Analysis of the Development of Allodynia: Correlation Between Migraine Duration and Severity B. Lu, X. Li, S. Zhao, E. Connors, S. Kori MAP Pharmaceuticals, Inc., Mountain View, CA CONCLUSIONS • In this study, the presence of allodynia at time of treatment was associated with the severity of migraine. • No correlation between the duration of migraine and the presence of allodynia was observed. • This retrospective analysis suggests that migraine severity is a signifcant factor in determining whether a subject will experience central sensitization as measured by allodynia. RESULTS METHODS RESULTS REFERENCES 1. Dodick D; Silberstein S. Central Sensitization theory of migraine: Clinical implications. Headache. 2006;S182-S191. 2. Burstein R; Collins B; Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann. Neurol. 2004;55:19-26. 3. Bigal ME; Ashina S; Burstein R; et al. Prevalence and characteristics of allodynia in headache sufferers. Neurology. 2008;70:1525-1533. 4. Burstein R; Cutrer MF; Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain. 2000;123:1703-1709. 5. Christoph-Diener H; Ferrari M; Mansbach H. Predicting the Response to Sumatriptan. Neurology. 2004;63:520-524. ADDITIONAL REFERENCE Tepper S; Kori S; Borland S; et al. Effcacy and Safety of MAP0004, Orally Inhaled DHE in Treating Migraines With and Without Allodynia.Headache. 2011;1-11. BACKGROUND Presented at the 54th Annual International Meeting of the American Headache Society Los Angeles, CA, USA June 21-24, 2012 FIGURE 3. Percentage of Subjects with Presence of Allodynia as a Function of Pain Level at the Time of Treatment (n=771) TABLE 1. Allodynia Presentation at the Time of Treatment Across All Baseline Characteristics and Demographics Study funded by MAP Pharmaceuticals, Inc. ©2012. All rights reserved. • Cutaneous allodynia is defned as the perception of pain from non-nociceptive stimuli applied to normal skin and is believed to be a clinical presentation of central sensitization. 1 • Central sensitization is a theory of migraine pathophysiology that describes abnormal neuronal excitability in the brainstem, specifcally the trigeminal nucleus caudalis. 1 • The presence of allodynia is a marker for resistant migraine. 2 Furthermore, the probability of a consistent, pain-free outcome when a migraine is treated with triptans has been shown to be reduced if the subject has developed allodynia. 2 • It has been reported that up to 70% of migraineurs experience allodynia sometime during the attack. 3 However, factors leading to the development of allodynia are not well understood. • The hypothesis that allodynia is time-dependent suggests a process where the peripheral nociceptors that innervate intracranial blood vessels and meninges become sensitized, followed by sensitization of second- and third-order trigeminovascular neurons. 4 This hypothesis implies that patients should take medication at the onset of a migraine attack. 4 • Pain severity at the time of treatment has been shown to be the most important predicting factor for the response to acute treatment of migraine 5 and may be related to the development of allodynia. To evaluate the relationship between allodynia and the duration and severity of migraine. OBJECTIVE This retrospective analysis included 792 subjects in the double- blind period of a Phase 3, placebo-controlled, randomized clinical trial of an investigational acute treatment for migraine (MAP0004). Duration of migraine (time from onset of migraine to the time of treatment as defned by the subject) and information on pain level at the time of treatment (scale of mild, moderate or severe) were recorded by subjects using an electronic diary. In addition, allodynia information was obtained at the time of treatment using a standard questionnaire (Figure 1) captured in real time by the electronic diary. This was a single migraine attack study and therefore frequency of migraines was not a factor that was evaluated as contributing to the presence of allodynia. Correlations between the percentage of subjects who experienced allodynia, the severity of migraine and the duration of migraine were analyzed by Fisher’s exact test and chi-square test where indicated. FIGURE 2. Percentage of Subjects with Presence of Allodynia at the Time of Treatment as a Function of Duration of Migraine 57% 51% 48% 56% 0% 20% 40% 60% 80% ≤ 1 hr >1-4 hr >4-8 hr >8 hr Allodynia Presence at the Time of Treatment Duration of Migraine n=132/230 n=162/321 n=58/122 n=55/198 56% 45% 43% 46% 0% 20% 40% 60% 80% ≤1 hr >1-4 hr >4-8 hr >8 hr Duration of Migraine Allodynia Presence at the Time of Treatment n=74/132 n=77/172 n=28/65 n=21/46 59% 57% 53% 65% 0% 20% 40% 60% 80% ≤1 hr >1-4 hr >4-8 hr >8 hr Duration of Migraine Allodynia Presence at the Time of Treatment n=58/98 n=85/149 n=30/57 n=34/52 The presence of allodynia at the time of treatment did not differ in relation to the duration of the migraine (chi-square p= 0.2182), regardless of migraine severity (moderate pain, chi-square p= 0.1807; severe pain, chi-square p= 0.5830). 48.2% 58.1% 0% 20% 40% 60% 80% MODERATE SEVERE Pain Symptom Score at Time of Treatment Allodynia Presence at the Time of Treatment *p= 0.0053 * n=200/415 n=207/356 Subjects reporting severe migraine pain experienced signifcantly more allodynia (58.4%) than subjects with moderate pain (48.2%; Fisher’s exact p= 0.0053). A. All Subjects (n=771*) B. Subjects with Moderate Pain at the Time of Treatment (n=415) DEMOGRAPHICS YES NO Total mITT 419 (52.9%) 373 (47.1%) Gender Female 390 (53.8%) 335 (46.2%) Male 29 (43.3%) 38 (56.7%) Age ≤40 years 190 (48.6%) 201 (51.4%) >40 years 229 (57.1%) 172 (42.9%) Race Caucasian 354 (51.8%) 329 (48.2%) Non-Caucasian 65 (59.6%) 44 (40.4%) Years Since First Headache Median 20 16 Min, Max 2, 54 2, 56 Years Since Migraine Diagnosis Median 13 11 Min, Max 1, 50 1, 54 Overall HIT-6 Score Median 66 65 Min, Max 53,78 48,78 The presence of allodynia at the time of treatment was defined as answering “Yes” to at least two of the following questions: 1. Is your scalp tender to touch? 2. Does combing your hair bother you? 3. Does wearing your glasses or sunglasses bother you? 4. Does washing your face bother you? 5. Are your teeth and gums tender to touch? 6. Is your skin over the face tender to touch? FIGURE 1. Allodynia Questionnaire 53% of subjects reported experiencing allodynia at the time of treatment. C. Subjects with Severe Pain at the Time of Treatment (n=356) METHODS RESULTS * Subjects that did not report time of treatment information were not included in the analysis