ORIGINAL CONTRIBUTION
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
Objective: To evaluate the safety and efficacy of intra-
nasal civamide solution for preventive treatment during
an episodic cluster headache period.
Subjects and Methods: This was a multicenter, doubleblind, 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 head-
aches per week during the treatment and posttreatment periods, pain intensity, presence of associated symptoms, and
the incidence of adverse events were assessed.
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 civamidetreated 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
Results: Subjects in the civamide group had a signifi-
50 µg may be modestly effective in the preventive treatment of episodic cluster headache.
cantly greater percent decrease in the number of headaches from baseline to posttreatment during days 1 through
Arch Neurol. 2002;59:990-994
C
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). A list of the
members of the Intranasal
Civamide Study Group appears
in the box on page 994.
LUSTER HEADACHES are se-
vere, 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 generelated 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
(REPRINTED) ARCH NEUROL / VOL 59, JUNE 2002
990
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
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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, vehiclecontrolled 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 computergenerated 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,
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
(REPRINTED) ARCH NEUROL / VOL 59, JUNE 2002
991
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.
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 neuroWWW.ARCHNEUROL.COM
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Table 1. Demographic and Baseline Variables
Age, mean ± SD (range), y
Weight, mean ± SD (range), kg
Sex, No. (%)
Male
Female
Race, No. (%)
Black
White
Asian
Hispanic
No. of cluster headache periods per year, mean ± SD (range)
Length of current episode, mean ± SD (range), d
No. of cluster headaches during last 3 days, mean ± SD (range)
Civamide
(n = 18)
Vehicle
(n = 10)
45.1 ± 10.5 (22-64)
86.6 ± 20.1 (61.4-150.5)
43.9 ± 16.3 (23-83)
87.7 ± 14.6 (65.9-109.5)
16 (89)
2 (11)
P Value*
.81
.88
⬎.99
9 (90)
1 (10)
.63
2 (11)
14 (78)
1 (6)
0
1.8 ± 0.73 (1-3)
38.9 ± 30.4 (3-90)
5.1 ± 2.0 (3-9)
0
9 (90)
0
1 (10)
2.0 ± 0.94 (1-4)
44.5 ± 59.2 (3-180)
4.9 ± 3.2 (3-13)
.49
.79
.87
*P values are from the 2-sample t test for continuous variables and the Fisher exact test for discrete variables.
Enrolled Subjects (N = 28)
Randomized Subjects (n = 28)
Randomized to Civamide (n = 18)
Randomized to Vehicle (n = 10)
Civamide Subjects (n = 3)
Received <3 Days of Study Medication
Vehicle Subjects (n = 1)
Received <3 Days of Study Medication
Efficacy Population (n = 24)
Received ≥3 Days of Study Medication
Civamide (n = 15)
Vehicle (n = 9)
Figure 1. Study flow chart.
transmitters,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.
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
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992
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.
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.
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).
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.
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Table 2. Change and Percent Change in the Number of Cluster Headaches per Week
Vehicle
Civamide
Days (Active/Vehicle)
No. per Week
Baseline period (15,9)
Treatment period
Days 1-7 (15,9)
Posttreatment period
Days 1-20 (15,9)
Days 1-7 (14,8)
Days 8-14 (14,8)
Days 15-20 (11,8)
12.5
⌬ No.
⌬%
No. per Week
P Value*
⌬ No.
⌬%
⌬ No.
⌬%
10.8
7.2
−4.9
−35.9
7.8
−3.4
−17.2
.57
.32
4.9
5.6
4.1
4.2
−7.6
−6.9
−8.4
−8.9
−61.4
−55.5
−66.9
−70.6
7.2
7.3
7.2
7.2
−3.6
−3.5
−3.6
−3.6
−30.9
−25.9
−32.3
−34.7
.11
.14
.09
.07
.05
.03
.07
.07
Mean % Change in No. of Headaches per Week
*P values are from the Fisher exact test.
Civamide
Vehicle
–17.2
–25.9
No. (%)
–32.3
–35.9
–34.7
Active
(n = 18)
Body System
–55.5
–66.9
Days 1-7 (P =.03)
Days 1-7
Treatment Period
(P =.32)
–70.6
Days 8-15 (P =.07) Days 15-20 (P =.07)
Posttreatment Period
(P =.054)
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.
Mean Change in No. of Headaches per Week
Table 3. Incidence of Common Adverse Events
Civamide
Vehicle
–3.4
–3.5
–3.6
–3.6
–4.9
–6.9
–8.4
–8.9
Days 1-7 (P =.14)
Days 1-7
Treatment Period
(P =.57)
Days 8-15 (P =.09) Days 15-20 (P =.07)
Posttreatment Period
(P =.11)
Figure 3. Change in the number of headaches per week from baseline to
treatment and posttreatment periods. P values from 2-sided t tests.
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 civamidetreated subjects. There were no serious adverse events reported. The most common events were nasal burning and
lacrimation.Atleast1treatment-relatedepisodeofnasalburn(REPRINTED) ARCH NEUROL / VOL 59, JUNE 2002
993
Central and peripheral
nervous system
Nasal burning
Respiratory system
Any adverse event
Pharyngitis
Rhinorrhea
Vision
Any adverse event
Lacrimation
Vehicle
(n = 10)*
P Value
14 (78)
1 (10)
.001
9 (50)
8 (44)
6 (33)
2 (20)
1 (10)
1 (10)
.23
.10
.36
10 (56)
9 (50)
0
0
⬍.001
.01
*P values are from the Fisher exact test.
ing 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.
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.
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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.
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
duringthestudythesubjectsdidnotknowforcertainwhether
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
(REPRINTED) ARCH NEUROL / VOL 59, JUNE 2002
994
of intranasal civamide as a safe and effective preventive treatment for episodic cluster headache.
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).
Corresponding author: Joel R. Saper, MD, Michigan
Headache Pain and Neurological Institute, 3120 Professional Dr, Ann Arbor, MI 48104.
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