Influence of metabolic state and body composition on the action of pharmacological treatment of migraine.

Migraine is a disabling neurovascular disorder among people of all ages, with the highest prevalence in the fertile years, and in women. Migraine impacts the quality of life of affected individuals tremendously and, in addition, it is associated with highly prevalent metabolic diseases, such as obesity, diabetes mellitus and thyroid dysfunction. Also, the clinical response to drugs might be affected in patients with metabolic disease due to body composition and metabolic change. Therefore, the efficacy of antimigraine drugs could be altered in patients with both migraine and metabolic disease. However, knowledge of the pharmacology and the related clinical effects of antimigraine drugs in patients with metabolic disease are limited. Therefore, and given the clinical relevance, this article provides a comprehensive overview of the current research and hypotheses related to the influence of metabolic state and body composition on the action of antimigraine drugs. In addition, the influence of antimigraine drugs on metabolic functioning and, vice versa, the influence of metabolic diseases and its hormonal modulating medication on migraine activity is outlined. Future exploration on personalizing migraine treatment to individual characteristics is necessary to enhance therapeutic strategies, especially given its increasing significance in recent decades.

Headache onset after vaccination against SARS-CoV-2: a systematic literature review and meta-analysis.

BACKGROUND: Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are used to reduce the risk of developing Coronavirus Disease 2019 (COVID-19). Despite the significant benefits in terms of reduced risk of hospitalization and death, different adverse events may present after vaccination: among them, headache is one of the most common, but nowadays there is no summary presentation of its incidence and no description of its main features. METHODS: We searched PubMed and EMBASE covering the period between January 1st 2020 and August 6th, 2021, looking for record in English and with an abstract and using three main search terms (with specific variations): COVID-19/SARS-CoV-2; Vaccination; headache/adverse events. We selected manuscript including information on subjects developing headache after injection, and such information had to be derived from a structured form (i.e. no free reporting). Pooled estimates and 95% confidence intervals were calculated. Analyses were carried out by vaccine vs. placebo, by first vs. second dose, and by mRNA-based vs. "traditional" vaccines; finally, we addressed the impact of age and gender on post-vaccine headache onset. RESULTS: Out of 9338 records, 84 papers were included in the review, accounting for 1.57 million participants, 94% of whom received BNT162b2 or ChAdOx1. Headache was generally the third most common AE: it was detected in 22% (95% CI 18-27%) of subjects after the first dose of vaccine and in 29% (95% CI 23-35%) after the second, with an extreme heterogeneity. Those receiving placebo reported headache in 10-12% of cases. No differences were detected across different vaccines or by mRNA-based vs. "traditional" ones. None of the studies reported information on headache features. A lower prevalence of headache after the first injection of BNT162b2 among older participants was shown. CONCLUSIONS: Our results show that vaccines are associated to a two-fold risk of developing headache within 7 days from injection, and the lack of difference between vaccine types enable to hypothesize that headache is secondary to systemic immunological reaction than to a vaccine-type specific reaction. Some descriptions report onset within the first 24 h and that in around one-third of the cases, headache has migraine-like features with pulsating quality, phono and photophobia; in 40-60% of the cases aggravation with activity is observed. The majority of patients used some medication to treat headache, the one perceived as the most effective being acetylsalicylic acid.

Medication overuse and drug addiction: a narrative review from addiction perspective.

Chronic headache is particularly prevalent in migraineurs and it can progress to a condition known as medication overuse headache (MOH). MOH is a secondary headache caused by overuse of analgesics or other medications such as triptans to abort acute migraine attacks. The worsening of headache symptoms associated with medication overuse (MO) generally ameliorates following interruption of regular medication use, although the primary headache symptoms remain unaffected. MO patients may also develop certain behaviors such as ritualized drug administration, psychological drug attachment, and withdrawal symptoms that have been suggested to correlate with drug addiction. Although several reviews have been performed on this topic, to the authors best knowledge none of them have examined this topic from the addiction point of view. Therefore, we aimed to identify features in MO and drug addiction that may correlate. We initiate the review by introducing the classes of analgesics and medications that can cause MOH and those with high risk to produce MO. We further compare differences between sensitization resulting from MO and from drug addiction, the neuronal pathways that may be involved, and the genetic susceptibility that may overlap between the two conditions. Finally, ICHD recommendations to treat MOH will be provided herein.

Long-term Inhibition of Soleus H-reflex with Epidural Adhesiolysis and Pulsed Radiofrequency in Lumbosacral Neuropathic Pain.

INTRODUCTION: Scientific data about neurophysiological changes subsequent to pulsed radiofrequency (PRF) are still lacking. The goal of this study was to evaluate sural nerve conduction and Hoffmann reflex (H-reflex) in soleus muscle following adhesiolysis and PRF in patients with unilateral chronic lumbosacral L5-S1 neuropathic radiating pain. METHODS: Seventeen patients received two cycles of 240 seconds high-voltage PRF and epidural adhesiolysis. Sural nerve action potential (SNAP) and the ratio of maximum H-reflex to maximum M response (H/M ratio) as well as pain scores were collected in both lower limbs before, immediately following, and 1 month after the treatment. RESULTS: At follow-up, a significant reduction in numeric rating scale (NRS) and Douleur Neuropathique 4 Questions (DN4) scores was observed in 53% of patients reporting pain improvement of ≥ 30% over baseline. The H/M ratio was decreased in the affected limb following PRF (P = 0.01) and 1 month after the treatment (P = 0.04). A direct correlation was observed between H/M ratio variation and NRS score at follow-up in the treated limb (P = 0.04). No significant difference in sural nerve latency, amplitude, and velocity was detected between affected and normal side after treatment and at follow-up. CONCLUSIONS: Epidural adhesiolysis and PRF of the dorsal root ganglion seem to significantly affect spinal reflexes in patients with lumbosacral neuropathic radiating pain.

PACAP38 and PAC1 receptor blockade: a new target for headache?

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated.Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacological targets need to be identified.Due to the ability of PACAP38 to induce migraine-like attacks, its location in structures previously associated with migraine pathophysiology and the 100-fold selectivity for the PAC1 receptor when compared to VIP, new attention has been drawn to this pathway and its potential role as a novel target for migraine treatment. In accordance with this, antibodies against PACAP38 (ALD 1910) and PAC1 receptor (AMG 301) are being developed, with AMG 301 already in Phase II clinical trials. No results have been published so far, but in preclinical studies, AMG 301 has shown responses comparable to those observed with triptans. If these antibodies prove to be effective for the treatment of migraine, several considerations should be addressed, for instance, the potential side effects of long-term blockade of the PACAP (receptor) pathway. Moreover, it is important to investigate whether these antibodies will indeed represent a therapeutic advantage for the patients that do not respond the CGRP (receptor)-antibodies.In conclusion, the data presented in this review indicate that PACAP38 and PAC1 receptor blockade are promising antimigraine therapies, but results from clinical trials are needed in order to confirm their efficacy and side effect profile.

Blocking CGRP in migraine patients - a review of pros and cons.

Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.

Reduced threshold for inhibitory homeostatic responses in migraine motor cortex? A tDCS/TMS study.

BACKGROUND AND OBJECTIVE: Neurophysiological studies in migraine have reported conflicting findings of either cortical hyper- or hypoexcitability. In migraine with aura (MwA) patients, we recently documented an inhibitory response to suprathreshold, high-frequency repetitive transcranial magnetic stimulation (hf-rTMS) trains applied to the primary motor cortex, which is in contrast with the facilitatory response observed in the healthy subjects. The aim of the present study was to support the hypothesis that in migraine, because of a condition of basal increased cortical responsivity, inhibitory homeostatic like mechanisms of cortical excitability could be induced by high magnitude stimulation. For this purpose, the hf-rTMS trains were preconditioned by transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique able to modulate the cortical excitability state. METHODS: Twenty-two MwA patients and 20 patients with migraine without aura (MwoA) underwent trains of 5-Hz repetitive transcranial magnetic stimulation at an intensity of 130% of the resting motor threshold, both at baseline and after conditioning by 15 minutes of cathodal or anodal tDCS. Motor cortical responses to the hf-rTMS trains were compared with those of 14 healthy subjects. RESULTS: We observed abnormal inhibitory responses to the hf-rTMS trains given at baseline in both MwA and MwoA patients as compared with the healthy subjects (P < .00001).The main result of the study was that cathodal tDCS, which reduces the cortical excitability level, but not anodal tDCS, which increases it, restored the normal facilitatory response to the hf-rTMS trains in both MwA and MwoA. CONCLUSIONS: The present findings strengthen the notion that, in migraine with and without aura, the threshold for inducing inhibitory mechanisms of cortical excitability might be lower in the interictal period. This could represent a protective mechanism counteracting cortical hyperresponsivity. Our results could be helpful to explain some conflicting neurophysiological findings in migraine and to get insight into the mechanisms underlying recurrence of the migraine attacks.

Transcranial direct current stimulation preconditioning modulates the effect of high-frequency repetitive transcranial magnetic stimulation in the human motor cortex.

Experimental studies emphasize the importance of homeostatic plasticity as a mean of stabilizing the properties of neural circuits. In the present work we combined two techniques able to produce short-term (5-Hz repetitive transcranial magnetic stimulation, rTMS) and long-term (transcranial direct current stimulation, tDCS) effects on corticospinal excitability to evaluate whether and how the effects of 5-Hz rTMS can be tuned by tDCS preconditioning. Twelve healthy subjects participated in the study. Brief trains of 5-Hz rTMS were applied to the primary motor cortex at an intensity of 120% of the resting motor threshold, with recording of the electromyograph traces evoked by each stimulus of the train from the contralateral abductor pollicis brevis muscle. This interventional protocol was preconditioned by 15 min of anodal or cathodal tDCS delivered at 1.5 mA intensity. Our results showed that motor-evoked potentials (MEPs) increased significantly in size during trains of 5-Hz rTMS in the absence of tDCS preconditioning. After facilitatory preconditioning with anodal tDCS, 5-Hz rTMS failed to produce progressive MEP facilitation. Conversely, when 5-Hz rTMS was preceded by inhibitory cathodal tDCS, MEP facilitation was not abolished. These findings may give insight into the mechanisms of homeostatic plasticity in the human cerebral cortex, suggesting also more suitable applications of tDCS in a clinical setting.

Impaired glutamatergic neurotransmission in migraine with aura? Evidence by an input-output curves transcranial magnetic stimulation study.

OBJECTIVE: An imbalance between activity of inhibitory and facilitatory intracortical circuits could play a central role in migraine etiology. We used input-output curves to achieve further information about intracortical excitability of motor cortex in migraine with aura. METHODS: Input-output curves were measured in the right abductor pollicis brevis muscle at rest in 12 patients suffering from migraine with aura and 8 healthy subjects. Stimuli were delivered at intensity ranging from 100% to 160% of resting motor threshold with 10-second inter-stimulus intervals. Seven patients were studied before and during treatment with levetiracetam. RESULTS: Results showed a greater motor-evoked potential amplitude in response to increasing intensity of stimuli in patients compared to controls (P < .02). This increased facilitatory effect was abolished by levetiracetam (P < .005). CONCLUSIONS: Our findings support the hypothesis of an interictal cortical hyper-responsivity in migraine patients that appears to be normalized by levetiracetam. This effect could support the potential therapeutic role of levetiracetam in migraine with aura prevention.

Electrocatheter-mediated High-voltage Pulsed Radiofrequency of the Dorsal Root Ganglion in the Treatment of Chronic Lumbosacral Neuropathic Pain: A Randomized Controlled Study.

OBJECTIVES: Despite the interest in scientific community, there is still poor evidence about pulsed radiofrequency (PRF) efficacy in the treatment of neuropathic pain. In order to determine whether high-voltage PRF and epidural adhesiolysis (PRF-EA) showed better results than epidural adhesiolysis alone (EA), a randomized, double-blind, comparative-effectiveness study was conducted in patients with chronic lumbosacral radiating pain and neuropathic features. MATERIALS AND METHODS: A total of 41 patients were randomly allocated to 2 groups. Twenty-one patients were randomized to receive 2 cycles of 240 seconds high-voltage PRF followed by the injection of local anesthetics, hyaluronidase, and betamethasone, whereas 20 patients underwent sham stimulation followed by adhesiolysis. The treatment was delivered at the affected lumbosacral roots and patients, treating physicians and assessors were blinded to intervention. RESULTS: A significant reduction of radiating pain was observed in mean Numeric Rating Scale score at follow-up. A change of -3.43 versus -1.75 (P=0.031) after 1 month and -3.34 versus -0.80 (P=0.005) after 6 months was reported in patients undergoing PRF-EA in comparison with EA, respectively. After 1 month, 57% of patients in the PRF-EA group experienced a pain reduction of ≥50% versus only 25% of patients allocated to EA (P=0.037). Improvement decreased to 48% in the PRF-EA group whereas only 10% of EA reported significant pain relief after 6 months (P=0.008). DISCUSSION: High-voltage PRF of dorsal root ganglion delivered through multifunctional electrode provided significant pain relief and may be considered a valuable treatment in chronic lumbosacral radicular pain with neuropathic features.

Locked-in Syndrome and 18F-fluorodeoxyglucose-positron Emission Tomography/Computed Tomography: Observations from a Case of Basilar Artery Thrombosis.

We report the case of a 59-year-old male patient suffering from locked-in syndrome (LIS) following basilar artery thrombosis despite an attempt of thrombolysis. Neurological examination showed quadriplegia and aphonia and a state of coma requiring mechanical ventilation was diagnosed. The use of 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) allowed to detect a normal 18F-FDG uptake in the main cerebral cortical areas and a significant reduction of 18F-FDG uptake in both cerebellar hemispheres, compatible with a functional deafferentation, helping confirming the clinical suspicion of LIS. The diagnosis of LIS, according to literature, is based on the clinical assessment and the utilization of scores as the Coma Recovery Scale-Revised. The standard neuroimaging techniques, although recognize the site of injury, are not able to differentiate the different conditions affecting a state of altered consciousness. Performing 18F-FDG-PET in patients with LIS might help addressing the correct diagnosis and prompting subsequent appropriate treatment, and therefore, ultimately improving the patient outcome. Therefore, 18F-FDG-PET should be taken into account in the early clinical assessment of doubtful cases.

Interventional treatment for neuropathic pain due to combined cervical radiculopathy and carpal tunnel syndrome: a case report.

The coexistence of median and cervical nerve root damage might hide a complex pathophysiology. Here, we describe and discuss the case of a patient suffering from numbness and painful tingling of the hand, whose symptoms were effectively treated with pulsed radiofrequency and epidural administration of bupivacaine and morphine.

Combined epidural morphine and bupivacaine in the treatment of lumbosacral radicular neuropathic pain: a noncontrolled prospective study.

OBJECTIVE: The aim of this study was to investigate the therapeutic effectiveness of epidural morphine and bupivacaine in patients with chronic lumbosacral radicular neuropathic pain after the cessation of treatment. METHODS: Twenty-two patients with chronic lumbosacral pain with neuropathic features were enrolled. An indwelling catheter was placed into the epidural space, and each patient received an epidural injection of morphine chlorhydrate and bupivacaine up to three times a day. The medication was administered for 4 weeks. The pain intensity score on a 0-10 numeric rating scale (NRS), the total pain rating index rank (PRIr-T), and its coefficients were evaluated before treatment and 1 month after catheter removal. P-value <0.05 was considered statistically significant. RESULTS: NRS and PRIr-T were significantly reduced at follow-up (P=0.001 and P=0.03, respectively), whereas the parallel evolution of the two scores (r=0.75 and P<0.001, respectively) confirmed significant pain relief lasting up to 1 month after treatment cessation. None of the four pain rating coefficients was significantly modified compared to the others in either responders or nonresponders. Successful clinical outcome (pain reduction >30% in NRS) was reached and maintained in half of the patients at follow-up. CONCLUSION: Combined epidural morphine and bupivacaine seems to be effective in the treatment of neuropathic pain.