Migraine: beyond pain

Most people who see, treat or experience migraine will be aware that its clinical manifestations exceed the symptom of head pain. However, available acute treatments so far have targeted migraine symptoms only in the context of the pain phase of an attack. The associated disability clearly involves more than just these symptoms, and the phenotype can include additional painless features, including alterations in mood,cognition and homeostasis and sensory sensitivities. Recognising these symptoms, understanding their neurobiological basis and systematically recording them prospectively in clinical therapeutic trials are likely to offer valuable pathophysiological and therapeutic insights into this complex brain disorder, ultimately helping to improve the quality of lives of sufferers. We aim to explore the multifaceted disorder that is migraine, with a particular focus on the non-painful non-aura symptoms.

A close association of freedom from pain, migraine-related functional disability, and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN

Background While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing. Methods Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom. Results Patients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time. Conclusions This study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint. Trial Registration SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Interleukin-6 induces spatially dependent whole-body hypersensitivity in rats: implications for extracephalic hypersensitivity in migraine

Background Migraine is a complex neurological disorder that is characterized by throbbing head pain, increased sensitivity to light, sound, and touch, as well as nausea and fatigue. It is one of the most common and most disabling disorders globally but mechanisms causing migraine are poorly understood. While head pain is a typical feature of attacks, they also often present with cutaneous hypersensitivity in the rest of the body. In contrast, primary pain conditions in the lower parts of the body are less commonly associated with cephalic hypersensitivity. Previous studies indicate that application of stimuli to the meninges of rodents causes cutaneous facial as well as hindpaw hypersensitivity. In the present study, we asked whether widespread hypersensitivity is a unique feature of dural stimulation or whether body-wide responses occur similarly when the same stimulus is given in other locations. Methods Rats were given the same dose of IL-6 either via dural, intraplantar, subcutaneous, intramuscular, intracisternal, or intrathecal injection. Cutaneous facial and hindpaw allodynia was assessed using Von Frey following injection into each location. Results Hindpaw allodynia was observed following dural and intraplantar injection of IL-6 in both males and females. Hindpaw allodynia was only observed in females following intracisternal and intrathecal IL-6 injections. In contrast, facial allodynia was only observed in either sex following dural and intracisternal injections, which would activate meningeal afferents and the trigeminal nucleus caudalis (TNC), respectively. Conclusions Here we show that while stimulation of upper body regions with IL-6 including the meninges and brainstem can cause widespread hypersensitivity spreading to the paws, similar stimulation of the lower body does not cause the spread of hypersensitivity into the head. These data are consistent with the observations that whole body hypersensitivity is specific to conditions such as migraine where pain is present in the head and they may provide insight into co-morbid pain states associated with migraine.

Interleukin-6 induces spatially dependent whole-body hypersensitivity in rats: implications for extracephalic hypersensitivity in migraine

Background: Migraine is a complex neurological disorder that is characterized by throbbing head pain, increased sensitivity to light, sound, and touch, as well as nausea and fatigue. It is one of the most common and most disabling disorders globally but mechanisms causing migraine are poorly understood. While head pain is a typical feature of attacks, they also often present with cutaneous hypersensitivity in the rest of the body. In contrast, pain conditions in the lower parts of the body do not generally lead to cutaneous hypersensitivity in the head. Previous studies indicate that application of stimuli to the meninges of rodents causes cutaneous facial as well as hindpaw hypersensitivity. In the present study, we asked whether widespread hypersensitivity is a unique feature of dural stimulation or whether body-wide responses occur similarly when the same stimulus is given in other locations.Methods: Rats were given the same dose of IL-6 either via dural, intraplantar, subcutaneous, intramuscular, intracisternal, or intrathecal injection. Cutaneous facial and hindpaw allodynia was assessed using Von Frey following injection into each location. Results: Hindpaw allodynia was observed following dural and intraplantar injection of IL-6 in both males and females. Hindpaw allodynia was only observed in females following intracisternal and intrathecal IL-6 injections. In contrast, facial allodynia was only observed in either sex following dural and intracisternal injections, which would activate meningeal afferents and the trigeminal nucleus caudalis (TNC), respectively. Conclusions : Here we show that while stimulation of upper body regions with IL-6 including the meninges and brainstem can cause widespread hypersensitivity spreading to the paws, similar stimulation of the lower body does not cause the spread of hypersensitivity into the head. These data are consistent with the observations that whole body hypersensitivity is specific to conditions such as migraine where pain is present in the head and they may provide insight into co-morbid pain states associated with migraine.

A close association of freedom from pain, migraine-related functional disability, and other outcomes: Results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN

BackgroundWhile pain freedom at 2h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2h post dosing.MethodsPatient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2h pain freedom compared to those who experienced 2h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom.ResultsParticipants who achieved 2h pain freedom (N = 913), in comparison with those with 2h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2h MBS freedom and 2h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom was lower (4.6%) than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time.ConclusionsThis study demonstrated that, at 2h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2h pain freedom is more robustly associated with other clinical outcomes than the 2h mild pain endpoint.Trial RegistrationSAMURAI (NCT02439320); SPARTAN (NCT02605174).

Metaphorical expressives in Tuvan lexicography

Fixation and assignment of labels to specific semantic derivation cases, namely metaphorical expressives (expressive lexical units) in Tuvan dictionaries, are considered and compared with their Russian equivalents. The Russian language influence on the semantic structure of the Tuvan lexemes is observed. Metaphorical expressives are lexemes formed by metaphorical derivation resulting in new (figurative) meanings without changing the form. The number of such units in the colloquial speech was found to increase under the Russian language influence in recent decades. New formation models non-typical for Tuvan but common in Russian have appeared. Also, the calques of Russian expressives based on models absent in Tuvan were found: bash aaryy (lit.: head pain) → “person or problem causing emotional pain or frustration to the speaker” from Russian golovnaya bol’ with the same meaning. The analysis showed Tuvan dictionaries not to reflect this phenomenon sufficiently, i.e., word figurative meanings, namely metaphorical expressives, are not represented there broadly enough. It may be because the labels marking certain words’ usage areas, particularly the label razg. (colloquial speech) is used rather liberally since the stylistic differentiation process is still ongoing in standard Tuvan. While actively used in oral colloquial speech, most expressive meanings of polysemantic words revealed in the study are not found in Tuvan dictionaries. In Russian, there are special colloquial dictionaries, as well as regional dictionaries with stylistic labels. There are no such dictionaries in Tuvan, mostly due to its vague stylistic differentiation. However, the Tuvan language is still evolving, with dictionaries updated accordingly.

Cranial suture headache: An extracranial head pain syndrome originating in the cranial sutures of the skull

Objective: To define a new type of head pain syndrome termed “cranial suture headache” which is a localized headache originating along the cranial suture lines of the skull. Background: Well localized headaches maybe extracranial in origin. As trigeminal nociceptors are localized within the cranial sutures of the skull, these fibrous joints maybe the source of head pain for some patients. Methods: Case series. To diagnose cranial suture headache, the patient’s pain had to be localized to the skull and elicited/mimicked by mild to moderate palpation over one or more distinct cranial suture lines. Results: Ten cases are presented. Most of the patients were women (9/10). The headache started daily from onset in all cases. Range of age of headache onset was 32–64 years. Headache was one sided, unless confined to the midline and typically lacked any migrainous and/or cranial autonomic symptoms. Most cranial suture headaches localized to either the sagittal, coronal or squamosal suture lines. Headache duration prior to diagnosis was on average 8.5 years. Triggering events: three began immediately after head trauma, two had very remote head trauma, one was post infectious, one was post craniotomy, while three patients had no known triggering event. All patients were treatment refractory failing at least three preventive medications. All improved with localized anesthetic injection to the suture line(s) and/or onabotulinum toxin A injection only to the cranial sutures. Discussion: Without the recognition of cranial suture-based pain, patients may have unremitting headaches that can last years to decades. The observation that “cranial suture” headache improves with localized treatment only to the cranial sutures would seem to suggest the extracranial origin of the pain.