Intranasal Civamide for the Acute Treatment of Migraine Headache

Abstract

The objective of this study was to investigate the safety and efficacy of intranasal civamide for the acute treatment of migraine headache with or without aura. Civamide is a vanilloid receptor agonist and neuronal calcium channel blocker that inhibits the neuronal release of excitatory neurotransmitters (e.g. calcitonin gene-related peptide (CGRP) and substance P (SP)) and depletes the neurones of the trigeminal plexus of their neurotransmitter content. Applied intranasally, the release of neurotransmitters to meningeal and dural blood vessels should be decreased, along with the resultant vasodilatation, plasma extravasation, and histamine/serotonin release. Subsequent migraine headache pain may also be diminished. Thirty-four patients were enrolled into a double-blind study of intranasal civamide, and randomized to receive a single dose of either 20 μg or 150 μg of civamide, for the treatment of a single migraine headache, with or without aura, of moderate to severe pain. At 2 h post-dose, 55.6% of patients treated with either dose had a decrease in pain severity, with 22.2% of patients being pain-free. At 4 h post-dose, 72.7% of patients treated with either dose had a decrease in pain severity, with 33.0% of patients being pain-free. Adverse events were similar for both dosages, with 91.2% of patients experiencing nasal burning and 44.1% of patients experiencing lacrimation. No systemic side-effects were observed. Based upon the results of this study, intranasal civamide may be effective in the acute treatment of migraine headache. Given civamide's proposed mechanism of action, intranasal civamide should be substantially more effective for prophylaxis than acute treatment of migraine. A study evaluating its efficacy in prophylaxis of migraine is currently planned.

Introduction

Civamide, cis-8-methyl-N-vanillyl-6-nonenamide, is a vanilloid receptor agonist and neuronal calcium channel blocker (1) that inhibits the neuronal release of excitatory neurotransmitters (2) including calcitonin gene-related peptide (CGRP) and substance P (SP), and depletes neurones of their neurotransmitter content (3). When civamide is applied intranasally to the mucosa, the release of neurotransmitters by the trigeminal plexus centrally to meningeal and dural blood vessels should be decreased. This results in a decrease in vasodilatation, plasma extravasation, and histamine/serotonin release with a potential for the amelioration of migraine headache pain. The trigeminal ganglia and the cerebral blood vessels together comprise the trigeminovascular system.

The trigeminal nerve, comprising three branches (maxillary, mandibular and ophthalmic), innervates the skin, muscles and joints of the face. Innervation of the nasal cavity is provided primarily by the maxillary and ophthalmic branches of the trigeminal nerve. Many of these fibres transverse the pterygopalatine ganglia which are located in the posterior wall of the nasal cavity. In addition to the nasal mucosa, the maxillary branch innervates the dura mater of the anterior and middle fossa of the cranial cavity as well as the pial blood vessels. The dura mater has been shown to be a pain-sensitive tissue which is capable of producing headaches in humans (4). The nociceptive and thermoceptive sensory function of the trigeminal nerve descends in the spinal tract and terminates in the spinal trigeminal nucleus of the brainstem.

Experimental studies suggest that type-C sensory fibres, which constitute over two-thirds of the fibres in the peripheral nerves (5), play a role in the vascular and secretory responses of the nasal mucosa (6). Sensory type fibres have been shown to contain tachykinins such as SP, CGRP, and vasoactive intestinal peptide (VIP) (6). These nerve fibres are distributed in a dense network under and within the epithelium of the nasal mucosa as well as around blood vessels. The release of SP, from the peripheral nerves into the surrounding tissues, triggers a cascade of chemical events associated with neurogenic inflammation and pain (7). Studies in the human nasal mucosa have shown that SP, CGRP and other neuropeptides induce glandular secretion and participate in axon reflex-mediated vasodilatation and plasma extravasation (8).

CGRP- and SP-containing trigeminal afferents innervate the pial and dural cephalic vessels. The release of CGRP and SP results in dilation of pial arteries, increases in vascular permeability and activation of an inflammatory response (4). When CGRP and SP are released by the trigeminal nerve into the walls of the cerebral blood vessels, headache pain results. Increases in CGRP concentrations in external jugular blood have been observed during migraine headache (9) and interictally in the peripheral circulation (10). The i.v. administration of CGRP has also been shown to induce migraine headache pain in patients suffering from migraine without aura (11). Cluster headache has also been ascribed to CGRP and SP release from both central (causing pain) and peripheral (causing rhinorrhoea, lacrimation and conjunctival injection) endings of trigeminal neurones (12). On this basis, intranasal capsaicin, a known neuropeptide depletor, has been utilized to treat cluster headache and has demonstrated efficacy (12–14).

The pharmacologic therapies used to treat migraine headaches are less than ideal both in efficacy and side-effect profiles. Even the most recent generation of such products, the selective serotonin agonists, have serious limitations to their usefulness. Civamide, a synthetic stereoisomer of capsaicin, has been demonstrated to be both significantly more potent at depleting SP and CGRP than capsaicin. This study is designed to evaluate the effectiveness of intranasally administered civamide in migraine headache disorders.

Patients and methods

Patients

Patients included in the study were men and women aged ≥18 years with at least a 1-year history of migraine with or without aura diagnosed according to the International Headache Society criteria (15). Patients had to have experienced at least two migraine attacks of at least moderate severity per month during the year prior to screening.

Patients were excluded from the study for any of the following reasons: pregnant or lactating mother; history of alcohol and/or drug abuse within the past year; history of clinical or laboratory evidence of significant cardiovascular, renal, gastrointestinal, pulmonary, hepatic, endocrine, neurological (not including migraine headaches), or other systemic disease; history of any disease that might confound the results of the study or pose an additional risk to the patient; participation in another investigational study or taken another investigational drug within the past 30 days; more than eight migraine attacks per month (or has basilar or hemiplegic migraine headaches); vomits more than 20% of the time or is confined to bed rest more than 50% of the time with the migraine attacks; has difficulty distinguishing his/her migraine attacks from other headaches, such as tension headaches; hypersensitivity to or previous serious adverse reaction to civamide intranasal solution or any of its excipients; pre-existing nasal disorder.

All patients provided written informed consent to participate in the study, which was approved by Western Institutional Review Board for each site.

Procedures

This was a double-blind, randomized, two-centre trial to assess the efficacy and safety of two intranasal doses of civamide (20 μg and 150 μg) as an acute treatment for patients with migraine attacks. In this pilot study a vehicle control was not used.

Screening procedures included a physical examination and review of medical and migraine histories. If eligible to participate, patients were assigned to receive one of the two treatments according to a pre-existing randomization schedule. Patients then were instructed in the administration of the study drug and completion of the patient diary. Patients were asked to treat the first migraine headache of moderate to severe pain occurring after the initial visit. Using a calibrated dropper, the patient instilled 100 μl of the study drug solution into each nostril with their head tilted back. Patients recorded self assessments of their pain and associated symptoms in the patient diary at specified time points starting from just prior to administration of study medication, time 0, to 24 h after dosing. If the patient still required relief from symptoms after 2 h, they were permitted to take rescue medication of their choice.

Patients were required to return to the study site within 3–7 days after treating the headache. At this final visit, the study medication was returned, the patient diary was reviewed and collected, and any adverse events were recorded.

Efficacy variables

To assess migraine headache symptoms, patients recorded in the diary headache severity (0 = no pain; 1 = mild pain; 2 = moderate pain; 3 = severe pain) and the presence or absence of associated nausea and/or vomiting, photophobia before dosing, time 0, and at 10, 20, 30 min, and 1, 2, 4, and 24 h post-dosing. Patients recorded their use of rescue medication, and time of headache recurrence (return of headache pain severity rating to moderate or severe after becoming none or mild at 2 h or 4 h, within 24 h post-dosing). Patients also indicated their global satisfaction with the medication at 24 h post-dosing (1 = completely satisfied, could not be better; 2 = very satisfied; 3 = somewhat satisfied; 4 = neither satisfied nor dissatisfied; 5 = somewhat dissatisfied; 6 = very dissatisfied; 7 = completely dissatisfied; could not be worse).

Safety variables

Patients recorded in the diary any adverse events experienced, during the time from randomization until the final visit, including those occurring after administration of the study medication. Adverse events were recorded regardless of their suspected relationship with the administration of study medication and were reviewed at the time of the final visit.

Statistical analysis

The primary measure of efficacy was the percentage of patients who experienced improvement in headache severity (improvement in at least one severity grade from baseline) at 2 h and 4 h post-dosing. Primary efficacy data were evaluated for each dose, as well as pooled, while secondary efficacy data were pooled. Secondary efficacy measures included percentage of patients experiencing nausea and/or vomiting and photophobia and/or phonophobia at 2 h and 4 h post-dosing compared with baseline, percentage of patients requiring rescue medication within 24 h of treatment, percentage of patients experiencing a headache recurrence within 24 h of treatment, and global satisfaction with the study medication. The primary measure of safety was the percentage of patients experiencing specific adverse events. Safety and demographic data were pooled from both treatment groups in this small pilot study.

For the primary efficacy variable at 2 h, the analysis was carried out on all eligible patients that treated a migraine headache of moderate to severe intensity at baseline, did not use rescue medication prior to 2 h, and provided a headache pain assessment through 2 h (27 patients). The analysis of the primary efficacy variable at 4 h was done similarly (22 patients). All patients using the study medication for any duration were included in the safety analysis (34 patients).

Results

Patients

There were 37 patients enrolled in the study and who received study medication according to the randomization schedule. Three patients were excluded from all analyses (two patients did not experience a headache with 8 weeks of randomization, one patient was lost to follow up). Six patients were excluded from the efficacy analysis as they treated a migraine headache of less than moderate severity at base line.

The patients' mean age was 36.5 years, and 70.6% were female (mean age 37.6 years) and 29.4% were male (mean age 33.9 years); 83.3% of patients had a history of migraine without aura and 16.7% had a history of migraine with aura. These demographic parameters were not significantly different between the dose groups.

Efficacy data

Primary analysis, headache severity

At 2 h post-dosing, improvement in headache severity was experienced by 55.6% of all patients. In the 20-μg dose group (n = 12), 58.3% improved, and in the 150-μg dose group (n = 15), 53.3% improved. At 4 h post-dosing, 72.7% of all patients improved, 70% of the 20-μg dose group (n = 10) and 75% of the 150-μg group (n = 12). At 2 h post-dosing, 22.2% of all patients (20-μg dose group = 16.7%, 150-μg dose group = 26.6%) were pain-free and 33.0% of all patients (20-μg dose group = 36.4%, 150-μg dose group = 30.8%) were pain-free at 4 h post-dosing (see Fig. 1).

Figure 1

Proportion of patients in both dose groups reporting improvement in headache pain severity at 2 h and 4 h after treatment. ▪, Improved from baseline; □, pain-free (grade 0).

Secondary analyses, associated symptoms

In patients receiving either dose, there was a progressive decrease from baseline in associated symptoms of nausea and/or vomiting, 21.4% at baseline to 14.3% and 3.6% at 2 h and 4 h post-dosing, respectively. Photophobia and/or phonophobia were reduced from 71.4% at baseline to 32.1% and 25.0% at 2 h and 4 h post-dosing, respectively (see Fig. 2).

Figure 2

Proportion of patients in both dose groups reporting nausea/vomiting and photophobia/phonophobia before treatment and at 2 h and 4 h after treatment.

Use of rescue medication within 24 h of dosing

Rescue medication was used within 24 h of dosing in 39.3% of patients receiving either dose. Of patients that experienced an improvement in headache severity only 11.8% used rescue medication, compared with 90.0% of patients that did not experience improvement.

Headache recurrence

No patients experienced recurrence of their headache within 24 h.

Global satisfaction with medication

Patients that experienced improvement in headache severity reported a global satisfaction of 4, corresponding to ‘neither satisfied nor dissatisfied’ on the scale used. Patients that were pain-free at 2 h and/or 4 h reported a global satisfaction with medication of 3, corresponding to ‘somewhat satisfied’. Patients that did not experience improvement in headache severity reported a global satisfaction of 6.67, corresponding to ‘very dissatisfied’.

Safety data

Adverse events

There were no serious or unusual adverse events. Specific adverse events experienced by four or more patients are shown in Table 1. These adverse events, with an average severity of between moderate and severe, included nasal burning 91.2%, lacrimation 44.1%, rhinorrhoea 23.5%, and throat irritation 11.8%, and were attributed to the study medication in all cases. Other adverse events reported by one to three patients, and with an average severity of mild to moderate, included tingling/numbness in nose, epistaxis (n = 2), ear pain, dizziness, nausea (n = 3), vomiting, coughing, sneezing (n = 3), skin irritation, facial redness, bad taste and drowsiness.

Table 1

Adverse events experienced by >4 patients

Adverse events	Total % (n=34)	Average severity	Average duration (min)
Nasal burning	91.2 (31)	2.6	34 (4–110)
Lucrimation	44.1 (15)	2.5	20 (1–45)
Rhinorrhoea	23.5 (8)	1.9	88 (10–390)
Throat burning irritation	11.8 (4)	2.3	47 (30–60)

Discussion

In pooled data from both dosage groups in this pilot study, improvement in migraine headache pain severity was experienced by 55.6% at 2 h post-dose and 72.7% at 4 h post-dose. Furthermore, patients experienced pain-free rates of 22.2% and 33.0% at 2 h and 4 h post-dose, respectively. Secondary efficacy variables of improvement in associated symptoms, a low requirement for rescue medication and a low incidence of headache recurrence also were observed in a majority of patients. The results suggest that intranasal civamide may be effective for the treatment of acute migraine pain and that larger, vehicle-controlled studies are warranted to confirm these results.

The proposed mechanism of action of civamide applied to the nasal mucosa at the site of the peripheral ganglia is that of producing a relative depletion of available neuropeptides, e.g. SP and CGRP, for central release by the neurones of the trigeminovascular system, consequently preventing the resultant vasodilatation of dural vessels and pain associated with migraine headache. This is probably accomplished by a variety of actions of civamide on the neurone. Civamide is thought to cause an initial release of neuropeptides from the trigeminal plexus, producing the nasal burning, lacrimation, and rhinorrhoea experienced by a majority of the patients in this study. Additionally, similar to capsaicin (16, 17) civamide may also interfere with the normal intraneural neuropeptide synthetic and transport systems. It is likely that over a period of time, with repeated applications of civamide, the quantity of neuropeptides available for release by the neurone is substantially reduced. This explains the tachyphylaxis observed with repeated cutaneous application of civamide on the symptom of local burning (18) as well as that seen in the nasal mucosa with repeated application of civamide over a 7-day period (19), and similarly with capsaicin (12).

Adverse events were non-systemic and self-limited in nature. The high incidence of nasal burning, lacrimation, and rhinorrhoea indicates that an improved delivery system, coupled with a reduction in drug concentration, and/or an alternate dosing schedule, should be considered. Such changes are currently being implemented to provide for a better tolerated treatment regimen for future clinical use and may result in an improved patient global satisfaction with the medication as well as a decreased potential for placebo effects and unblinding of patient and investigator.

Currently available medications for migraine treatment have their own limitations, beyond not being effective for all patients. The current triptans and ergotamine preparations have cardiovascular effects and must be used with caution in patients with histories of coronary artery disease and hypertension. Divalproex sodium is contraindicated in hepatic disease and is a teratogen. Additionally, all of these medications have drug interactions. If civamide is found to be efficacious for migraine treatment, and its local tolerability improved, it will be a valuable addition to these medications.

We believe that this initial study suggests the potential value of intranasal civamide in the treatment of migraine headaches and supports further investigation, despite its being done with small numbers, without a placebo control, and with improvement defined as any (≥ 1) decrease in severity grade from baseline. In fact, based upon the proposed mechanism of action of civamide, a potent neuronal depletor of neuropeptides, from the trigeminovascular system, such as SP and CGRP, as well as the observations of tachyphylaxis to its local irritant effects described above, it is reasonable to propose that intranasal civamide might be more useful as a prophylactic medication than for the treatment of acute attacks. Such prophylaxis studies are currently being designed.