Acta Neurol Scand 2013: 128: 65–72 DOI: 10.1111/ane.

12081 Ó 2013 John Wiley & Sons A/S

ACTA NEUROLOGICA
SCANDINAVICA

Amitriptyline vs divalproate in migraine

prophylaxis: a randomized controlled trial
Kalita J, Bhoi SK, Misra UK. Amitriptyline vs divalproate in J. Kalita, S. K. Bhoi, U. K. Misra
migraine prophylaxis: a randomized controlled trial. Department of Neurology, Sanjay Gandhi Post
Acta Neurol Scand 2013: 128: 65–72. Graduate Institute of Medical Sciences, Lucknow, India
© 2013 John Wiley & Sons A/S.
Objective – This study compares efficacy and safety of divalproate
extended release (DVA-ER) and amitriptyline (AMT) in migraine.
Materials and methods – Three hundred migraineurs having >4 attacks
monthly were randomized into DVA-ER or AMT. The primary end
points were >50% reduction in frequency,  1 grade improvement in
the severity, and >50% improvement in a visual analogue scale (VAS).
Secondary end points were functional disability, rescue medication,
and adverse events. Results – The median age was 32 years, and 241
were women. 150 patients each received DVA-ER and AMT. At
3 months, 74.7% in DVA-ER and 62% patients in AMT group
improved in headache frequency (P = 0.02) and at 6 months, 65.3%
Key words: migraine; divalproate; amitriptyline;
and 54%, respectively (P = 0.90). At 3 months, the VAS score antiepileptic; sodium valproate; tricyclic antidepressant;
improved by >50% in 80.7% in DVA-ER and 64% in AMT randomized controlled trial; prophylaxis
(P = 0.005). At 6 months, there was no significant difference between
J. Kalita, Department of Neurology, Sanjay Gandhi
the two groups in VAS score (69.3% vs 56%; P = 0.47) and other Post Graduate Institute of Medical Sciences,
outcome parameters. The composite side effects were also not Raebareily Road, Lucknow-226014, Uttar Pradesh, India
different between the two groups (68% vs 81%); however, hair fall, Tel.: +091-522-2494167
menstrual irregularity, polycystic ovary, and weight gain were Fax: +91 522 2668811
commoner in DVA-ER group. Conclusion – Divalproate extended e-mail: jayanteek@yahoo.com; jkalita@sgpgi.ac.in
release is more effective at 3 months than AMT; however, at
6 months, both are equally effective in migraine prophylaxis. Accepted for publication December 14, 2012

Amitriptyline (AMT) was first used in the

Introduction
Headache is a common health problem and affects
more people than asthma and diabetes mellitus
combined (1, 2). Headache results in moderate to
severe disability in more than 50% patients (3). As
per World Health Organization, migraine is one of
the topmost disabling health disorders and leads to
a lower quality of life compared with diabetes,
heart disease, and depression (4–6). Migraine is
more than just an episodic disorder, which has led
to emphasis on prophylactic therapy to prevent or
reduce the frequency of acute attacks and improve
the level of functioning by reducing disability. For
migraine prophylaxis, a number of drugs of differ-
ent classes are used and include antidepressants
(amitriptyline, fluoxetine, and venlaflexine), anti-
epileptics (valproate, divalproate, and topiramate),
beta-adrenergic blockers (propranolol, atenolol,
and metoprolol), and calcium channel blocker (flu-
narizine).
treatment of migraine in 1964, and in this study
on 27 subjects, AMT resulted in significant
improvement in 56% patients (7). AMT was also
found to be superior to placebo in reducing the
headache frequency (55% vs 34%) (8). In a ran-
domized controlled trial (RCT), AMT resulted in
significant improvement in headache frequency at
8 and 16 weeks compared with placebo in chronic
daily headache (9). AMT was found to be as
effective as topiramate in a recent RCT (10). Di-
valproate extended release (DVA-ER) has been
recommended for migraine prophylaxis since
2005, and its efficacy has been reported in 45%
to 75% of patients (11). In a retrospective analy-
sis of 642 patients on sodium valproate (SVA),
there was 65% improvement, which was indepen-
dent of age, gender, and duration of treatment
(12). The majority of studies on DVA/SVA are
randomized placebo-controlled. There are only
few studies comparing the efficacy of DVA/SVA

65
Kalita et al.
with other migraine prophylactic drugs. In a
study, SVA resulted improvement in migraine in
71% and flunarizine in 65% of patients (13).
Sodium valproate and topiramate were found to
be equally effective in reducing the number of
headache days (14). Both DVA and amitriptyline
have class 1 recommendation for migraine pro-
phylaxis. There is, however, no study comparing
the relative efficacy and tolerability of DVA and
AMT. In this communication, we report the effi-
cacy and tolerability of DVA-ER (extended
release) vs AMT in migraine prophylaxis.
Materials and methods
Study design
This is a single-center prospective study with ran-
domized controlled open-labelled design and eval-
uates the efficacy and safety of DVA-ER and
AMT. The study was done in a tertiary care
teaching hospital, and patients were enrolled
from the neurology outpatient service. The proto-
col was designed and written by the first and
third authors. The trial was not registered; how-
ever, it was approved by the Institute Ethics
Committee. All the patients gave informed con-
sent. The sample size was calculated keeping the
type 1 error a = 0.05 and type II error b = 0.1
using Z-test of proportion. The critical response
between the study drugs was considered to be sig-
nificant as 20% considering the efficacy of DVA-
ER as 70%. The sample size was calculated to be
134 on each arm with the power of test 90%.
One hundred and fifty patients in each treatment
arm were decided to be enrolled in this study.
Selection of the study patients and their evaluation
Inclusion criteria – Migraine patients between 15
and 60 years of age having more than four mod-
erate to severe attacks were included in this
study. The diagnosis of migraine was based on
International Headache Society Criteria (15).
Exclusion criteria – The patients with history of
drug allergy, severe hypertension, coronary artery
disease, pregnancy, menstrual irregularity, liver or
kidney dysfunction, polycystic ovary, systemic or
psychiatric disease, malignancy, glaucoma, dysau-
tonomia, and those unwilling were excluded.
Clinical evaluation – A medical history including
duration of migraine, distribution, frequency and
triggering factors, family history of headache,
diabetes, hypertension, and other medical illness
66
was enquired. The severity of headache was
graded on a 0–3 scale (0 = none, 1 = mild,
2 = moderate, 3 = severe). The functional disabil-
ity was graded on a 0–4 scale (0 = none,
1 = mild, 2 = moderate, 3 = severe impairment of
daily activity, 4 = inability to perform daily activ-
ity requiring bed rest). The severity of associated
symptoms such a nausea, vomiting, photophobia,
and phonophobia was recorded on a 0–3 scale
(0 = none, 1 = mild, 2 = moderate, 3 = severe).
General medical and neurological examinations
were performed in all. All the patients maintained
a headache diary 1 month prior to the randomi-
zation and during the study period.
Investigations – Blood counts, hemoglobin, ESR,
urinalysis, fasting and post-prandial blood sugar,
serum creatinine, electrolytes, bilirubin, transam-
inases, and serum calcium were estimated. Electro-
cardiogram was performed in all, and abdominal
ultrasonography was carried out in the females
who had menstrual irregularities.
Randomization and treatment – The patients were
randomized to amitriptyline or DVA-ER using
the computer-generated random table numbers.
The randomization, treatment, and evaluation of
the patients were performed by different investi-
gators. The identity of the drug was not con-
cealed. Amitriptyline was prescribed in a dose of
12.5 mg per oral for 2 weeks, thereafter 25 mg
daily which was increased to 50 mg if needed
depending on the response or tolerability. Dival-
proate extended release was prescribed in a dose
of 250 mg daily for 2 weeks followed by 500 mg
daily and increased to 1000 mg depending on the
response and tolerability. Ibuprofen 400 mg was
used as rescue medication. The patients were
advised to report if there was any adverse effect.
Follow-up – The patients were followed up at 3
and 6 months, and their headache frequency,
severity, functional disability, number of rescue
medication, and overall improvement on a 0–100
visual analogue scale (VAS) were recorded.
Patients’ body weight, liver function tests, and
abdominal ultrasonography in the females who
had menstrual irregularities were carried out.
Outcome – The primary outcome parameters were
(i) more than 50% reduction in the headache
frequency, (ii) more than 50% improvement in
the overall headache on VAS score, and (iii) one
or more grade reduction in the headache severity
scale. The secondary outcome parameters
included (i) one grade or more improvement in

Assessed for eligibility
Enrollment
Divalproate ER (n = 150)
Lost follow up (n = 7)
Divalproate ER (n = 143)
Lost follow up (n = 4)
Withdrawn (n = 32)
Side effect (n = 6)
Lack of response (n = 26)
Divalproate ER (n = 107)
Figure 1. Flowchart showing consort statement.
the functional disability, (ii) reduction in the
number of rescue medication, and (iii) adverse
events.
Statistical analysis – The demographic, clinical,
and laboratory parameters in amitriptyline and
DVA-ER groups were compared using various
parametric and non-parametric tests. The severity
and frequency of headache, number of rescue
medication, and functional disability at baseline
3 months and 6 months following treatment
within the group were compared using analysis of
variance (ANOVA). The number of patients with
the primary and secondary end points at 3 and
6 months was compared by chi-square test with
Yates’ correction. The intention to treat analysis
was done for primary and secondary end points.
The variables were considered significant if the
two-tailed P-value was less than 0.05. The statisti-
cal analysis was performed using SPSS for Win-
dows, version 12 (SPSS Inc., Chicago, IL, USA)
and GraphPad Prism for windows, Version 3
(GraphPad software Inc., Sandiego, CA, USA).
Results
Recruitment of the patients
During the study period, 360 patients with
migraine having more than four attacks per
month were screened. Sixty patients were
Amitriptyline and divalproate in migraine
(n = 360)
Excluded (n = 60 )
¨ Not meeting inclusion criteria (n = 30)
Randomized ¨ Declined to participate (n = 20)
(n = 300) ¨ Other reasons (n = 10)
Allocation
Amitriptyline (n = 150)
Lost follow up (n = 6)
Analysis 3 month Amitriptyline (n = 144)
Lost follow up (n = 6)
Withdrawn (n = 49)
Side effect (n = 4)
Lack of response
(n = 45)
Analysis 6 month Amitriptyline (n = 89)
excluded because of associated tension-type head-
ache in 14, deranged liver and renal function in
8, connective tissue disease in 6, pregnancy or lac-
tation in 4, coronary artery disease in 3, enlarged
prostate in 2, major depression in 2, acute close-
angle glaucoma in 1, and lack of consent in 20
patients (Fig. 1). Our results are therefore based
on 300 patients with migraine whose age ranged
between 15 and 60 (median 32) years and 241
were women. The median duration of migraine
was 5 years (6 months to 40 years). The family
history of headache in the first-degree relatives
was present in 86 patients. All the patients had
moderate to severe headache. The median head-
ache frequency was 6 per month prior to ran-
domization. All the patients had migraine
without aura except 19. The median severity of
headache was 2.91 (range 2–3), and the func-
tional disability was 3. Divalproate extended
release and amitriptyline were prescribed to 150
patients each. The demographic and clinical fea-
tures in both the groups were not significantly
different (Table 1).
Outcome
Primary outcome – All the primary and secondary
end points showed significant improvement at 3
and 6 months compared with baseline in the both
DVA-ER and the AMT groups. The frequency of
headache and number of rescue medications were
67
Kalita et al.

Table 1 Baseline characteristics of migraine patients receiving amitriptyline group, 93 (62%) patients improved. At 6 months,
and divalproate
however, there was no significant difference in
the response between the DVA-ER and the AMT
Amitriptyline
Parameters Divalproate (n = 150) (n = 150) P-value group (65.3% vs 54%, P = 0.90). In the DVA-
ER group, one patient at 3 months and nine
Age (years) 31.03  10.5 32.80  9.41 0.13
Education (years) 10.22  5.05 9.78  5.11 0.45
patients at 6 months and in the AMT group two
Female 123 (82%) 118 (78.7%) 0.56 patients at 3 months and nine patients at
Rural/urban 65/85 76/74 0.25 6 months were headache free. The severity of
Family history of 48 (32%) 38 (25.3%) 0.25 headache reduced in both the groups at 3 and
headache
Duration of illness 7.23  6.44 7.41  6.54 0.81
6 months compared with baseline, but it was not
(years) significantly different between DVA-ER and
Total number of 10.44  2.88 10.24  2.97 0.55 AMT group both at 3 months (P = 0.09) as well
triggers as at 6 months (P = 0.05). 138 (92%) patients in
Migraine with aura 14 (9.3%) 5 (3.3%) 0.06
Frequency of 10.49  9.04 11.19  9.65 0.51
the DVA-ER group had improvement at
migraine/month 3 months and 102 (68.0%) at 6 months, whereas
Severity of headache 2.95  0.22 2.88  0.38 0.06 in the AMT group, these were 131 (87.3%) and
Functional disability 3.19  0.62 3.05  0.69 0.06 78 (52%), respectively. In the VAS score, 121
Rescue analgesics/month 10.38  6.95 10.17  7.95 0.81
(80.7%) patients had more than 50% improve-

Figure 2. Error bar diagram shows significant improvement in frequency of migraine attack/month and its severity following di-
valproate (DVA) and amitriptyline (AMT) at 3 and 6 months compared with baseline. Patients on DVA had significant reduction
in frequency of headache at 3 months compared with AMT.

Figure 3. Error bar diagram shows significant improvement in functional disability and reduction in number of analgesics use fol-
lowing divalproate (DVA) and amitriptyline (AMT) at 3 and 6 months compared with baseline. The improvement in different
time points, however, was not significantly different between DVA and AMT groups.

not significantly changed at 6 months compared
with 3 months in the DVA-ER group (Figs 2 and
3). On comparing the efficacy between the ami-
triptyline and the DVA-ER group at 3 months,
there was significant improvement in the head-
ache frequency in DVA-ER compared with AMT
group (P = 0.02). In the DVA-ER group, 112
(74.7%) patients had improved with respect to
the headache frequency, whereas in the AMT
ment at 3 months and 104 (69.3%) at 6 months
in DVA-ER group. In the AMT group, these
were 96 (64%) and 84 (56%), respectively. The
details are presented in the Table 2.
The secondary end points were also improved in
both the groups from the baseline, but the differ-
ence between the DVA-ER and AMT groups was
not significant. The details of the response in the
functional disability, number of rescue medications,

68
 Amitriptyline and divalproate in migraine

Table 2 The primary and secondary outcome parameters at 3 and 6 month following divalproate and amitriptyline prophylaxis in patients with migraine using intention
to treat analysis

Scale Divalproate N (ITT%) Amitriptyline N (ITT%) P-value

Primary outcome
VAS (0–100)
0–3 months >50% 121 (80.7) 96 (64) 0.005
<50% 23 (19.3) 50 (36) OR-2.74 (1.51–5)
0–6 months >50% 104 (69.3) 84 (56) 0.47
<50% 3 (30.7) 5 (44) OR-2.06 (0.41–11.26)
Frequency of migraine/month
0–3 months >50% improvement 112 (74.7) 93 (62) 0.02
<50% improvement 31 (25.3) 51 (38) OR-1.9 (1.09–3.34)
0–6 months >50% improvement 98 (65.3) 81 (54) 0.90
<50% improvement 9 (34.7) 8 (46) OR-1.08 (0.36–3.21)
Severity of headache  1grade improvement
0–3 months Improvement 138 (92) 131 (87.3) 0.09
No improvement 5 (8) 13 (12.7) OR-2.74 (0.08–9.08)
0 vs 6 months Improvement 102 (68) 78 (52) 0.05
No improvement 5 (32) 11 (48) OR-2.88 (0.88–9.96)
Secondary outcome
Functional disability  1grade improvement
0–3 months Improvement 141 (94) 137 (91.3) 0.17
No improvement 2 (6) 7 (8.7) OR-3.6 (0.67–25.6)
0–6 months Improvement 106 (70.7) 87 (58) 0.60
No improvement 1 (29.3) 2 (42) OR-2.44 (0.17–69.07)
Average number of analgesic/month Baseline 10.38  6.95 10.17  7.95 0.81
3 month 2.92  2.28 3.45  2.44 0.06
6 month 1.21  0.94 1.43  1.4 0.20

ITT, intention to treat analysis; VAS, visual analogue scale.

[Baseline: Divalproate (n = 150), Amitriptyline (n = 150); 3 month: Divalproate (n = 143), Amitriptyline (n = 144); 6 month: Divalproate (n = 107), Amitriptyline (n = 89)].

Table 3 Side effects of amitriptyline and divalproate at 3 and 6 months in months, DVA-ER resulted significant improvement
migraine patients in VAS score at 3 months (80% vs 62.7%,
P = 0.001) as well as at 6 months (69.3% vs 56%,
Divalproate Amitriptyline
Side effects N (%) N (%) P-value
P = 0.02) compared with AMT. There was, how-
ever, no difference in the response in the other out-
Total side 3 months 68 (47.6) 81 (56.3) 0.16 come parameters. The effect of AMT was not
effects 6 months 41 (38.3) 30 (33.7) 0.6
Drowsiness 3 months 7 (4.9) 69 (47.3) 0.001 significantly different between those having <10 or
6 months 4 (3.7) 9 (10.1) 0.09 more than >10 migraine days per month at
Hair fall 3 months 55 (38.5) 2 (1.4) 0.001 3 months (68.4% vs 63.2%, P = 0.52) and
6 months 10 (9.3) 1 (1.1) 0.01 6 months (66.7% vs 52.9%, P = 0.10) follow-up.
Menstrual 3 months 6 (4.8) 0 0.02
irregularity 6 months 9 (8.4) 1 (1.1) 0.001
Dry mouth 3 months 13 (9.1) 78 (56.5) 0.001 Side effects – At 3 months, 68 patients in the DVA-
6 months 4 (3.7) 24 (27) 0.02 ER and 81 in the AMT group had side effects
G.I. symptoms 3 months 18 (12.6) 12 (8.3) 0.25 (P = 0.16). Majority of side effects were mild; DVA-
6 months 16 (15) 4 (4.5) 0.001
Giddiness 3 months 3 (2.1) 4 (3.6) 1.0 ER was discontinued in six patients and AMT in
6 months 6 (5.6) 3 (3.4) 0.5 four due to side effects. Drowsiness and dry mouth
Vomiting 3 months 0 1 (0.7) 1.0 were more frequent in AMT, whereas hair fall, men-
6 months 0 0 NA strual irregularity, gastro intestinal symptoms,
PCOS 6 months 6 (5.4) 0 0.03
Weight gain 3 months 79 (61.7) 71 (58.7) 0.7 weight gain, and polycystic ovarian syndrome
6 months 66 (66.7) 27 (37) 0.001 (PCOS) were more common in DVA-ER group.
Weight gain (66 vs 27, P = 0.001) and PCOS (6 vs 0,
PCOS, polycystic ovarian syndrome. P = 0.03) were significant at 6 rather than 3 months.
[Baseline: Divalproate (n = 150), Amitriptyline (n = 150); 3 month: Divalproate
The side effects are summarized in the Table 3.
(n = 143), Amitriptyline (n = 144); 6 month: Divalproate (n = 107), Amitriptyline
(n = 89)].

Discussion
and side effects are presented in Tables 2 and 3. On
subanalysis intention to treat analysis (ITT) of the In this study on migraine prophylaxis, both DVA-
patients having migraine days  10 and >10 per ER and AMT resulted in significant improvement

69
Kalita et al.
in all the outcome parameters at 3 and 6 months
compared with baseline. At 3 months, DVA-ER
significantly reduced headache frequency (74.7%
vs 62%) and improved in VAS score (80.7% vs
64%) compared with AMT. At 6 months, how-
ever, the difference in the response between the
DVA-ER and the AMT group was not significant.
In the available literature, there is no study com-
paring the efficacy of DVA-ER and AMT in
migraine prophylaxis. The reported efficacy of
DVA/SVA has ranged between 45% and 86.2%
(11, 13–23). Most of these studies have compared
the efficacy of DVA or SVA with placebo. The
head to head comparisons are available in small
series in reference to topiramate (14, 23). Most of
these studies have compared the headache fre-
quency as the primary end point except 2; one
study compared duration, frequency, and severity
of migraine (16), and the other study compared the
severity, general pain VAS score, and frequency of
headache (18). In addition to headache frequency,
we have also included severity, overall improve-
ment in headache, functional disability, and num-
ber of rescue medications, which have lead to a
more comprehensive evaluation.
The advantage of DVA-ER over AMT at
3 months was not sustained at 6 months. The effi-
cacy with respect to 50% reduction in headache
frequency in AMT and DVA-ER was similar at
6 months. This may be due to a quicker response
of DVA-ER and slower and sustained response of
AMT. Most of the earlier studies have evaluated
the response at 4–12 weeks (8, 24). Intravenous
sodium valproate has also been used in a dose of
900 mg to 1200 mg as an abortive therapy in 36
patients with severe migraine. It resulted in pain
reduction or relief in 75% patients at 1 h without
any adverse event (25). In a recent study, the effi-
cacy and tolerability of topiramate and AMT were
compared in 331 patients with migraine. The mean
monthly number of migraine attacks was not sig-
nificantly different between the two groups. The
secondary outcome measures such as severity of
migraine-associated symptoms, mean monthly
migraine days, and total headache days were also
not different between the topiramate and the AMT
group. Patients on topiramate, however, had
improvement in functional disability and reduction
in body weight compared with those on AMT (10).
In this study, amitriptyline was titrated up to
100 mg, which is double the dose in comparison
with our study. A large trial of AMT was per-
formed in 1976–1979 (8). The report was delayed
due to loss of patent protection in 1980, and
reanalysis of these data was published in 2011 (9).
There is no large study on smaller dose of AMT.
70
Even with smaller dose of AMT in our study, 81
patients developed side effects necessitating with-
drawal of drug in four patients. The improvement
in headache parameters in our study, however, was
comparable with other studies using higher dose of
amitriptyline. The efficacy of smaller dose of ami-
triptyline in our study may be due to smaller body
configuration of Indians, different metabolic rate,
or genetic basis.
In a study, AMT has been reported to reduce
the migraine frequency by 42% at 8 weeks, 47%
at 12 weeks, 48% at 16 weeks, and 51% at
20 weeks, suggesting progressive improvement in
the response. The severity and the duration of
migraine also had a sustained effect, and the
maximum response was reported at 3 months (9).
In our study, however, the improvement in the
frequency and severity of headache, VAS score,
and functional disability was significant even at
6 months compared with 3 months, confirming
ongoing improvement.
Tricyclic antidepressants (TCAs) upregulate the
GABA-B receptor, downregulate histamine recep-
tor, and reduce the neuronal sensitivity to sub-
stance-P. Tricyclic antidepressants also interact
with endogenous adenosine systems in the central
nervous system by inhibiting neurogenic uptake
of adenosine and augmenting the action of aden-
osine. The enhanced availability of adenosine
and adenosine receptors contributes to antinoci-
ception (26). The mechanism of action of SVA in
migraine prophylaxis includes facilitation of
GABA-ergic neurotransmission, decrease in the
activity of serotonergic cells, and reduction in
neurogenic inflammation. Thereby, SVA/DVA
acts both at the stimulus and at the site of pain
resulting in reduction of neurogenic inflammation
(27). The cumulative side effects in the patients
receiving DVA-ER and those receiving AMT,
although, were not different, but anticholinergic
side effects and sedation were common in the
AMT group, and hair fall, menstrual irregularity,
and PCOS were common in the DVA-ER group.
In a study on 194 patients with migraine who
were on AMT; the adverse events were dry
mouth in 68, constipation in 23, urinary retention
in 6, dizziness in 21, and somnolence in 53
patients which were significantly more compared
with placebo. At least one side effect was noted
in 111 patients in the AMT and in 53 patients in
the placebo group (9). In a long-term study of
DVA in chronic daily headache, adverse events
occurred in 35% patients. Weight gain was noted
in 7.1% patients. None had severe adverse events
necessitating drug withdrawal (12). In another
study, no significant difference in side effects was

noted between the DVA and the placebo group
(17). The common side effects leading to drug
withdrawal were anorexia, nausea, and distur-
bance in attention (22). Higher frequency of side
effects in our study especially in females may be
due to greater susceptibility and vigor of moni-
toring, as in the abovementioned study, and pel-
vic ultrasonography was not discussed.
We have not used a placebo arm in our study.
Placebo effect, however, is reported in variable
proportion of migraine patients, both in abortive
and in prophylactic treatment. In a meta-analysis
of 22 placebo-controlled trials, the percentage of
placebo responders (>50% improvement) was
23.5%  8.0% (28). The response has been
reported to be more pronounced in invasive pla-
cebo treatment (29). The analysis of pooled data
of 2 randomized placebo-controlled trial on on-
abotulinum toxin A revealed placebo effect in
35.1% at 24 weeks (30). In view of available drug
options, it may not be ethical to follow placebo
orthodoxy. Our aim was to compare the efficacy
and tolerability of these two class I drugs recom-
mended for migraine prophylaxis. The dose of
the AMT was comparatively lower in our study
than in the reported literature; although, even
with this dose, the efficacy of AMT was compa-
rable to DVA at 6 months.
It can be concluded from this class I study that
DVA-ER is more effective at 3 months, but
AMT is equally effective at 6 months and seems
to be safer and more desirable in females.
Acknowledgements
We would also like to acknowledge Rakesh Kumar Nigam
and Rupali Mishra for secretarial help.
Conflict of interest
There is no conflict of interest to declare.
Source of funding
No Funding support.
Author’s Contribution
Jayantee Kalita and Usha K Misra performed Planning,
interpretation, and writing of manuscript. Sanjeev K Bhoi
carried out data collection and analysis.
Ethics approval
The research has been approved by the Institutional Ethics
Committee, SGPGIMS, Lucknow.
Amitriptyline and divalproate in migraine
References
1. Centers for Disease Control and Prevention (CDC). Sta-
tistics: Prevalence of diabetes in the U.S. http://www.cdc.
gov/diabetes/pubs/pdf/DiabetesReportCard.pdf (accessed
1 January 2013).
2. Centers for Disease Control and Prevention (CDC).
Asthma prevalence, health care use, and mortality, 2000–
2001; http://www.cdc.gov/nchs/products/ pibs/pubd/he-
stats/asthma/asthma.htm (accessed 1 April 2007).
3. LIPTON RB, STEWART WF, DIAMOND S, DIAMOND ML,
REED M. Prevalence and burden of migraine in the Uni-
ted States: data from the American Migraine Study II.
Headache 2001;41:646–57.
4. World Health Organization (WHO). World Heath
Report 2001. Mental health: new understanding, new
hope. Geneva, Switzerland: WHO Library Cataloguing
in Publication Data, 2001.
5. LIPTON RB, DIAMOND S, REED M, DIAMOND ML, STEWART
WF. Migraine diagnosis and treatment: results from the
American Migraine Study II. Headache 2001;41:638–45.
6. LIPTON RB, SCHER AI, KOLODNER K, LIBERMAN J, STEI-
NER TJ, STEWART WF. Migraine in the United States: epi-
demiology and patterns of health care use. Neurology
2002;58:885–94.
7. LANCE JW, CURRAN DA. Treatment of chronic tension
headache. Lancet 1964;1:1236–9.
8. COUCH JR, HASSANEIN RS. Amitriptyline in migraine pro-
phylaxis. Arch Neurol 1979;36:695–99.
9. COUCH JR. Amitriptyline Versus Placebo Study Group.
Amitriptyline in the prophylactic treatment of migraine
and chronic daily headache. Headache 2011;51:33–51.
10. DODICK DW, FREITAG F, BANKS J et al. CAPSS-277
Investigator Group. Topiramate versus amitriptyline in
migraine prevention: a 26-week, multicenter, randomized,
double-blind, double-dummy, parallel-group noninferiori-
ty trial in adult migraineurs. Clin Ther 2009;31:542–59.
11. FREITAG FG, COLLINS SD, CARLSON HA et al. A random-
ized trial of divalproex sodium extended-release tablets in
migraine prophylaxis. Neurology 2002;58:1652–9.
12. FREITAG FG, DIAMOND S, DIAMOND ML, URBAN GJ. Di-
valproex in the long-term treatment of chronic daily
headache. Headache 2001;41:271–8.
13. MITSIKOSTAS DD, POLYCHRONIDIS I. Valproate versus flu-
narizine in migraine prophylaxis: a randomized, double
open, clinical trial. Funct Neurol 1997;12:267–76.
14. BARTOLINI M, SILVESTRINI M, TAFFI R et al. Efficacy of
topiramate and valproate in chronic migraine. Clin Neu-
ropharmacol 2005;28:277–9.
15. Headache Classification Subcommittee of the Interna-
tional Headache Society. The international classification
of headache disorders. Cephalalgia 2004;24:1–160.
16. HERING R, KURITZKY A. Sodium valproate in the pro-
phylactic treatment of migraine: a double-blind study
versus placebo. Cephalalgia 1992;12:81–4.
17. JENSEN R, BRINCK T, OLESEN J. Sodium valproate has a pro-
phylactic effect in migraine without aura: a triple-blind, pla-
cebo-controlled crossover study. Neurology 1994;44:647–51.
18. YUREKLI VA, AKHAN G, KUTLUHAN S, UZAR E, KOYUN-
CUOGLU HR, GULTEKIN F The effect of sodium valproate
on chronic daily headache and its subgroups. J Headache
Pain 2008;9:37–41.
19. MATHEW NT, SAPER JR, SILBERSTEIN SD et al. Migraine
prophylaxis with divalproex. Arch Neurol 1995;52:281–6.
71
Kalita et al.
20. KANIECKI RG. A comparison of divalproex with pro-
pranolol and placebo for the prophylaxis of migraine
without aura. Arch Neurol 1997;54:1141–5.
21. KLAPPER J. Divalproex sodium in migraine prophylaxis: a
dose-controlled study. Cephalalgia 1997;17:103–8.
22. APOSTOL G, CADY RK, LAFORET GA et al. Divalproex
extended-release in adolescent migraine prophylaxis:
results of a randomized, double-blind, placebo-controlled
study. Headache 2008;48:1012–25.
23. SHAYGANNEJAD V, JANGHORBANI M, GHORBANI A, ASHTARY F,
ZAKIZADE N, NASR V. Comparison of the effect of topira-
mate and sodium valproate in migraine prevention: a ran-
domized blinded crossover study. Headache 2006;46:642–8.
24. ZIEGLER DK, HURWITZ A, PRESKORN S, HASSANEIN R,
SEIM J. Propranolol and amitriptyline in prophylaxis of
migraine. Pharmacokinetic and therapeutic effects.. Arch
Neurol 1993;50:825–30.
25. SHAHIEN R, SALEH SA, BOWIRRAT A. Intravenous sodium
valproate aborts migraine headaches rapidly. Acta Neu-
rol Scand 2011;123:257–65.
72
26. SILBERSTEIN SD, GOADSBY PJ. Migraine: preventive treat-
ment. Cephalalgia 2002;22:491–512.
27. RALL TW, SCHLEIFER LS. Drugs effective in the therapy
of epilepsies. In: Gilman AG, Rall TW, Nies AS, Taylor
P, eds. Goodman and Gilman’s the pharmacologic basis
of therapeutics, 8th edn. New York: Pergamon Press,
1990;436–62.
28. VAN DER KUY PH, LOHMAN JJ. A quantification of the
placebo response in migraine prophylaxis. Cephalalgia
2002;22:265–70.
29. LAKE AE 3rd. Placebo, chronic daily headache, and pain:
ten points to ponder. Curr Pain Headache Rep 2006;10:
4–6.
30. DODICK DW, TURKEL CC, DEGRYSE RE et al. on
behalf of the PREEMPT Chronic Migraine Study
Group. Onabotulinumtoxin A for treatment of
chronic migraine: pooled results from the double-
blind, randomized, placebo-controlled phases of the
PREEMPT clinical program. Headache 2010;50:
921–36.