The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice.

OBJECTIVE: To incorporate recent research findings, expert consensus, and patient perspectives into updated guidance on the use of new acute and preventive treatments for migraine in adults. BACKGROUND: The American Headache Society previously published a Consensus Statement on the use of newly introduced treatments for adults with migraine. This update, which is based on the expanded evidence base and emerging expert consensus concerning postapproval usage, provides practical recommendations in the absence of a formal guideline. METHODS: This update involved four steps: (1) review of data about the efficacy, safety, and clinical use of migraine treatments introduced since the previous Statement was published; (2) incorporation of these data into a proposed update; (3) review and commentary by the Board of Directors of the American Headache Society and patients and advocates associated with the American Migraine Foundation; (4) consideration of these collective insights and integration into an updated Consensus Statement. RESULTS: Since the last Consensus Statement, no evidence has emerged to alter the established principles of either acute or preventive treatment. Newly introduced acute treatments include two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (ubrogepant, rimegepant); a serotonin (5-HT1F ) agonist (lasmiditan); a nonsteroidal anti-inflammatory drug (celecoxib oral solution); and a neuromodulatory device (remote electrical neuromodulation). New preventive treatments include an intravenous anti-CGRP ligand monoclonal antibody (eptinezumab). Several modalities, including neuromodulation (electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation) and biobehavioral therapy (cognitive behavioral therapy, biofeedback, relaxation therapies, mindfulness-based therapies, acceptance and commitment therapy) may be appropriate for either acute and/or preventive treatment; a neuromodulation device may be appropriate for acute migraine treatment only (remote electrical neuromodulation). CONCLUSIONS: The integration of new treatments into clinical practice should be informed by the potential for benefit relative to established therapies, as well as by the characteristics and preferences of individual patients.

Therapeutic strategies that act on the peripheral nervous system in primary headache disorders.

Introduction: Acute and preventive treatment of primary headache disorders is not completely resolved with regard to efficacy, safety, and tolerability. Hence, peripheral and central neuromodulation can provide therapeutic alternatives in drug-resistant cases. Peripheral targets of neuromodulation include invasive and non-invasive neurostimulation and electrical and chemical nerve and ganglion blockades. Areas covered: A PubMed search of papers published from January 2012 to October 2018 was conducted. The goal of this review was to analyze the efficacy and safety of invasive (implantable) peripheral neurostimulation methods (the occipital nerve, the cervical branch of vagal nerve, the sphenopalatine ganglion) and non-invasive (transcutaneous) peripheral neurostimulation methods (the occipital nerve, the supraorbital nerve, and the cervical and auricular branches of the vagal nerve), based on the results of published clinical trials and case series. Acting also on the peripheral nervous system, peripheral nerve (i.e. greater occipital nerve) and ganglion (i.e. sphenopalatine ganglion) blockades, botulinum neurotoxin type A-hemagglutinin complex therapies, and calcitonin gene-related peptide-related monoclonal antibody treatments in this patient population are also discussed. Expert opinion: This review summarizes the latest results on the therapeutic strategies acting on the periphery in primary headache disorders. These therapeutic options are minimally invasive or non-invasive, efficacious, safe, and well tolerated.

New strategies for the treatment and prevention of primary headache disorders.

The primary headache disorders, which include migraine, cluster headache and tension-type headache, are among the most common diseases and leading causes of disability worldwide. The available treatment options for primary headache disorders have unsatisfactory rates of efficacy, tolerability and patient adherence. In this Review, we discuss promising new approaches for the prevention of primary headache disorders, such as monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor, and small-molecule CGRP receptor antagonists. Neuromodulation approaches employing noninvasive or implantable devices also show promise for treating primary headache disorders. Noninvasive treatments, such as transcranial magnetic stimulation and transcutaneous peripheral nerve stimulation, are delivered by devices that patients can self-administer. Implantable devices targeting the occipital nerves, sphenopalatine ganglion or high cervical spinal cord are placed using percutaneous and/or surgical procedures, and are powered either wirelessly or by surgically implanted batteries. These new and emerging treatments have the potential to address unmet patient needs and reduce headache-associated disability.

Evidence for the existence of nociceptors in rat thoracolumbar fascia.

Recently, the existence of nociceptive fibers in fascia tissue has attracted much interest. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, little is known about the properties of fascia nociceptors and possible changes of the fascia innervation by nociceptors under pathological circumstances. In this histologic study, the density of presumably nociceptive fibers and free nerve endings was determined in the three layers of the rat TLF: inner layer (IL, covering the multifidus muscle), middle layer (ML) and outer layer (OL). As markers for nociceptive fibers, antibodies to the neuropeptides CGRP and SP as well as to the transient receptor potential vanilloid 1 (TRPV1) were used. As a pathological state, inflammation of the TLF was induced with injection of complete Freund's adjuvant. The density of CGRP- and SP-positive fibers was significantly increased in the inner and outer layer of the inflamed fascia. In the thick middle layer, no inflammation-induced change occurred. In additional experiments, a neurogenic inflammation was induced in the fascia by electrical stimulation of dorsal roots. In these experiments, plasma extravasation was visible in the TLF, which is clear functional evidence for the existence of fascia nociceptors. The presence of nociceptors in the TLF and the increased density of presumably nociceptive fibers under chronic painful circumstances may explain the pain from a pathologically altered fascia. The fascia nociceptors probably contribute also to the pain in non-specific low back pain.

Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide.

Calcitonin gene-related peptide (CGRP) is a well-validated target for migraine therapy and a known potent systemic vasodilator. LBR-101 is a monoclonal antibody against CGRP in clinical development for the preventive treatment of episodic and chronic migraine. Understanding the hemodynamic and cardiovascular consequences of chronic CGRP inhibition is therefore warranted. Given the conservation in CGRP sequence between monkeys and humans, addressing this question in monkeys is ideal as it allows dosing at super-therapeutic levels. To this end, two independent studies were conducted in monkeys: a single dedicated cardiovascular safety study and a repeat-dose, chronic study, both with electrocardiogram and hemodynamic assessments. LBR-101 was very well tolerated in both studies, with no clinically significant changes noted in any hemodynamic parameter, nor any relevant changes noted in any ECG parameter. In cynomolgus monkeys, cardiovascular and hemodynamic parameters do not appear to be affected by long-term inhibition of CGRP with LBR-101.

Inhibition of calcitonin gene-related peptide (CGRP) has the potential to extend first-phase insulin secretion.

The neuropeptide calcitonin gene-related peptide (CGRP), known to have a strong vasodilation effect, has also been reported to inhibit insulin secretion. However, the physiological effect of CGRP related to insulin secretion is still unknown. Here, we evaluated the effect of whole-body CGRP inhibition by anti-CGRP antibodies in mice using an oral glucose tolerance test. CGRP has 2 isotypes, alpha-CGRP and beta-CGRP, and we confirmed the antibody used in this study inhibits function of both. Then, we evaluated the effect of CGRP inhibition on insulin secretion and discovered that CGRP inhibition lead to extend first-phase insulin secretion in an antibody dose-dependent manner and nearly plateaued at 10 mg/kg, although the effect was not so large and didn't affect plasma glucose level. We then measured the plasma antibody concentration and it was increased depending on administration dose. So, the effect of first-phase insulin secretion extension was determined to be the result of complete inhibition of CGRP by the antibody. These results indicate that CGRP has the potential to inhibit insulin secretion and shorten first-phase insulin secretion. However the effect of CGRP inhibition was not so large at least on healthy condition, and it indicates the effect of CGRP related to insulin secretion on healthy physiological condition may be limited.

[Effects of warm needle moxibustion on nerve root local inflammatory factors (NOS and CGRP) in the lumbar nerve root compress model rats].

OBJECTIVE: To explore the mechanism of acupuncture for treatment of lumbar nerve root compression injury. METHODS: Fifty healthy SD rats were randomly divided into 5 groups, a normal group, a model group treated by saline, a medication group treated with Caerulein, an acupuncture group treated with acupuncture at L5, L6 Jiaji (EX-B 2) and a warm needle group treated with acupuncture and moxibustion at L5, L6 Jiaji (EX-B 2). The lumbar nerve root compress injury model was made by placing microsilica gel tablet. After they were treated for 14 days, the compressed nerve root was taken and the ultra-microstructure changes of the injured nerve root were observed by electron microscope and changes of nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP) expressions were investigated by ELISA assay. RESULTS: The changes of ultra-microstructure of the nerve root were the most obvious in the model group and the changes in the medication group, the acupuncture group and the warming needle group reduced in order; the NOS activity and CGRP content in the nerve root tissue of the compressed area in the warm needle group were significantly reduced as compared with the model group (P < 0.05), but with no significant difference as compared with those in the normal group (P > 0.05). CONCLUSION: Warm needle treatment can effectively maintain cellular form, and ultra-microstructures of nerve root dorsal root ganglia, and effectively inhibit the release of inflammatory factors NOS and CGRP.

Calcitonin gene related peptide and N-procalcitonin modulate CD11b upregulation in lipopolysaccharide activated monocytes and neutrophils.

OBJECTIVE: Circulating levels of calcitonin gene related peptide (CGRP) and calcitonin precursors, including procalcitonin (PCT) and its free aminopeptide N-procalcitonin (N-PCT), have been found dramatically increased in septic patients. PCT is known to attenuate the chemotaxis of monocytes in response to chemoattractants. This study examined whether CGRP and N-PCT modulate the LPS-induced expression of CD11b, which is one of the major integrins involved in monocyte and neutrophil chemotaxis during a response to microbial infections. DESIGN AND SETTING: In vitro cell culture study in the immunology laboratory of a university hospital. PARTICIPANTS: Healthy volunteers. MEASUREMENTS AND RESULTS: We assessed the effects of N-PCT and CGRP on CD11b expression on monocytes and neutrophils after LPS (2 ng/ml) or fMLP (10(-8) M) challenges. We used a human whole blood model, and measurements were made by flow cytometry. Both peptides in a dose-dependent manner decreased the LPS- and fMLP-induced rise in CD11b in monocytes and neutrophils. As these peptides are thought to act by raising cAMP, we also mimicked their effects with the use of rolipram and forskolin and found similar results. CONCLUSIONS: These findings are in line with recent studies demonstrating anti-inflammatory properties for this family of peptides. CGRP and calcitonin precursors may function as factors suppressing the propagation of inflammation through the inhibition of several processes involved during a response to a bacterial stimulus.

Quantitation of calcitonin gene-related peptide mRNA and neuronal cell death in facial motor nuclei following axotomy and 633 nm low power laser treatment.

BACKGROUND AND OBJECTIVES: A persistent increase in calcitonin gene-related peptide (CGRP) immunoreactivity in motoneurons may serve as an indicator for regeneration after peripheral nerve injury [Borke et al., J Neurocytol 1993;22:141-153]. STUDY DESIGN/MATERIALS AND METHODS: We examined the effects of low power laser treatment (633 nm) on axotomy-induced changes in alpha-CGRP mRNA and long-term neuronal survival in facial motoneurons. A quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay for alpha-CGRP mRNA was used to detect changes in the response to axotomy and laser irradiation. Cell counts of neurons in injured and non-injured facial motor nuclei of laser-treated and non-treated rats were done to estimate neuronal survival. RESULTS: A 10-fold increase (P < 0.0001) in mRNA for alpha-CGRP at 11 days post-transection and an almost threefold increase (P < 0.0001) in neuronal survival at 6-9 months post-transection were found in 633 nm light treated rats. DISCUSSION: These findings demonstrate that 633 nm laser light upregulates CGRP mRNA and support the theory that laser irradiation increases the rate of regeneration, target reinnervation, and neuronal survival of the axotomized neuron.

CGRP in the trigeminal nucleus, spinal cord and hypothalamus: effect of gonadal steroids.

Calcitonin gene-related peptide (CGRP) contents were assayed in cervical spinal cord, trigeminal nucleus and hypothalamus throughout the estrous cycle and in male and ovariectomized rats. In the trigeminal nucleus, neither testosterone nor 17 beta-estradiol seem to affect CGRP accumulation, but progesterone seems to decrease it. In the cervical spinal cord, ovarian steroids seem to decrease CGRP while testosterone does not seem to influence it. In the hypothalamus, CGRP was only detectable in the male rat suggesting a positive effect of testosterone. It had marked circadian rhythm. In conclusion, CGRP content appears to be affected by gonadal steroids in the hypothalamus, the cervical spinal cord and the trigeminal nucleus in the rat.

A lobster cysteine protease with immunoreactivity and activities of calcitonin and CGRP.

The high concentrations of molecules immunologically related to salmon calcitonin (CT) and/or to human calcitonin gene-related peptide (CGRP) in the oesophagus of the norway lobster Nephrops norvegicus have been examined. In the present study. We report the purification of these molecules by means of a specific radioimmunoassay for calcitonin and calcitonin gene related peptide. The immunoreactive molecules were tested for their functional similarities with CT and CGRP. This was investigated by measuring their ability to interact with CGRP and CT radioreceptor assays and to stimulate the adenylate cyclase activity in rat liver and kidney membranes, respectively. In addition, the purified product was injected in young rats in order to check for a CT-like biological activity of these molecules. The combination of these tests led us to purify a molecular form of 33 kDa. N-terminal sequence analysis of this protein revealed a considerable homology with the lobster cysteine proteases and the human cathepsin L. Control experiments performed with the highly purified American lobster cysteine protease I showed that crustacean cysteine proteases given in vivo to rats induce a fall in the plasma calcium and phosphate levels. This study therefore adds further documentation for a common ancestral origin of CT, CGRP and the much large cysteine proteases from invertebrates.

Adrenalectomy increases the number of substance P and somatostatin immunoreactive nerve cells in the rat lumbar dorsal root ganglia.

Using an immunocytochemical technique we have analyzed changes in substance P, somatostatin, calcitonin gene-related peptide, and galanin immunoreactivity pattern in the rat dorsal root ganglia. After 7 days of adrenalectomy, sham operated rats were compared with adrenalectomized animals either receiving a daily intraperitoneal injection of 10 mg/kg b.wt. corticosterone or vehicle. Three lumbar ganglia from each animal were blocked, serially cut, and immunostained for each neuropeptide by means of the biotin-avidin-peroxidase technique. A systematic sampling of immunoreactive ganglion cells was performed and the sample number of immunoreactive ganglion cells was calculated. After adrenalectomy, the number of substance P and somatostatin immunoreactive ganglion cells markedly increased ((means +/- S.E.M.): 245 +/- 68 versus 123 +/- 12 for sham operated animals, P < 0.01 (substance P) and 42 +/- 8 as compared to 22 +/- 9 for sham operated animals, P < 0.01 (somatostatin)). No significant changes were found in the number of calcitonin gene-related peptide and galanin immunoreactive cells after adrenalectomy. These results suggest that adrenal steroid hormones may reduce the synthesis of both substance P and somatostatin in the dorsal root ganglion cells. Daily treatment with a high dose of corticosterone, mimicking its serum levels after stress, failed to prevent the increase of peptide contents after adrenalectomy. These observations also indicate that a tonic action of corticosterone on mineralocorticoid receptors may be crucial for peptide regulation in the spinal ganglia. These results may be of relevance to adrenalectomy induced changes in sensory mechanisms, neurogenic inflammation and pain transmission and to a role of substance P and somatostatin in these processes.

Behavioral and immunohistochemical changes in an experimental arthritis model in rats.

An experimental arthritis induced by injection of kaolin and carrageenan into the knee joint resulted in a temporal relationship between glutamate dorsal horn content and paw withdrawal latency (PWL) which was positively correlated. Limping, guarding, increased response to heat stimuli (hyperalgesia) and altered staining patterns for glutamate (GLU), substance P (SP), and calcitonin gene-related peptide (CGRP) were monitored in the awake behaving arthritic rat over a 1 week time course. A decrease in PWL occurred on the side ipsilateral to the inflamed knee as early as 4 h after the induction of arthritis indicating the animals are hyperalgesic. The PWL remained decreased through the first 24 h. Computer-assisted quantification of the density of immunohistochemical staining indicated the content of GLU, SP and CGRP was altered differentially throughout the time course of the arthritis. The changes observed for all three substances occurred across the entire superficial dorsal horn. There was an initial depletion of SP followed by an increase in both SP and CGRP content which was maintained through 1 week. The GLU content was increased during the hyperalgesic period. The GLU changes followed the same time course and were positively correlated with the changes in PWL. In a small group of animals injected with kaolin and carrageenan, hyperalgesia did not develop. In this group of animals, no change in dorsal horn GLU or SP content occurred. Rather, there was an increase in CGRP content in the middle portion of the superficial dorsal horn which is the termination site of knee joint afferents. These data indicate that the development of heat hyperalgesia is dependent on GLU and possibly SP. Since inflammation of the knee joint does not involve the foot pad, the heat hyperalgesia observed during the first 24 h following induction of arthritis represents a central neuronal sensitization.

Neonatal capsaicin treatment prevents the development of the thermal hyperalgesia produced in a model of neuropathic pain in the rat.

Loose ligation of the sciatic nerve with 4-0 chromic gut sutures in rats produces behavioral evidence of neuropathic pain. In the present experiments we examined the involvement of capsaicin-sensitive afferents in mediating the thermal hyperalgesia produced by this model. Male Sprague-Dawley rats, treated as neonates (within 48 h of birth) with capsaicin (50 mg/kg, s.c.) or vehicle, were used at 16-18 weeks of age. Chromic gut sutures (4-0) were tied around the left sciatic nerve and withdrawal latencies of both hind paws to radiant heat were determined on postoperative days 3, 5, 10 and 20. Whereas there was a pronounced thermal hyperalgesia which lasted for up to 20 days in vehicle-treated rats, there was no evidence of thermal hyperalgesia in capsaicin-treated rats. There was no difference in baseline (pre-surgery) withdrawal latencies between the two groups. Radioimmunoassay revealed that there was a significant depletion of substance P (43.8%) and calcitonin-gene-related peptide (72.6%) in the lumbar spinal cord of neonatal capsaicin-treated rats compared to vehicle-treated rats. These results demonstrate that the chromic gut-induced thermal hyperalgesia is mediated by capsaicin-sensitive afferents and suggest that central mechanisms which process and control the reflex response to heat are different than mechanisms involved in thermal hyperalgesia.

Neonatal capsaicin-treatment in mice: effects on pancreatic peptidergic nerves and 2-deoxy-D-glucose-induced insulin and glucagon secretion.

It is not known whether sensory nerves are involved in the insulin, glucagon or glucose responses to autonomic nerve activation induced by 2-deoxy-D-glucose (2-DG). We therefore treated mice neonatally with capsaicin which permanently destroys sensory afferent nerve fibers. Immunohistochemistry of the pancreas at 13-14 weeks of age revealed a substantial reduction of calcitonin gene-related peptide (CGRP)-immunoreactive nerves and a partial reduction of substance P-immunoreactive nerves. In contrast, no effect was observed on galanin-immunoreactive nerves. At age 10-12 weeks, the mice were injected intravenously with 2-DG (500 mg/kg). In controls, 2-DG stimulated insulin and glucagon secretion and induced hyperglycemia (P less than 0.01). Capsaicin treatment partially reduced the glucose and glucagon responses to 2-DG (P less than 0.01). In contrast, the insulin response to 2-DG was not affected by capsaicin. It is concluded that the mouse pancreas contains capsaicin-sensitive sensory CGRP- and substance P-immunoreactive nerve fibers, whereas the galanin-immunoreactive nerve fibers are not sensitive to capsaicin. Furthermore, capsaicin-sensitive sensory nerve fibers are partially involved in 2-DG-induced glucagon secretion and hyperglycemia, whereas sensory nerves are not involved in 2-DG-induced insulin secretion.

Calcitonin gene-related peptide (CGRP) immunoreactivity in the afferents to the caudate-putamen and perirhinal cortex of rats.

The posterior caudate-putamen and perirhinal cortex are innervated by fibers immunoreactive to calcitonin gene-related peptide (CGRP). We investigated the origins of these fibers by using immunohistochemistry combined with lesion experiments and fluorescent dye tracers. Lesions of the posterior thalamus surrounding the medial geniculate nucleus, in which groups of CGRP-like immunoreactive (CGRP-LI) cells exist, decreased the number of ipsilaterally CGRP-LI fibers in the posterior caudate-putamen and partly in the perirhinal cortex. Some of CGRP-LI neurons in several posterior thalamic nuclei surrounding the medial geniculate nucleus were labeled with both Fast blue injected into the posterior caudate-putamen and fluoro-gold administered into the anterior perirhinal cortex. Our results indicate that CGRP-LI cells in the posterior thalamus, such as posterior intralaminar, lateral subparafascicular and subparafascicular nuclei, project either separately or simultaneously to innervate the posterior caudate-putamen and perirhinal cortex.

The role of calcitonin gene-related peptide in the control of growth hormone and prolactin release.

In order to evaluate the actions of calcitonin gene-related peptide (CGRP), a neuropeptide which is found within the hypothalamus, male and ovariectomized (OVX) female rats were injected intraventricularly (third ventricle, 3V) with varying doses of CGRP or antiserum directed against the peptide and the effect on plasma growth hormone (GH) and prolactin (Prl) concentrations studied. Intraventricular injection of the peptide (0.5 or 5.0 micrograms; 0.125 or 1.25 nmol) induced a suppression of GH release in conscious, OVX female and intact male rats. Conversely, intraventricular injection of diluted (1:10) highly specific antiserum against the peptide produced the reverse effect and a transient elevation in plasma GH occurring 2 h after the injection in males. A longer-lasting elevation occurred in OVX females which persisted for the 24-hour duration of the experiment. The elevation was delayed as has been the case with other antisera suggesting that the site of action was at some distance from the site of injection into the 3V. Since the peptide had an action to inhibit GH release from dispersed, overnight cultured anterior pituitary cells in vitro at doses of 10(-11) M, it is not certain from these results whether or not the effects of the peptide are exerted directly on the hypothalamus or the pituitary, but the results indicate a physiologically significant action of this peptide to suppress GH release. Similarly, intraventricular injection of the peptide produced a dose-related suppression of Prl release in OVX animals; however, antiserum directed against the peptide failed to alter Prl release. In males, only the lower 0.5-microgram dose effectively inhibited Prl release.(ABSTRACT TRUNCATED AT 250 WORDS)