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The efficacy of gabapentin in migraine prophylaxis: An observational open label study

  • University Hospital Center "Sestre Milosrdnice"
  • International Institute for Brain Health, Zagreb, Croatia


Migraine is often a chronic and disabling disorder. The objective of our study was to assess the efficacy and safety of gabapentin in the prophylaxis of migraine in patients refractory to other prophylactic treatments. The study included 67 migraine patients, 55 women and 12 men; 52 patients completed this prospective, open-label study. Patients were given 900-1800 mg of gabapentin in 3 doses; the mean duration of treatment was 7.2 months. Reduction in the number of days with headache, pain intensity and number of acute medications was assessed through patient diary. The mean number of migraine days/4 weeks was reduced from 15.8 to 8.6, yielding a reduction of 7.2 migraine days/4 weeks (P=0.001). Pain intensity was reduced by 25% in 14 (26.9%), by 50% in 29 (55.7%) and by 75% in three (5.7%) patients, whereas no improvement was reported by six (11.5%) patients at the end of follow up. A significant reduction was recorded in acute medication use (P=0.001). Adverse events were reported by 32/67 (47.8%) patients, in 15 (22.4%) of them causing discontinuation of the drug. The most frequently reported adverse events were drowsiness, dizziness and slowness. Prophylactic treatment with gabapentin was found to be associated with a significant reduction in the number of days with headache, use of acute medications and pain intensity.
Acta Clin Croat, Vol. 48, No. 2, 2009 145
V. Vukoviæ et al. The efficacy of gabapentin in migraine prophylaxis: an observational open label study
Acta Clin Croat 2009; 48:145-151 Original Scientific Paper
Vlasta Vukoviæ, Arijana Lovrenèiæ-Huzjan, Marijana Bosnar-Puretiæ and Vida Demarin
University Department of Neurology, Sestre milosrdnice University Hospital, Zagreb, Croatia
1) Reference center for neurovascular disorders of the Ministry of health of Croatic
2) Reference center for headaches of the Ministry of health of Croatia
SUMMARY  Migraine is often a chronic and disabling disorder. The objective of our study was to assess
the efficacy and safety of gabapentin in the prophylaxis of migraine in patients refractory to other
prophylactic treatments. The study included 67 migraine patients, 55 women and 12 men; 52 patients
completed this prospective, open-label study. Patients were given 900-1800 mg of gabapentin in 3 doses;
the mean duration of treatment was 7.2 months. Reduction in the number of days with headache, pain
intensity and number of acute medications was assessed through patient diary. The mean number of
migraine days/4 weeks was reduced from 15.8 to 8.6, yielding a reduction of 7.2 migraine days/4 weeks
(P=0.001). Pain intensity was reduced by 25% in 14 (26.9%), by 50% in 29 (55.7%) and by 75% in three
(5.7%) patients, whereas no improvement was reported by six (11.5%) patients at the end of follow up.
A significant reduction was recorded in acute medication use (P=0.001). Adverse events were reported
by 32/67 (47.8%) patients, in 15 (22.4%) of them causing discontinuation of the drug. The most frequently
reported adverse events were drowsiness, dizziness and slowness. Prophylactic treatment with gabapentin
was found to be associated with a significant reduction in the number of days with headache, use of acute
medications and pain intensity.
Key words: Migraine  therapy; Migraine  prevention and control; Headache therapy; Headache  prevention and
Correspondence to: Vlasta Vukoviæ, MD, University Department of
Neurology, Sestre milosrdnice University Hospital, Vinogradska c. 29,
HR-10000 Zagreb, Croatia
Received January 12, 2009, accepted in revised form May 15, 2009
Migraine is a common episodic headache disorder.
The prevalence has been estimated to 6%-29% in wom-
en and 3%-12% in men1. Patients with migraine have a
reduced quality of life compared with non-migraine pa-
tients1,2. Preventive therapy is recommended in migraine
patients with frequent, severe, long-lasting attacks, in
cases where acute therapy is not efficient, if there is a
contraindication to the drug, failure or unbearable side
effects from acute treatments, overuse of acute medi-
cations, or in special cases such as hemiplegic migraine.
Treatment should be chosen individually, taking into
consideration co-morbidities, drug efficacy, adverse re-
actions, patient preference, availability and costs3-9. The
drug chosen should be introduced in a low dose and grad-
ually increased, and should be given an adequate trial
(at least three months)10.
Medications used in migraine prophylaxis come from
different pharmacological classes and most have prima-
ry indications for other medical conditions3,5,8. Beta-
blockers and tricyclic antidepressants have been often
used as first-line therapy for migraine prevention. Oth-
er preventive drugs include pizotifen, flunarizine, and
However, in some patients where these medications
are contraindicated or that suffer from comorbid diseas-
es, antiepileptic drugs (AEDs) may be offered as an ap-
propriate first-line prophylactic treatment. Gabapentin
is among AEDs that have been evaluated for efficacy in
migraine and cluster headache prevention11-15. Gabap-
146 Acta Clin Croat, Vol. 48, No. 2, 2009
V. Vukoviæ et al. The efficacy of gabapentin in migraine prophylaxis: an observational open label study
entin has anticonvulsant and analgesic properties and
has been used primarily as an adjunctive treatment of
partial seizures, but is also accepted for the treatment
of neuropathic pain conditions such as diabetic neurop-
athy, trigeminal neuralgia, and postherpetic neuralgia16.
Case reports of successful treatment with gabapentin
in SUNCT, idiopathic stabbing headache, thunderclap
headache and nummular headache have also been pub-
The aim of this study was to evaluate the efficacy
and safety of gabapentin in the prophylaxis of migraine
previously successfully or unsuccessfully treated with
other prophylactic medications. We also present an over-
view of trials with the AEDs valproate, gabapentin,
topiramate and lamotrigine in the prophylaxis of mi-
Patients and Methods
This was an open prospective study that evaluated
the efficacy and safety of gabapentin in the prophylaxis
of migraine with or without aura in patients attending
Headache Clinic at University Department of Neurolo-
gy. Migraine was defined according to the ICHD-2 cri-
Patients were included according to the following
criteria: migraine attacks with or without aura for at least
one year before study entry; and frequency of attacks of
three or more per month during at least previous three
months. Furthermore, patients were included as follows:
1) previous prophylactic treatment with other medica-
tions had failed, or was discontinued due to adverse
events; 2) patients agreed to take no concurrent pro-
phylactic treatment for headaches (pharmacological or
non-pharmacological); 3) patients had no serious con-
current diseases; and 4) patients were willing to be avail-
able for follow up for at least 3 months.
Patients were not eligible if noncompliance was like-
ly, if the patient required medication for other medical
conditions that might confound the results, women if
planning pregnancy or were lactating, or patients with a
history of illicit drug or alcohol abuse in the past year.
All patients signed their informed consent.
The patients taking other prophylactic medications
were told to start gabapentin at 3 weeks of the previous
prophylactic drug discontinuation. The majority of pa-
tients were taking beta-blockers, tricyclic antidepres-
sants or selective serotonin reuptake inhibitors (SSRIs)
for prophylaxis.
Gabapentin was then started at a dose of 300 mg,
one capsule at bed time for 5 days, followed by 300 mg
twice daily for 5 days, and finally 900 mg daily divided
in three doses. During the follow up, the dose was in-
creased if no improvement was recorded at the initial
dose of 900 mg. The titration phase was followed by at
least a 12-week maintenance phase.
Before initiating gabapentin treatment, patients were
asked to keep a headache diary for at least 3 months,
which was used to count the average number of days
with headache and number of acute medications taken
(baseline data). Upon introducing gabapentin in thera-
py, patients were instructed to keep a diary and note all
days with headache, decrease in headache intensity if
observed, increase in gabapentin dosage, acute medica-
tions taken for severe migraine, and occurrence of ad-
verse events. Patients were told to use their usual ther-
apy for acute attacks.
The primary efficacy endpoint was the change from
baseline in the mean monthly (28 days) number of mi-
graine days, decrease in headache intensity and reduc-
tion in the mean number of acute medications use. The
change in headache intensity was recorded as percent-
age (no change, decrease by 25%, 50%, 75% or 100%).
Assessments of safety and tolerability included physi-
cal, neurological and laboratory examinations, and spon-
taneous reports of adverse events. The patients were
included into the study group if they were taking med-
ication for at least 3 months; if they were satisfied with
therapy and had no side effects, they continued therapy
for up to 12 months if necessary (observational period
was therefore expected to be from 3 to 12 months).
On statistical analysis, Wilcoxons signed rank test
was used to compare baseline and end-point values.
The study included 67 patients, 55 women and 12
men (age 46±12 years). The mean duration of treatment
was 7.2 (range 3-12) months. The patients started the
treatment according to our instructions, e.g., the dose of
gabapentin was increased every five days to a minimal
dose of 900 mg daily divided in three doses. The mainte-
nance dose of gabapentin in all patients was in the range
from 900 mg to 1800 mg: 29 patients with migraine were
taking 900 mg/day, 18 patients 1200 mg/day and five pa-
tients 1800 mg/day. The dose of gabapentin was not in-
creased over 1800 mg because either an improvement
was achieved or adverse events occurred at this dosage.
Acta Clin Croat, Vol. 48, No. 2, 2009 147
V. Vukoviæ et al. The efficacy of gabapentin in migraine prophylaxis: an observational open label study
In 52 migraine patients that completed the follow
up, the mean number of headache days/4 weeks was
reduced from 821 (mean 15.8) at baseline to 449 (mean
8.6) at study endpoint evaluation, yielding a reduction
of 7.2 migraine days/4 weeks (P=0.001), or by 45.3% in
headache frequency.
Headache intensity was reduced by 25% in 14
(26.9%), by 50% in 29 (55.7%), and by 75% in three
(5.7%) patients, whereas no improvement was reported
by six (11.5%) patients at the end of follow up.
Before starting gabapentin, the number of medica-
tions was 987 (mean 18.9) tablets/4 weeks. At the end
of follow up, the figure fell to 388 (mean 7.4), yielding a
reduction of 11.5 tablets/4 weeks (P=0.001). A 25% re-
duction in the use of acute medication was recorded in
four (7.6%), by 50% in 28 (53.8%) and by 75% in 14
(26.9%) patients, whereas no change in the use of acute
medication was reported by six (11.5%) patients. Ac-
cordingly, 88.5% of treated patients reported using less
acute medications. Before and during treatment with
gabapentin, the patients were using their usual type of
acute therapy. The range of gabapentin doses, reduc-
tion of headache intensity and reduction of medication
use are shown in Table 1.
Adverse events were reported by 32/67 (47.8%) pa-
tients and were generally of mild or moderate severity.
However, in 15/67 (22.4%) patients, the drug associat-
ed adverse events led to discontinuation of the drug and
in these patients the efficacy of gabapentin was not eval-
uated due to the short observational period (less than 3
months). Adverse events were the only reason for dis-
continuation of the study. The most frequently report-
ed adverse events were drowsiness, dizziness and slow-
ness, followed by constipation, ataxia, swollen face or
body, and weight gain. There were no serious adverse
events. The number of adverse events and withdrawals
are shown in Table 2.
Prophylactic therapy for migraine should be based
on guidelines from evidence-based medicine. Although
double-blind placebo-controlled studies provide unbi-
ased results, they are sometimes difficult to carry out,
therefore open-label studies offer additional data on the
efficacy of pharmacological or non-pharmacological treat-
ment3-7. Trials with AEDs as prophylactic drugs in mi-
graine have shown that certain AEDs can be offered in
patients refractory to usual prophylactic treatments.
Valproate and topiramate are approved by the Food
and Drug Administration (FDA) for prophylactic treat-
ment of migraine; especially topiramate has been stud-
ied in a large number of patients in double-blind place-
bo-controlled and thus methodologically powerful stud-
ies22-24. Gabapentin is still omitted from recommenda-
tions for headache prevention, mostly due to the lack of
double-blind placebo-controlled trials.
Results of our study showed gabapentin to be effec-
tive in the prophylactic treatment of migraine in patients
refractory to previous prophylactic therapy. We found
significant reduction in headache frequency, intensity
and medication use during the follow up period. We com-
pared our results with other trials that evaluated the
efficacy of AEDs in headache prophylaxis.
Valproate was the first AED recommended for mi-
graine prevention. In controlled studies, divalproex so-
dium and sodium valproate showed consistent efficacy
in reducing headache frequency compared with place-
bo25-28; compared with propranolol, there was no signifi-
Table 1. (A) Range of gabapentin doses; (B) reduction of pain
intensity; and (C) reduction of acute medication use
(A) Gabapentin dose (mg)
900 1200 1800 2400
N=52 (%) 29 (55.8) 18 (34.6) 5 (9.6) 0
(B) Reduction of pain intensity by %
0% 25% 50% 75%
N=52 (%) 6 (11.5) 14 (26.9) 29 (55.7) 3 (5.7)
(C) Reduction of medication use by %
0% 25% 50% 75%
N=52 (%) 6 (11.5) 4 (8.0) 28 (53.8) 14 (26.9)
Table 2. Adverse events in patients with migraine treated with
gabapentin; some patients experienced several adverse events
Adverse event Migraine (N=67)
n (%)
Number of patients with adverse events 32 (47.8)
Drowsiness 15 (22.4)
Dizziness 5 (5.9)
Slowness 8 (11.9)
Constipation 5 (5.9)
Ataxia 2 (3.0)
Swollen face/body 2 (3.0)
Weight gain 2 (3.0)
Withdrawal 15 (22.4)
148 Acta Clin Croat, Vol. 48, No. 2, 2009
V. Vukoviæ et al. The efficacy of gabapentin in migraine prophylaxis: an observational open label study
cant difference in efficacy29. Low dosages of valproic acid
between 300 and 900 mg were effective in migraine
prophylaxis30,31. Long-term safety of divalproex sodium
was evaluated in an open-label study; the most frequent-
ly reported adverse events were nausea, infection, alo-
pecia, tremor, dyspepsia, and somnolence32.
In a double-blind, placebo-controlled trial with
topiramate up to 200 mg, the mean 28-day reduction in
migraine frequency was significant in the topiramate
group: from 4.2 (baseline) to 3.0, while in the placebo
group the reduction was from 4.1 to 3.833. In another
double-blind placebo-controlled study with 100 mg and
200 mg of topiramate, significantly more (54% and
52.3%) topiramate treated patients experienced a 50%
or greater reduction in the monthly migraine frequency
as compared with placebo treated patients (22.6%)24. A
similar study showed a mean 28-day migraine frequen-
cy reduction by 36% in patients receiving topiramate vs.
14% in placebo group; 26% achieved a 50% reduction in
migraine frequency vs. 9.5% in placebo group; two of 19
topiramate treated patients discontinued treatment due
to adverse events23. The >50% reduction of headache
frequency was recorded in 58.3% of episodic migraine
patients and 38.0% of chronic migraine patients on
topiramate up to 100 mg twice daily; the mean head-
ache severity was reduced from 6.2 to 4.8 on a 10-point
scale; both results were significant34. The most com-
mon adverse events in topiramate treated patients were
cognitive difficulties, weight loss, paresthesias, somno-
lence, diarrhea, and altered taste, and were present in
26.6%-58.1% of patients24,33,34.
A double-blind, crossover clinical trial compared the
efficacy of topiramate and sodium valproate in migraine
prevention and the two drugs appeared to be equiva-
lent in efficacy and safety; a significant decrease in du-
ration, monthly frequency and intensity of headache
occurred in both groups: in valproate group, the mean
monthly frequency decreased from 5.4 to 4.0 and in
topiramate group from 5.4 to 3.2, while headache inten-
sity decreased from 7.7 to 5.8 and from 6.9 to 3.7, re-
In a 12-week open-label study, gabapentin in a dos-
age of 600-1800 mg was effective in episodic and chron-
ic migraine, headache frequency decreased from 25.2 to
11.6 per month and side effects were minimal12. A pla-
cebo-controlled study in 98 patients receiving gabapen-
tin and 45 placebo showed that gabapentin in a dosage
of 1800-2400 mg was effective in reducing the frequen-
cy of migraine attacks: the responder rate (50% decrease
in attack frequency) was 46.4% in gabapentin group and
16.1% in placebo group; furthermore, a 4-week migraine
headache rate decreased from 4.2 to 2.7 in gabapentin
group and from 4.1 to 3.5 in placebo group, yielding a
significant difference14. Discontinuation rate due to ad-
verse events was 16.3% in gabapentin group (8.2% due
to somnolence and dizziness) and 8.9% in placebo group.
In one placebo-controlled, double-blind study, gabap-
entin was not found to be effective13. A double-blind,
placebo-controlled study including 133 patients with
chronic headaches (two thirds had a combination of mi-
graine and tension-type headache) showed that patients
taking gabapentin 2400 mg/day had by 9.1% more head-
ache-free days as compared with placebo group; adverse
events were reported by 39% and 14% of patients in
gabapentin and placebo group, respectively15. However,
the Cochrane database found limited evidence for the
use of gabapentin for acute pain36. The most commonly
reported adverse events associated with gabapentin in
these trials were somnolence, dizziness, drowsiness,
ataxia, fatigue and nausea, while weight gain and hair
loss were rare14,15.
Lamotrigine has been shown to be efficient in the
prophylaxis of migraine with aura. Three open-label
studies showed that lamotrigine reduced the number of
migraine auras and the frequency of migraine attacks.
In 13 of 21 patients receiving lamotrigine 100 mg, mi-
graine attacks resolved completely, and one patient was
unresponsive to the treatment at the end of third
month37. In another two studies, lamotrigine significant-
ly reduced the number of migraine auras (from 4.2 to
0.7) 38, the duration of migraine auras and the frequency
of migraine attacks39.
Low-dose topiramate (50 mg in 2 divided doses) was
demonstrated to be superior in reduction of headache
frequency compared to both lamotrigine (50 mg in 2
doses) and placebo; however, in this cross-over study
patients were receiving the drug for only one month40.
In our study, a significantly lower 28-day migraine
frequency was observed: the frequency of mean head-
ache days decreased from 15.9 to 8.6, yielding a reduc-
tion of 7.2 days or 45.3%; it was somewhat lower com-
pared to another gabapentin study where the decrease
in the frequency of attacks reached 54%12. A 50% reduc-
tion in migraine frequency was achieved by 61.5% of
our patients that were evaluated at the end of the fol-
low up period. In comparison with our results, the re-
sponse rate of reduction in migraine frequency was low-
er in a similar study with gabapentin (46.6%)14 or topira-
Acta Clin Croat, Vol. 48, No. 2, 2009 149
V. Vukoviæ et al. The efficacy of gabapentin in migraine prophylaxis: an observational open label study
mate (54%)24,34. A reduction in headache frequency by
83% was observed in a study with lamotrigine38 and res-
olution of attacks was observed in 62%37, which is much
higher compared to our results or even with similar stud-
In our study, headache intensity was reduced by at
least 50% in 32/52 (61.5%) patients and by less than
50% in 14/52 (26.9%) patients. In trials with other AEDs,
a 25% reduction of headache intensity was observed with
valproate and by 46% with topiramate35.
The decrease in the frequency and intensity of head-
ache attacks was within the range of results observed in
other studies with gabapentin, topiramate and valproate;
only studies with lamotrigine showed better results.
Most of these studies (double-blind placebo-controlled
and open-label studies) have reported significant reduc-
tion in headache frequency and intensity, and one (pla-
cebo-controlled) study reports unfavorable results13.
Most studies evaluated only the decrease in head-
ache frequency and intensity; we also evaluated decrease
in the use of acute medication, which is another very
important evaluation point in such studies because pre-
ventive treatment of migraine reduces the possibility
of medication overuse headache. In our study, 88.5% of
patients reported using less acute medications.
A high percentage of our patients reported adverse
events (47.8%), which is higher compared to a similar
study with gabapentin, where 39% of patients reported
adverse events15. Studies with topiramate showed the
rate of adverse events to range from 26.6% to 58.1%27,29.
In our study, 22.4% of patients discontinued the treat-
ment due to adverse events, which is much higher com-
pared to another study with gabapentin, where the drop-
out rate was 8.2%14.
Our study suffered from some shortcomings; it was
not a placebo-controlled double-blind study and the
number of patients was relatively small. We are aware
that the study design is crucial in order to minimize bias
of the results; trials in migraine prevention should be
randomized, preferably in a homogeneous study popu-
lation, double-blind and placebo-controlled41. Howev-
er, we hope that the results of our study will provide
additional information that will help decide on the most
preferable preventive medication for the individual pa-
tient, especially in patients that have failed to respond
to prior trials of preventive medications.
In conclusion, gabapentin treatment in patients with
migraine at daily doses of 900-1800 mg resulted in a sig-
nificant mean reduction of migraine days, reduction in
pain intensity and in the use of acute medications. Al-
though adverse events occurred in a relatively high
percentage, the treatment with gabapentin was safe and
well tolerated in the majority of patients. Due to a small
number of studies with gabapentin as a prophylactic drug
for migraine, general recommendations cannot be given
yet. Our findings warrant further trials, preferably dou-
ble-blind placebo-controlled studies in a greater number
of patients.
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Acta Clin Croat, Vol. 48, No. 2, 2009 151
V. Vukoviæ et al. The efficacy of gabapentin in migraine prophylaxis: an observational open label study
V. Vukoviæ, A. Lovrenèiæ-Huzjan, M. Bosnar-Puretiæ i V. Demarin
Migrena je èest poremeæaj koji smanjuje kvalitetu ivota. Cilj ove studije bio je ustanoviti uèinkovitost i sigurnost
gabapentina u profilaksi migrene kod bolesnika refraktornih na drugu profilaktiènu terapiju. Studija je ukljuèivala 67 bolesnika
s migrenom, 55 ena i 12 mukaraca; 52 bolesnika je zavrilo ovu prospektivnu otvorenu studiju. Bolesnici su uzimali 900-
1800 mg gabapentina podijeljeno u 3 doze; prosjeèno trajanje lijeèenja je bilo 7,2 mjeseci. Smanjenje broja dana s glavoboljom,
intenziteta i broja lijekova u akutnim napadajima procijenjeno je pomoæu dnevnika. Prosjeèan broj dana s migrenom/4 tjedna
smanjen je s 15,8 na 8,6, tj. smanjenje za 7,2 dana (P=0,001). Intenzitet boli smanjen je za 25% kod 14 (26,9%) ispitanika,
za 50% kod 29 (55,7%), za 75% kod 3 (5,7%) ispitanika, dok promjene nisu zabiljeene kod 6 (11,5%) ispitanika na kraju
razdoblja praæenja. Zabiljeeno je i znaèajno smanjenje broja lijekova koji su se rabili u akutnim napadajima (P=0,001).
Nuspojave je prijavilo 32/67 (47,8%) ispitanika, od kojih je 15 (22,4%) moralo prekinuti studiju. Najèeæe nuspojave su bile
pospanost, oamuæenost i usporenost. Profilaktièno lijeèenje gabapentinom kod bolesnika s migrenom dovodi do znaèajnog
smanjenja broja dana s glavoboljom, intenziteta boli i broja konzumiranih lijekova u akutnim napadajima.
Kljuène rijeèi: Migrena  terapija; Migrena  prevencija i kontrola; Glavobolja  terapija; Glavobolja  prevencija i kontrola
152 Acta Clin Croat, Vol. 48, No. 2, 2009
V. Vukoviæ et al. The efficacy of gabapentin in migraine prophylaxis: an observational open label study
... Both GBP doses similarly reduced headache frequency and intensity, approximately 60% and 40% reduction compared with baseline, respectively [23]. In another open label, but observational study, 67 migraine patients prophylactically received 900-1,800 mg/day GBP, with a decrease of 7.2 migraine days per month and a 50% reduction in acute medication use [30]. In a study by Mathew et al., (double-blind, randomized, multicenter trial, n ¼ 143), 46.4% of patients at 2,400 mg/day (titrated from 300 mg/day) responded with >50% reduction in monthly migraine frequency compared with 16.1% in the placebo group. ...
... Although it did show a statistically significant reduction in duration of migraine headache for the GBP group compared with the placebo group. The published article [22] has two less patients [23,24,30]. In another unpublished, internal industry trial, study# 945-217 (double-blind, randomized, multicenter trial, n ¼ 157), 83.2% of patients receiving 1,800 mg/day GBP had no change or "decreased frequency" of migraines compared with only 58.2% in the placebo group [32]. ...
Objective: Gabapentin (GBP), originally an antiepileptic drug, is more commonly used in the treatment of pain, including headache disorders. Off-label GBP is used in headache disorders with some success, some failure, and much debate. Due to this ambiguity, a clinical evidence literature review was performed investigating GBP's efficacy in headache disorders. Methods: Bibliographic reference searches for GBP use in headache disorders were performed in PUBMED and OVID Medline search engines from January 1, 1983 to August 31, 2014. Based on abstracts read by two reviewers, references were excluded if: GBP was not a study compound or headache symptoms were not studied. The resulting references were then read, reviewed, and analyzed. Results: Fifty-six articles pertinent to GBP use in headache disorders were retained. Eight headache clinical trials were quality of evidence Class 2 or higher based on American Academy of Neurology criteria. Seven of the eight clinical trials showed statistically significant clinical benefit from GBP in various headache syndromes (though modest affects at times). One study, Mathew et al., had concerns about intention-treat analysis breaches and primary outcomes. Conclusion: Despite the conflicting evidence surrounding select studies, a significant amount of evidence shows that GBP has benefit for a majority of primary headache syndromes, including chronic daily headaches. GBP has some efficacy in migraine headache, but not sufficient evidence to suggest primary therapy. When primary headache treatments fail, a GBP trial may be considered in the individual patient.
... 66 Vuković et al assessed the efficacy and safety of gabapentin at 900-1800 mg of drug in 3 doses in 67 migraine patients refractory to other prophylactic treatments, of which 52 completed the prospective, open-label study. 67 They found a significant reduction in the number of days with headache, the use of acute medications and pain intensity in the prophylaxis of migraine. ...
... The role of psychiatric disorders or other comorbidities and uncertainty as to which types of headaches respond to this type of treatment argue against its use at the present time. 67 ...
... The anticonvulsants gabapentin and pregabalin, which are structurally similar to GABA and showed good results in the prophylactic treatment of migraine [213][214][215], chronic daily [216], and cluster [217][218][219] headaches, have no direct GABA mimetic action, and data on their influence on GABA synthesis and synap tic or extrasynaptic release in the CNS are extremely contradictory [22,[220][221][222][223][224][225][226]. Therefore, it seems not quite correct to attribute these drugs to GABA ergic agents, although such a description is quite common in the literature [48,217,227]. ...
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Migraine is one of the most common forms of primary headaches; it affects nearly 10% of the population in developed countries. All major CNS neurotransmitter systems are implicated in migraine pathogenesis, indicating the polyneurochemical nature of the nosology. This review is focused on the role of gamma-aminobutyric acid (GABA) and its receptors in the neurobiology of migraine. The report describes evidence for the existence of a cause-effect relationship between impaired GABA metabolism and development of the disease. It summarizes data on the distribution of GABA-A and GABA-B receptors in the trigeminovascular system and on the contribution of GABA to the modulation of nociceptive neurotransmission in the trigemino-thalamo-cortical pathway. As well, it provides detailed information on the mechanisms that underlie GABA-ergic inhibition at the peripheral, spinal, and suprasegmental levels. In the end, we discuss the pharmacodynamics of some GABA-positive drugs that are used for prophylactic and acute treatments of migraine, as well as other primary headaches.
... According to the treatment guideline, the antiepileptic drugs (ADEs) are the first line (A-C) in migraine prevention, however, the reason why only a few antiepileptic drugs (AEDs) (valproate, VPA and topiramate, TPM) are effective (Silberstein, 2009; Vargas and Dodick, 2009) in migraine prevention is still unknown. Even if enhanced GABAergic inhibition is considered, why only these two are effective, whereas the effect of gabapentin (GPT) is uncertain (Mathew et al., 2001; Vukovic et al., 2009; Silberstein et al., 2013) and levetiracetam is ineffective (Pakalnis et al., 2007) is unknown. Furthermore, although VPA, TPM and GPT are all reported to act on the GABAergic system, by acting as GABA transaminase inhibitors (Lo¨scherLo¨scher, 1981), enhancing chloride flux through GABA A receptors (White et al., 1997; White, 2003), or increasing cerebral GABA concentration (Mesdjian et al., 1982; Kuzniecky et al., 1998), only TPM has been observed to reduce neuronal excitation in the Sp5C via a GABA-mediated mechanism (White et al., 2000). ...
Using two-dimensional gel electrophoresis (2-DE), we examined proteomic changes in the caudal part of the spinal trigeminal nucleus induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus (ES-SSS) in conscious rats. After image analysis of 2-DE gels, nine protein spots of interest were excised from the gels and identified by liquid chromatography-tandem mass spectrometry. Among the nine, succinate semialdehyde dehydrogenase (SSADH) was found to be down-regulated after ES-SSS. This result was validated with Real-time PCR and western blot analyses. Because SSADH degrades GABA, decreased expression of it increases the local concentration of GABA in the caudal part of the spinal trigeminal nucleus after ES-SSS; this has not been reported before and may participate in the modulation of trigeminovascular headache.
... GBP is among AEDs that have been evaluated for efficacy in migraine and cluster headache prevention198199200201202. Vokovie et. al., [203] performed an open label study to evaluate the efficacy and safety of GBP in the prophylaxis of migraine in which daily doses of 900 – 1800mg GBP resulted in a significant mean reduction of migraine days, reduction in pain intensity and in the use of acute medications. Although adverse events occurred in a relatively high percentage, the treatment with GBP was safe and well tolerated in the majority of patients. ...
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Gabapentin (GBP) is a second generation anticonvulsant whose exact mode of action is not known. It was approved as adjunctive treatment in patients 12 years or older with partial seizures, with or devoid of secondary generalization. Soon after, it was approved by the German regulatory authorities for “Neuropathic pain in adults” particularly painful diabetic neuropathy and post herpetic neuralgia. Recently GBP has proved as an efficient multimodal perioperative drug in the field of anaesthesia. It is also effective in improving symptoms of Restless Leg Syndrome by reducing the frequency of periodic leg movements and improving sleep quality. GBP appears to be effective and well tolerated treatment modality for hot flashes in post menopausal women. Moreover, it is also being prescribed as a prophylactic treatment for migraine. In view of its multiple pharmacotherapeutic effects combined with its favourbale side effect profile in various patient groups (including the elderly) and lack of drug interaction, makes it an attractive agent. Link:
New-onset movement disorders have been frequently reported in association with the use of antiseizure medications (ASMs). The frequency of specific motor manifestations and the spectrum of their semiology for various ASMs have not been well characterized. We carried out a systematic review of literature and conducted a search on CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and Scopus from inception to April 2021. We compiled the data for all currently available ASMs using the conventional terminology of movement disorders. Among 5123 manuscripts identified by the search, 437 met the inclusion criteria. The largest number of reports of abnormal movements were in association with phenobarbital, valproic acid, lacosamide, and perampanel, and predominantly included tremor and ataxia. The majority of attempted interventions for all agents were discontinuation of the offending drug or dose reduction which led to the resolution of symptoms in most patients. Familiarity with the movement disorder phenomenology previously encountered in relation with specific ASMs facilitates early recognition of adverse effects and timely institution of targeted interventions.
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To compare the efficacy and safety of topiramate with gabapentin in the prophylaxis of migraine patients. A 12-week randomised open label control trial was conducted at the Department of Pharmacology and Therapeutics, Basic Medical Sciences Institute, Jinnah Postgraduate Medical Centre (JPMC), Karachi from January to March 2011 involving 80 outpatients who had a history of migraine. The sample was divided into two equal groups. Primary efficacy measure was changed into mean monthly migraine frequency. Secondary efficacy measure included reduction in severity and average duration of an attack. Chi square test and paired t-test were used to analyse the data through SPSS 15. Reduction in mean monthly migraine frequency (10.67 +/- 4.25 to 1.82 +/- 2.02) in the topiramate group was significantly greater compared with (11.97 +/- 4.452 to 2.73 +/- 2.59) that in the gabapentin group (p < 0.001). Reduction in severity from 6.60 +/- 2.122 to 1.03 +/- 0.92 in the topiramate group was also significantly greater compared with 6.93 +/- 1.90 to 1.18 +/- 1.01 in the gabapentin group (p < 0.001). Reduction in the average duration of attacks from 25.77 +/- 22.32 hours to 1.05 +/- 1.06 hours in the topiramate group was significantly greater compared with 22.20 +/- 20.72 to 1.08 +/- 1.40 hours in the gabapentin group (p < 0.001). Weight loss and numbness were common adverse effects in the topiramate group. Dizziness, weight gain and somnolence were reported in the gabapentin group. Gabapentin appeared well tolerated in 30 (75%) patients compared to topiramate in 23(57.5%) patients. Both drugs were equally effective in migraine prophylaxis.
Migraine is a very common primary headache disorder associated with intermittent attacks and great suffering. Despite extensive research efforts in the recent years, many pathophysiological aspects remain unclear. An altered cortical adaptability and the brainstem as a migraine generator are probably involved in the initiation of a (silent) cortical spreading depression and other processes that lead to neurogenic inflammation of the meninges causing the headache. Numerous studies in the last years have examined somatic, especially cerebrovascular and also psychological comorbidities. For attack therapy, CGRP antagonists have emerged as promising non-vasoconstrictive acting alternatives for triptans. However, they were so far not approved due to liver enzyme elevations in safety studies. Another new approach without vasoconstrictive action are the selective 5-HT1F agonists (especially Lasmiditan). Large placebo-controlled and triptan-controlled trials need to be awaited. For migraine prophylaxis, a comparable effect of sports and pharmacological prophylaxis using topiramate could be found. Particularly the combination of drug and non-drug therapies (such as the combination of stress management training with a beta-blocker treatment) achieves high efficacy. Also interdisciplinary, multimodal treatment approaches are important options. Two large multicentre studies have demonstrated the efficacy of botulinum toxin A as a prophylactic treatment for chronic migraine. Neuromodulative and neurostimulative procedures are promising but still experimental treatment options for patients with refractory migraine. © Georg Thieme Verlag KG Stuttgart · New York.
Objective: The objective of this article is to evaluate the efficacy and safety of gabapentin enacarbil (GEn) for migraine prophylaxis. Methods: In this randomized, double-blind, parallel-group study, patients with International Headache Society-defined migraine who met criteria suggesting the need for prophylactic therapy were randomized 2:1:2:2:1 to one of the following five groups, designated according to target daily dose of study medication during the 20-week treatment period: placebo, GEn 1200 mg, GEn 1800 mg, GEn 2400 mg, or GEn 3000 mg. Results: The intent-to-treat population included 523 patients (n = 128 placebo, n = 66 GEn 1200 mg, n = 134 GEn 1800 mg, n = 133 GEn 2400 mg, n = 62 GEn 3000 mg). No statistically significant difference between active treatment (the average of 1800 mg and 2400 mg treatment groups) and placebo was found for change from baseline in the number of migraine headache days during the last four weeks of treatment prior to taper (the primary endpoint). Results of analyses of the primary endpoint using the per protocol population, analyses using imputation methods different from those of the primary analysis, and nonparametric analyses were consistent with the primary analysis in showing no difference between active treatment and placebo. The pattern of results was similar for the secondary efficacy endpoints. Pharmacokinetic data demonstrate that patients had adequate estimated exposure to GEn. The adverse event profile of GEn was consistent with that in previous studies. Conclusion: GEn did not significantly differ from placebo for migraine headache prophylaxis. A high placebo effect should be considered when interpreting these results.
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A proportion of headache patients should be evaluated by a neurologist. These guidelines are developed to help physicians in making appropriate choice in the work-up and treatment of headache patients. Most migraine sufferers have not been diagnosed by a physician and are not receiving medical guidance to effectively address their migraine attacks. In the past 15 years new therapies (acute and preventive) have been introduced. In migraine patients nonresponders to analgesics, especially in patients with moderate to severe migraine, triptans should be introduced. In migraine with frequent attacks or long lasting attacks, preventive treatment according to comorbid diseases should be recommended. In tension type headache, an underlying pathology should be excluded; management includes pharmacological and non-pharmacological treatment. Although rare, patients with cluster headache experience major pain and disability; in acute management oxygen inhalation or triptans are recommended, in certain cases prophylaxis is indicated. These guidelines contain classification, diagnostic criteria, and principles of management of all primary headaches. These recommendations for headache treatment are based on a comprehensive review and meta-analysis of scientific literature with regard to treatment possibilities in Croatia.
Committee members: W Amery, Belgium, M-G Bousser (Chairman of Subcommittee), France, D Gerber, Germany, D Greenwood, UK, C Hedman, Sweden, R Kunkel, USA, H Massiou, France, G Micieli, Italy, V Pfaffenrath, Germany, ELH Spierings, USA, S Solomon (Chairman of Subcommittee), USA, TJ Steiner (Secretary), UK, P Tfelt-Hansen (Chairman), Denmark, M Wilkinson, UK
The adverse event profile of long-term divalproex therapy for epilepsy is well established, but little is known about the tolerability or safety of divalproex in long-term migraine prophylaxis. Evaluate the long-term safety and efficacy of divalproex sodium in migraine prophylaxis. Open-label, long-term study, of up to 3 years, of patients who completed one of two multicenter, double-blind, randomized, placebo-controlled studies. Eighteen headache/neurology centers throughout the United States. One hundred sixty-three patients: 46 treated with placebo, 117 treated with divalproex for migraine in previous studies. Divalproex therapy initiated at 500 mg/day (250 mg twice daily), with adjustment in dose and dosing frequency possible after 1 to 3 days. Number and proportion of patients reporting treatment-emergent adverse events, prevalence and incidence for each treatment-emergent adverse event, vital signs, body weight, 4-week migraine rates and proportion of patients with 50% or greater reduction in rate over time. Treatment lasted more than 180 days for 71% of patients and more than 360 days for 48% of patients. Improvements in the 4-week, change-from-baseline migraine rates were seen during each of the 3- and 6-month time intervals. Divalproex is effective for migraine prophylaxis, and initial benefits are maintained for periods in excess of 1080 days.
Objective.—To compare gabapentin with placebo for use as a prophylactic agent in patients with migraine (with or without aura). Study Design and Treatment.—After screening, a 4-week, single-blind, placebo baseline period was followed by a 12-week, double-blind, treatment period. The 12-week treatment period consisted of a 4-week titration phase and an 8-week stable-dosing phase. During the 4-week titration phase, patients were started on one 300-mg capsule of gabapentin or matching placebo. Patients were titrated weekly from 900 mg/day (end of week 1) to 2400 mg/day (end of week 4) and had to be receiving a stable dose of study medication by the end of the titration period. Study medication was to be given on a three-times-a-day dosing regimen. Methods.—The study hypothesis was defined a priori as a lower 4-week migraine rate during the second stabilization period for the gabapentin-treated patients as compared with the placebo-treated patients. The analyses were performed with the 4-week migraine rate at baseline as a covariate and center as a blocking factor. Results.—At seven participating centers, 143 patients with migraine were randomized in a 2:1 ratio and received either gabapentin (n = 98) or matching placebo (n = 45). Thirty-three patients (24.1%) discontinued prematurely from the study, including 24 (24.5%) of 98 gabapentin-treated patients and 9 (20.0%) of 45 placebo-treated patients; the majority of patients discontinued due to adverse events (16 [16.3%] of 98 gabapentin-treated patients; 4 [8.9%] of 45 placebo-treated patients). Patients included in the analysis were evenly balanced for age, sex, race, weight, and height. The majority of these patients were white (80 [92.0%] of 87) and women (72 [82.8%] of 87), with a mean age of approximately 39.4 years and a history of migraine episodes for a mean of about 21 years. At the end of the 12-week treatment phase, the median 4-week migraine rate was 2.7 for the gabapentin-treated patients maintained on a stable dose of 2400 mg/day and 3.5 for the placebo-treated patients (P = .006), compared with 4.2 and 4.1, respectively, during the baseline period. Additionally, 26 (46.4%) of 56 patients receiving a stable dose of 2400 mg/day gabapentin and 5 (16.1%) of 31 patients receiving placebo showed at least a 50% reduction in the 4-week migraine rate (P = .008). The average number of days per 4 weeks with migraine was also statistically significant and favored gabapentin (P = .006) during stabilization period 2. The median change in 4-week headache rate was statistically significant as well (P = .013). The most frequently reported adverse events for both treatment groups were asthenia, dizziness, somnolence, and infection. Adverse events determined by the investigator to be associated with study drug resulted in patient withdrawal in 13 (13.3%) of 98 gabapentin-treated patients and 3 (6.7%) of 45 placebo-treated patients. Somnolence and dizziness accounted for many of the premature withdrawals among those taking gabapentin. Conclusion.—Gabapentin is an effective prophylactic agent for patients with migraine. In addition, gabapentin appears generally well tolerated with mild to moderate somnolence and dizziness.
Migraine is one of the most frequent disabling neurological conditions with a major impact on the patients’ quality of life. To give evidence-based or expert recommendations for the different drug treatment procedures of the different migraine syndromes based on a literature search and an consensus in an expert panel. All available medical reference systems were screened for all kinds of clinical studies on migraine with and without aura and on migraine-like syndromes. The findings in these studies were evaluated according to the recommendations of the EFNS resulting in level A,B, or C recommendations and good practice points. For the acute treatment of migraine attacks, oral non-steroidal anti-inflammatory drugs (NSAIDs) and triptans are recommended. The administration should follow the concept of stratified treatment. Before intake of NSAIDs and triptans, oral metoclopramide or domperidon is recommended. In very severe attacks, intravenous acetylsalicylic acid or subcutaneous sumatriptan are drugs of first choice. A status migrainosus can probably be treated by steroids. For the prophylaxis of migraine, betablockers (propranolol and metoprolol), flunarizine, valproic acid, and topiramate are drugs of first choice. Drugs of second choice for migraine prophylaxis are amitriptyline, naproxen, petasites, and bisoprolol.
The efficacy of sodium valproate (Depalept) versus placebo in the treatment of migraine was evaluated in a double-blind randomized cross-over study in twenty-nine patients. The patients were divided into two groups each of which was alternately given 400 mg of sodium valproate B.I.d or placebo for eight weeks and then crossed over for an additional eight weeks. Our results show that in 86.2% of the patients sodium valproate was effective in preventing migraine or reducing the frequency, severity and duration of the attacks. In general, the drug was well tolerated and proved to be an effective treatment in migraine.
To compare the effectiveness and safety of divalproex sodium (Depakote) and placebo in the prophylaxis of migraine headache. Multicenter, double-blind, randomized, placebo-controlled investigation, having a 4-week, single-blind placebo baseline phase and a 12-week treatment phase (4-week dose adjustment, 8-week maintenance). Eight headache/neurology clinics throughout the United States. One hundred seven patients randomized to divalproex or placebo (2:1 ratio): 70 receiving divalproex and 37 receiving placebo. Divalproex and placebo dosages titrated in blinded fashion during dose adjustment period to achieve actual/sham trough valproate sodium concentrations of approximately 70 to 120 mg/L. During the treatment phase, the mean migraine headache frequency per 4 weeks was 3.5 in the divalproex group and 5.7 in the placebo group (p < or = .001), compared with 6.0 and 6.4, respectively, during the baseline phase. Forty-eight percent of divalproex-treated patients and 14% of placebo-treated patients showed a 50% or greater reduction in migraine headache frequency from the baseline phase (P < .001). Among those with migraine headaches, divalproex-treated patients reported significantly less functional restriction than placebo-treated patients and used significantly less symptomatic medication per episode. No significant treatment group differences were observed in average peak severity or duration of individual migraine headaches. Treatment was stopped in 13% of divalproex-treated patients and 5% of placebo-treated patients because of intolerance (P, not significant). Divalproex is an effective prophylactic drug for patients with migraine headaches and is generally well tolerated.
To evaluate the efficacy and safety of divalproex sodium (DVPX) when used as prophylactic monotherapy in patients with migraine. Multicenter, double-blind, placebo-controlled, parallel group. Patients were previously untreated or had failed no more than two adequate trials of prophylactic therapy. During the 4-week (single-blind) baseline, patients received placebo and completed a headache diary. Patients with two or more migraine attacks during the baseline were randomized to receive a DVPX daily dose of 500, 1000, or 1500 mg, or to placebo. The experimental phase (EP) lasted 12 weeks, the first 4 weeks for dose escalation to randomized dose, and the remaining 8 weeks for maintenance at that dose. The primary efficacy variable was 4-week migraine attack frequency during the EP. One-hundred-and-seventy-six patients (44 placebo, 132 DVPX) were randomized; 171 provided efficacy data and 137 completed the study. During the EP, after adjustment for differences in baseline migraine attack frequencies, mean reductions in the DVPX groups were 1.7 (500 mg), 2.0 (1000 mg) and 1.7 (1500 mg) migraine attacks per 4 weeks compared to a mean reduction of 0.5 migraine attacks in the placebo group (p < or = 0.05 vs placebo). Forty-four to 45% of DVPX-treated patients compared to 21% of patients in the placebo group achieved > or = 50% reduction in their migraine attack frequencies (p < or = 0.05 vs placebo). The recommended initial dose of DVPX in migraine prophylaxis is 500 mg per day, although some patients may benefit from higher doses. Adverse events were similar in the DVPX and placebo treatment groups except for nausea, dizziness and tremor in which incidence rates were significantly higher in the DVPX 1500 mg group (nausea was also higher in 500 mg group) than in the placebo group. Divalproex sodium is an effective prophylactic treatment in migraine and is generally well tolerated.