A single infusion of intravenous lidocaine for primary headaches and trigeminal neuralgia: a retrospective analysis.

Introduction: Intravenous (IV) lidocaine has been used as a transitional treatment in headache and facial pain conditions, typically as an inpatient infusion over several days, which is costly and may increase the risk of adverse effects. Here we report on our experience using a single one-hour IV lidocaine infusion in an outpatient day-case setting for the management of refractory primary headache disorders with facial pain and trigeminal neuralgia. Methods: This is a retrospective, single-center analysis on patients with medically refractory headache with facial pain and trigeminal neuralgia who were treated with IV lidocaine between March 2018 and July 2022. Lidocaine 5 mg.kg-1 in 60 mL saline was administered over 1 h, followed by an observation period of 30 min. Patients were considered responders if they reported reduction in pain intensity and/or headache frequency of 50% or greater. Duration of response was defined as short-term (< 2 weeks), medium-term (2-4 weeks) and long-term (> 4 weeks). Results: Forty infusions were administered to 15 patients with trigeminal autonomic cephalalgias (n = 9), chronic migraine (n = 3) and trigeminal neuralgia (n = 3). Twelve patients were considered responders (80%), eight of whom were complete responders (100% pain freedom). The average duration of the treatment effect for each participant was 9.5 weeks (range 1-22 weeks). Six out of 15 patients reported mild and self-limiting side effects (40%). Conclusion: A single infusion of IV lidocaine might be an effective and safe transitional treatment in refractory headache conditions with facial pain and trigeminal neuralgia. The sustained effect of repeated treatment cycles in some patients may suggest a role as long-term preventive therapy in some patients.

OnabotulinumtoxinA in elderly patients with chronic migraine: insights from a real-life European multicenter study.

INTRODUCTION: Although migraine prevalence decreases with aging, some older patients still suffer from chronic migraine (CM). This study aimed to investigate the outcome of OnabotulinumtoxinA (OBT-A) as preventative therapy in elderly CM patients. METHODS: This is a post hoc analysis of real-life prospectively collected data at 16 European headache centers on CM patients treated with OBT-A over the first three treatment cycles (i.e., Cy1-3). We defined: OLD patients aged ≥ 65 years and nonOLD those < 65-year-old. The primary endpoint was the changes in monthly headache days (MHDs) from baseline to Cy 1-3 in OLD compared with nonOLD participants. The secondary endpoints were the responder rate (RR) ≥ 50%, conversion to episodic migraine (EM) and the changes in days with acute medication use (DAMs). RESULTS: In a cohort of 2831 CM patients, 235 were OLD (8.3%, 73.2% females, 69.6 years SD 4.7). MHDs decreased from baseline (24.8 SD 6.2) to Cy-1 (17.5 SD 9.1, p < 0.000001), from Cy-1 to Cy-2 (14.8 SD 9.2, p < 0.0001), and from Cy-2 to Cy-3 (11.9 SD 7.9, p = 0.001). DAMs progressively reduced from baseline (19.2 SD 9.8) to Cy-1 (11.9 SD 8.8, p < 0.00001), to Cy-2 (10.9 SD 8.6, p = 0.012), to Cy-3 (9.6 SD 7.4, p = 0.049). The 50%RR increased from 30.7% (Cy-1) to 34.5% (Cy-2), to 38.7% (Cy-3). The above outcome measures did not differ in OLD compared with nonOLD patients. CONCLUSION: In a population of elderly CM patients with a long history of migraine OBT-A provided a significant benefit, over the first three treatment cycles, as good as in non-old patients.

Single-Pulse Transcranial Magnetic Stimulation for the preventive treatment of difficult-to-treat migraine: a 12-month prospective analysis.

BACKGROUND: Initial evidence have shown the short-term efficacy of sTMS in the acute and preventive treatment of migraine. It is unknown whether this treatment approach in the long-term is effective and well tolerated in difficult-to-treat migraine. METHODS: This is a prospective, single centre, open-label, real-world analysis conducted in difficult-to-treat patients with high-frequency episodic migraine (HFEM) and chronic migraine (CM) with and without medication overuse headache (MOH), who were exposed to sTMS therapy. Patients responding to a three-month sTMS treatment, continued the treatment and were assessed again at month 12. The cut-off outcome for treatment continuation was reduction in the monthly moderate to severe headache days (MHD) of at least 30% (headache frequency responders) and/or a ≥ 4-point reduction in headache disability using the Headache Impact test-6 (HIT-6) (headache disability responders). RESULTS: One hundred fifty-three patients were included in the analysis (F:M = 126:27, median age 43, IQR 32.3-56.8). At month 3, 93 out of 153 patients (60%) were responders to treatment. Compared to baseline, the median reduction in monthly headache days (MHD) for all patients at month 3 was 5.0 days, from 18.0 (IQR: 12.0-26.0) to 13.0 days (IQR: 5.75-24.0) (P = 0.002, r = - 0.29) and the median reduction in monthly migraine days (MMD) was 4.0 days, from 13.0 (IQR: 8.75-22.0) to 9.0 (IQR: 4.0-15.25) (P = 0.002, r = - 0.29). Sixty-nine out of 153 patients (45%) reported a sustained response to sTMS treatment at month 12. The percentage of patients with MOH was reduced from 52% (N = 79/153) at baseline to 19% (N = 29/153) at month 3, to 8% (N = 7/87) at month 12. There was an overall median 4-point reduction in HIT-6 score, from 66 (IQR: 64-69) at baseline to 62 at month 3 (IQR: 56-65) (P < 0.001, r = - 0.51). A total of 35 mild/moderate adverse events were reported by 23 patients (15%). One patient stopped sTMS treatment due to scalp sensitivity. CONCLUSIONS: This open label analysis suggests that sTMS may be an effective, well-tolerated treatment option for the long-term prevention of difficult-to-treat CM and HFEM.

The fifth cranial nerve in headaches.

The fifth cranial nerve is the common denominator for many headaches and facial pain pathologies currently known. Projecting from the trigeminal ganglion, in a bipolar manner, it connects to the brainstem and supplies various parts of the head and face with sensory innervation. In this review, we describe the neuroanatomical structures and pathways implicated in the sensation of the trigeminal system. Furthermore, we present the current understanding of several primary headaches, painful neuropathies and their pharmacological treatments. We hope that this overview can elucidate the complex field of headache pathologies, and their link to the trigeminal nerve, to a broader field of young scientists.

Prospective real-world analysis of OnabotulinumtoxinA in chronic migraine post-National Institute for Health and Care Excellence UK technology appraisal.

BACKGROUND AND PURPOSE: The National Institute for Health and Care Excellence (NICE) in the UK recommends the use of OnabotulinumtoxinA (BoNTA, Botox® ) in the management of chronic migraine (CM) following specific guidelines within the National Health Service. In view of the lack of data on the efficacy of this therapy following implementation of these guidelines in clinical practice and on the evaluation of guidance compliance, we aimed to evaluate the effectiveness and safety of BoNTA in patients with CM following the NICE guidelines. METHODS: This was a prospective real-life audit study. RESULTS: After two treatments, 127 of 200 patients (63.5%) obtained at least a 30% reduction in headache days. Those who continued the treatment up to 3 years reported a stable beneficial effect compared with baseline. Amongst responders, 68 patients (53.5%) were reclassified as episodic migraineurs. A total of 57 of these patients (83.8%) converted to an episodic migraine pattern at 6-month follow-up. The majority of those whose migraine became episodic after BoNTA extended the treatment intervals beyond 3 months (range 4-8 months) before noticing any worsening of headache. We observed no significant differences in the efficacy measures in patients treated with 155 U BoNTA compared with those treated with >155 U BoNTA. CONCLUSIONS: When administered according to the NICE guidance, BoNTA produced a clinically meaningful effect in the long-term management of CM with and without medication overuse headache. Treatment discontinuation when CM becomes episodic may be useful in clinical practice to identify those who may benefit from extended treatment intervals. Our clinical experience indicates a lack of additional benefit from using the 'follow-the-pain' paradigm.

Pharmacology of reflex blinks in the rat: a novel model for headache research.

BACKGROUND: Migraineurs are highly sensitive to the nitric oxide donor glyceryl trinitrate which triggers attacks in many sufferers. In animal studies, glyceryl trinitrate increases neuronal activity in the trigeminovascular pathway and elevates neurotransmitter levels in the brainstem. Many migraineurs also display alterations in blink reflexes, known to involve brainstem circuits. We investigated the effect of GTN on evoked blinks in the anaesthetised rat to determine whether such reflexes may prove useful as the basis for a novel animal model to evaluate potential anti-migraine therapeutic agents. METHOD: In anaesthetised rats the electromyogram associated with the reflex blink evoked by corneal airpuff was recorded. Rats were infused with glyceryl trinitrate, sumatriptan plus glyceryl trinitrate or vehicle control. Changes in the magnitude of the reflex blink-associated electromyogram following these treatments were measured. RESULTS: Glyceryl trinitrate potentiated the evoked reflex blink-associated EMG response from 2 h after infusion. That effect was abolished by simultaneous infusion of sumatriptan with glyceryl trinitrate. CONCLUSIONS: These results show that simple skin surface measurements of evoked electromyographic activity in the rat can reliably detect the evoked blink reflex that can be potentiated by nitric oxide donors. This novel model may be an effective tool for evaluating putative anti-migraine therapeutic agents.

Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics.

The last decade has witnessed an explosion in novel findings relating to the molecules involved in mediating the sensation of pain in humans. Transient receptor potential (TRP) ion channels emerged as the greatest group of molecules involved in the transduction of various physical stimuli into neuronal signals in primary sensory neurons, as well as, in the development of pain. Here, we review the role of TRP ion channels in primary sensory neurons in the development of pain associated with peripheral pathologies and possible strategies to translate preclinical data into the development of effective new analgesics. Based on available evidence, we argue that nociception-related TRP channels on primary sensory neurons provide highly valuable targets for the development of novel analgesics and that, in order to reduce possible undesirable side effects, novel analgesics should prevent the translocation from the cytoplasm to the cell membrane and the sensitization of the channels rather than blocking the channel pore or binding sites for exogenous or endogenous activators.

Activation of iGluR5 kainate receptors inhibits neurogenic dural vasodilatation in an animal model of trigeminovascular activation.

BACKGROUND AND PURPOSE: Migraine is a disabling neurological disorder involving activation, or the perception of activation, of trigeminovascular afferents containing calcitonin gene-related peptide (CGRP). Released CGRP from peripheral trigeminal afferents causes dilatation of dural blood vessel, and this is used to measure trigeminal nerve activation. Kainate receptors with the GluR5 subunit (iGluR5, ionotropic glutamate receptor) are present in the trigeminal ganglion and may be involved in nociception. We investigated the possible involvement of prejunctional iGluR5 kainate receptors on CGRP release from trigeminal afferents. EXPERIMENTAL APPROACH: We used neurogenic dural vasodilatation, which involves reproducible vasodilatation in response to CGRP release after electrical stimulation of the dura mater surrounding the middle meningeal artery. The effects of the specific iGluR5 receptor antagonist UBP 302 and agonist (S)-(-)-5-iodowillardiine were investigated on neurogenic and CGRP-induced dural vasodilatation in rats, by using intravital microscopy. KEY RESULTS: Administration of 10 and 20 mg.kg(-1) of iodowillardiine inhibited electrically induced dural vessel dilatation, an effect blocked by pretreatment with 50 mg.kg(-1) UBP 302. Administration of the iGluR5 receptor antagonist UBP 302 alone had no significant effect. CGRP (1 mg.kg(-1))-induced dural vasodilatation was not inhibited by the iGluR5 receptor agonist iodowillardiine. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that activation of the iGluR5 kainate receptors with the selective agonist iodowillardiine is able to inhibit neurogenic dural vasodilatation probably by inhibition of prejunctional release of CGRP from trigeminal afferents. Taken together with recent clinical studies the data reinforce CGRP mechanisms in primary headaches and demonstrate a novel role for kainate receptor modulation of trigeminovascular activation.

Neurobiology of migraine.

Migraine is a complex disorder of the brain whose mechanisms are only now being unraveled. It is common, disabling and economically costly. The pain suggests an important role of the nociceptive activation, or the perception of activation, of trigeminal cranial, particularly intracranial afferents. Moreover, the involvement of a multi-sensory disturbance that includes light, sound and smells, as well as nausea, suggests the problem may involve central modulation of afferent traffic more broadly. Brain imaging studies in migraine point to the importance of sub-cortical structures in the underlying pathophysiology of the disorder. Migraine may thus be considered an inherited dysfunction of sensory modulatory networks with the dominant disturbance affecting abnormal processing of essentially normal neural traffic.