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Intranasal Civamide for the Treatment of Episodic Cluster Headaches
Joel R. Saper, MD;
Jack Klapper, MD;
Ninan T. Mathew, MD;
Alan Rapoport, MD;
Scott B. Phillips, MD;
Joel E. Bernstein, MD;
for the Intranasal Civamide Study Group
Arch Neurol. 2002;59:990-994.
ABSTRACT
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Objective To evaluate the safety and efficacy of intranasal civamide solution
for preventive treatment during an episodic cluster headache period.
Subjects and Methods This was a multicenter, double-blind, randomized, vehicle-controlled
study with a 7-day treatment period and a 20-day posttreatment period performed
at 14 headache/neurology centers in the United States. Twenty-eight subjects
were randomized to receive civamide or its vehicle in a 2:1 ratio; 18 received
civamide and 10 received the vehicle. Subjects received 100 µL of 0.025%
civamide (25 µg) or 100 µL of the vehicle to each nostril via
dropper once daily for 7 days. The total daily dose of civamide was 50 µg.
Main Outcome Measures The number of cluster headaches per week during the treatment and posttreatment
periods, pain intensity, presence of associated symptoms, and the incidence
of adverse events were assessed.
Results Subjects in the civamide group had a significantly greater percent decrease
in the number of headaches from baseline to posttreatment during days 1 through
7 (-55.5% vs -25.9%; P = .03) and a trend
toward significance during days 8 through 14 (-66.9% vs -32.3%; P = .07) and days 15 through 20 (-70.6% vs -34.9%; P = .07), as well as a near-significant decrease during
the entire posttreatment period (days 1 through 20 [P
= .054]) compared with the vehicle group. There were larger decreases in the
number of headaches per week during the posttreatment period in the civamide-treated
group, with trends toward significance during posttreatment days 8 through
14 (-8.6 vs -3.6; P = .09) and days 15
through 20 (-8.9 vs -3.6; P = .07). There
were no significant differences between groups in cluster headache pain intensity,
number of severe headaches, or associated symptoms. The most common adverse
events included nasal burning (14 of 18 civamide-treated subjects, 1 of 10
vehicle-treated subjects; P = .001) and lacrimation
(9 of 18 civamide-treated subjects, 0 of 10 vehicle-treated subjects; P = .01).
Conclusion Intranasal civamide solution at a dose of 50 µg may be modestly
effective in the preventive treatment of episodic cluster headache.
INTRODUCTION
CLUSTER HEADACHES are severe, unilateral headaches often accompanied
by ipsilateral lacrimation, conjunctival hyperemia, and nasal congestion.
Nausea is not commonly associated with cluster headaches as it is with migraine
headaches. Cluster headaches are usually brief (15-180 minutes) but involve
intense pain from the outset in and around the orbit. Most subjects have episodic
rather than chronic cluster headaches. They have 1 or more headaches daily
for several weeks to several months, often at the same time each day, but
the headaches then disappear and may not return for many months or years.
The etiology of cluster headaches is poorly understood. Neuropeptide
release from central and peripheral endings of trigeminal neurons, particularly
substance P (SP) and calcitonin gene-related peptide (CGRP), has been suggested
to be a cause.1-3
The role of nitric oxide, both centrally (hypothalamic) and distally (trigeminal
nerve), has also been suggested,4 and plasma
nitrates are increased in both the active and remission phases of episodic
cluster headaches.5
Calcitonin gene-related peptide and SP-containing trigeminal afferent
nerves innervate the pial and dural cephalic vessels.6
The release of CGRP and SP results in dilation of pial arteries, increases
in vascular permeability, and activation of an inflammatory response.7 When CGRP and SP are released by the trigeminal nerve
into the walls of the cerebral blood vessels, headache results. Increases
in CGRP concentrations in external jugular blood have been observed during
a migraine headache8 and interictally in the
peripheral circulation.9 The intravenous administration
of CGRP has also been shown to induce migraines in patients with migraines
without aura.10 Cluster headache has also been
ascribed to the release of CGRP and SP from both central (causing pain) and
peripheral (causing rhinorrhea, lacrimation, and conjunctival hyperemia) endings
of trigeminal neurons.11
Capsaicin is a derivative of homovanillic acid found in hot peppers.
It is a known neuropeptide depletor that has been shown to cause the release
of SP and other neuropeptides from primary sensory neurons,12
with eventual desensitization by depletion of SP and CGRP from nerve terminals.
On this basis, studies of intranasal capsaicin have been performed and have
demonstrated some effectiveness in relieving cluster headaches.11, 13-14
Capsaicin's extreme irritant effects, however, have limited the clinical use
of this therapy.
Civamide (cis-8-methyl-N-vanillyl-6-nonenamide), a synthetic isomer of capsaicin, is a vanilloid
receptor agonist and a neuronal calcium channel blocker15
that inhibits the neuronal release of excitatory neurotransmitters,16 including CGRP and SP, and depletes neurons of their
neurotransmitter content.2 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 would then result in less vasodilation, plasma extravasation,
and histamine/serotonin release, with a potential for the amelioration of
neurogenic inflammation and cluster headache pain.
Civamide has been demonstrated to be significantly more potent at depleting
SP and CGRP than capsaicin,17-18
as well as significantly less irritating than capsaicin.19
This study was designed to assess the safety and efficacy of intranasal civamide
vs vehicle control for preventive treatment of cluster headaches during an
episodic cluster period.
SUBJECTS AND METHODS
The protocol was approved by the institutional review board at each
center and informed consent was obtained from each subject prior to enrollment.
Subjects were 18 years or older with at least a 2-year history of cluster
headaches and had 1 to 3 cluster headache periods during the previous 2 years,
with at least 1 cluster headache daily on each of the 3 days prior to study
entry. Headaches had to meet slightly modified International Headache Society
Diagnostic Criteria for episodic cluster headache20:
1 to 4 attacks per day of severe, unilateral, orbital, supraorbital, and/or
temporal pain lasting 15 to 240 minutes untreated, associated with at least
1 of the following: conjunctival hyperemia, lacrimation, nasal congestion,
rhinorrhea, forehead and facial sweating, miosis, ptosis, or eyelid edema.
Subjects were otherwise in generally good health and had normal electrocardiogram
results at baseline. Subjects were excluded from the study if they were pregnant
or lactating; had a history of alcohol or drug abuse within the past year;
had clinical, historical, or laboratory evidence of significant cardiovascular,
renal, gastrointestinal, pulmonary, hepatic, endocrine, or other neurological
or systemic disease; or had taken preventive medication for cluster headaches
within 2 days of starting the study.
This was a randomized, double-blind, vehicle-controlled study designed
to assess the safety and efficacy of intranasal civamide for the preventive
treatment of episodic cluster headaches. Civamide and the vehicle were supplied
in identical packaging and assigned to subjects in a ratio of 2 civamide to
1 vehicle according to a computer-generated randomization code. Subjects and
investigators were blinded to drug assignment throughout the treatment and
posttreatment periods of the study.
SUBJECTS
Subjects were treated with either 100 µL of 0.025% civamide (25
µg) or 100 µL of the vehicle delivered into each nostril once
daily for the 7-day treatment period. Treatments were self-administered using
a calibrated dropper. Following the treatment period, subjects were then monitored
for a 20-day posttreatment period. During the entire study, subjects were
allowed abortive treatment of individual headaches after 15 minutes with 100%
oxygen, dihydroegotamine mesylate injection, subcutaneous or oral sumatriptan,
oral zolmitripan, and opiate or nonopiate analgesics.
Subjects recorded details of their cluster headaches daily in a diary
for the 27 days of the study. The frequency of headaches, rating of cluster
headache pain intensity, presence or absence of symptoms associated with cluster
headaches, and the need for abortive therapies were recorded. The investigator
evaluated subjects at 4 visits (on day 1, day 7, day 17, and day 27). Evaluations
included a nasal mucosa examination, odor detection test, serum chemistry
and hematologic assessment, and urinalysis. Adverse experiences were monitored
and recorded throughout the study.
The primary efficacy end point was the change in frequency of cluster
headaches per week during the posttreatment period. Secondary efficacy end
points included the change in frequency of headaches experienced during each
approximately 1-week period of the posttreatment period, pain intensity (0-3),
presence or absence of associated symptoms, and use of abortive therapies.
Safety outcomes included the incidence of adverse events and treatment-related
adverse events, odor detection tests, nasal mucosa examinations, laboratory
tests, and electrocardiogram results. Adverse events were classified according
to the preferred term and body system.
STATISTICAL ANALYSES
The population analyzed for efficacy included all randomized subjects
who had a diagnosis of cluster headaches, had received at least 3 days of
study medication, and did not receive any disallowed concomitant medications.
All subjects who took at least 1 dose of study medication were included in
the safety analyses. All comparisons of the treatment groups were performed
using 2-sided tests at a .05 overall level of significance ( = .05).
The null hypothesis for all analyses was that there is no difference between
the treatment groups.
Demographic and baseline variables were compared between treatment groups
by a 2-sample t test for continuous variables and
by the Fisher exact test for discrete variables. Baseline headache frequency
was calculated from a retrospective report by the subject of the number of
cluster headaches experienced during the 3 days prior to treatment, and this
number was then adjusted to represent a weekly (7-day) rate. Efficacy end
points, including the total number of headaches per week, the number of severe
headaches per week, mean pain intensity, and the number of headaches requiring
abortive therapy during the treatment and posttreatment periods were compared
between treatment groups by 2-sample t tests. The
change and percent change in the total number of headaches from treatment
to posttreatment and from baseline to the specified periods were also compared
by 2-sample t tests. The subject's assessment of
drug effectiveness was compared by the Fisher exact test. The number of headaches
associated with specific symptoms was compared between treatment groups by
the Wilcoxon rank sum test. No adjustments for multiplicity of testing were
made for the secondary efficacy end points. Safety results, including the
incidence of adverse events, odor detection test results, nasal mucosa examination
results, and laboratory test results were compared between treatment groups
by the Fisher exact test.
RESULTS
SUBJECT DISPOSITION AND CHARACTERISTICS
Twenty-eight subjects, 18 subjects randomized to receive civamide and
10 to receive the vehicle, were enrolled at 14 headache centers in the United
States. Most subjects were men (90%) and white (82%); the mean age for all
subjects was 44.7 years (22-83 years) (Table 1). There were no significant differences between treatment
groups for any demographic or baseline variables.
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Table 1. Demographic and Baseline Variables
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A total of 24 subjects received at least 3 days of study medication
and were included in the efficacy analysis (Figure 1): 15 subjects in the civamide group (13 subjects received
7 days, 1 subject 6 days, and 1 subject 5 days of treatment) and 9 subjects
in the vehicle group (9 subjects received 7 days of treatment). The 4 subjects
who were not included received just 1 day of study medication: 3 subjects
(17%) in the civamide group who withdrew owing to an adverse event and 1 subject
(10%) in the vehicle group who withdrew owing to lack of improvement.
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Figure 1. Study flow chart.
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During the posttreatment period, 3 subjects (17%) in the civamide group
withdrew from the study due to lack of improvement and one subject (10%) in
the vehicle group was lost to follow-up. Posttreatment data from 3 subjects
were excluded from the efficacy analysis from the time they took other prohibited
preventive medications.
EFFICACY VARIABLES
Subjects in the civamide group had a significantly greater percent decrease
in the number of headaches from baseline to posttreatment days 1 through 7
(-55.5 vs –25.9; P = .03) and a trend
toward significance during days 8 through 14 (-66.9 vs –32.3; P = .07) and days 15 through 20 (-70.6 vs –34.9; P = .07), as well as a near-significant decrease during
the entire posttreatment period (days 1 through 20 [P
= .054]) compared with the vehicle group (Table 2 and Figure 2).
Greater decreases in the number of headaches per week during the posttreatment
period were observed in the civamide-treated group, with trends toward significance
during posttreatment days 8 through 14 (-8.4 vs –3.6; P = .09) and days 15 through 20 (-8.9 vs –3.6; P = .07) (Table 2 and Figure 3).
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Table 2. Change and Percent Change in the Number of Cluster Headaches
per Week
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Figure 2. Percent change in the mean number
of headaches per week from baseline to treatment and posttreatment periods.
P values from 2-sided t tests.
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Figure 3. Change in the number of headaches
per week from baseline to treatment and posttreatment periods.
P values from 2-sided t tests.
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There were no significant differences between the treatment groups in
the number of severe headaches, mean cluster headache pain intensity, the
presence or absence of associated symptoms, or the requirement for abortive
medications at any visit.
SAFETY RESULTS
Most subjects (17/18 [94%] in the civamide-treated group and 7/10 [70%]
in the vehicle group) had 1 or more adverse events during the study (Table 3). The initial onset of most adverse
events was on treatment day 1 for most civamide-treated subjects. There were
no serious adverse events reported. The most common events were nasal burning
and lacrimation. At least 1 treatment-related episode of nasal burning was
reported for 14 of 18 subjects (78%) in the civamide group and 1 of 10 subjects
(10%) in the vehicle group (P = .001). Most nasal
burning was moderate or severe and was transient, lasting less than 20 minutes
after application. Significantly more subjects in the civamide group also
had lacrimation (P = .01) than in the vehicle group.
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Table 3. Incidence of Common Adverse Events
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There were no clinically significant changes in systolic or diastolic
blood pressure, heart rate, respiration rate, or oral temperature during the
study. All subjects could detect the test odor at both visits and there were
no clinically significant differences between the treatment groups with respect
to the examination of the nasal mucosa. No subjects in either treatment group
had clinically significant abnormalities on results of their electrocardiograms
or laboratory tests.
COMMENT
This pilot study has shown that intranasal civamide may hold promise
as a preventive therapy for episodic cluster headaches during active cluster
periods. There are no medications for the prevention of cluster headaches
currently approved by the Food and Drug Administration, and subcutaneous sumatriptan
is the only approved medication for abortive therapy of individual cluster
headache attacks.21-23
Since cluster headaches are among the most severe headaches known and result
in significant disability during active cluster periods, any therapy that
can reduce their frequency would be valuable.
Our results demonstrate an early, significant decrease in cluster headache
frequency in subjects receiving civamide compared with those receiving the
vehicle in the first 7 days of the posttreatment period following as few as
5 days of active therapy. During each of the subsequent posttreatment follow-up
weeks and during the entire 20-day posttreatment follow-up period, the decrease
in frequency trended toward significance despite the small number of subjects.
Other efficacy parameters, including headache severity and rescue medication
use, were not significantly different throughout the study within or between
groups without any indications that headaches of different severity were affected
differently. The small number of subjects may have contributed to the lack
of significance of the secondary efficacy parameters.
The safety data indicate that while tolerated by most, most active-treated
subjects in our study experienced transient nasal burning, rhinorrhea, and
lacrimation. Although during the study the subjects did not know for certain
whether the vehicle solution produced similar symptoms as the active solution,
in our future studies of this medication, several modifications will be made
for better blinding. A spray pump will be used to deliver 100 µL of
a less concentrated (0.01%) solution of civamide to decrease the incidence
and severity of burning.24 The spray will be
administered twice daily so the total amount of delivered drug each day (40
µg) will be approximately equal to the daily dose used in this study
(50 µg). Additionally, the vehicle may be modified to produce some burning
in vehicle-treated patients.
Our results provide tentative support to the putative role of CGRP and
SP in the pathogenesis of cluster headaches. The adverse effect profile that
was observed can be understood as part of the mechanism of action of intranasal
civamide, ie, there is a distal release of neuropeptides SP, CGRP, etc, by
the terminal branches of the trigeminal nerve in the nasal mucosa.
Study design and rigorous inclusion and exclusion criteria made enrollment
difficult in this study despite the number of centers. Our future studies
will have more subjects since the protocol will permit them to continue stable
doses of other preventive medications and be enrolled if they are still experiencing
a significant number of cluster headaches. A prospective rather than retrospective
baseline will be determined using diaries. Additionally, there will be a longer
posttreatment period to evaluate continued responses to therapy and to help
evaluate a necessity for a second course.
In conclusion, the results of this study demonstrate that intranasal
civamide significantly decreases the frequency of cluster headaches during
the first 7 days of the posttreatment period with a continued decrease during
the entire 20-day posttreatment period. Intranasal civamide use was not associated
with any systemic adverse effects; however, local adverse effects limited
tolerability for some subjects. This study offers early support for the possible
value of intranasal civamide as a safe and effective preventive treatment
for episodic cluster headache.
AUTHOR INFORMATION
Accepted for publication August 17, 2001.
This study was funded in part by Winston Laboratories Inc, Vernon Hills,
Ill.
Author contributions: Study concept and design (Drs Saper, Mathew, Rapoport, Phillips, Bernstein); acquisition
of data (Drs Klapper, Mathew, Rapoport); analysis
and interpretation of data (Drs Phillips, Bernstein);
drafting of the manuscript (Drs Saper, Rapoport, Phillips); critical revisions of the manuscript for important intellectual content (Drs Klapper, Mathew, Rapoport, Phillips, Bernstein); obtained funding (Drs Phillips, Bernstein);
administrative, technical, and material support (Drs Rapoport,
Phillips, Bernstein); study supervision (Drs Saper,
Mathew, Phillips, Berstein).
Intranasal Civamide Study Group
Roger K. Cady, MD; James R. Couch, MD; Seymour Diamond, MD; Arthur H.
Elkind, MD; Jack Klapper, MD; David Kudrow, MD; Ninan T. Mathew, MD; Lawrence
Newman, MD; Joseph Nicolas, MD; Alan M. Rapoport, MD; Joel R. Saper, MD; Timothy
R. Smith, MD; Stewart J. Tepper, MD.
Corresponding author: Joel R. Saper, MD, Michigan Headache Pain and
Neurological Institute, 3120 Professional Dr, Ann Arbor, MI 48104.
From the Michigan Headache Pain and Neurological Institute, Ann Arbor
(Dr Saper); Colorado Neurology and Headache Center, Denver (Dr Klapper); Houston
Headache Clinic, Houston, Tex (Dr Mathew); New England Center for Headache,
Stamford, Conn (Dr Rapoport); and Winston Laboratories Inc, Vernon Hills,
Ill (Drs Phillips and Bernstein).
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