Randomized controlled study of telcagepant plus Ibuprofen or acetaminophen in migraine

(Headache 2011;51:533‐543) Objective.— To evaluate the efficacy and tolerability of telcagepant when co‐administered with ibuprofen or acetaminophen for the acute treatment of migraine. Background.— Telcagepant is an oral calcitonin gene‐related peptide receptor antagonist which is being evaluated for the acute treatment of migraine. Combining telcagepant with analgesics that have a different mechanism of action could produce greater efficacy. Methods.— Randomized, double‐blind, placebo‐controlled study. Patients were randomized to treat a moderate or severe migraine headache with either telcagepant 280 mg + ibuprofen 400 mg (N = 171), telcagepant 280 mg + acetaminophen 1000 mg (N = 171), telcagepant 280 mg (N = 170), or placebo (N = 171). The primary efficacy endpoint was 2‐hour pain freedom. The study had approximately 88% power to detect an additive effect of at least 15 percentage points (telcagepant combination vs telcagepant monotherapy) and 48% power to detect an additive effect of at least 10 percentage points. Safety and tolerability were assessed by adverse events and laboratory tests. Results.— The percentages of patients with 2‐hour pain freedom were greater in each active treatment group compared to placebo (P < .001): telcagepant + ibuprofen = 35.2%, telcagepant + acetaminophen = 38.3%, telcagepant = 31.2%, placebo = 10.9%. No significant differences were seen for either of the combination groups vs telcagepant monotherapy, but both were numerically larger than telcagepant monotherapy. All the active treatments were generally well tolerated. The percentage of patients reporting any adverse event within 48 hours was higher in the active treatment groups than placebo: telcagepant + ibuprofen = 30.3%, telcagepant + acetaminophen = 31.6%, telcagepant = 24.8%, placebo = 18.2%. The most common adverse events reported by ≥4 patients in one or more of the treatment groups that included telcagepant were fatigue, nausea, dizziness, somnolence, dry mouth, and tremor. Conclusions.— The combination of telcagepant 280 mg with either ibuprofen 400 mg or acetaminophen 1000 mg did not show a statistically significant difference from telcagepant alone. Numerically greater treatment effects in the combination treatment groups over the telcagepant 280 mg monotherapy suggest that telcagepant combination treatments may merit further evaluation in studies powered to detect smaller additive benefits. (Clinicaltrials.gov; NCT00758836).     

Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial

(Headache 2011;51:73‐84) Objective.— To evaluate the long‐term tolerability of telcagepant for acute treatment of intermittent migraine attacks. Background.— Telcagepant is a calcitonin gene‐related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine. Methods.— Migraine patients were randomized 2:1 to double‐blind treatment with telcagepant 280/300 mg or rizatriptan 10 mg for an acute mild, moderate, or severe migraine. Patients could administer a second dose within 2‐24 hours for nonresponse or migraine recurrence. Patients could treat up to 8 attacks per month for up to 18 months. Safety assessments included spontaneous reports of adverse events and collection of vital signs, electrocardiograms, and laboratory assessments. The primary endpoint was the percentage of patients with ≥1 triptan‐related adverse events in the 14‐day period post dose. Results.— Of 1068 patients randomized, 641 (90%) patients treated ≥1 attack with telcagepant and 313 (88%) treated ≥1 attack with rizatriptan. A total of 19,820 attacks were treated with telcagepant (mean per patient = 31) and 10,981 with rizatriptan (mean per patient = 35). Fewer triptan‐related adverse events (difference: ?6.2%; 95% CI ?10.4, ?2.6; P < .001) and drug‐related adverse events (difference: ?15.6%; 95% CI ?22.2, ?9.0) were reported for telcagepant vs rizatriptan. The most common adverse events appeared to have generally similar incidence proportions between the treatment groups. Those with an incidence >5% in the telcagepant group were dry mouth (9.7%, rizatriptan = 13.7%), somnolence (9.2%, rizatriptan = 16.6%), dizziness (8.9%, rizatriptan = 10.2%), and nausea (9.0%, rizatriptan = 6.4%). Conclusions.— Telcagepant was generally well tolerated when administered for the acute intermittent treatment of migraine for up to 18 months. The incidences of triptan‐related and drug‐related adverse events favored telcagepant over rizatriptan.     

Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine

Calcitonin gene-related peptide (CGRP) is linked to migraine and other primary headache disorders. It is found in every location described in migraine genesis and processing, including meninges, trigeminal ganglion, trigeminocervical complex, brainstem nuclei, and cortex. It is released in animal models following stimulation of the CNS similar to that seen in migraine, and triptans inhibit this release. Injection of CGRP into migraineurs results in delayed headache similar to migraine. Elevation of CGRP occurs during migraine, resolving following migraine-specific treatment. Finally, and most importantly, CGRP receptor antagonists terminate migraine with efficacy similar to triptans. Both intravenous olcegepant (BIBN 4096 BS) and oral telcagepant (MK-0974) have been effective, safe, and well tolerated in phase I and II studies. Telcagepant is currently in phase III trials, and preliminary results are favorable. The potential for a migraine-specific medication without vasoconstrictive or vascular side effects is enormous. CGRP receptor blockade may also have applications in other pathologic and pain syndromes.     

Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease

Objective.— To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease. Background.— Calcitonin gene‐related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated. Methods.— Randomized, double‐blind, two‐period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: telcagepant (280‐mg tablet/300‐mg capsule), Period 2: acetaminophen (1000‐mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of telcagepant. The primary efficacy analysis evaluated telcagepant vs placebo on 2‐hour pain freedom during the first attack of Period 1. Results.— One hundred and sixty‐five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2‐hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing. Conclusion.— The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.     

Calcitonin gene-related peptide does not cause migraine attacks in patients with familial hemiplegic migraine

(Headache 2011;51:544‐553) Background.— Calcitonin gene‐related peptide (CGRP) is a key molecule in migraine pathogenesis. Intravenous CGRP triggers migraine‐like attacks in patients with migraine with aura and without aura. In contrast, patients with familial hemiplegic migraine (FHM) with known mutations did not report more migraine‐like attacks compared to controls. Whether CGRP triggers migraine‐like attacks in FHM patients without known mutations is unknown. Objective.— In the present study we therefore examined the migraine‐inducing effect of CGRP in FHM patients without known mutations and healthy controls. Methods and design.— Eleven patients suffering from FHM without known mutations and 11 controls received an intravenous infusion of 1.5 µg/minute CGRP over 20 minutes. The study design was a balanced and controlled provocation study. Headache and other migraine symptoms were scored for 1 hour and self‐recorded hourly thereafter until 13‐hour postinfusion. Results.— We found no difference in the incidence of migraine‐like attacks between the 2 groups, with 9% (1 of 11) of patients and 0% (0 of 10) of controls reporting migraine‐like headache (P = 1.00). CGRP infusion did not induce aura symptoms in any of the participants. There was no difference in the incidence of CGRP‐induced delayed headaches between the groups (P = .18). Conclusion.— In contrast to patients suffering from migraine with aura and without aura, CGRP infusion did not induce more migraine‐like attacks in FHM patients without known mutations compared to controls. It seems that the majority of FHM patients with and without known mutation display no sensitivity to CGRP signaling compared to common types of migraine.     

Calcitonin gene-related peptide and size of the atrial septal defect in new-onset migraine after transcatheter closure: results of a preliminary study

Background.— New‐onset migraine headache attacks (MHAs) can occur after atrial septal device implantation in patients without previous migraine. Plasma calcitonin gene‐related peptide (CGRP), which plays a crucial role in migraine pathophysiology, has shown to be released from specific cardiac tissues. Methods and Results.— We prospectively collected patients before and after closure and measured plasma CGRP levels using enzyme‐linked immunosorbent assay. Forty atrial septal defect (ASD) patients who had no migraine previously were enrolled. Four (23.5%) of the 17 consecutive patients whose CGRP levels were checked before ASD closure had new‐onset MHAs. The patients with MHAs had bigger ASD size (20 ± 0.9 vs 16 ± 1 mm, P = .009) and lower CGRP levels before closure (21.1 ± 3.9 vs 90.1 ± 27.1 pg/mL, P = .042) than those without. Among the 5 patients with blood samplings both during and between attacks, a paired comparison revealed a significantly increased level during attack (257.2 ± 45.5 vs 45.6 ± 25.5 pg/mL, P = .03). Conclusion.— Bigger ASD size and lower plasma CGRP levels before closure can be a potential predictor of new‐onset MHAs. Furthermore, a significant increase of CGRP levels during migraine attack implies that the occurrences of new‐onset MHAs after ASD closure correlate with the release of CGRP. This suggests CGRP sensitization from a lower baseline may be involved in the occurrence of new‐onset MHAs after ASD closure.     

Inhibition of calcitonin gene-related peptide function: a promising strategy for treating migraine

The neuropeptide calcitonin gene-related peptide (CGRP) is implicated in the underlying pathology of migraine. Serum levels of CGRP, which are elevated during a migraine attack, have been reported to return to normal with alleviation of pain. In addition, CGRP administration has been shown to cause a migraine-like headache in susceptible individuals. Importantly, CGRP receptors are found on many cell types within the trigeminovascular system that are thought to play important roles in controlling inflammatory and nociceptive processes. Based on these findings, it was proposed that blockage of CGRP receptor function and, hence, the physiological effects of CGRP would be effective in aborting a migraine attack. This review will summarize key preclinical data that support the therapeutic potential of using CGRP receptor antagonists or molecules that bind CGRP within the context of current neurovascular theories on migraine pathology.     

Calcitonin Gene‐Related Peptide (CGRP) and Migraine Current Understanding and State of Development

Calcitonin gene‐related peptide (CGRP) is a ubiquitous neuropeptide found at the very centers of the migraine process, both centrally and peripherally. It has been under careful study for approximately 25 years. Several CGRP‐receptor antagonists are being evaluated for acute treatment of episodic migraine. Three monoclonal antibodies are being studied for prevention of episodic migraine, and 1 monoclonal antibody is being studied for prevention of chronic migraine. In this review, we discuss the role of CGRP in normal physiology and the consequences of CGRP inhibition for human homeostasis. We then review the current state of development for CGRP‐receptor antagonists and CGRP monoclonal antibodies. We close by speculating on the potential clinical role of CGRP antagonism in the acute and preventive treatment of episodic and chronic migraine.     

Once-daily oral atogepant for the long-term preventive treatment of migraine: Findings from a multicenter,randomized, open-label,phase 3 trial

Objective

To assess long-term safety, tolerability, and efficacy of once-daily oral atogepant 60 mg in adults with migraine.

Background

Atogepant is an oral, small-molecule, calcitonin gene–related peptide receptor antagonist approved for the preventive treatment of episodic migraine.

Methods

A 52-week, multicenter, randomized, open-label trial of adults (18–80 years) with migraine. Lead-in trial completers or newly enrolled participants with 4–14 migraine days/month were enrolled and randomized (5:2) to atogepant 60 mg once daily or oral standard care (SC) migraine preventive medication. The primary objective was to evaluate the safety and tolerability of atogepant; safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, vital signs, and Columbia-Suicide Severity Rating Scale scores. Efficacy assessments (atogepant only) included change from baseline in mean monthly migraine days (MMDs) and the proportion of participants with reductions from baseline of ≥50%, ≥75%, and 100% in MMDs.

Results

The trial included 744 participants randomized to atogepant 60 mg (n = 546) or SC (n = 198). The atogepant safety population was 88.2% female (n = 479/543) with a mean (standard deviation) age of 42.5 (12.0) years. TEAEs occurred in 67.0% (n = 364/543) of participants treated with atogepant 60 mg. The most commonly reported TEAEs (≥5%) were upper respiratory tract infection (10.3%; 56/543), constipation (7.2%; 39/543), nausea (6.3%; 34/543), and urinary tract infection (5.2%; 28/543). Serious TEAEs were reported in 4.4% (24/543) for atogepant. Mean (standard error) change in MMDs for atogepant was −3.8 (0.1) for weeks 1–4 and −5.2 (0.2) at weeks 49–52. Similarly, the proportion of participants with ≥50%, ≥75%, and 100% reductions in MMDs increased from 60.4% (310/513), 37.2% (191/513), and 20.7% (106/513) at weeks 1–4 to 84.2% (282/335), 69.9% (234/335), and 48.4% (162/335), at weeks 49–52.

Conclusion

Daily use of oral atogepant 60 mg for preventive treatment of migraine during this 1-year, open-label trial was safe, well tolerated, and efficacious.     

Sex differences in behavior and expression of CGRP-related genes in a rodent model of chronic migraine

(Headache 2011;51:674‐692) Objective.— The objectives of this study were to develop a preclinical rodent model that produces migraine‐like behaviors based on International Headache Society diagnostic criteria, to determine whether sex differences are present, and to determine whether expression of calcitonin gene‐related peptide (CGRP) and the genes encoding its receptor in trigeminal ganglion or medulla correlates with those behaviors. Background.— Few animal studies of migraine have tested behaviors associated with migraine diagnostic criteria. In this study, changes in activity and in mechanical sensitivity of facial regions following application of inflammatory soup (IS) or vehicle (phosphate‐buffered saline [PBS]) to the dura were measured to model changes in routine activity and allodynia. CGRP, an important mediator of migraine pathogenesis, and the 3 components of its receptor, calcitonin‐like receptor (CLR), receptor activity‐modifying protein 1 (RAMP1), and receptor component protein (RCP) mRNAs were quantified in the trigeminal ganglion and medulla to identify baseline sex differences and changes associated with application of IS or PBS to the dura. Methods.— Male and female Sprague‐Dawley rats were implanted with a dural cannula. Groups of rats were treated with 10 or 20 µL volumes of IS or PBS. Baseline behavioral testing was conducted prior to surgery and again at 7 days postsurgery, and dural application of IS or PBS was performed repeatedly for a total of 8 applications. Locomotor activity was assessed using force plate actimetry during and following application to provide information on distance traveled, bouts of low mobility, spatial confinement, and focused energy. Periorbital and perimasseter sensory testing was performed 20 minutes post‐application to measure allodynia. The rats were sacrificed 30 minutes following the final dural treatment, tissue was dissected and total RNAs were isolated from ipsilateral trigeminal ganglia and ipsilateral medulla. Quantitative real‐time polymerase chain reactions were used to measure the expression of amplified constructs using gene‐specific primers for CGRP, RAMP1, CLR, and RCP. Results.— Both males and females showed behavioral effects of IS application, but there were pronounced sex differences. Females showed effects at the lower dose, and activity changes were present for a longer duration, but males required fewer applications of IS to exhibit behavioral changes. Females showed increased withdrawal responses for periorbital and perimasseter mechanical testing (10 µL IS groups), and males showed increased perimasseter withdrawal responses (20 µL IS group). In the trigeminal ganglion, there were no baseline sex differences in CGRP‐encoding mRNA, but females had lower baseline expression of RAMP1, CLR, and RCP‐encoding mRNAs. In the medulla, females had higher baseline levels of CGRP‐encoding mRNAs and lower baseline levels of RAMP1, CLR, and RCP‐encoding mRNAs than males. Both IS and PBS increased expression of mRNAs encoding CGRP, RAMP1, RCP, and CLR in the trigeminal ganglion in males, but in females, only CLR and RCP were increased. In the medulla both IS and PBS increased expression of CGRP, CLR in males and CLR and RCP in females. Thus, expression of CGRP‐related genes did not mirror the behavioral differences between IS and PBS groups. Instead, CGRP‐related genes were upregulated by both IS and PBS applications. Conclusions.— This study demonstrates significant changes in locomotor activity and facial allodynia associated with application of IS to the dura as well as significant sex differences, demonstrating that International Headache Society diagnostic criteria can be used to design a rodent behavioral model of migraine. In addition, there were prominent baseline sex differences in expression of CGRP and its receptor in both the trigeminal ganglion and medulla, but the majority of changes in expression of CGRP and its receptor were present in both the IS and PBS treated rats. This suggests that the CGRP pathway responds to changes in intracranial pressure or meningeal stretch, while migraine‐like behaviors occur after meningeal inflammation.     

Efficacy,Safety, and Tolerability of Telcagepant in the Treatment of Acute Migraine: A meta‐Analysis

Although triptans are widely used for treating acute migraine, they are contraindicated or not effective in a large proportion of patients. Hence, alternative treatments are needed. Calcitonin gene–related peptide receptor antagonists, such as telcagepant, have been under investigation as a treatment for acute migraine. A meta‐analysis of the efficacy of telcagepant vs. placebo and triptans (zolmitriptan or rizatriptan) was performed. Randomized controlled trials were indentified from databases using the following search terms: migraine; calcitonin gene‐related peptide; calcitonin gene‐related peptide receptor antagonists; efficacy; safety, and telcagepant. The primary outcome measure was pain freedom 2 hours after first treatment. The secondary outcome measure was pain relief 2 hours after first treatment. Eight trials were included in the meta‐analysis (telcagepant = 4011 participants). The difference in pain freedom at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.70, 95% confidence interval = 2.27–3.21, P < 0.001) and triptans over telcagepant (odds ratio = 0.68, 95% confidence interval = 0.56–0.83, P < 0.001). The difference in pain relief at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.48, 95% confidence interval = 2.18–2.81, P < 0.001). The difference in pain relief at 2 hours did not significantly favor telcagepant over triptans or vice versa (odds ratio = 0.76, 95% confidence interval = 0.57–1.01, P = 0.061). These findings indicate that telcagepant can be effective for treating acute migraine. Calcitonin gene‐related peptide receptor antagonists represent a potentially important alternative means of treating acute migraine.     

针刺对偏头痛大鼠脑内降钙素基因相关肽基因表达的影响

目的探讨偏头痛大鼠脑内降钙素基因相关肽(CGRP)的表达强度及针刺对CGRP基因表达的调控机制及针刺防治偏头痛的作用机制。方法参照Knyihar-Csillik方法复制大鼠偏头痛模型,将动物随机分成正常对照组、模型对照组、针刺预防组和针刺治疗组,每组10只,采用放射免疫分析法测定CGRP浓度;采用RT-PCR法测定CGRPmRNA表达。结果颈静脉血CGRP含量:正常大鼠保持低水平恒定量,模型对照组大鼠CGRP含量显著升高(P<0.01),针刺预防组及针刺治疗组与正常大鼠相近,但与模型对照组比较,显著降低(P<0.01);脑干及三叉神经节CGRPmRNA的表达变化:正常对照组表达在较低水平,模型对照组表达显著增强(P<0.01),针刺治疗组及针刺预防组与模型对照组比较,表达显著减弱(P<0.01)。结论实验性偏头痛大鼠脑内CGRP的过度表达,可能是偏头痛发作的分子机制之一;针刺调控CGRPmRNA表达可能是针刺防治偏头痛的机制之一。     

Sumatriptan for the treatment of migraine attacks-a review of controlled clinical trials

Sumatriptan, a 5HT₁-like receptor agonist, is a completely new treatment principle for migraine. In an extensive international programme of controlled clinical trials, sumatriptan, 6 mg subcutaneously and 100 mg orally, was superior to placebo in reducing headache and associated symptoms. The response rate for subcutaneous sumatriptan (70–84% after 1 h and 81–87% after 2 h) was higher than for oral sumatriptan (50–67% after 2 h). Additional doses did not increase efficacy. Oral sumatriptan was superior to Cafergot (2 mg ergotamine plus 200 mg caffeine) and somewhat better than aspirin (900 mg) plus metoclopramide (10 mg). Recurrence of migraine occurred in approximately 40% of attacks. Side effects were generally mild and short-lived in the controlled clinical trials. However, in clinical practice sumatriptan has subsequently caused rare cases of heart ischemia and sumatriptan is contraindicated in patients with a history of ischemic heart disease.