ISSN 0017-8748

Headache doi: 10.1111/j.1526-4610.2010.01800.x

© 2010 American Headache Society Published by Wiley Periodicals, Inc.

Research Submission
Amitriptyline in the Prophylactic Treatment of Migraine and
Chronic Daily Headache head_1800 33..51

James R. Couch, MD, PhD for the Amitriptyline Versus Placebo Study Group

Objective and Background.—Amitriptyline is one of the most commonly used medications in migraine prophylaxis. There
have been relatively few placebo-controlled studies of amitriptyline in migraine prophylaxis or in treatment of chronic daily
headache (CDH). This report deals with a large placebo-controlled trial of amitriptyline vs placebo of 20 weeks duration that
included subjects with intermittent migraine (IM) as well as CDH. The study was carried out between 1976 and 1979; however,
results have never been fully reported.
Methods.—Patients with a history of migraine as defined by the 1962 Ad Hoc Committee report were recruited for this study.
Subjects had at least 2 headaches per month, and no limit was placed on the number of headaches per month that could be
experienced. The study format included a 4-week baseline period (Period A) in which all subjects received placebo in a dose of
2 pills per day for one week, 3 pills per day for one week and then 4 pills per day for 2 weeks. Subjects with at least 2 migraine
headaches in this period were then entered into Period B and randomized into either amitriptyline or placebo tracks. Medication
consisted of identical tablets containing either 25 mg amitriptyline or placebo. Period B was 4 weeks in duration with dose titration
identical to Period A.The dose could be reduced if necessary to reduce side effects.The minimum dose was one pill per day. Period
C was a 12-week maintenance or stabilization period in which the patient continued the dose established by week 8 with visits at
weeks 12, 16, and 20. Patients kept a headache calendar that was used for data collection. Headache frequency (per month),
severity, and duration (hours) were the primary measurement parameters employed for data analysis.
Results.—For the entire group, 391 subjects were entered into Period A, 338 were randomized into Period B, 317 (81%)
subjects completed the first post-randomization visit (8 weeks), 255 (65%) completed week 12, 210 (54%) completed week 16,
and 186 (48%) completed week 20. Using headache frequency and evaluating parameters of (a) improvement, (b) no change,
or (c) worsening relative to baseline, there was a significant improvement in headache frequency for amitriptyline over placebo
at 8 weeks (P = .018) but not at 12, 16, or 20 weeks. When amitriptyline and placebo patients were compared for headache
frequency at 8, 12, 16, and 20 weeks to their own placebo stabilization period at 4 weeks, statistically significant improvement
vs worsening was seen in headache frequency at each evaluation point for both amitriptyline and placebo groups (P ⱕ .01)
reaching 50% reporting a decrease in frequency in each group and approximately 10% reporting worsening by week 20. There
were no significant differences in headache severity or duration between amitriptyline and placebo groups at anytime during the
study. Within the study sample, there were 36 amitriptyline and 22 placebo subjects who had headaches ⱖ17 days/month that
fit the current definition of CDH by the Silberstein-Lipton criteria. These were analyzed separately as a subgroup for
comparison of amitriptyline vs placebo using a metric of (1) no change or worsening; (2) up to a 50% improvement; and (3)
ⱖ50% improvement in headache frequency. Amitriptyline was superior to placebo in number with improvement in frequency
of ⱖ50% at 8 weeks (25% vs 5% [P = .031]) and at 16 weeks (46% vs 9% [P = .043]). There was a trend for amitriptyline to be
superior to placebo at 12 and 20 weeks but this did not reach significance.
Conclusions.—In this study, using headache frequency as the primary metric, for the entire group, amitriptyline was
superior to placebo in migraine prophylaxis at 8 weeks but, because of a robust placebo response, not at subsequent time points.

From the University of Oklahoma Medical School, Oklahoma City, OK, USA.
Address all correspondence to J.R. Couch, University of Oklahoma Medical School, Oklahoma City, OK 73104, USA.

Accepted for publication September 19, 2010.

Funding source: The study was initially funded by a grant from Merck, Sharp, and Dohme Research Laboratories, West Point, PA
(1976-1980). A re-analysis of study data was funded by an individual investigator grant from Merck & Co. (2006).

33
34 January 2011

For the subgroup with CDH, amitriptyline was statistically significantly superior to placebo at 8 weeks and 16 weeks with a
similar but nonsignificant trend at 12 and 20 weeks. Compared with placebo amitriptyline is effective in CDH. Amitriptyline was
also significantly effective in IM compared intragroup to its own baseline; however, placebo was equally effective in the same
analysis. The reason for the robust placebo response in the IM group is not clear, but has been occasionally reported.
Key words: migraine, prophylaxis, amitriptyline, placebo, chronic daily headache

(Headache 2011;51:33-51)

Amitriptyline has been a mainstay in the prophy-
lactic therapy of migraine for over 35 years and today
remains one of the most commonly used agents for
this purpose.1-5 Despite its wide usage, there have
been relatively few placebo-controlled studies of this
agent in migraine prevention.
Amitriptyline was first mentioned in treatment of
headache by Lance and Curran in 1964,6 with treat-
ment of “chronic tension headache” defined as head-
ache occurring ⱖ10 days/month; however, 85% of
their subjects had daily headache. In a small double-
blind crossover study of 27 subjects treated with ami-
triptyline and placebo, 56% were more than 50%
improved; however, the measure of headache
improvement is not well stated. In 1965, these authors
published a broader study of preventative agents for
chronic tension headache defined as 10-30 headaches
per month, again with the majority having daily head-
ache.7 They noted that 60% of 187 tension headache
subjects were at least 50% improved with amitrip-
tyline. Diamond and Baltes, in 1971, reported on
treatment of “chronic headache” using amitriptyline
in doses of 10 or 25 mg per day.8 A subjective global
score was employed and showed beneficial effect of
10 mg but not 25 mg of amitriptyline per day in com-
parison with placebo. Gomersall and Stuart in 1973
employed a placebo-controlled double-blind cross-
over format in 20 subjects to study the effect of ami-
triptyline in doses of 10-60 mg in treating migraine.9
Using headache frequency as a metric, they found
that amitriptyline produced ⱖ50% improvement in
50% of subjects while placebo did so in 25%. In an
uncontrolled study of 110 subjects Couch, Ziegler,
and Hassanein, in 1976, reported that 72% were
improved by ⱖ50% with amitriptyline.10 In a subse-
quent placebo-controlled study using a headache
index calculated from frequency, duration, and inten-
sity of headache, Couch and Hassanein reported that
55% of migraine and 34% of placebo-treated subjects
were ⱖ50% improved with doses of 50-100 mg/day of
amitriptyline.11 Ziegler et al in 1987 reported on a
double-blind, crossover study in which subjects with
intermittent migraine (IM) underwent a placebo
baseline period and then all subjects received either
amitriptyline or propranolol in random order.12,13 A
headache index employing frequency, duration, and
intensity was employed to measure outcome. Both
drugs decreased headache index in comparison with
placebo by 16-20%; however, there was no significant
difference in effect of amitriptyline vs propranolol. In
2001, Holroyd et al compared amitriptyline to psy-
chological and relaxation therapies and found that
the combination of these therapies was more effective
than either alone and more effective than placebo.14
In 2005, Rafieian-Kopaei, Mehvari, and Shirzadi com-
pared amitriptyline (25 mg bid) and propranolol
(40 mg bid) to placebo in treatment of IM using a 3
parallel track, completer design with 35 patients
entered into each track.15 The number of completers
was not given for each track but overall 90% of sub-
jects completed the study. There was approximately
33% improvement in average frequency, duration,
and intensity of headache with amitriptyline and
40-50% improvement with propranolol.
Two more recent studies have dealt with tension
headache. In 1994, Pfaffenrath et al compared ami-
triptyline (75 mg/day), amitriptyline oxide (90 mg/
day), and placebo in treatment of tension-type
headache in a 3-way study employing 197 subjects.16
Compared with placebo, they found a trend for
decreased headache intensity in the 2 drug tracks but
no significant difference in the primary endpoint of
>50% improvement. Bendtsen, Jensen, and Olesen
tested amtitiptyline vs citalopram vs placebo in a
3-way trial of prophylactic therapy of chronic tension-
type headache in 34 subjects using double-blind
Headache
crossover format to have each subject take all 3
agents.17 They found that amitriptyline produced a
28% reduction in headache compared with placebo
(P = .002) while citalopram showed no difference
from placebo.
The above studies represent the placebo-
controlled studies of amitriptyline in treatment of
headache including migraine. Most studies subse-
quent to 1987 have been primarily comparison
studies of amitriptyline vs another potential prophy-
lactic antimigraine drug without a placebo
comparison.18-25 These studies have generally shown
that amitriptyline is comparable with or better than
other known or potential prophylactic antimigraine
agents.
The current report deals with a double-blind, 20
week, parallel track study of amitriptyline to deter-
mine its efficacy in prophylaxis of migraine headache.
For the study, amitriptyline in doses of 50-100 mg/day
was tested against placebo in a 1:1 randomization
schedule. The study involves 391 subjects entered and
317 who completed the eighth week for the first post-
randomization evaluation. This is the largest placebo-
controlled study of amitriptyline in migraine
prophylaxis ever undertaken. The study was carried
out between 1976 and 1979 with completion of the
analysis in 1980. The report has been delayed by a
series of events including change of academic posi-
tion by the author and loss of patent protection of
amitriptyline by the sponsor (Merck, Sharp, and
Dohme Research Laboratories). Initial analysis was
not promising; however, re-analysis with focus on the
area of chronic daily headache (CDH) does demon-
strate significant results in favor of amitriptyline.
METHODS
This study was a double-blind, placebo-
controlled study comparing amitriptyline in doses of
25-100 mg/day, depending on the tolerance of the
patient, with a matched placebo. The study was spon-
sored by the Merck, Sharp, and Dohme Research
Laboratories. Dr. D. Nibbelink was the Medical
Affairs Clinical Monitor for Merck Laboratories. The
study was approved by the University of Kansas
Human Subjects Experimentation Committee in
35
Table 1.—Investigators for the Study and Number of Subjects
Recruited
Number of Subjects
Investigator Recruited
H.E. Schear 30
V.H. Rivera 41
R.R. Carruthers 47
S. Diamond 36
S. Stellar 50
J.R. Couch 86
B.J. Baltes 16
L. Kudrow 20
R. North 25
R.J. Whaley 40
Total 391
1976. The re-analysis of the study was approved by
the University of Oklahoma Investigational Review
Board in 2010.
Investigators.—The investigators involved in the
study and the numbers of subjects randomized from
each center are presented in Table 1.
Patients.—The definition of migraine was that used
in the earlier reports of Couch, Ziegler, and Hassa-
nein.10,11,26 This definition generally followed the guide-
lines of the 1962 Ad Hoc National Institutes of Health
Committee report27 but was more specific. These
guidelines had been used in the previous single center
placebo-controlled trial of amitriptyline in migraine
prophylaxis.11 This definition specified that a migraine
could be diagnosed in a patient without other medical
condition that could cause headache, for a headache
associated with at least 3 of the following 5 criteria: (1)
nausea; (2) vomiting; (3) photophobia; (4) headache-
associated neurological symptoms; or (5) a positive
history of recurrent benign headache in a first degree
family member. These guidelines are generally com-
patible with the diagnosis of migraine by the Interna-
tional Classification of Headache Disorders (ICHD)
published in 1988.28
Inclusion criteria specified patients between 18
and 70 years of age with at least 2 moderate or worse
migraine headaches by the above definition per
month (see below for definition of severity).
Exclusion criteria included the following: (1)
absence of migraine headache; (2) secondary head-
36
ache; (3) pregnant females or nursing mother; (4)
known allergy to amitriptyline; (5) urinary retention;
(6) glaucoma; (7) any cardiac disease; (8) sustained
hypertension; (9) subjects taking guanethidine or
monoamine oxidase inhibitors; (10) prostatic hyper-
trophy; (11) thyroid disease or taking thyroid medi-
cation; (12) seizure disorder; (13) patients taking any
known (at that time) preventative antimigraine agent
including methysergide, propranolol, cyproheptadine,
antianxiety agents, or other tricyclic antidepressants.
All patients received a complete physical and neu-
rological examination, complete blood count, chemis-
try profile including electrolytes, glucose, blood urea
nitrogen (BUN), creatinine, aspartate aminotrans-
ferase (AST), alanine aminotransferase (ALT), alka-
line phosphatase, calcium, and phosphorus as well as
an electrocardiogram on entering the study and at the
end of the study.
Study Format.—After signing a consent form and
induction into the study, patients received placebo for
4 weeks (Period A – baseline period). The dosing
schedule was as follows: week 1 – 2 pills at night (HS),
week 2 – 1 pill in am and 2 HS, weeks 3 and 4 – 1 pill
bid and 2 pills HS. After 4 weeks patients with at least
2 moderate or worse migraine headaches during
Period A could be randomized into the double-blind
period of 5-20 weeks (Periods B and C). Figure 1
provides a flow diagram of the study format. During
Figure.—Flow chart of study format with notation of important points.
January 2011
this time the patient received pills that were identical
to each other and identical to those dispensed in
Period A, which contained either amitriptyline 25 mg
or placebo. For the first 4 weeks after randomization
(Period B), the randomized patient repeated the esca-
lating dose titration of Period A. Patients were ran-
domized to either amitriptyline or placebo therapy on
a 1:1 basis in blocks of 4 subjects. Randomization of
medications was carried out by Merck, Sharp, and
Dohme Research Laboratories. Each investigator
received study medication in blocks of 4 subjects and
had to dispense all of one block before moving to the
next block. Investigators were blind as to the medica-
tion dispensed. During Period A or B, the investigator
could tell the patient to diminish the dose of medica-
tion by one pill if side effects occurred. The patient
was instructed to begin titration upward again after
one week. If a repeat attempt at upward titration was
unsuccessful, the patient would remain on the toler-
ated dose. The minimum dose to remain in the study
was one pill or 25 mg/day.
After completion of Period B at the eighth week,
the patient remained on the maximum tolerated dose
of medication for the remainder of the study, 8-20
weeks (Period C).
Patients were told they might receive active drug
or placebo at any time during the study.They were not
told they would receive only placebo in the first 4
Headache
weeks.This was to avoid the problem and possible bias
factor of worsening of headache because of the patient
knowing the treatment for the first 4 weeks (Period A).
If the patient desired to discontinue medication
because of lack of effect or relapse of the migraine,
the patient was considered a treatment failure. A final
visit was performed with a count of tablets to deter-
mine if dosage had been carried out.
Medications were supplied by Merck, Sharp,
and Dohme Research Laboratories as amitriptyline
25 mg or placebo in identically appearing tablets.
The minimum period of treatment to be counted
in the analysis of the data was 8 weeks, including
Periods A and B.
After induction into the study at the end of week
4, patients were seen at 8, 12, 16, and 20 weeks.
Follow-up at each evaluation included vital signs,
physical and neurological examination. The complete
blood count, chemistry profile, and electrocardiogram
were repeated at the final visit of the study.
A target sample size of 400 subjects was chosen as
likely to show a difference between amitriptyline and
placebo.
Recruitment was initiated in 1977 and stopped in
1979.
Clinical Measures.—The patients were given a data
form to fill out for each headache experienced.
The severity and duration of each headache were
recorded along with presence or absence of the fol-
lowing symptoms: (1) nausea; (2) vomiting; (3) pho-
tophobia; (4) visual impairment (blurring, teichopsia,
scotoma); (5) paresthesia; (6) weakness of arms or
legs; (7) dizziness; (8) loss of consciousness; (9) throb-
bing pain; (10) unilateral pain; (11) bilateral pain;
(12) neck pain; (13) steady pain; and (14) speech
disturbance.
Headache frequency was measured as number of
days per 4 weeks with a headache of any degree of
severity (see below for severity scale).
Headache severity was measured on a 5-point
scale as follows: disabling (4) – a headache so severe
the patient must lie down; severe (3) – a headache
severe enough that usual activity is diminished by
50% or more; however, some activity is possible; mod-
erate (2) – a headache that limits usual activity by less
than 50%; mild (1) – a headache that is present but
37
does not limit activity; no headache (0). For data
analysis, the headache severity grades were summed
for each month and then divided by the number of
headaches to get an average headache severity for
that 4-week period.
Headache Duration was measured in hours. For
analysis of duration, the number of hours the head-
ache lasted was tabulated for each headache. For data
analysis, these hours were then added and divided by
the number of headaches in the month to get an
average duration.
Efficacy Measures.—The major efficacy measures
for this study are the frequency, duration, and severity
of headaches as noted above. These were all consid-
ered separately. Secondary measures included a sub-
jective measure by the physician of Global Pathology,
which included the extent to which the headache
problem was impacting the patient’s life, and Global
Improvement, which was a subjective evaluation of
change since the last visit. No formal questionnaire or
set of evaluative questions was used to make this
assessment. This assessment was made by the indi-
vidual investigator based on his experience.
Adverse Events.—Adverse events (AE) in both
the clinical and laboratory spheres were evaluated as
mild, moderate or severe. These were tabulated and
compared for amitriptyline and placebo groups.
Statistics.—The initial analysis was carried out by
Ms. R.B. Lee of Merck, Sharp, and Dohme Research
Laboratories in 1980. A re-analysis of the data was
carried out in 2010 by Dr. J. Stoner (Associate
Professor of Biostatistics, University of Oklahoma
Health Sciences Center). For this re-analysis, data
were analyzed using sas (SAS System for Windows,
ver. 9.1, SAS Institute Inc., Cary, NC, USA). Random-
ization and retention of patients during the course of
the study was summarized using descriptive statistics.
Analyses were based on subjects who completed each
study visit. Comparisons of the distribution of cat-
egorical variables between amitriptyline and placebo
groups was carried out using a chi-square test for
trend when considering ordered response categories
or a chi-square test when considering nominal catego-
ries. Fisher’s exact test was used to compare the dis-
tribution of categorical variables between treatment
groups when at least 20% of the expected cell counts
38 January 2011

Table 2.—Distribution by Age and Sex of Subjects Who Were Randomized Into the Study

Characteristic Amitriptyline (n = 194) Placebo (n = 197) Total (n = 391)

Sex
Male 40 (21%) 34 (17%) 74 (19%)
Female 154 (79%) 163 (83%) 317 (81%)
Mean age (years) 34.1 35.7 34.9
Age (years) Male Female Total Male Female Total Male Female Total
<20 1 (3%) 7 (5%) 8 (4%) 0 (0%) 4 (2%) 4 (2%) 1 (1%) 11 (3%) 12 (3%)
20-29 13 (33%) 61 (40%) 74 (38%) 10 (29%) 51 (31%) 61 (31%) 23 (31%) 112 (35%) 135 (35%)
30-39 8 (20%) 43 (28%) 51 (26%) 11 (32%) 59 (36%) 70 (36%) 19 (26%) 102 (32%) 121 (31%)
40-49 14 (35%) 26 (17%) 40 (21%) 9 (26%) 29 (18%) 38 (19%) 23 (31%) 55 (17%) 78 (20%)
50-59 3 (8%) 16 (10%) 19 (10%) 4 (12%) 16 (10%) 20 (10%) 7 (9%) 32 (10%) 39 (10%)
ⱖ60 1 (3%) 1 (1%) 2 (1%) 0 (0%) 4 (2%) 4 (2%) 1 (1%) 5 (2%) 6 (2%)

The values represent the count (column percentage) for categorical measures and the mean for continuous measures.

were less than 5. Changes in frequency, average sever-
ity, and average duration were categorized as a
decrease, no change, or increase. In a second analysis,
an ordered categorical variable was created relative
to a 50% improvement in frequency, with categories
of (1) no change or worsening (I ⱕ 0); (2) 1-49%
improvement (I < 50); and (3) at least a 50% or
greater improvement (I ⱖ 50). Cumulative logistic
regression analysis was used to assess the significance
of the difference in the effect of amitriptyline vs
placebo between groups defined as CDH (ⱖ17 head-
aches per month) or intermittent headache (ⱕ16
headaches per month). The 3 ordered outcome cat-
egories were I ⱕ 0, I < 50, and I ⱖ 50 as defined
above. The regression model included the treatment
effect, a CDH or intermittent headache indicator
variable, and the interaction between treatment and
headache. A separate model was fit for each study
visit. A 2-sided 0.05 alpha level was used to define
statistical significance and no adjustments were made
for multiple comparisons over time.
As there was significant loss of subjects over each
ensuing 4-week period, each 4-week period was ana-
lyzed independently.
With regard to the CDH analysis, at the time of
this study, the terms “chronic daily headache” and
“chronic migraine” had not been defined. The pres-
ence of chronic headache was certainly known;
however, the terminology for very frequent head-
aches was not standardized. The usual terms
employed at that time were tension headache with
secondary vascular headache, migraine with interpar-
oxysmal headache, or simply migraine-tension head-
ache. The presence in this dataset of subjects with
migraine who had 17+ headaches per month allows
identification of a group of subjects who would fit the
category of CDH of the transformed migraine type as
described by Silberstein and Lipton in 1996.29 The
data are not available at this time to identify the
characteristics of each individual headache, and con-
sequently a diagnosis or classification of chronic
migraine or chronic tension-type headache by the cri-
teria of the revised ICHD published in 200430 cannot
be made for the subjects in this study.
RESULTS
There were 391 subjects who entered the baseline
phase of this study, of whom 194 (21% male) were
randomized to receive amitriptyline and 197 (17%
male) to receive placebo. Table 2 depicts the age and
sex distribution of the subjects in each treatment
group. There were no significant differences in the age
and sex distribution between the groups. The study
was analyzed as a “completer “ study in which those
subjects who completed 8 weeks, 12 weeks, 16 weeks,
and 20 weeks were analyzed separately at each time
point.
Table 3 depicts the subjects who discontinued
participation in the study prior to the 20-week
completion date and the reason for discontinuation.
Headache 39

Table 3.—Tabulation of Randomized Subjects Who Discontinued Participation and Reason for Discontinuation

Reason for
Discontinuation Amitriptyline (n = 194) Placebo (n = 197) Total (n = 391)

Clinical adverse event 23 (12%) 13 (7%) 36 (9%)

Poor response 7 (4%) 15 (8%) 22 (6%)
Withdrew consent 34 (18%) 36 (18%) 70 (18%)
Lost to follow-up 10 (5%) 16 (8%) 26 (7%)
Prophylaxis ceased 6 (3%) 10 (5%) 16 (4%)
Total relief 1 (1%) 0 (0%) 1 (<1%)
Protocol deviation 4 (2%) 5 (3%) 9 (2%)
Other 8 (4%) 11 (6%) 19 (5%)
Total 93 (48%) 106 (54%) 199 (51%)

The values represent the count (column percentage) for categorical measures.

Overall, 93/194 (48%) of amitriptyline subjects and
106/197 (54%) of placebo subjects discontinued the
study before 20 weeks. Among those who dropped
out, the most common reason given was unwillingness
to continue in a clinical research project, which
included 34 amitriptyline and 36 placebo subjects.
Another 10 amitriptyline subjects and 16 placebo
subjects were lost to follow-up without providing a
reason for discontinuation bringing the total for sub-
jects discontinuing for “personal reasons” to 44
(23%) for the amitriptyline group and 52 (26%) for
the placebo group, which did not differ significantly
between groups (P = .39). Beyond these items, the
most common reason for discontinuation in the ami-
triptyline track was clinical AE (n = 23 [12%]) and for
the placebo track was poor response to the treatment
(n = 15 [8%]). Table 7 provides further detail regard-
ing the clinical AE.
Table 4 provides summary data for all patients
for change at each evaluation point from the 0- to
4-week baseline in the individual parameters of head-
ache frequency (Table 4a), severity (Table 4b), and

Table 4a.—Frequency of Headache

Frequency of Headache

Decrease No Change Worse P Value

Within-Group
Amitriptyline vs Comparison vs 0- to
Week Group n n (%) n (%) n (%) Placebo† 4-Week Baseline‡

4 vs 8 Amitriptyline 154 64 (42) 78 (51) 12 (8) P = .018 P < .0001

Placebo 163 60 (37) 68 (42) 35 (21) P = .01
4 vs 12 Amitriptyline 125 59 (47) 53 (42) 13 (10) P = .54 P < .0001
Placebo 130 58 (45) 55 (42) 17 (13) P < .0001
4 vs 16 Amitriptyline 103 49 (48) 45 (44) 9 (9) P = .39 P < .0001
Placebo 107 47 (44) 46 (43) 14 (13) P < .0001
4 vs 20 Amitriptyline 93 47 (51) 37 (40) 9 (10) P = .83 P < .0001
Placebo 93 48 (52) 33 (35) 12 (13) P < .0001

†Chi-square test for trend between treatment groups.

‡Chi-square test of equality of proportions decreased and increased in frequency.
40 January 2011

Table 4b.—Severity of Headache

Severity of Headache

Decrease No Change Worse P Value

Within-Group
Amitriptyline vs Comparison vs 0- to
Week Group n n (%) n (%) n (%) Placebo† 4-Week Baseline‡

4 vs 8 Amitriptyline 154 28 (18) 94 (61) 32 (21) P = .50 P = .61

Placebo 163 43 (26) 81 (50) 39 (24) P = .66
4 vs 12 Amitriptyline 126 32 (25) 58 (46) 36 (29) P = .27 P = .63
Placebo 130 38 (29) 63 (48) 29 (22) P = .27
4 vs 16 Amitriptyline 103 23 (22) 54 (52) 26 (25) P = .29 P = .67
Placebo 107 33 (31) 49 (46) 25 (23) P = .29
4 vs 20 Amitriptyline 94 25 (27) 40 (43) 29 (31) P = .20 P = .59
Placebo 92 30 (33) 41 (45) 21 (23) P = .21

†Chi-square test for trend between treatment groups.

‡Chi-square test of equality of proportions decreased and increased in severity.

duration (Table 4c) at 8, 12, 16, or 20 weeks. The or categories of occurrence. For analysis of each
change was categorized as: (a) improvement, (b) no parameter, the individual subject was categorized at 4
change, or (c) worse. In order to measure the change, weeks after completing the baseline period and recat-
the headache parameters were subdivided into ranges egorized at the 8-, 12-, 16-, or 20-week time point. The

Table 4c.—Duration of Headache

Duration of Headache

Decrease No Change Worse P Value

Within-Group
Amitriptyline vs Comparison vs 0- to
Week Group n n (%) n (%) n (%) Placebo† 4-Week Baseline‡

4 vs 8 Amitriptyline 154 53 (34) 60 (39) 41 (27) P = .36 P = .22

Placebo 163 44 (27) 75 (46) 44 (27) P > .99
4 vs 12 Amitriptyline 126 49 (39) 40 (32) 36 (29) P = .62 P = .16
Placebo 130 44 (34) 49 (38) 37 (28) P = .27
4 vs 16 Amitriptyline 103 37 (36) 36 (35) 30 (29) P = .85 P = .44
Placebo 107 38 (36) 36 (34) 33 (31) P = .39
4 vs 20 Amitriptyline 93 33 (35) 35 (38) 25 (27) P = .78 P = .55
Placebo 92 31 (34) 35 (38) 26 (28) P = .29

†Chi-square test for trend between treatment groups.

‡Chi-square test of equality of proportions decreased and increased in duration.
Presentation of data on frequency, severity, and duration of headache showing changes as decrease, no change, or worse. Data are
shown as comparison for each subject at a given week against the subject’s 0- to 4-week baseline and for comparison of amitriptyline
vs placebo groups at that week. Time periods are designated by the end of the 4-week period: 0-4 weeks = 4, 4-8 weeks = 8,
8-12 weeks = 12, 12-16 weeks = 16, 16-20 weeks = 20.
Headache 41

Table 5.—Representation of Data Grid Prepared from the Raw Data. This table depicts the format in which data were
organized for headache frequency in comparing headache frequency at week 8 (end of period B) with that at week 4 (end of
baseline period, period A). Similar tables were constructed for weeks 12, 16, and 20. Similar tables were used for categorical
analysis for headache parameters of severity and duration for comparison of these parameters at 8, 12, 16, and 20 weeks versus
the values at baseline at the end of week 4

Frequency of Frequency of Headaches at Week 8

Treatment Headache at Baseline
Group (Week 4) 0 1-4 5-8 9-16 17-28 >28 No Frequency† Total

Elavil 0 3 0 0 0 0 0 0 3
1-4 2 24 2 1 0 0 3 32
5-8 1 19 19 6 0 0 0 45
9-16 1 7 15 15 3 0 1 42
17-28 1 3 5 10 15 0 0 34
>28 0 0 0 0 0 2 0 2
No frequency† 0 0 1 0 0 0 1 2
Total patients 8 53 42 32 18 2 5 160
Placebo 0 0 1 0 0 0 0 0 1
1-4 1 16 11 1 1 0 3 33
5-8 1 17 17 16 1 0 1 53
9-16 1 14 21 19 3 0 1 59
17-28 0 0 1 4 16 1 0 22
>29 0 0 0 0 0 0 0 0
No frequency† 0 2 0 0 0 0 0 2
Total patients 3 50 50 40 21 1 5 170

†No frequency data recorded.

Representation of data grid prepared from the raw data for analysis of headache frequency at 0-4 weeks (week 4) and 5-8 weeks
(week 8). This is part of the data analysis prepared by Ms. R.B. Lee, statistitian, in 1980 working under the auspices of Merck, Sharp,
and Dohme Research Laboratories.

first comparison was the number of subjects who had
changed or not in comparison with baseline. A second
comparison was carried out to compare changes in
the amitriptyline vs the placebo groups for possible
differences.
To illustrate the analysis, Table 5 provides a grid
showing the data dealing with headache frequency at
8 weeks vs that at the 4-week baseline. Headache
frequency was divided into categories of 0-4, 5-8, 9-16,
and 17+ headaches per month. In the Figure, note that
the subjects were assigned to a frequency category at
4 weeks on the vertical axis and are then recatego-
rized at 8 weeks on the horizontal axis. The subjects
categorized at 4 weeks remain distinct and identifi-
able for the display of the 8-week data. The data are
analyzed by evaluating how the subjects in a particu-
lar frequency category at 4 weeks were redistributed
in terms of better, unchanged, or worse at 8 weeks.
Similar grids were constructed for data for 12, 16,
and 20 weeks, which allowed completers in placebo
and amitriptyline groups at those times to be tracked
through the remainder of the study.
All 3 parameters of headache were analyzed in
the same fashion. For frequency, the measurement
categories chosen were 0-4, 5-8, 9-16, and 17+ head-
aches per month. For severity, the categories were
those noted in the Methods section of disabling,
severe, moderate, mild, or no headache. Headache
duration was measured in hours with 7 categories of
0-2, 3-6, 7-10, 11-14, 15-18, 19-24, and >24 hours
employed (Table 5).
In this first analysis of the data, an improvement
or worsening was considered a shift of at least one
category from baseline (4 weeks) to the data collec-
tion week under consideration (8, 12, 16, or 20 weeks).
For both amitriptyline and placebo groups, the data
for each subject at the specified week were first com-
pared intragroup to the baseline value established at
42 January 2011

Table 6.—Frequency of Headache for Each 4-Week Time Period and Comparison With Baseline for Chronic Daily Headache
Group (ⱖ17 Headaches per Month)

Frequency Category

Comparison I ⱖ 50 I < 50 Iⱕ0

Weeks Group n n (%) n (%) n (%) P Value† P Value‡

4 vs 8 Amitriptyline 36 9 (25%) 10 (28%) 17 (47%) .043 .031

Placebo 22 1 (5%) 4 (18%) 17 (77%)
4 vs 12 Amitriptyline 31 10 (32%) 5 (16%) 16 (52%) .40 .71
Placebo 16 3 (19%) 5 (31%) 8 (50%)
4 vs 16 Amitriptyline 24 11 (46%) 5 (21%) 8 (33%) .11 .043
Placebo 11 1 (9%) 3 (27%) 7 (64%)
4 vs 20 Amitriptyline 22 8 (36%) 5 (23%) 9 (41%) .70 .65
Placebo 10 2 (20%) 3 (30%) 5 (50%)

†P value for 2 ¥ 3 Fisher’s exact test (cumulative logistic regression modeling).

‡P value for 2 ¥ 2 Fisher’s exact test comparing the proportion of I ⱖ 50 vs I ⱕ 0 between groups.
Comparison with baseline is given as no change or worse (I ⱕ 0), improvement of up to 50% (I < 50), or improvement greater than
50% (I ⱖ 50). Time periods are designated by the end of the 4-week period: 0-4 weeks = 4, 4-8 weeks = 8, 8-12 weeks = 12, 12-16
weeks = 16, 16-20 weeks = 20.

week 4 to determine if there was a significant change
from baseline. Following this determination, the
number of subjects with change from baseline for
the amitriptyline and placebo groups was then com-
pared for significance of differences between these 2
groups.
As can be seen in Tables 4b and c, the severity
and duration parameters showed no significant differ-
ences from baseline or in comparison of amitriptyline
to placebo for each follow-up visit. These parameters
were not employed in further analyses.
The frequency parameter did show statistically
significant change for both amitriptyline and placebo
groups at 8, 12, 16, and 20 weeks when compared,
intragroup, to the 4-week baseline (P ⱕ .01 for all).At
weeks 12, 16, and 20, 45-50% of both groups showed
decreased headache frequency when compared with
the 4-week baseline. Intergroup comparison demon-
strated that the amitriptyline group was significantly
better than the placebo group at 8 weeks (P = .018).
Beyond 8 weeks amitriptyline and placebo groups
improved about the same amount and there was no
significant difference.
For further analysis, the subjects in the study were
divided by headache frequency at the 4-week baseline
visit into categories of CDH consisting of those with
ⱖ17 headaches per month, and IM designated as
those with ⱕ16 headaches per month (see Methods).
For this analysis, the ordered categories of improve-
ment of I ⱕ 0, I < 50, and I ⱖ 50 as described above
were employed (Tables 6 and 7).
Table 6 demonstrates the results for the CDH
group divided by headache frequency into the above
categories. Cumulative logistic regression modeling
indicated that the effect of amitriptyline vs placebo
on the odds of greater reductions in the frequency of
headache differed significantly between CDH groups
at the 8-week time point (P = .043). A second analysis
comparing the results for I ⱖ 50 vs I ⱕ 0 for amitrip-
tyline and placebo groups demonstrated significant
improvement for the amitriptyline group at 8 weeks
(P = .031) and at 16 weeks (P = .043) based on a
formal test of interaction. The differences between
the I ⱖ 50 and I ⱕ 0 groups were more striking with
25-46% of amitriptyline subjects at the various time
comparison periods showing I ⱖ 50 as compared with
only 5-20% of placebo subjects in this category.
Table 7 shows the comparison of headache fre-
quency data for the intermittent headache group by
the same ordered category analysis. No significant
differences were noted between the amitriptyline and
placebo groups. Note that at least some improvement
Headache 43

Table 7.—Frequency of Headache for Each 4-Week Time Period and Comparison With Baseline for the Intermittent Migraine
Group (1-16 Headaches per Month)

Frequency Category
Comparison
Weeks Group n I ⱖ 50 I < 50 Iⱕ0 No data P Value† P Value‡

4 vs 8 Amitriptyline 122 9 (7%) 36 (30%) 73 (60%) 4 (3%) P = .59 P = .39

Placebo 146 16 (11%) 39 (27%) 86 (59%) 5 (3%)
4 vs 12 Amitriptyline 101 11 (11%) 33 (33%) 50 (50%) 7 (7%) P = .94 P > .99
Placebo 121 13 (11%) 37 (31%) 64 (53%) 7 (6%)
4 vs 16 Amitriptyline 87 12 (14%) 21 (24%) 46 (53%) 8 (9%) P = .67 P = .82
Placebo 101 12 (12%) 31 (31%) 53 (53%) 5 (5%)
4 vs 20 Amitriptyline 79 9 (11%) 25 (23%) 37 (47%) 8 (10%) P = .88 P = .81
Placebo 85 12 (14%) 31 (36%) 39 (46%) 3 (4%)

†P value for 2 ¥ 3 Fisher’s exact test (cumulative logistic regression modeling).

‡P value for 2 ¥ 2 Fisher’s exact test comparing the proportion of I ⱖ 50 vs I ⱕ 0 between groups.
Comparison with baseline is given as no change or worse (I ⱕ 0), improvement of up to 50% (I < 50), or improvement ⱖ50%
(I ⱖ 50). Time periods are designated by the end of the 4-week period as in Table 5.

was reported by at least 38-52% of subjects in both
amitriptyline and placebo groups at each time point.
In the intermittent headache group, however, only
7-14% of subjects in either amitriptyline or placebo
groups reached the criterion of I ⱖ 50%.
The principle investigators at each site were
asked to provide an evaluation of “Global Response,”
which was a subjective evaluation of the patient’s
overall improvement in headache. For this subjective
measure, there was significant improvement at the
level of P < .01 at all time periods for both placebo
and amitriptyline groups when compared with the
4-week baseline. Intergroup comparison showed
improvement in the amitriptyline as compared with
the placebo groups at 8 (P = .062) and 12 weeks
(P = .029), but not at 16 and 20 weeks.
Data were collected on a group of 54 possible AE
that could be related to medications. Overall, 111 ami-
triptyline and 53 placebo subjects had at least one
AE. Severe AE were recorded in 30 amitriptyline and
in 10 placebo subjects. Table 8 shows the 10 categories
in which AE were collected and the comparison of
occurrence between amitriptyline and placebo sub-
jects. The AE were segregated into categories of mild,
moderate, and severe. Individual AE for whom ⱖ5
total or ⱖ3 severe AE were reported are listed under
the particular categorical title. The major individual
AE for which there were significant differences in
occurrence between amitriptyline and placebo groups
included: dry mucous membranes, constipation,
urinary retention, dizziness, and somnolence. Of note,
weight gain was not noted to be a major problem.
There were no deaths and no serious injuries
reported.
DISCUSSION
The major findings of this study are the following.
(1) As to parameters of headache measurement,
headache frequency was the major metric to use for
analysis of the data. (2) In comparison with placebo,
amitriptyline produced significant improvement with
decrease in headache frequency for the overall group
at 8 weeks; however, a strong placebo response after
that point negated differences between amitriptyline
and placebo. (3) In the subgroup of subjects with
CDH, there was significant improvement at weeks 8
and 16 with 25% and 46% of amitriptyline subjects as
compared with 5% and 9% of placebo subjects
having ⱖ50% improvement (I ⱖ 50) at those points
(Table 6). (4) For the intermittent headache group
there was a much lower response at the ⱖ50% level
and no differentiation from placebo (Table 7). (5)
There was a relatively high rate of placebo response
seen in this study for headache frequency, severity,
44 January 2011

Table 8.—Adverse Events (AE) Related to Medication

Amitriptyline Placebo

Category Item Mild Moderate Severe Total Mild Moderate Severe Total

Body as a whole 25* 13

Weight gain 2 1 – 3 1 1 – 2
Aesthenia 7 8 1 16 4 4 1 9
Fatigue/tired 6 8 1 15 4 4 – 8
Chest pain 1 2 – 3 – 1 – 1
Integument 68** 18
Dry mucous membrane 50 16 2 68** 9 4 1 14
Sweat discoloration 3 2 1 6 3 2 – 5
Rash 1 – – 1 – 3 – 3
Musculoskeletal – 2
Respiratory 1 –
Cardiovascular 10 8
Tachycardia 4 3 – 7 2 4 – 6
Digestive 28** 15
Constipation 15 6 2 23** 4 3 1 8
Nausea 1 2 1 4 1 2 – 3
Urogenital Urinary retention 2 3 1 6* – – – –
Nervous system 21 16
Dizziness 6 12 3 21** 5 6 – 11
Paresthesia 2 1 – 3 2 – – 2
Tremor 2 2 2 6 2 2 – 4
Organs – special sense 6 7
Visual disturbance 2 2 – 4 2 2 1 5
Psychiatric 61** 30
Agitation 5 8 1 14 2 6 – 8
Insomnia – 7 – 7 4 8 2 14
Nervousness 4 6 – 10 7 9 – 16
Somnolence 30 18 5 53** 7 10 – 17
Depression 1 – 3 4 – 1 1 2

*P < .05 for comparison of amitriptyline vs placebo group.

**P < .01.
Data were collected on 54 AE divided into 10 categories. The summary data for each category are presented. Severity of AE was
categorized as mild, moderate, or severe. Those AE with ⱖ5 occurrences or ⱖ3 severe occurrences are presented with numbers of
subjects with the AE given. Statistically significant changes between amitriptyline and placebo groups are noted.

and duration. For headache frequency the placebo
response seen primarily in the patients in the category
of 0 to <50% (I < 50) improvement in headache
frequency.
Of the 3 major parameters used to characterize
headache in this study, frequency, severity, and dura-
tion, the latter 2 changed little over the course of the
study suggesting that the headaches which occurred
were just as intense and lasted just as long after, as
before presentation of a possible preventative antimi-
graine agent. The major impact of the potential pro-
phylactic effect was to change the frequency of
headache allowing comparisons to be made primarily
on this parameter. Other studies involving amitrip-
tyline in prophylaxis of migraine have shown changes
in duration and intensity of migraine.11,13,15,18,22 For dis-
cussion of this study, the focus will be primarily on
changes in frequency of headache as a measure of
headache prophylaxis.
The analysis of the data differs from the previous
single center study11 in that the parameters of fre-
quency, duration, and intensity were analyzed sepa-
rately in the present study, while a combined
headache score was used in the prior trial. In addition,
Headache
for the prior study the analysis considered only severe
and disabling headaches and disregarded moderate
and mild ones. The “migraine score“ (M) used for that
study was constructed as follows:
M = 2 ( F × D)disabling + 1 ( F × D)severe
where F = frequency per month and D = duration in
hours averaged over the month. “Disabling” and
“severe” refer to the intensity of the headache. The
parameters of frequency, duration, and severity were
measured in the same way as for the present study.
In the current analysis all headaches were treated
the same in the individual parameter analyses so that
the duration or frequency of a mild headache contrib-
uted the same as a disabling one. This may help to
account for the absence of effect on duration and
severity of headache between amitriptyline and
placebo. This approach enhances the strength of the
significant findings in the analysis regarding CDH.
It should also be noted that use of a headache
index that involves multiplication of parameters will
magnify differences. Obtaining a significant differ-
ence based on only one parameter, such as frequency
in this case, is more difficult. Again, this tends to
enhance the significant findings here, especially in the
case of CDH where there was a difference in head-
ache frequency at the I ⱖ 50 level between amitrip-
tyline and placebo groups of 20% at week 8 and 37%
at week 16 (P < .05 for both, Table 6).
Using headache frequency as a metric, the overall
study format can be viewed as showing presence or
absence of an initial preventative antimigraine effect
that is manifested by the end of the 4-week titration
period (Period B, 4-8 weeks), and then presence or
enhancement of this effect or absence of maintenance
of this effect over the next 12 weeks (Period C, 8-20
weeks). This type of evaluation was presented in the
report of the single center study of amitriptyline vs
placebo in migraine prophylaxis that preceded the
present study.11 In that study of 12 weeks duration and
with a similar Y-type format but using a migraine
score, only 14% of patients who did not improve by
week 8 (after 4 weeks of amitriptyline therapy)
showed improvement of ⱖ50% by the 12th week. A
similar level of late response was seen in the placebo
group. These data suggested the framework of initial
45
response and then maintenance of response was
valid.
In the present study, for the entire group includ-
ing headache of all frequencies, the statistical signifi-
cance beyond 8 weeks is lost because of a robust
placebo response that rose to meet the level of
response of the amitriptyline group. This may be
due, in part, to attrition of subjects remaining in the
study at subsequent evaluation points. At the first
comparison of amitriptyline vs placebo at the eighth
week there were 154 amitriptyline and 163 placebo
subjects who had completed the 4-week baseline
and the first 4 weeks after randomization to amitrip-
tyline or placebo tracks (Table 4a). At that time,
both amitriptyline and placebo subjects showed a
significant improvement compared with baseline
(P < .0001); however, direct comparison of amitrip-
tyline vs placebo subjects showed that 42% of ami-
triptyline subjects had improved and 8% had
worsened while for placebo subjects, 37% had
improved and 21% had worsened (P = .018 in favor
of amitriptyline). By the 12th and 16th week evalu-
ation, 18-20% of subjects had been lost in each
group at each time point, and by week 20 an addi-
tional 10% of amitriptyline and 13% of placebo sub-
jects were lost. This level of subject attrition has
been seen in other studies.11,22 This problem of loss
of subjects was approached by analyzing each of the
data collection points (8, 12, 16, 20 weeks) separately
as a completer study. Previous studies of amitrip-
tyline in headache10,11,16,17 indicate that amitriptyline
has its major prophylactic effect by the third to
fourth week of administration. This suggests that, for
this study, the 8-week data that compare the first 4
weeks of treatment after randomization (Period B)
to the baseline placebo period (Period A) are a
major data point. In this study, measurements
beyond the eighth week could be distorted by
the study dropouts who are more likely to reflect the
nonresponders while the responders remain in the
study. As such it is quite possible that more placebo
responders than the placebo nonresponders
remained in the study, thus enhancing the placebo
response rate. This, in turn, suggests that the 8-week
data probably are more reflective of the prophylac-
tic antimigraine potential of amitriptyline.
46
The major effect of amitriptyline was seen in
the CDH group with ⱖ17 headaches per month
(Table 6). Of CDH subjects receiving amitriptyline,
25% were noted to have improvement in headache
frequency to I ⱖ 50 at 8 weeks rising further to 46%
of CDH subjects at 16 weeks. At these 2 time points
the placebo group showed only 5% and 9% of sub-
jects having I ⱖ 50. The differences were significant at
8 weeks (P = .031) and at 16 weeks (P = .043). This
suggests that amitriptyline has a greater effect in the
more severely affected headache patient and that the
effect continues to increase over time up to a point.
The prior single center study of amitriptyline vs
placebo also indicated that subjects with a more
severe migraine problem in terms of headache fre-
quency and intensity had a better response to ami-
triptyline.11 This supports the concept that
amitriptyline has a greater effect in the subject with
more severe migraine and may not be as appropriate
for the less severely affected patients.
In a recent review, Goadsby noted that the
expected standard for a putative preventative antimi-
graine medication to show effectiveness is an increase
over placebo of at least 25% in the number of subjects
who are at least 50% improved.5 For the analysis of
I ⱖ 50 vs I ⱕ 0 amitriptyline meets this standard for
change in headache frequency for the CDH group at
16 weeks and is close to the standard at 8 weeks.
Evaluating the IM group with headache fre-
quency or ⱕ16 headaches per month (Table 7), those
with I ⱖ 50% constituted only 7-14% of either treat-
ment group and the differences between amitrip-
tyline and placebo were not significant at any time
period. Evaluating the parameter of any improve-
ment for the IM group there was no difference
between the placebo and amitriptyline groups at any
time point. For the amitriptyline IM group 38-48% of
subjects showed any improvement at the various time
points while 39-52% of placebo subjects did so. This
analysis did not use a weighted score to account for
frequency of headaches of different severity. It is pos-
sible that use of such a tool might have produced a
different result.
There have been 7 studies of amitriptyline in pro-
phylaxis of migraine or tension headache that were
placebo-controlled and which employed quantifiable
January 2011
measures of headache occurrence.6,9,11,12,15-17 Another
study by Diamond and Baltes used only a “global
response” measurement for headache and is difficult
to interpret.8 Lance and Curran, in 1964, studied
“chronic tension headache” and carried out a double-
blind, crossover study of 27 subjects comparing ami-
triptyline to placebo.6 They noted that 55% of
subjects were ⱖ50% improved on amitriptyline as
compared with only 22% on placebo. Gomersall and
Stuart, in 1973, employed a double-blind crossover
study of 20 migraine subjects, and reported that 42%
of subjects were >50% improved on amitriptyline.9 A
comparable figure for placebo was not given. Couch
and Hassanein11 evaluated amitriptyline vs placebo in
a controlled study of migraine prophylaxis with a Y
type of design similar to the one used here. In this
study with 47 amitriptyline and 53 placebo subjects,
which utilized a combined headache score, improve-
ment of ⱖ50% was seen in 55% of amitriptyline as
opposed to 34% of placebo subjects (P < .05). Ziegler
et al evaluated amitriptyline against propranolol fol-
lowing a placebo run-in period and noted that both
drugs were equally effective.12,13 A placebo response
rate, however, was not reported. Rafieian-Kopaei et al
reported a parallel, 3-track study of amitriptyline, pro-
pranolol, and placebo in a trial that involved a 45-day
baseline period followed by 45 days of therapy in one
of the 3 tracks.15 Compared with the baseline period,
they found improvement in headache frequency in
33% of amitriptyline subjects and in 50% of propra-
nolol subjects. They did not report the results of those
who received only placebo. This study did note
improvement in severity and duration of headache
with both agents. Pfaffenrath et al compared amtrip-
tyline and amitriptyline oxide to placebo in a 3-way
parallel track study of 197 subjects evaluating pro-
phylaxis of chronic tension-type headache.16 They
found no significant difference in headache frequency
or duration but did find a trend toward decreasing
intensity of headache with amitriptyline and amitrip-
tyline oxide. Bendtsen et al compared amitriptyline
and citalopram to placebo in treatment of chronic
tension-type headache a 3-way double-blind cross-
over study of 34 subjects.17 They found amitriptyline
but not citalopram to be significantly better than
placebo.
Headache
There have been 7 other studies comparing ami-
triptyline to other potential prophylactic antimigraine
drugs without using a placebo track.18,20-24 Other com-
parator drugs included fluvoxamine, venlafaxine, and
topiramate. All seemed to perform reasonably well in
comparison with amitriptyline as far as headache
relief.18,22-24 Only topiramate was studied in a nonin-
feriority protocol comparing 178 topiramate with 169
amitriptyline subjects, and the study showed topira-
mate and amitriptyline equal in prophylactic antimi-
graine therapy.24 Two other studies evaluated
fluoxetine20 and citalopram21 as add-on therapy to
amitriptyline and neither showed a beneficial effect.
Lampl evaluated 2 different doses of an extended
release preparation of amitriptyline in headache
prevention.25
In the evaluation of drugs for migraine prophy-
laxis there have been 4 drugs that have been
approved for this purpose by the Food and Drug
Administration (FDA) of the USA. In historical
order, these include methysergide, propranolol, val-
proate, and topiramate.1,2 These agents all have Class
I data showing efficacy. The studies have varied in
format and in analysis of primary and secondary out-
comes. Generally, a criterion of improvement of
ⱖ50% in a headache parameter or index was one of
the primary or secondary outcomes.1,2,5 For all of
these agents the Class I Studies have shown improve-
ment of this level in approximately 50% of subjects.
In the studies with gabapentin, this approximate level
of response was achieved.31,32 In the present study,
amitriptyline has met this criterion for patients with
CDH. Amitriptyline and gabapentin have never been
presented to the FDA for approval primarily because
of expiration of patent rights. Amitriptyline, however,
remains one of the most commonly used, first line
medications for migraine prophylaxis,1,2,5 and has
been a comparator against which new drugs are
tested.15-17,24
The results here suggest that amitriptyline is
more effective in the more frequent and severe
migraine or, in this case the CDH subjects. The
reports of Lance and colleagues6,7 and of Diamond
and Baltes8 dealt with frequent headache termed
“chronic tension headache.” The former group
defined chronic tension headache as subjects having
47
headaches 10+ days per month and they noted that
most had daily headache. The latter group did not
state their criteria for chronic tension headache, but
they may have been similar to the definition that
Lance et al employed. As there was no standard defi-
nition of “chronic tension headache” at that time
comparisons are difficult. It would not be difficult to
assume that at least some of the patients had some
migraine headaches and might meet the Silberstein-
Lipton criteria for Transformed Migraine.29
In the study by Couch and Hassanein,11 a
migraine score (M) was employed that had dimen-
sions of headache frequency, duration, and intensity
formulated as noted above. A score of M = 100 after a
4-week placebo run-in was used to differentiate more
severe from less severe headache problems. For the
amitriptyline group, 51% of those with M < 100 and
67% of those with M ⱖ 100 were ⱖ50% improved. In
the placebo group, however, 31% of those with
M < 100 and 46% of those with M ⱖ 100 had ⱖ50%
improvement. This suggests that greater improve-
ment in the more severely affected patients might
be an expected outcome; however, amitriptyline
enhances this outcome. The data presented here
agree with this concept.
In the study of prophylactic antimigraine agents
there have been relatively few placebo-controlled
studies dealing with CDH because of the challenge of
designing an effective study dealing with this difficult
entity. Five placebo-controlled studies were identified
of which 2 dealt with amitriptyline,16,17 one with cit-
alopram,17 one with gabapentin,32 and 2 with topira-
mate.33,34 Table 9 summarizes these studies and
compares the results to those reported here for the
CDH group. The study formats and reporting of the
data varied; however, 2 of the studies did report a
statistic of number with ⱖ50% improvement over
baseline (I ⱖ 50).32,34 For gabapentin using a double-
blind, crossover format in 95 evaluable subjects,
I ⱖ 50 was seen in 23% when on gabapentin and only
7.6% of subjects when on placebo (p not given).32 For
topiramate, in a study using a Y type of design, 22% of
topiramate subjects and 0% of placebo subjects
showed I ⱖ 50 (P = .02).34 For the CDH group here,
by week 8 at the end of the 4-week titration period,
25% of amitriptyline subjects and 5% of placebo sub-
 48

Table 9.—Comparison of Studies of Treatment of Chronic Daily Headache With Gabapentin or Topiramate and Comparison With the Current Amitriptyline Study

Stabilization
Period – Response to P (Compare
Number of Baseline Titration Weeks of Response to Drug Placebo Drug vs
Study and Format Drug Patients Period Period Study Statistic Used (Improve) (Improve) Placebo)

Pfaffenrath et al16 Amitriptyline 197 4 weeks 8 weeks 4 weeks I ⱖ 50% in HA index 22% 21.9% .32
Amitriptyline (frequency ¥ duration) 30.3% .32
oxide
Bendtsen et al17 Amitriptyline 34 4 weeks 2 weeks 6 weeks HA index 28% better than .002
DBC Citalopram duration ¥ intensity placebo .68
12% better than
placebo
Spira et al 200330 Gabapentin 95 evaluable patients 4 weekss 2 weeks 6 weeks Change in +26.6% +17.5% P = .0001
DBC headache-free days
over 6 weeks vs
baseline
I ⱖ 50% 23% 7.6% Not given
Silberstein 200731 Topiramate 328 randomized 4 weeks 4 weeks Weeks 8-20 Decrease in migraine 6.4 ⫾ 5.8 avg 37.4% 4.7 ⫾ 6.1 avg 27.6% P = .01
Y type 182 completed averaged days
(55.5%)
Diener et al 200732 Topiramate 59 randomized 4 weeks 4 weeks 4 weeks Decrease in migraine 3.5 ⫾ 6.3 +0.2 ⫾ 4.7 P = .02
Y type 38 completed Week 16-20 days 22.6% +.012%
(64.4%) I > 50 22% 0%
Couch current study Amitriptyline 34 A 4 weeks 4 weeks End of titration I ⱖ 50 25% 5% P = .031
End of week 8 22 P to week 8
Y type Amitriptyline 24 A 4 weeks 4 weeks End of week 16 I ⱖ 50 46% 9% P = .043
End of week 16 11 P

A = amitriptyline; DBC = double-blind crossover study; P = placebo.

January 2011
Headache
jects achieved I ⱖ 50 (P = .03). For weeks 12-16, 46%
of amitriptyline subjects and only 9% of placebo sub-
jects showed I ⱖ 50. Comparing number of subjects at
the end of weeks 8 and 16, however, 33% of amitrip-
tyline subject and 50% of placebo subjects were lost
by week 16. The data here do suggest that amitrip-
tyline compares favorable with gabapentin and topi-
ramate in treating CDH.
The side effects seen in the study were those that
would be expected with amitriptyline (Table 8).
Overall, side effects occurred twice as often in the
amitriptyline as in the placebo group. The most
frequent side effects were those of dry mouth, consti-
pation agitation, somnolence, and dizziness. Urinary
retention was noted in 6 subjects but in no placebo
subjects. Of note, weight gain in the amitriptyline
group was not reported as a major problem, as it has
been in more recent studies.35
Using headache frequency as the metric, the
placebo response was quite high in this study for any
improvement (Table 4a). For the initial analysis tabu-
lating improvement, no change or worse over the
analyses for weeks 8-20, 37-52% of the placebo group
and 42-51% of the amitriptyline group showed
improvement. When the response was subdivided
into groups of improvement of ⱖ50% (I ⱖ 50)
and < 50% (I ⱕ 0, I < 50) only the CDH group receiv-
ing amitriptyline showed a good response for ⱖ50%
improvement with 25-46% reaching this criterion
while only 5-20% of placebo CDH subjects did so.
Van der Kuy and Lohman36 and Macedo et al37
carried out meta-analyses of placebo response in
studies of migraine prophylaxis and found the
average placebo response for a criterion of ⱖ50%
improvement in headache frequency was 21.0-23.5%
of subjects reaching this level with the highest
placebo response being 55%. For this study, the
response of the placebo group for the CDH and IM
comparisons falls within acceptable limits with 5-20%
of placebo subjects showing response of ⱖ50%
improvement in headache frequency.
There are several significant weaknesses to this
study. First there was no standard definition of
migraine at the time the study was carried out. The
International Headache Society (IHS) provided a
much clearer definition of migraine in the first and
49
second versions of the ICHD 1 and 2.30,32 The modi-
fications to the 1962 classification27 employed
here10,11,26 (see Methods) did provide definition signifi-
cantly closer to that of the ICHD. For this study, a
clear listing of migraine associated symptoms was
obtained from each subject (see Methods) and these
symptoms were utilized in the definition of migraine.
This definition is more strict than the 1962 Ad Hoc
committee definition,27 but significant possibility for
deviation from the IHS Guidelines remains. Second,
the study is marred by a high dropout rate of 52%;
however, this is a dropout rate similar to that of the
earlier study by Couch and Hassanein,11 and also for
the recent comparator study by Dodick et al.24 Third,
the present study was analyzed as a “Completer”
study and not as an “Intent to Treat” study. The Intent
to Treat format was not being used in 1976 when the
study protocol was developed. It is possible that use
of this format might have significantly altered the
study results.
The study does have strengths that need mention.
First, this is the largest double-blind, placebo-
controlled study of amitriptyline in the treatment of
migraine that has been carried out. Second, the study
covered the spectrum of headaches from less fre-
quent (1-4 per month) to CDH (ⱖ17 per month).
While this might be considered a weakness in study
design, the study does approximate the situation seen
in the clinic to a greater extent than studies that limit
the headache frequency to 14 or fewer headaches per
month. In this respect, the study helps identify the
patients who are more likely to respond to amitrip-
tyline, that is the more severely affected ones.
CONCLUSION
This double-blind, placebo-controlled study dem-
onstrates that amitriptyline is effective, in comparison
with placebo, in treating CDH, which fits the defini-
tion of transformed migraine.29 Amitriptyline reduced
the frequency of headache over the initial 4-week
period of therapy and continued to provide further
reduction in headache frequency up to week 16.
Severity and duration of headache were altered very
little and not to a greater extent than in the placebo
group. For IM, there was some improvement, but not
to a greater extent than placebo. AE were seen
50
roughly twice as often in the amitriptyline group;
however, no severe AE were reported.
Acknowledgments: The original study was sup-
ported by Merck, Sharp, and Dohme Research Labora-
tories. The re-analysis and development of this
manuscript was supported in part by a research grant
from the Investigator Initiated Studies Program of Merck
& Co. Inc. The opinions expressed in this paper are those
of the authors and do not necessarily represent those of
Merck & Co. Inc. Julie Stoner, PhD, Associate Professor
of Biostatistics University of Oklahoma Health Sciences
Center provided the re-analysis of the data presented in
this manuscript and provided significant help in the sta-
tistical interpretation of the data.
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