survey. Techniques of water resources investigations: book 4. Alternative methods for regression. In: Helsel DR, Hirsch RM, editors Statistical methods in water resources [online]. Available from URL: http://water.usgs.gov/pubs/twri/twri4a3/pdf/chapterl0new.pdf [Accessed 2004 Aug 18]
  26. 26.
    Prins J, McCormack D, Michelson D, et al. What are outliers in the data? In: National Institute of Standards and Technology, Information Technology Laboratory. NIST/SEMATECH e-handbook of statistical methods [online]. Available from URL: http://www.itl.nist.gov/div898/handbook/prc/sectionl/prcl6.htm [Accessed 2004 Aug 18]
  27. 27.
    Dodick D, Martin V. Triptans and CNS side-effects: pharmacokinetic and metabolic mechanisms. Cephalalgia 2004; 24(6): 417–24PubMedCrossRefGoogle Scholar
  28. 28.
    Pascual J, Munoz P. Correlation between lipophilicity and triptan outcomes. Headache 2005; 45(1): 3–6PubMedCrossRefGoogle Scholar
  29. 29.
    Oxford Centre for Evidence-Based Medicine. Levels of evidence and grades of recommendation [online]. Available from URL: http://www.cebm.net/levels_of_evidence.asp [Accessed 2004 May 1]
  30. 30.
    Nappi G, Sandrini G, Sances G. Tolerability of the triptans: clinical implications. Drug Saf 2003; 26(2): 93–107PubMedCrossRefGoogle Scholar
  31. 31.
    Sheftell FD, Feleppa M, Tepper SJ, et al. Assessment of adverse events associated with triptans—methods of assessment influence the results. Headache 2004; 44(10): 978–82PubMedCrossRefGoogle Scholar
  32. 32.
    Mathew N. A long-term open-label study of oral almotriptan 12.5mg for the treatment of acute migraine attacks. Headache 2002; 42: 32–40Google Scholar
  33. 33.
    Pascual J, Falk R, Docekal R, et al. Tolerability and efficacy of almotriptan in the long-term treatment of migraine. Eur Neurol 2001; 45(4): 206–13PubMedCrossRefGoogle Scholar
  34. 34.
    Spierings EL, Gomez-Mancilla B, Grosz DE, et al. Oral almotriptan vs oral sumatriptan in the abortive treatment of migraine: a double-blind, randomized, parallel-group, optimum-dose comparison. Arch Neurol 2001; 58(6): 944–50PubMedCrossRefGoogle Scholar
  35. 35.
    Dodick DW, Sandrini G. Relationship between sustained pain-free and adverse events: a comparison of almotriptan 12.5mg and other oral triptans in acute migraine. Headache 2004; 44: 468–9CrossRefGoogle Scholar
  36. 36.
    Freedman DA. Ecological inference and the ecological fallacy [online]. Available from URL: http://stat-www.berkeley.edu/~census/549.pdf [Accessed 2004 May 1]
  37. 37.
    Mancini GB, Schulzer M. Reporting risks and benefits of therapy by use of the concepts of unqualified success and unmitigated failure: applications to highly cited trials in cardiovascular medicine. Circulation 1999; 99(3): 377–83PubMedCrossRefGoogle Scholar
  38. 38.
    Schulzer M, Mancini GB. ‘Unqualified success’ and ‘unmitigated failure’: number-needed-to-treat-related concepts for assessing treatment efficacy in the presence of treatment-induced adverse events. Int J Epidemiol 1996; 25(4): 704–12PubMedCrossRefGoogle Scholar
  39. 39.
    Dowson AJ, Mathew NT, Pascual J. Review of clinical trials using early acute intervention with oral triptans for migraine management. Int J Clin Pract 2006; 60(6): 698–706PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • David W. Dodick
    • 1
  • Giorgio Sandrini
    • 2
  • Paul Williams
    • 3
  1. 1.Department of NeurologyMayo ClinicScottsdaleUSA
  2. 2.University Center for Adaptive Disorders and Headache, IRCCS C. Mondino Foundation, University of PaviaPaviaItaly
  3. 3.PAREXEL InternationalUxbridgeUK

Personalised recommendations