Ezogabine (KCNQ2/3 channel opener) prevents delayed activation of meningeal nociceptors if given before but not after the occurrence of cortical spreading depression.

We proposed recently that induction of delayed activation of trigeminovascular neurons by cortical spreading depression (CSD) can explain the delayed onset of headache after the migraine aura ("aura"). This prompted us to search for ways to block the neuronal activation by CSD - a preclinical correlate of an attempt to find a drug that can block the initiation of headache when administered shortly after onset of aura (i.e., preemptively). Because migraine headache and epileptic seizures are comorbid chronic neurological disorders characterized by hyperexcitable brain networks, we began the search for such goal with an M-type potassium channel opener. We opted to use ezogabine, recently approved by the FDA as adjunctive treatment of partial onset seizures in adults, because it is a selective KCNQ2/3 channel opener. When CSD was induced before ezogabine injection (8.25 mg/kg, i.p.), 40% (6/15) of the units doubled their firing rate about 45 min later for about 95 min. Similarly, when CSD was induced before vehicle was injected (4% DMSO, 0.5% methylcellulose), 50% (3/6) of the units doubled their firing rate about 30 min later for about 120 min. When CSD was triggered 1h after ezogabine injection, it activated only 8% of the units. By itself, ezogabine injection resulted in a 30% attenuation of ongoing firing in all 10 control units. Thus, activation of KCNQ2/3 channels during the aura is unlikely to preempt the onset of headache but may reduce the incidence of migraine if given during prodromes that precede the headache by hours. Given the mechanistic similarities between migraine aura and epileptic seizures, it may be worthwhile to determine whether preemptive administration of ezogabine can prevent oncoming seizures in patients whose warning signs precede their seizures by more than an hour.

Cortical projections of functionally identified thalamic trigeminovascular neurons: implications for migraine headache and its associated symptoms.

This study identifies massive axonal arbors of trigeminovascular (dura-sensitive) thalamic neurons in multiple cortical areas and proposes a novel framework for conceptualizing migraine headache and its associated symptoms. Individual dura-sensitive neurons identified and characterized electrophysiologically in first-order and higher-order relay thalamic nuclei were juxtacellularly filled with an anterograde tracer that labeled their cell bodies and processes. First-order neurons located in the ventral posteromedial nucleus projected mainly to trigeminal areas of primary (S1) as well as secondary (S2) somatosensory and insular cortices. Higher-order neurons located in the posterior (Po), lateral posterior (LP), and lateral dorsal (LD) nuclei projected to trigeminal and extra-trigeminal areas of S1 and S2, as well as parietal association, retrosplenial, auditory, ectorhinal, motor, and visual cortices. Axonal arbors spread at various densities across most layers of the different cortical areas. Such parallel network of thalamocortical projections may play different roles in the transmission of nociceptive signals from the meninges to the cortex. The findings that individual dura-sensitive Po, LP, and LD neurons project to many functionally distinct and anatomically remote cortical areas extend current thinking on projection patterns of high-order thalamic neurons and position them to relay nociceptive information directly rather than indirectly from one cortical area to another. Such extensive input to diverse cortical areas that are involved in regulation of affect, motor function, visual and auditory perception, spatial orientation, memory retrieval, and olfaction may explain some of the common disturbances in neurological functions during migraine.

Activation of central trigeminovascular neurons by cortical spreading depression.

OBJECTIVE: Cortical spreading depression (CSD) has long been implicated in migraine attacks that begin with visual aura. Having shown that a wave of CSD can trigger long-lasting activation of meningeal nociceptors--the first-order neurons of the trigeminovascular pathway thought to underlie migraine headache--we now report that CSD can activate central trigeminovascular neurons in the spinal trigeminal nucleus (C1-2). METHODS: Stimulation of the cortex with pinprick or KCl granule was used to induce CSD in anesthetized rats. Neuronal activity was monitored in C1-2 using single-unit recording. RESULTS: In 25 trigeminovascular neurons activated by CSD, mean firing rate (spikes/s) increased from 3.6 ± 1.2 before CSD (baseline) to 6.1 ± 1.8 after CSD (p < 0.0001) for a period >13 minutes. Neuronal activity returned to baseline level after 30.0 ± 3.1 minutes in 14 units, and remained elevated for 66.0 ± 8.3 (22-108) minutes through the entire recording period in the other 11 units. Neuronal activation began within 0.9 ± 0.4 (0-2.5) minutes after CSD in 7 neurons located in laminae I-II, or after a latency of 25.1 ± 4.0 (7-75) minutes in 9 neurons located in laminae I-II, and 9 neurons located in laminae III-V. In 27 trigeminovascular neurons not activated by CSD, mean firing rate was 2.0 ± 0.7 at baseline and 1.8 ± 0.7 after CSD. INTERPRETATION: We propose that CSD constitutes a nociceptive stimulus capable of activating peripheral and central trigeminovascular neurons that underlie the headache of migraine with aura.

Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura.

Attacks of migraine with aura represent a phenomenon in which abnormal neuronal activity in the cortex produces sensory disturbances (aura) some 20-40 min before the onset of headache. The purpose of this study was to determine whether cortical spreading depression (CSD)--an event believed to underlie visual aura--can give rise to activation of nociceptors that innervate the meninges--an event believed to set off migraine headache. CSD was induced in anesthetized male rats by stimulation of the visual cortex with electrical pulses, pin prick, or KCl; single-unit activity of meningeal nociceptors was monitored in vivo in the rat before and after CSD. Regardless of the method of cortical stimulation, induction of CSD was recorded in 64 trials. In 31 of those trials, CSD induced a twofold increase in meningeal nociceptor firing rate that persisted for 37.0 +/- 4.6 min in trials in which activity returned to baseline, or >68 min in trials in which activity remained heightened at the time recording was interrupted. In two-thirds of the trials, onset of long-lasting neuronal activation began approximately 14 min after the wave of CSD. The findings demonstrates for the first time that induction of CSD by focal stimulation of the rat visual cortex can lead to long-lasting activation of nociceptors that innervate the meninges. We suggest that migraine with aura is initiated by waves of CSD that lead up to delayed activation of the trigeminovascular pathway.

Thalamic sensitization transforms localized pain into widespread allodynia.

OBJECTIVE: Focal somatic pain can evolve into widespread hypersensitivity to nonpainful and painful skin stimuli (allodynia and hyperalgesia, respectively). We hypothesized that transformation of headache into whole-body allodynia/hyperalgesia during a migraine attack is mediated by sensitization of thalamic neurons that process converging sensory impulses from the cranial meninges and extracephalic skin. METHODS: Extracephalic allodynia was assessed using single unit recording of thalamic trigeminovascular neurons in rats and contrast analysis of blood oxygenation level-dependent (BOLD) signals registered in functional magnetic resonance imaging (fMRI) scans of patients exhibiting extracephalic allodynia. RESULTS: Sensory neurons in the rat posterior thalamus that were activated and sensitized by chemical stimulation of the cranial dura exhibited long-lasting hyperexcitability to innocuous (brush, pressure) and noxious (pinch, heat) stimulation of the paws. Innocuous, extracephalic skin stimuli that did not produce neuronal firing at baseline (eg, brush) became as effective as noxious stimuli (eg, pinch) in eliciting large bouts of neuronal firing after sensitization was established. In migraine patients, fMRI assessment of BOLD signals showed that brush and heat stimulation at the skin of the dorsum of the hand produced larger BOLD responses in the posterior thalamus of subjects undergoing a migraine attack with extracephalic allodynia than the corresponding responses registered when the same patients were free of migraine and allodynia. INTERPRETATION: We propose that the spreading of multimodal allodynia and hyperalgesia beyond the locus of migraine headache is mediated by sensitized thalamic neurons that process nociceptive information from the cranial meninges together with sensory information from the skin of the scalp, face, body, and limbs.

A prospective assessment of sedation-related adverse events and patient and endoscopist satisfaction in ERCP with anesthesiologist-administered sedation.

BACKGROUND: Despite the increasing use of anesthesiologist-administered sedation for monitored anesthesia care (MAC) or general anesthesia in patients undergoing ERCP, limited prospective data exist on the effectiveness, safety, and cost of this approach. OBJECTIVE: To prospectively assess sedation-related adverse events (SRAEs), patient- and procedure-related risk factors associated with SRAEs, and endoscopist and patient satisfaction with anesthesiologist-administered sedation. DESIGN: Single-center, prospective cohort study. SETTING: Tertiary-care referral center. PATIENTS: A total of 528 consecutive patients undergoing ERCP. INTERVENTIONS: Anesthesiologist-administered MAC or general anesthesia. MAIN OUTCOME MEASUREMENTS: SRAEs, endoscopist and patient satisfaction. RESULTS: There were 120 intraprocedure SRAEs during 109 of the 528 ERCPs (21% of cases). Intraprocedure SRAEs included hypotension (38 events), arrhythmia (20 events), O(2) desaturation to less than 85% (66 events), unplanned intubation (16 events), and procedure termination (1 event). Thirty postprocedure SRAEs occurred in a total of 22 patients (4% of cases), including hypotension (5 events), endotracheal intubation (2 events), and arrhythmia (12 events). Patient-related variables associated with adverse intraprocedure events were American Society of Anesthesiologists class (P = .004) and body mass index (kg/m(2)) (P = .02). On a 10-point scale, mean endoscopist satisfaction with sedation was 9.2 (standard deviation 1.8) and patient satisfaction with sedation was 9.9 (standard deviation 0.7). LIMITATIONS: The approach to sedation was not randomized. CONCLUSIONS: Higher American Society of Anesthesiologists class and body mass index are associated with an increased rate of cardiac and respiratory events during ERCP. Cardiac and respiratory events are generally minor, and MAC can be considered a safe option for most ERCP patients. Despite the frequency of minor sedation-related events, procedure interruption or premature termination was rare in the setting of anesthesiologist-administered sedation.

Localization of COX-1 and COX-2 in the intracranial dura mater of the rat.

Primary headaches such as migraine can be aborted by systemic administration of non-steroidal anti-inflammatory drugs (NSAIDs), potentially through the non-selective inhibition of cyclooxygenase (COX) activity in the intracranial meninges. In this study we have used single and double labeling immunohistochemistry to examine the distribution of the COX-1 and COX-2 isoforms in the intracranial dura mater of the rat and identify cell types that express them. COX-1 immunoreactivity was found in medium and small dural blood vessels and was co-expressed with the endothelial cell markers vimentin and the endothelial isoform of nitric oxide synthase (ecNOS). COX-1 was also found to be present in most dural mast cells. COX-2 was mainly expressed in ED2-positive resident dural macrophages. Constitutive COX-2 expression was also found in some axonal profiles, many of which were co-labeled with the nociceptor peptide marker CGRP. The findings suggest that NSAIDs may abort headache, at least in part, by inhibiting either neuronal or non-neuronal COX activity in the dura mater.

Revisiting the efficacy of sumatriptan therapy during the aura phase of migraine.

OBJECTIVE: To reexamine the efficacy of terminating migraine headache by administration of sumatriptan during the visual-aura phase of the attack. Background.- Although the antimigraine action of triptans is most effective soon after onset of the headache, treatment during the aura phase has been found to be ineffective. METHODS: Nineteen subjects having migraine with aura were studied using a 4-way crossover, open-label design. Each patient was asked to treat 8 consecutive attacks with 100 mg of sumatriptan RT: 3 attacks treated at a timing of the patient's discretion (baseline); 1 attack treated 4 hours after onset of pain (late); 2 attacks treated within 1 hour of onset of pain (early); 2 attacks treated during the aura phase - before the onset of pain (aura). Pain level and cutaneous allodynia were reported by the patients at the onset of pain, at the time of treatment, and 2 and 24 hours after treatment. RESULTS: Sumatriptan treatment during the aura preempted the development of headache in 34/38 (89%) attacks. The same patients were rendered pain-free in 30/38 (79%) of attacks treated within 1 hour of pain onset, and in 4/19 (21%) of attacks treated 4 hours after the onset of pain. The incidence of allodynia at the time of treatment was 2/38 (5%) in attacks treated during aura, 8/38 (21%) in attacks treated early, and 14/19 (74%) in attacks treated late. CONCLUSION: Considering the discrepancy between the present and previous clinical studies, it is worthwhile revisiting the efficacy of preemptive triptan therapy during the aura phase of migraine attacks, using larger-scale, 3-way, crossover, placebo-controlled studies.

Sensitization of meningeal nociceptors: inhibition by naproxen.

Migraine attacks associated with throbbing (manifestation of peripheral sensitization) and cutaneous allodynia (manifestation of central sensitization) are readily terminated by intravenous administration of a non-selective cyclooxygenase (COX) inhibitor. Evidence that sensitization of rat central trigeminovascular neurons was also terminated in vivo by non-selective COX inhibition has led us to propose that COX inhibitors may act centrally in the dorsal horn. In the present study, we examined whether COX inhibition can also suppress peripheral sensitization in meningeal nociceptors. Using single-unit recording in the trigeminal ganglion in vivo, we found that intravenous infusion of naproxen, a non-selective COX inhibitor, reversed measures of sensitization induced in meningeal nociceptors by prior exposure of the dura to inflammatory soup (IS): ongoing activity of Adelta- and C-units and their response magnitude to mechanical stimulation of the dura, which were enhanced after IS, returned to baseline after naproxen infusion. Topical application of naproxen or the selective COX-2 inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) onto the dural receptive field of Adelta- and C-unit nociceptors also reversed the neuronal hyper-responsiveness to mechanical stimulation of the dura. The findings suggest that local COX activity in the dura could mediate the peripheral sensitization that underlies migraine headache.

Unitary hypothesis for multiple triggers of the pain and strain of migraine.

Migraine headache is triggered by and associated with a variety of hormonal, emotional, nutritional, and physiological changes. The perception of migraine headache is formed when nociceptive signals originating in the meninges are conveyed to the somatosensory cortex through the trigeminal ganglion, medullary dorsal horn, and thalamus. Is there a common descending pathway accounting for the activation of meningeal nociceptors by different migraine triggers? We propose that different migraine triggers activate a wide variety of brain areas that impinge on parasympathetic neurons innervating the meninges. According to this hypothesis, migraine triggers such as perfume, stress, or awakening activate multiple hypothalamic, limbic, and cortical areas, all of which contain neurons that project to the preganglionic parasympathetic neurons in the superior salivatory nucleus (SSN). The SSN, in turn, activates postganglionic parasympathetic neurons in the sphenopalatine ganglion, resulting in vasodilation and local release of inflammatory molecules that activate meningeal nociceptors. Are there ascending pathways through which the trigeminovascular system can induce the wide variety of migraine symptoms? We propose that trigeminovascular projections from the medullary dorsal horn to selective areas in the midbrain, hypothalamus, amygdala, and basal forebrain are functionally positioned to produce migraine symptoms such as irritability, loss of appetite, fatigue, depression, or the quest for solitude. Bidirectional trafficking by which the trigeminovascular system can activate the same brain areas that have triggered its own activity in the first place provides an attractive network of perpetual feedback that drives a migraine attack for many hours and even days.

Anti-migraine action of triptans is preceded by transient aggravation of headache caused by activation of meningeal nociceptors.

Consistent with previous accounts, some of the patients visiting our pain clinic during the course of a migraine attack have indicated-without solicitation-that sumatriptan injection initially intensified their headache before they were able to appreciate any pain relief. In this study, those patients who came forward complaining about pain exacerbation were asked to rate their headache intensity every 5 min. Within 5-15 min of sumatriptan injection, 17 of the 31 patients studied (55%) reported that their migraine pain intensified for 10-15 min before they started to notice any pain relief. Similar pattern of pain exacerbation was also observed in migraine attacks treated with oral formulation of almotriptan, eletriptan, rizatriptan, and zolmitriptan. To investigate the possible mechanism underlying this transient exacerbation of pain, we examined whether intravenous administration of sumatriptan can alter the response properties of C- and Adelta-meningeal nociceptors in the rat. Five to twenty minutes after intravenous administration of 300 microg/kg sumatriptan, 8/10 C-units and 2/8 Adelta-units increased their firing rate, and 6/10 C-units and 7/8 Adelta-units developed mechanical hyper-responsiveness to dural indentation. The minimal effective dose for activation and sensitization of meningeal nociceptors by sumatriptan was 3 microg/kg, suggesting that relatively low levels of triptans entering the circulation shortly after their administration can alter the physiological properties of meningeal nociceptors and produce a transient exacerbation of headache.

Altered placebo and drug labeling changes the outcome of episodic migraine attacks.

Information provided to patients is thought to influence placebo and drug effects. In a prospective, within-subjects, repeated-measures study of 66 subjects with episodic migraine, we investigated how variations in medication labeling modified placebo and drug effects. An initial attack with no treatment served as a control. In six subsequent migraine attacks, each participant received either placebo or Maxalt (10-mg rizatriptan) administered under three information conditions ranging from negative to neutral to positive (told placebo, told Maxalt or placebo, told Maxalt) (N = 459 documented attacks). Treatment order was randomized. Maxalt was superior to placebo for pain relief. When participants were given placebo labeled as (i) placebo, (ii) Maxalt or placebo, and (iii) Maxalt, the placebo effect increased progressively. Maxalt had a similar progressive boost when labeled with these three labels. The efficacies of Maxalt labeled as placebo and placebo labeled as Maxalt were similar. The efficacy of open-label placebo was superior to that of no treatment. Relative to no treatment, the placebo, under each information condition, accounted for more than 50% of the drug effect. Increasing "positive" information incrementally boosted the efficacy of both placebo and medication during migraine attacks. The benefits of placebo persisted even if placebo was honestly described. Whether treatment involves medication or placebo, the information provided to patients and the ritual of pill taking are important components of care.

The science of migraine.

The cardinal symptom of migraine is headache pain. In this paper we review the neurobiology of this pain as it is currently understood. In recent years, we discovered that the network of neurons that sense pain signals from the dura changes rapidly during the course of a single migraine attack and that the treatment of an attack is a moving target. We found that if the pain is not stopped within 10-20 minutes after it starts, the first set of neurons in the network, those located in the trigeminal ganglion, undergo molecular changes that make them hypersensitive to the changing pressure inside the head, which explains why migraine headache throbs and is worsened by bending over and sneezing. We found that if the pain is not stopped within 60-120 minutes, the second group of neurons in the network, those located in the spinal trigeminal nucleus, undergoes molecular changes that convert them from being dependent on sensory signals they receive from the dura by the first set of neurons, into an independent state in which they themselves become the pain generator of the headache. When this happens, patients notice that brushing their hair, taking a shower, touching their periorbital skin, shaving, wearing earrings, etc become painful, a condition called cutaneous allodynia. Based on this scenario, we showed recently that the success rate of rendering migraine patients pain-free increased dramatically if medication was given before the establishment of cutaneous allodynia and central sensitization. The molecular shift from activity-dependent to activity-independent central sensitization together with our recent conclusion that triptans have the ability to disrupt communications between peripheral and central trigeminovascular neurons (rather than inhibiting directly peripheral or central neurons) explain their clinical effects. Both our clinical and pre-clinical findings of the last five years point to possible short- and long-term advantages in using an early-treatment approach in the treatment of acute migraine attacks.

Managing migraine associated with sensitization.

The majority of migraineurs seeking secondary or tertiary medical care experience throbbing pain and cutaneous allodynia during the course of migraine. Underlying the origin of these symptoms are peripheral and central trigeminovascular neurons, whose cell bodies are located in the trigeminal ganglion and the spinal dorsal horn, respectively. The development of throbbing in the initial phase of migraine is mediated by sensitization of peripheral trigeminovascular neurons, whereas the development of cutaneous allodynia later in the attack is propelled by sensitization of central trigeminovascular neurons which, unfortunately, are not equipped to respond to triptans directly. Triptans appear to act presynaptically in the dorsal horn, such as to inhibit signal transmission from peripheral to central trigeminovascular neurons. Reining in the central neurons using triptan treatment is possible as long as their excitability remains driven by incoming signals from the meninges, but not after they develop autonomous activity. Accordingly, attacks with allodynia can be effectively terminated, provided that the patient vigilantly resorts to triptan therapy before or soon after the onset of allodynia, but not after allodynia has become firmly established. On the other hand, allodynic patients who missed the critical window for effective triptan therapy can still be rendered pain-free using an intravenous infusion of non-steroidal anti-inflammatory drugs.

A neural mechanism for exacerbation of headache by light.

The perception of migraine headache, which is mediated by nociceptive signals transmitted from the cranial dura mater to the brain, is uniquely exacerbated by exposure to light. We found that exacerbation of migraine headache by light is prevalent among blind individuals who maintain non-image-forming photoregulation in the face of massive rod/cone degeneration. Using single-unit recording and neural tract tracing in the rat, we identified dura-sensitive neurons in the posterior thalamus whose activity was distinctly modulated by light and whose axons projected extensively across layers I-V of somatosensory, visual and associative cortices. The cell bodies and dendrites of such dura/light-sensitive neurons were apposed by axons originating from retinal ganglion cells (RGCs), predominantly from intrinsically photosensitive RGCs, the principle conduit of non-image-forming photoregulation. We propose that photoregulation of migraine headache is exerted by a non-image-forming retinal pathway that modulates the activity of dura-sensitive thalamocortical neurons.

Sensory innervation of the calvarial bones of the mouse.

Migraine sufferers frequently testify that their headache feels as if the calvarial bones are deformed, crushed, or broken (Jakubowski et al. [2006] Pain 125:286-295). This has lead us to postulate that the calvarial bones are supplied by sensory fibers. We studied sensory innervation of the calvaria in coronal and horizontal sections of whole-head preparations of postnatal and adult mice, via immunostaining of peripherin (a marker of thinly myelinated and unmyelinated fibers) or calcitonin gene-related peptide (CGRP; a marker more typical of unmyelinated nerve fibers). In pups, we observed nerve bundles coursing between the galea aponeurotica and the periosteum, between the periosteum and the bone, and between the bone and the meninges; as well as fibers that run inside the diploë in different orientations. Some dural fibers issued collateral branches to the pia at the frontal part of the brain. In the adult calvaria, the highest concentration of peripherin- and CGRP-labeled fibers was found in sutures, where they appeared to emerge from the dura. Labeled fibers were also observed in emissary canals, bone marrow, and periosteum. In contrast to the case in pups, no labeled fibers were found in the diploë of the adult calvaria. Meningeal nerves that infiltrate the periosteum through the calvarial sutures may be positioned to mediate migraine headache triggered by pathophysiology of extracranial tissues, such as muscle tenderness and mild trauma to the skull. In view of the concentration of sensory fibers in the sutures, it may be useful to avoid drilling the sutures in patients undergoing craniotomies for a variety of neurosurgical procedures.

Mast cell degranulation activates a pain pathway underlying migraine headache.

Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell-induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal pain pathway believed to underlie intracranial headaches such as that of migraine.

Exploding vs. imploding headache in migraine prophylaxis with Botulinum Toxin A.

Migraine headache is routinely managed using medications that abort attacks as they occur. An alternative approach to migraine management is based on prophylactic medications that reduce attack frequency. One approach has been based on local intramuscular injections of Botulinum Toxin Type A (BTX-A). Here, we explored for neurological markers that might distinguish migraine patients who benefit from BTX-A treatment (100 units divided into 21 injections sites across pericranial and neck muscles). Responders and non-responders to BTX-A treatment were compared prospectively (n=27) and retrospectively (n=36) for a host of neurological symptoms associated with their migraine. Data pooled from all 63 patients are summarized below. The number of migraine days per month dropped from 16.0+/-1.7 before BTX-A to 0.8+/-0.3 after BTX-A (down 95.3+/-1.0%) in 39 responders, and remained unchanged (11.3+/-1.9 vs. 11.7+/-1.8) in 24 non-responders. The prevalence of aura, photophobia, phonophobia, osmophobia, nausea, and throbbing was similar between responders and non-responders. However, the two groups offered different accounts of their pain. Among non-responders, 92% described a buildup of pressure inside their head (exploding headache). Among responders, 74% perceived their head to be crushed, clamped or stubbed by external forces (imploding headache), and 13% attested to an eye-popping pain (ocular headache). The finding that exploding headache was impervious to extracranial BTX-A injections is consistent with the prevailing view that migraine pain is mediated by intracranial innervation. The amenability of imploding and ocular headaches to BTX-A treatment suggests that these types of migraine pain involve extracranial innervation as well.

Can allodynic migraine patients be identified interictally using a questionnaire?

OBJECTIVE: The gradual development of cutaneous allodynia during the course of a migraine attack is commonly detected by quantitative sensory testing (QST) in migraineurs seeking secondary and tertiary medical help. In this study, the authors developed a questionnaire that tested the recollection of the patients on their skin sensitivity during past migraine attacks. METHODS: The authors devised a series of questions regarding skin sensitivity during migraine and posed them to 89 migraineurs when they were free of migraine (Visit 1). To validate their recollections, the authors determined the patients' pain thresholds to mechanical and thermal skin stimuli in the absence of migraine (Visit 1) and during an attack (Visit 2), using QST. RESULTS: Whereas 75.3% of the patients testified to at least one type of skin hypersensitivity during migraine, 24.7% were unaware of any abnormal skin sensitivity. The questionnaire correctly identified 84.8% of the 66 patients classified as allodynic by QST and mislabeled the remaining 15.2% as nonallodynic (false negatives). Among the 23 patients classified as nonallodynic by QST, 47.8% were mislabeled as allodynic using the questionnaire (false positives). Among the total number of 89 patients studied, the questionnaire produced 62.9% true positives and 13.5% true negatives (= 76.4% correct labeling) vs 12.4% false positives and 11.2% false negatives (= 23.6% mislabeling). CONCLUSION: The reliability of the questionnaire as a diagnostic tool of allodynia varies with the proportion of allodynic patients in a given clinic. The major source of variability is the misconception of nonallodynic patients that their skin is hypersensitive during migraine.

Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2 inhibitors.

OBJECTIVE: To determine whether delayed infusion of COX1/COX2 inhibitors (ketorolac, indomethacin) will stop migraine in allodynic patients, and suppress ongoing sensitization in central trigeminovascular neurons in the rat. BACKGROUND: The majority of migraineurs seeking secondary or tertiary medical care develop cutaneous allodynia during the course of migraine, a sensory abnormality mediated by sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus. Triptan therapy can render allodynic migraineurs pain free within a narrow window of time (20 to 120 minutes) that opens with the onset of pain and closes with the establishment of central sensitization. Can drugs that tackle ongoing central sensitization render allodynic migraineurs pain free after the window for triptan therapy has expired? METHODS: Patients exhibiting migraine with allodynia were divided in two groups (n=14, each): group 1 received delayed sumatriptan injection (6 mg) 4 hours after onset of attack--which failed to render them pain free-and ketorolac infusion (two 15-mg boluses) 2 hours later; group 2 received delayed ketorolac monotherapy 4 hours after onset of attack. Pain intensity (visual analog scale) and skin sensitivity (quantitative sensory testing) were measured when the patients were migraine free (baseline); 4 hours after onset of migraine (just before treatment); 2 hours after sumatriptan; 1 hour after ketorolac. In the rat, we tested whether infusion of ketorolac (0.4 mg/kg) or indomethacin (1 mg/kg) will block ongoing sensitization in peripheral and central trigeminovascular neurons. The induction of sensitization (using topical application of inflammatory soup on the dura) and its suppression by COX1/COX2 inhibitors were assessed by monitoring changes in spontaneous activity and responses to mechanical and thermal stimuli. RESULTS: Patients had normal skin sensitivity in the absence of migraine, and presented cutaneous allodynia 4 hours after onset of migraine. In group 1, all patients continued to exhibit allodynia 2 hours after sumatriptan treatment, and none of them became pain free. However, 71% and 64% of the patients in groups 1 and 2, respectively, were rendered free of pain and allodynia within 60 minutes of ketorolac infusion. Nonresponders from both groups, in contrast to the responders, had had a history of opioid treatment. In the rat, infusion of COX1/COX2 inhibitors blocked sensitization in meningeal nociceptors and suppressed ongoing sensitization in spinal trigeminovascular neurons. This inhibitory action was reflected by normalization of neuronal firing rate and attenuation of neuronal responsiveness to mechanical stimulation of the dura, as well as mechanical and thermal stimulation of the skin. CONCLUSIONS: The termination of migraine with ongoing allodynia using COX1/COX2 inhibitors is achieved through the suppression of central sensitization. Although parenteral administration of COX1/COX2 inhibitors is impractical as routine migraine therapy, it should be the rescue therapy of choice for patients seeking emergency care for migraine. These patients should never be treated with opioids, particularly if they had no prior opioid exposure.