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Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults

  1. Mattias Linde1,*,
  2. Wim M Mulleners2,
  3. Edward P Chronicle3,
  4. Douglas C McCrory4,5

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 24 JUN 2013

Assessed as up-to-date: 15 JAN 2013

DOI: 10.1002/14651858.CD010609


How to Cite

Linde M, Mulleners WM, Chronicle EP, McCrory DC. Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010609. DOI: 10.1002/14651858.CD010609.

Author Information

  1. 1

    Norwegian University of Science and Technology, Department of Neuroscience, Trondheim, Norway

  2. 2

    Canisius Wilhelmina Ziekenhuis, Department of Neurology, Nijmegen, Netherlands

  3. 3

    University of Hawaii at Manoa, (Deceased) Department of Psychology, Manoa, USA

  4. 4

    Duke University Medical Center, Department of Medicine, Durham, NC, USA

  5. 5

    Durham Veterans Affairs Medical Center, Center for Health Services Research in Primary Care, Durham, NC, USA

*Mattias Linde, Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. mattias.linde@ntnu.no.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 24 JUN 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of the condition

Migraine is a common and disabling health problem among children and predominantly young and middle-aged adults. Surveys from the main regions of the world suggest that the global prevalence of migraine is 14.7% (18.8% among women and 10.7% among men) (GBD 2010 Study). This disorder results in significant disability and work loss, and several studies have addressed the issue of the costs of migraine. In one of the most recent publications, aggregate direct and indirect costs to society due to migraine among adults in the European Union were estimated to amount to 50 billion Euros (67 billion US dollars) annually, or about 1222 Euros (1634 US dollars) annually per sufferer (Linde 2012).

 

Description of the intervention

Drug therapy for migraine falls into two categories: acute and preventive. Acute therapy aims at the symptomatic treatment of the head pain and other symptoms associated with an acute attack of migraine. The primary goals of preventive treatment are to reduce attack frequency, severity, and duration. Moreover, such therapy is commonly employed in an attempt to improve responsiveness to acute treatment, enhance functional status, and reduce disability. Evidence-based guidelines on the drug treatment of migraine have been developed and published by the European Federation of Neurological Societies (EFNS; Evers 2009). These guidelines suggest that prophylactic therapy should be considered for patients with migraine when quality of life, business duties, or school attendance are severely impaired; when the frequency of attacks is two or more per month; when there is a lack of response to acute drug treatment; and when frequent, very long, or uncomfortable auras occur.

This review considers the evidence for the efficacy and tolerability of the antiepileptic drugs gabapentin and pregabalin for preventing episodic migraine in adults. The prophylactic treatment of migraine in children is the subject of a separate Cochrane review (Victor 2003).

Gabapentin (systematic name 2-[1-(aminomethyl)cyclohexyl]acetic acid) was originally synthesised to mimic the chemical structure of the neurotransmitter gamma-aminobutyric acid (GABA). Following oral administration, peak plasma concentration of gabapentin is reached within two to three hours. Gabapentin bioavailability (fraction of dose absorbed) tends to decrease with increasing dose. The absolute bioavailability of a 300 mg capsule is approximately 60%. Food, including a high-fat diet, has no clinically significant effect on gabapentin pharmacokinetics. The distribution volume for women is approximately 50% that of men. There is no evidence of gabapentin metabolism in humans. Gabapentin does not induce hepatic enzymes responsible for drug metabolism. Gabapentin is excreted exclusively by the kidneys in unchanged form. The elimination half-life of gabapentin is independent of dose and averages five to seven hours. In elderly patients and patients with impaired renal function, gabapentin plasma clearance is reduced.

Gabapentin enacarbil is a prodrug for gabapentin. It was designed for increased oral bioavailability over gabapentin, and human trials showed it to produce extended release of gabapentin with almost twice the overall bioavailability, especially when taken with a fatty meal. Even in the therapeutic range, the intestinal absorption mechanisms of gabapentin are readily saturated, which impedes bioavailability of the drug. This does not pertain to gabapentin enacarbil. Due to the enhanced absorption of gabapentin enacarbil compared to gabapentin, the two drugs are not dose equivalent.

Pregabalin is related in structure to gabapentin. Compared to gabapentin, pregabalin is more potent, more quickly absorbed, and has greater bioavailability.

 

How the intervention might work

We use the term 'antiepileptics' here to refer generally to those drugs in common use for the treatment of epilepsy. The pharmacological treatment of epilepsy can be traced back as far as 1857, but the period of greatest development of antiepileptics was between 1935 and 1960, when 13 drugs were developed and marketed (Porter 1992). In recent decades, renewed interest has led to the development of several novel antiepileptics which may confer advantages in tolerability (Dalkara 2012), and these are beginning to be used in migraine also.

The use of antiepileptics for the prophylactic treatment of migraine is theoretically warranted by several known modes of action which relate either to the general modulation of pain systems or more specifically to systems involved in the pathophysiology of migraine (Silberstein 2008; Wiffen 2010). It is necessary to point out, however, that it is still not possible to state with any certainty which particular mode or modes of action of antiepileptics are relevant to the prophylaxis of migraine. The evidence is against these drugs, to the extent that they are a class. Only two antiepileptics (topiramate and valproate) out of 12 scientifically investigated for migraine prophylaxis have shown unequivocal efficacy, and it is not known how these are different from the others.

 

Why it is important to do this review

Some antiepileptic drugs are marketed specifically for migraine prophylaxis. The EFNS (Evers 2009) and the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein 2012) list topiramate and valproic acid among first-line migraine prophylactics. Regarding gabapentin, the EFNS lists it as a drug of third choice (only probable efficacy; Evers 2009), and the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein 2012) list it as Level U (inadequate or conflicting data to support or refute medication use). By contrast, a strong recommendation for the use of gabapentin for the prophylaxis of episodic migraine was recently given by the Canadian Headache Society Prophylactic Guidelines Development Group (Pringsheim 2012). The above-mentioned guidelines do not comment specifically on gabapentin enacarbil or pregabalin.

There is a fairly substantial body of evidence from controlled trials supporting the efficacy of many of the agents used for preventing migraine, yet such therapies are used by only a small percentage of patients with migraine — 3% to 12% in various studies (Clarke 1996; Edmeads 1993; Mehuys 2012). It is hoped that this review and others like it will increase awareness of migraine prophylactic treatment options and help to provide a systematic basis for making the best possible choice of such therapy in those individuals in need of it.

The present review is part of a series of reviews which, taken together, represent an update of a Cochrane review on 'Anticonvulsant drugs for migraine prophylaxis' (Chronicle 2004; Mulleners 2008; first published in 2004, and previously updated (conclusions not changed) in 2007). The old review has been split into four separate reviews for updating:

  1. Topiramate for the prophylaxis of episodic migraine in adults (Linde 2013a)
  2. Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults (Linde 2013b)
  3. Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults (the present review; Linde 2013c)
  4. Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults (Linde 2013d)

Unpublished data from industry-sponsored clinical trials that tested the efficacy of gabapentin for off-label use in migraine have recently entered the public domain, not through the usual channels of scientific publication, but through the legal process in two recent US litigations against the sponsor (Landefeld 2009; Saris 2010). Three randomised clinical trials of gabapentin versus placebo are documented in internal company research reports, which are standardised documents prepared by or for the sponsor. These reports describe the research conducted using a standardised format similar to that of a scientific manuscript, but in much greater detail, and may include the study protocol and protocol amendments, a listing and description of adverse events, data analyses, and a statistical analysis plan.

One of the three migraine research reports was never published, but the other two correspond in some way to publications in the peer-reviewed literature. Important discrepancies between the results described in the research reports and the corresponding published manuscripts have been noted (Vedula 2009). One of us obtained and examined the migraine prophylaxis research reports as an expert witness in one of the US litigations (McCrory 2008).

Of the three randomised clinical trials of gabapentin versus placebo that are included among these data:

  1. Study 945-220, described in RR 995-00074, corresponds to a full-length publication (Mathew 2001) which, however, misrepresents the findings in RR 995-00074.
  2. Study 879-200, described in RR 4301-00066, was partially reported in abstract form (Wessely 1987 — appears to be an interim analysis), but was never published in full or final form.
  3. Study 945-217, described in RR 995-00085, was never published in any form.

In addition to these new data, we also obtained unpublished data from a published trial (Di Trapani 2000) through correspondence with the senior author (Prof Alessandro Capuano).

The addition of all of these new data augments our previous review substantially and markedly changes the conclusions. In the previous review (Chronicle 2004; Mulleners 2008), we expressed cautious support for gabapentin, as follows:

"The evidence derived from trials of gabapentin suggests a beneficial effect in migraine prophylaxis, but this drug needs further evaluation. Although three clinical trials of reasonable size have been reported, the interpretation of two [Di Trapani 2000; Mathew 2001] is hampered by some aspects of their method or data analysis, while the third [Jimenez 1999] does not provide unequivocal evidence for efficacy, as it is primarily a dose comparison study. In the meantime, it may be advocated with some reservation that gabapentin may be used for those cases that are difficult to manage with other currently available strategies, since it has a reasonable tolerability and safety profile."

After incorporation of the previously unpublished data, this updated review now suggests with more certainty that gabapentin does not meet the standard of a statistically significant benefit in reducing migraine frequency.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

To describe and assess the evidence from controlled trials on the efficacy and tolerability of gabapentin/gabapentin enacarbil or pregabalin for preventing migraine attacks in adult patients with episodic migraine.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

The International Headache Society (IHS) has provided a useful document setting out guidelines for the conduct of clinical trials in migraine, to which current investigators are encouraged to adhere (Tfelt-Hansen 2012). This document was not used as the sole basis for considering studies in this review, as too many potentially informative past studies would likely have been excluded on methodological grounds. However, many of its recommendations have been used as a basis for what follows.

Included studies were required to be prospective, controlled trials of self administered gabapentin or pregabalin taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. We included trials only if allocation to treatment groups was randomised or pseudo-randomised (based on some non-random process unrelated to the treatment selection or expected response). Blinding was not required. We excluded concurrent cohort comparisons and other non-experimental designs.

 

Types of participants

Study participants were required to be adults (at least 16 years of age) and to meet reasonable criteria designed to distinguish migraine from tension-type headache. If patients with both types of headache were included in a trial, results were required to be stratified by headache diagnosis. We did not require the use of a specific set of diagnostic criteria (eg, Ad Hoc Cttee 1962; IHS Cttee 1988; ICHD-II 2004), but migraine diagnoses had to be based on at least some of the distinctive features of migraine, eg, nausea/vomiting, severe head pain, throbbing character, unilateral location, phono/photophobia, or aura. Secondary headache disorders had to be excluded using reasonable criteria.

We anticipated that some of the trials identified would include patients described as having mixed migraine and tension-type headaches or combination headaches, and the protocol for this review described detailed procedures for dealing with such trials. In the end, no such precautions were necessary. We excluded studies evaluating treatments for chronic daily headache, chronic migraine, and transformed migraine. The reasons for this are: (a) the definition of chronic migraine is still heavily debated, and a revision of the 2004 IHS criteria for this condition has been proposed (Olesen 2006); (b) transformed migraine and chronic daily headache, although commonly used terms, are insufficiently validated diagnoses; (c) the separation of these conditions from headache due to medication overuse is not always clear in many studies; and (d) there is some evidence that suggests that chronic migraine may be more refractory to standard prophylactic treatment than episodic migraine. We explicitly excluded trials and treatment groups including only patients with tension-type headache.

 

Types of interventions

Included studies were required to have at least one arm in which gabapentin or pregabalin (without concomitant use of other migraine prophylactic treatment) was given regularly during headache-free intervals with the aim of preventing the occurrence of migraine attacks, improving migraine-related quality of life, or both. Acceptable comparator groups included placebo, no intervention, active drug treatment (ie, with proven efficacy, not experimental), the same drug treatment with a clinically relevant different dose, and non-pharmacological therapies with proven efficacy in migraine. The analysis included only drugs and dosages that are commercially available.

We recorded any data reported on treatment compliance in the Characteristics of included studies table. After examination of these data, it did not seem necessary to stratify the analysis by compliance.

We anticipated that most trials would permit the use of medication for acute migraine attacks experienced during the trial period. We therefore recorded descriptions of trial rules concerning the use of acute medication in the Characteristics of included studies table whenever such information was provided. We did not otherwise model or adjust for this factor in our analysis.

 

Types of outcome measures

We collected and analysed trial data on headache frequency, responders (patients with ≥ 50% reduction in headache frequency), quality of life, and adverse events.

 

Search methods for identification of studies

Search strategies used in our earlier review (Chronicle 2004; Mulleners 2008) are detailed in Appendix 1 (last search date 31 December 2005). For the present update, trained information specialists developed detailed search strategies for each database searched (Appendix 2). The new searches overlapped the old searches by a full year to ensure complete coverage. The last search date for all updated searches was 15 January 2013.

Databases searched for this update were:

  • Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12; years searched = 2005 to 2012);
  • MEDLINE (via OVID), 2005 to 15 January 2013;
  • MEDLINE In-Process (via OVID), current week, 15 January 2013;
  • EMBASE (via OVID), 2005 to 15 January 2013.

Additional strategies for identifying trials included searching the reference lists of review articles and included studies, searching books related to headache, and consulting experts in the field. We attempted to identify all relevant published trials, irrespective of language. We handsearched two journals, Headache and Cephalalgia, in their entirety through January 2013.

 

Data collection and analysis

 

Selection of studies

Two of us independently screened titles and abstracts of studies identified by the literature search for eligibility. Papers that could not be excluded with certainty on the basis of information contained in the title and/or abstract were retrieved in full for screening. Disagreements were resolved through discussion. We retrieved papers passing this initial screening process, and two of us independently reviewed the full texts. Disagreements at the full-text stage were resolved through internal discussion and, in a few cases, through correspondence with members of the editorial staff of the Cochrane Pain, Palliative and Supportive Care Review Group. We were not blinded to study investigators' names and institutions, journal of publication, or study results at any stage of the review.

The search strategy described above identified a large number of short conference and journal abstracts. The majority of these either (a) reported partial results of ongoing trials; (b) provided insufficient information on trial design or results; (c) were early reports of included studies; or (d) were reproductions of abstracts of papers published in full (for example, the journal Headache reproduces abstracts of interest to readers, and these are found by PubMed). We agreed that short abstracts of this kind would be excluded from consideration.

 

Data extraction and management

Two of us independently abstracted information on patients, methods, interventions, efficacy outcomes, and adverse events from the original reports onto specially designed, pre-tested paper forms. Disagreements were again resolved through discussion.

We anticipated that trials would vary in length, that outcomes would be measured over various units of time (eg, number of attacks per two weeks versus number of attacks per four weeks), and that results would be reported for numerous different time points (eg, four-week headache frequency at two months versus at four months). We attempted to standardise the unit of time over which headache frequency was measured at 28 days (four weeks) wherever possible. We recorded outcomes beginning four weeks after the start of treatment and continued through all later assessment periods. We made decisions about which time points to include in the final analysis once the data had been collected.

We anticipated that outcomes measured on a continuous scale (eg, headache frequency) would be reported in a variety of ways, eg, as mean pre-treatment, post-treatment, and/or change scores. Among change scores, we preferred the mean of within-patient changes (from baseline to on-treatment in a parallel-group trial) over the change in group means because the first both results in a lower variance (taking into account the correlation between baseline and post-treatment scores in each patient) and adjusts for imbalances in baseline headache frequencies, while the latter has only the second advantage. When neither type of change score was reported, we compared post–treatment means between groups, assuming that baseline data would be balanced due to randomisation. We anticipated that many trials would report group means, without reporting data on the variance associated with these means. In such cases, we attempted to calculate or estimate variances based on primary data, test statistics, and/or error bars in graphs.

When efficacy outcomes were reported in dichotomous form (success/failure), we required that the threshold for distinguishing between treatment success and failure be clinically significant; for example, we interpreted a ≥ 50% reduction in headache frequency as meeting this criterion. In such cases, we recorded, for each treatment arm, the number of patients included in the analysis and the number with each outcome.

The protocol for this review specified rules for dealing with outcome data reported on an ordinal scale (eg, for reduction in headache frequency: 0%, 1% to 24%, 25% to 49%, 50% to 74%, 75% to 99%, 100%) but, in fact, none of the included trials reported ordinal data for outcomes of interest.

We envisaged that the preferred methods of collecting and presenting data on quality of life would most likely be the Migraine-Specific Questionnaire (MSQ) and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). However, other instruments and other types of outcomes related to quality of life (eg, work absenteeism) were not excluded a priori, and these data were kept under review before specifying rules for analysing outcome data in this domain.

We recorded the proportion of patients reporting adverse events for each treatment arm wherever possible. The identity and rates of specific adverse events were also recorded. We anticipated that reporting of adverse events would vary greatly across trials with regard to the terminology used, method of ascertainment, and classification of adverse events as drug-related or not and as severe or not.

 

Assessment of risk of bias in included studies

We completed a 'Risk of bias' table for each study, using assessments of random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). For new studies identified in the present update, two of us completed this assessment independently; for older studies, one of us performed the assessment and a second author reviewed and commented on it. Disagreements were resolved through discussion.

We also assessed the methodological quality of individual trials using the scale devised by Jadad and colleagues (Jadad 1996), operationalised as follows:

  1. Was the study described as randomised? (1 = yes; 0 = no)
  2. Was the method of randomisation well described and adequate? (0 = not described; 1 = described and adequate; -1 = described, but not adequate)
  3. Was the study described as double-blind? (1 = yes; 0 = no)
  4. Was the method of double-blinding well described and adequate? (0 = not described; 1 = described and adequate; -1 = described, but not adequate)
  5. Was there a description of withdrawals and dropouts sufficient to determine the number of patients in each treatment group entering and completing the trial? (1 = yes; 0 = no)

Each trial thus received a score of 0 to 5 points, with higher scores indicating higher quality in the conduct or reporting of the trial. Two review authors scored the studies independently, and a consensus score was then arrived at through discussion. The consensus score is reported for each study in the Characteristics of included studies table and was not used as a weighting in statistical analyses.

 

Measures of treatment effect

The primary outcome considered for the efficacy analysis was headache frequency. Among headache frequency measures, we preferred number of migraine attacks to number of days with migraine. The latter measure confusingly incorporates attack duration into the measure of headache frequency. Moreover, attack duration is affected by the use of symptomatic medication, which is permitted in most trials. We also analysed headache frequency in terms of a responder rate, or the proportion of patients with a ≥ 50% reduction in headache frequency from pre- to post-treatment.

As noted above (Data extraction and management), we kept patient-reported quality of life data under review as studies were selected. The only quality of life data available for a rigorous analysis were measured, in RR 995-00085, by the SF-36 (nine domains).

The analysis considered only outcome data obtained directly from the patient and not those judged by the treating physician or study personnel. Efficacy data based on contemporaneous and timed (usually daily) recording of headache symptoms were preferred to those based on global or retrospective assessments.

In addition, we tabulated adverse events for each included study.

 

Unit of analysis issues

In the case of cross-over trial designs, we anticipated that the data reported would normally not permit analysis of paired within-patient data. We thus planned to analyse cross-over trials as if they were parallel-group trials, combining data from all treatment periods. In fact, none of the included trials used a cross-over design.

 

Dealing with missing data

Where data were missing or inadequate, we attempted to obtain these data by correspondence with study authors.

 

Assessment of heterogeneity

We tested estimates of efficacy (both mean differences (MDs) and odds ratios (ORs)) for homogeneity. When significant heterogeneity was present, we made an attempt to explain the differences based on the clinical characteristics of the included studies. We did not statistically combine studies that were clinically dissimilar. However, when a group of studies with statistically heterogeneous results appeared to be clinically similar, we did combine study estimates. We performed all pooled analyses using a random-effects model.

As a sensitivity analysis, we also planned to calculate a pooled effect estimate using a fixed-effect model for major outcomes (headache frequency, responder rate, and any adverse event) when the random-effects result was near-significant (0.05 ≤ P ≤ 0.15) and the pooled studies were homogeneous (heterogeneity statistics: P > 0.15/I2 < 30%). Such a sensitivity analysis would evaluate whether conclusions might differ based on the statistical model used for pooling in situations where a fixed-effect model might reasonably be considered instead of a random-effects model. In fact, however, no such sensitivity analyses were warranted in the present review.

 

Data synthesis

We anticipated that continuous outcome measures of headache frequency would be reported on different and often incompatible scales. Although we attempted to standardise the extraction of headache frequency data to a 28-day (four-week) period, this was not possible in every case. In our previous review (Chronicle 2004; Mulleners 2008), we therefore analysed these data using the standardised mean difference (SMD, with 95% confidence intervals (CIs)) rather than the mean difference (MD). The introduction of change scores in the newly included studies for some of the reviews in this series necessitated a change in the analysis plan from SMDs to MDs. The latter also has the advantage of giving a result in clinically meaningful units (ie, x fewer migraines per 28 days).

We used dichotomous data meeting our definition of a clinically significant threshold to calculate odds ratios (ORs), with 95% CIs. We additionally computed numbers needed to treat (NNTs), with 95% CIs, as the reciprocal of the risk difference (RD) versus placebo (McQuay 1998).

In the same way, we used data on the proportion of patients reporting adverse events to calculate RDs and numbers needed to harm (NNHs).

We analysed data on gabapentin and gabapentin enacarbil separately, since the two drugs are not dose equivalent.

 

Subgroup analysis and investigation of heterogeneity

We considered subgroup analyses undertaken by dose, method of randomisation, and by completeness of blinding, but did not undertake them because of insufficient data.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

 

Results of the search

The PubMed search strategy for our previous review (Chronicle 2004; Mulleners 2008) yielded 1089 potentially eligible citations, while the EMBASE and CENTRAL searches yielded 290 and 6952 citations, respectively. No additional citations were retrieved from the Cochrane Pain, Palliative & Supportive Care Trials Register or from other sources. After title and abstract screening, we obtained 58 published papers on antiepileptics for full-text scrutiny. Of these, eight (three included, five excluded) investigated gabapentin. No paper investigated pregabalin.

The MEDLINE search strategy for the present update (from 2005 on) yielded 188 citations as possible candidates for the current series of reviews on antiepileptic drugs for migraine prophylaxis; the search of MEDLINE In-Process identified an additional 20 citations. The EMBASE and CENTRAL updates identified 484 and 85 citations, respectively. After title and abstract screening, we obtained 37 published papers on antiepileptics for full-text scrutiny. Of these, none investigated gabapentin or pregabalin, and one (included) investigated gabapentin enacarbil.

In addition, as described above (Why it is important to do this review), three previously confidential research reports (RR 4301-00066; RR 995-00074; RR 995-00085) investigating gabapentin recently became public by virtue of being entered into evidence in a legal proceeding in 2008. All three are included here. The inclusion of RR 995-00074 led to the exclusion of Mathew 2001 (see Characteristics of excluded studies), which was included in our previous review (Chronicle 2004; Mulleners 2008).

Thus, for the present update, we reviewed a total of 12 papers (nine published and three unpublished) at the full-text screening stage. Of these, we included six papers and excluded six.

 

Included studies

The six included papers reported data from six unique studies, including five that compared gabapentin (Di Trapani 2000; RR 4301-00066; RR 995-00085; RR 995-00074) or gabapentin enacarbil (Silberstein 2013) to placebo, and two that generated data that enabled dose comparisons of gabapentin (Jimenez 2002) or gabapentin enacarbil (Silberstein 2013). No trial compared gabapentin to another active intervention.

All six trials had a parallel-group design.

The doses of gabapentin investigated in the trials were 900 to 2400 mg/day. This can be compared to the range of doses used in epilepsy, which is 900 to 3600 mg/day.

The doses of gabapentin enacarbil investigated in the trial were 1200 to 3000 mg/day. This drug is not approved by the FDA for the treatment of epilepsy but rather for the treatment of moderate-to-severe restless legs syndrome and postherpetic neuralgia in adults. The standard dosing for treatment of restless legs syndrome is 600 mg/day.

The median duration of the treatment phase of the included trials was 12 weeks (mean 14; range 12 to 20 weeks).

See Characteristics of included studies for further details.

 

Excluded studies

Of the 12 papers obtained for full-text scrutiny, six were excluded for reasons given in the Characteristics of excluded studies table.

 

Risk of bias in included studies

We scored methodological quality using the Jadad scale as indicated in the Assessment of risk of bias in included studies section, with a maximum attainable score of 5. The median quality score was 4 (mean 3.7; range 2 to 5).

Of 36 risk of bias items scored for the six studies, the majority of ratings were either 'unclear' (18 (50%)) or 'low' (11 (31%); we judged three studies (Di Trapani 2000; RR 4301-00066; Silberstein 2013) as having a 'high' risk of bias for two or more items (Figure 1).

 FigureFigure 1. 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

Only one of the six studies provided an adequate methodological description of how allocation sequences were generated (by a computer-generated randomisation schedule), and only three provided an adequate methodological description of attempts to conceal allocation of intervention assignment (see Figure 1 and the Characteristics of included studies table). We judged that there was a high risk of selection bias for Jimenez 2002, where the very unequal numbers of patients in the two dosage groups are unlikely to have been achieved by strict randomisation.

 

Blinding

Participants and clinicians were reported as blinded during the conduct of five of the six studies (see Characteristics of included studies table). The procedure described for double-blinding in RR 4301-00066, RR 995-00085, and RR 995-00074 was packaging and labelling identical-appearing tablets according to the randomisation codes. However, given that the number of gabapentin subjects erroneously receiving other prophylaxis in RR 4301-00066 was nearly three times higher in the gabapentin group than in the placebo group, it is likely that the blinding was inadequate. Details of the methodology used were not reported for Di Trapani 2000. Jimenez 2002 was an open-label trial and therefore also suffers from a high risk of performance bias. We judged the risk of detection bias as unclear in all studies, since none explicitly stated blinding of outcome assessment.

 

Incomplete outcome data

Completeness of data was adequately reported for four studies (Figure 1). Usually an intention-to-treat (ITT) analysis was applied (see the Characteristics of included studies table). We were concerned about the high number of protocol violators due to the initiation or continuation of other prophylactics (19 of those allocated to gabapentin; seven of those allocated to placebo) in RR 4301-00066. It is not clear whether the majority initiated other prophylaxis prior to or after randomisation. The higher efficacy means in the gabapentin ITT population (with violators) compared to the efficacy population (without violators) suggest that a significant number may have been initiated after randomisation, possibly because of lack of efficacy. Only the data for the smaller efficacy population of RR 4301-00066 are included in this review. We used the modified intention-to-treat (mITT) and safety evaluable populations for analysis of efficacy outcomes and adverse events, respectively, in RR 995-00074; RR 995-00085. In Silberstein 2013, subjects were randomised despite missing baseline values.

 

Selective reporting

We judged the risk of reporting bias as low only in Di Trapani 2000. The senior author confirmed that statistical variance estimates reported in the paper were standard errors of the mean (SEMs) and provided additional unpublished data for this review. It is remarkable that the negative results in the research reports of RR 4301-00066 and RR 995-00085 were classified as confidential and would have remained unobtainable had it not been for the discovery process in a legal case. Reporting bias is obvious in Jimenez 2002, since adverse events are not reported separately for each group. Within-group changes (with standard deviations (SDs)) from baseline in mean migraine frequencies during the double-blind period were lacking in Silberstein 2013 and were not provided upon request to the corresponding author.

 

Other potential sources of bias

Statistically significant results are more likely to be published than trials affirming a null result. The tendency for negative or inconclusive results to remain unpublished has been particularly problematic in the context of the present review, and there is no guarantee that other unpublished studies do not exist.

 

Effects of interventions

 

Gabapentin or gabapentin enacarbil versus placebo

 

Methodological considerations

Although there was methodological variation, as described above (Risk of bias in included studies), the included trials were fundamentally similar with regard to basic design, patients, and measures.

All doses reported below are given in terms of mg/day.

 

Headache frequency

One trial each of gabapentin in a stable dose of 900 mg (RR 4301-00066; 53 patients), titrated to 1200 mg (Di Trapani 2000; 63 patients), and titrated to 1800 mg (RR 995-00085; 122 patients) failed to show a statistically significant reduction in headache frequency with active treatment compared to placebo, whereas one trial of gabapentin titrated to 1800 to 2400 mg (RR 995-00074; 113 patients) demonstrated a small but statistically significant superiority of active treatment over placebo for this outcome (mean difference (MD) -0.80; 95% confidence interval (CI) -1.55 to -0.05). The pooled results of these four studies (MD -0.44; 95% CI -1.43 to 0.56; 351 patients) do not demonstrate a significant difference between gabapentin and placebo ( Analysis 1.1). To put the above MD estimates into context, the median baseline headache frequency in the gabapentin groups of the four placebo-controlled trials was 5.1 attacks per 28 days (mean 5.1; range: 4.9 to 6.1).

The sole trial of gabapentin enacarbil versus placebo (Silberstein 2013) did not report sufficient data for us to calculate MDs for this outcome.

 

Responders (patients with ≥ 50% reduction in headache frequency)

One trial of gabapentin titrated to 1800 mg (RR 995-00085; 122 patients) failed to demonstrate a significant difference between active treatment and placebo in the proportion of responders (odds ratio (OR) 0.97; 95% CI 0.45 to 2.11), whereas one trial of gabapentin titrated to 1800 to 2400 mg (RR 995-00074; 113 patients) demonstrated a small but statistically significant superiority of active treatment over placebo for this outcome (OR 2.79; 95% CI 1.09 to 7.17). The pooled results (OR 1.59; 95% CI 0.57 to 4.46; 235 patients) do not support an effect of gabapentin ( Analysis 1.2).

One trial of gabapentin enacarbil (Silberstein 2013) failed to demonstrate a significant difference between the active drug titrated to 1200 mg (59 patients), 1800 mg (114 patients), 2400 mg (123 patients), or 3000 mg (58 patients), and placebo (120 patients) in the proportion of responders ( Analysis 2.1).

 

Quality of life

The only quality of life data available in the included trials were comparisons between gabapentin 1800 mg and placebo in nine dimensions of the SF-36 (RR 995-00085). Because these two interventions did not differ significantly with regard to reduction of headache frequency, we undertook no further analyses of these data.

 

Dose comparisons for gabapentin or gabapentin enacarbil

Jimenez 2002 (135 patients) compared gabapentin 1200 mg and 2000 mg. There were no significant differences between the groups, either in headache frequency (MD -0.50; 95% CI -1.11 to 0.11;  Analysis 3.1) or in the proportion of responders (OR 0.89; 95% CI 0.41 to 1.91;  Analysis 3.2).

Silberstein 2013 compared gabapentin enacarbil 1200 mg (59 patients), 1800 mg (114 patients), 2400 mg (123 patients), and 3000 mg (58 patients). Data were insufficient for us to calculate MDs for headache frequency, our preferred outcome measure. There were no significant differences between the groups in the proportion of responders ( Analysis 4.1).

 

Safety

Safety data from placebo-controlled trials of gabapentin and gabapentin enacarbil are summarised in  Table 1 and  Table 2, respectively. For gabapentin, we calculated risk differences (RDs) versus placebo for any adverse event ( Analysis 1.3) and for each of the five most prevalent adverse events, namely, asthenia/fatigue ( Analysis 1.4), dizziness ( Analysis 1.5), flu syndrome ( Analysis 1.6), somnolence ( Analysis 1.7), and abnormal thinking ( Analysis 1.8). Numbers needed to harm (NNHs; with 95% CIs) for the pooled analyses of gabapentin 900 to 2400 mg versus placebo were as follows:

  • Any adverse event: NNH not calculated, since 95% CI for RD includes zero.
  • Asthenia/fatigue: NNH not calculated, since 95% CI for RD includes zero.
  • Dizziness: NNH 7 (5 to 13).
  • Flu syndrome: NNH not calculated, since 95% CI for RD includes zero.
  • Somnolence: NNH 9 (6 to 33).
  • Abnormal thinking: NNH 20 (11 to 100).

All four placebo-controlled trials of gabapentin reported unambiguous data on the percentage of patients in active treatment groups who withdrew because of adverse events. These percentages were 11% for gabapentin 900 mg in RR 4301-00066, 0% for gabapentin 1200 mg in Di Trapani 2000, 17% for gabapentin 1800 mg in RR 995-00085, and 14% for gabapentin 1800 to 2400 mg in RR 995-00074.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Summary of main results

Meta-analysis of the studies included in this review provides little evidence that gabapentin, in any dose, is efficacious for the prophylaxis of migraine. In pooled analyses, mean headache frequency was not significantly reduced with gabapentin as compared to placebo (four studies with 351 patients contributed to this analysis). Furthermore, and perhaps of greater clinical relevance (though less informative scientifically), patients were not more likely to have a ≥ 50% reduction in headache frequency with gabapentin (two studies with 235 patients contributed to this analysis). The majority of patients experienced adverse events from gabapentin.

Dose comparisons suggest that gabapentin 2000 mg/day is no more effective than 1200 mg/day.

Statistically significant findings for both efficacy outcomes (headache frequency and responders) from a single trial of the highest gabapentin dose studied (1800 to 2400 mg/day; RR 995-00074; 113 patients) did not change our overall conclusions given that, for both outcomes, (a) findings from the other individual trials, and from the pooled analyses combining all trials, were statistically insignificant; (b) estimates of effect from the pooled analyses were small; and (c) there was little evidence to suggest a dose-response trend in effect.

The only trial of gabapentin enacarbil versus placebo (Silberstein 2013) did not report sufficient data for us to calculate mean differences (MDs) for headache frequency, our preferred outcome measure, and showed no significant difference between any dose studied (1200, 1800, 2400, and 3000 mg/day) and placebo in the proportion of responders.

We identified no studies evaluating pregabalin for migraine prophylaxis, and no studies comparing gabapentin or gabapentin enacarbil to other active interventions.

 

Overall completeness and applicability of evidence

The main results of this meta-analysis do not harmonise with current practice, where clinicians regularly prescribe gabapentin as a migraine prophylactic intervention (Drugs.com 2013; Mayo Clinic Staff 2011; Pringsheim 2012).

The studies identified were not sufficient to address all of the objectives of the review for two reasons. First, no controlled trials of pregabalin for the prophylaxis of episodic migraine were identified. Therefore, well-designed trials of pregabalin against placebo or other interventions with demonstrable efficacy in the prophylaxis of migraine are desirable. Second, trials comparing gabapentin with active comparators were not found.

Several important issues need to be taken into account in any assessment of the efficacy of a drug for migraine prophylaxis. Diagnostic criteria, baseline headache frequency, washout periods for previous medication, rules for rescue medication, and the statistical power of the comparison were handled very variably in the six included studies. As investigations of the efficacy of various agents become more commonplace, it seems increasingly important that scientists and clinicians are at least aware of the trial guidelines suggested by the International Headache Society (Tfelt-Hansen 2012). Even if these guidelines cannot — for operational or scientific reasons — be adhered to in their entirety, they provide a useful consultative framework at the early stages of trial design.

 

Quality of the evidence

The identified body of evidence does not support the use of gabapentin in the prophylaxis of episodic migraine in adults, but does not robustly refute it. As usual in the context of clinical trials research, there was considerable heterogeneity in both headline results and general levels of analytic and statistical sophistication. The highest gabapentin dose studied (1800 to 2400 mg/day), evaluated in a single trial (RR 995-00074; 113 patients) demonstrated a small but statistically significant effect for both efficacy outcomes (headache frequency and responders). For reasons described under Summary of main results, this did not change our overall conclusions. It is fair to say that we faced several difficulties in deriving adequate information from the results of some studies. First, means and standard deviations were not always fully reported for each phase of trials. In tandem with this problem, measures of variability were not always adequately described or labelled. Second, patient numbers did not always seem internally consistent. Third, there was considerable variability in how intention-to-treat analyses were performed.

 

Potential biases in the review process

Of 36 risk of bias items scored for the six studies, the majority of ratings were either 'unclear' (18 (50%)) or 'low' (11 (31%)) (Figure 1). As described in detail above (Risk of bias in included studies), we judged three trials as having a 'high' risk of bias for at least two items, as follows: random sequence generation (Jimenez 2002), blinding of participants and personnel (RR 4301-00066; Jimenez 2002), incomplete outcome data (RR 4301-00066; Silberstein 2013), and/or selective reporting (Jimenez 2002; Silberstein 2013). A strength of this review is that the methods used for searching and study selection make it highly likely that most relevant trial results in the public domain were identified. As demonstrated in the cases of RR 4301-00066, RR 995-00085, and RR 995-00074, there is nevertheless an obvious risk that the reports of some trials may have been classified as confidential and thus remain unobtainable.

 

Agreements and disagreements with other studies or reviews

It is remarkable that our analyses would have been biased in favour of gabapentin had it not been for the inclusion of previously confidential research reports which, after several years, became available in the public domain by virtue of being entered into evidence in a legal proceeding. The overall conclusion in this review, that available data provide little evidence that gabapentin, in any dose, is efficacious for preventing attacks in adult patients with migraine, is in line with the conclusions drawn by the EFNS (Evers 2009) and the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein 2012) but not with those reached by the Canadian Headache Society Prophylactic Guidelines Development Group (Pringsheim 2012).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice

The evidence derived from trials of gabapentin suggests that it has little or no beneficial effect in migraine prophylaxis while generating side effects in the majority of patients. It may therefore be advocated that it should not be used in routine clinical practice.

The conclusions in this review cannot be extrapolated to chronic migraine, transformed migraine, or chronic daily headache. None of these conditions was considered for this review, as properly validated definitions are as yet lacking. There is no firm evidence for an effect of pregabalin for the prophylaxis of migraine.

 
Implications for research

Published research on gabapentin for migraine prophylaxis has misled clinicians for a number of years. Enquiry is needed into the causes of this, and the harms that may have resulted.

While efficacy for high doses of gabapentin has not been ruled out, the evidence for this drug, overall, is not promising and does not lead us to recommend further studies with any degree of priority.

There are no controlled trials of pregabalin in the prophylaxis of migraine. Well-designed studies comparing it to placebo and interventions with proven efficacy in migraine are needed.

In general, we feel that the quality of both methods and reporting is disappointing in this area of investigation. In particular, investigators wishing to report intention-to-treat analyses should carefully consider the recommendations of medical statisticians (eg, Hollis 1999). Future trialists should also be encouraged to follow the recommendations of the International Headache Society (Tfelt-Hansen 2012) with regard to both trial design and reporting of data.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Professor EP Chronicle, PhD, sadly passed away on 9 February 2007. We wish to acknowledge Professor Chronicle's major contribution and tremendous effort in compiling all statistical analyses and much of the text of the original review on antiepileptics (Chronicle 2004; Mulleners 2008). Without his relentless dedication it would have never seen the light of day.

The protocol for the original review was developed while Dr Chronicle was a Visiting Scholar at the University of California, Berkeley. Dr Sally Hollis, Lancaster University, and Dr Kentaro Hayashi, University of Hawaii at Manoa, provided helpful advice on statistical matters. Several pharmaceutical companies kindly provided information about trials in progress.

We thank Ruth Foxlee, Jane Hayes, and Joanne Abbott for assistance in designing search strategies and running searches; Prof Timothy Steiner for editorial guidance; and Dr Rebecca Gray for editorial assistance and technical support.

Lifting The Burden: the Global Campaign against Headache and the International Headache Society provided financial support for the editorial process (see Sources of support).

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Gabapentin versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache frequency (change from baseline to post-treatment, or post-treatment alone)4351Mean Difference (IV, Random, 95% CI)-0.44 [-1.43, 0.56]

    1.1 Gabapentin 900 mg/day stable dosage
153Mean Difference (IV, Random, 95% CI)-0.90 [-3.19, 1.39]

    1.2 Gabapentin titrated to 1200 mg/day
163Mean Difference (IV, Random, 95% CI)-1.92 [-4.66, 0.82]

    1.3 Gabapentin titrated to 1800 mg/day
1122Mean Difference (IV, Random, 95% CI)0.5 [-0.27, 1.27]

    1.4 Gabapentin titrated to 1800 to 2400 mg/day
1113Mean Difference (IV, Random, 95% CI)-0.80 [-1.55, -0.05]

 2 Responders (patients with ≥ 50% reduction in headache frequency)2235Odds Ratio (M-H, Random, 95% CI)1.59 [0.57, 4.46]

    2.1 Gabapentin titrated to 1800 mg/day
1122Odds Ratio (M-H, Random, 95% CI)0.98 [0.45, 2.11]

    2.2 Gabapentin titrated to 1800 to 2400 mg/day
1113Odds Ratio (M-H, Random, 95% CI)2.79 [1.09, 7.17]

 3 Any adverse event3382Risk Difference (M-H, Random, 95% CI)0.05 [-0.04, 0.14]

    3.1 Gabapentin 900 mg/day stable dosing
189Risk Difference (M-H, Random, 95% CI)0.03 [-0.14, 0.20]

    3.2 Gabapentin titrated to 1800 mg/day
1150Risk Difference (M-H, Random, 95% CI)0.06 [-0.09, 0.22]

    3.3 Gabapentin titrated to 1800 to 2400 mg/day
1143Risk Difference (M-H, Random, 95% CI)0.05 [-0.09, 0.19]

 4 Asthenia/fatigue3382Risk Difference (M-H, Random, 95% CI)-0.03 [-0.08, 0.03]

    4.1 Gabapentin 900 mg/day stable dosing
189Risk Difference (M-H, Random, 95% CI)-0.02 [-0.10, 0.05]

    4.2 Gabapentin titrated to 1800 mg/day
1150Risk Difference (M-H, Random, 95% CI)-0.02 [-0.12, 0.07]

    4.3 Gabapentin titrated to 1800 to 2400 mg/day
1143Risk Difference (M-H, Random, 95% CI)-0.04 [-0.20, 0.11]

 5 Dizziness3382Risk Difference (M-H, Random, 95% CI)0.15 [0.08, 0.22]

    5.1 Gabapentin 900 mg/day stable dosing
189Risk Difference (M-H, Random, 95% CI)0.08 [-0.03, 0.20]

    5.2 Gabapentin titrated to 1800 mg/day
1150Risk Difference (M-H, Random, 95% CI)0.21 [0.11, 0.31]

    5.3 Gabapentin titrated to 1800 to 2400 mg/day
1143Risk Difference (M-H, Random, 95% CI)0.14 [0.02, 0.27]

 6 Flu syndrome2293Risk Difference (M-H, Random, 95% CI)0.03 [-0.03, 0.08]

    6.1 Gabapentin titrated to 1800 mg/day
1150Risk Difference (M-H, Random, 95% CI)0.04 [-0.03, 0.11]

    6.2 Gabapentin titrated to 1800 to 2400 mg/day
1143Risk Difference (M-H, Random, 95% CI)0.00 [-0.10, 0.10]

 7 Somnolence2293Risk Difference (M-H, Random, 95% CI)0.11 [0.03, 0.18]

    7.1 Gabapentin titrated to 1800 mg/day
1150Risk Difference (M-H, Random, 95% CI)0.09 [-3.58, 0.19]

    7.2 Gabapentin titrated to 2400 mg/day
1143Risk Difference (M-H, Random, 95% CI)0.13 [0.01, 0.26]

 8 Abnormal thinking3382Risk Difference (M-H, Random, 95% CI)0.05 [0.01, 0.09]

    8.1 Gabapentin 900 mg/day stable dosing
189Risk Difference (M-H, Random, 95% CI)0.04 [-0.03, 0.11]

    8.2 Gabapentin titrated to 1800 mg/day
1150Risk Difference (M-H, Random, 95% CI)0.07 [0.01, 0.13]

    8.3 Gabapentin titrated to 1800 to 2400 mg/day
1143Risk Difference (M-H, Random, 95% CI)0.03 [-0.03, 0.09]

 
Comparison 2. Gabapentin enacarbil (GEn) versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 GEn titrated to 1200 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 GEn titrated to 1800 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.3 GEn titrated to 2400 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.4 GEn titrated to 3000 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. Gabapentin dose comparisons

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache frequency (post-treatment)1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 Responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

 
Comparison 4. Gabapentin enacarbil (GEn) dose comparisons

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 GEn 1200 mg versus 1800 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 GEn 1200 mg versus 2400 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.3 GEn 1200 mg versus 3000 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.4 GEn 1800 mg versus 2400 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.5 GEn 1800 mg versus 3000 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.6 GEn 2400 mg versus 3000 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. Search strategies for the previous review

For the identification of studies considered for the original review and the 2007 update (Chronicle 2004; Mulleners 2008), detailed search strategies were developed for each database searched. These were based on the search strategy for PubMed, but revised appropriately for each database. The search strategies combined the subject searches described below with the Cochrane highly sensitive search strategy for RCTs current at the time (Alderson 2004). The subject searches used a combination of controlled vocabulary and free-text terms based on the search strategy for PubMed presented below.

Databases searched were:

  • Cochrane Pain, Palliative & Supportive Care Trials Register;
  • Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2005, Issue 3);
  • PubMed 1966 to 31 December 2005;
  • EMBASE 1974 to 31 December 2005.

Additional strategies for identifying trials included searching the reference lists of review articles and included studies, searching books related to headache and consulting experts in the field. Two journals, Headache and Cephalalgia, were handsearched in their entirety, through April 2006.

Detailed descriptions of the subject search strategies used for PubMed, EMBASE, and CENTRAL are given below.

 

PubMed

 

Phase 1

#1 (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animals [mh] NOT human [mh]) Limits: Humans

 

Phase 2

#2 HEADACHE Field: MeSH Terms, Limits: Humans
#3 HEADACHE DISORDERS Field: MeSH Terms, Limits: Humans
#4 headache* OR migrain* OR cephalgi* OR cephalalgi* Field: All Fields, Limits: Humans
#5 #2 OR #3 OR #4 Limits: Humans

 

Phase 3

#6 anticonvulsant* OR antiepileptic* OR acetazolamide OR carbamazepine OR chlormethiazole OR clobazam OR clonazepam OR clorazepate OR diazepam OR divalproex OR ethosuximide OR felbamate OR fosphenytoin OR gabapentin OR lamotrigine OR levetiracetam OR lidocaine OR lignocaine OR lorazepam OR mephobarbital OR methsuximide OR midazolam OR nitrazepam OR oxcarbazepine OR paraldehyde OR pentobarbital OR phenobarbital OR phenytoin OR primidone OR valproate OR tiagabine OR topiramate OR valproic OR vigabatrin OR zonisamide Field: All Fields, Limits: Humans
#7 #1 AND #5 AND #6

 

EMBASE

#1 'migraine'/exp AND [embase]/lim
#2 migrain* OR cephalgi* OR cephalalgi* AND [embase]/lim
#3 headache*:ti
#4 #1 OR #2 OR #3
#5 'anticonvulsive agent'/de AND [embase]/lim
#6 anticonvulsant* OR antiepileptic* OR 'acetazolamide'/de OR 'carbamazepine'/de OR 'chlormethiazole'/de OR 'clobazam'/de OR 'clonazepam'/de OR 'clorazepate'/de OR 'diazepam'/de OR 'divalproex'/de OR 'ethosuximide'/de OR 'felbamate'/de OR fosphenytoin OR 'gabapentin'/de OR 'lamotrigine'/de OR 'levetiracetam'/de OR 'lidocaine'/de OR 'lignocaine'/de OR 'lorazepam'/de OR 'mephobarbital'/de OR 'methsuximide'/de OR 'midazolam'/de OR 'nitrazepam'/de OR 'oxcarbazepine'/de OR 'paraldehyde'/de OR 'pentobarbital'/de OR 'phenobarbital'/de OR 'phenytoin'/de OR 'primidone'/de OR 'valproate'/de OR 'tiagabine'/de OR 'topiramate'/de OR valproic OR 'vigabatrin'/de OR 'zonisamide'/de AND [embase]/lim
#7 #5 OR #6
#8 #4 AND #7
#9 ((random*:ti,ab) OR (factorial*:ab,ti) OR (crossover*:ab,ti OR 'cross over':ab,ti OR 'cross over':ab,ti) OR (placebo*:ab,ti) OR ('double blind' OR 'double blind') OR ('single blind':ab,ti OR 'single blind':ab,ti) OR (assign*:ti,ab OR allocat*:ti,ab) OR (volunteer*:ab,ti) OR ('randomized controlled trial'/exp AND [embase]/lim) OR ('single blind procedure'/exp AND [embase]/lim) OR ('double blind procedure'/exp AND [embase]/lim) OR ('crossover procedure'/exp AND [embase]/lim)) NOT ((animal/ OR nonhuman/ OR 'animal'/de AND experiment/ AND [embase]/lim) NOT ((human/ AND [embase]/lim) AND (animal/ OR nonhuman/ OR 'animal'/de AND experiment/ AND [embase]/lim)) AND [embase]/lim) AND [embase]/lim
#10 #8 AND #9

 

CENTRAL

(migrain* OR headache*) AND (randomized controlled trial OR controlled clinical trial) Field: All Fields

 

Appendix 2. Search strategies for this update

 

CENTRAL

#1 MeSH descriptor: [Migraine Disorders] explode all trees
#2 (migrain* or cephalgi* or cephalalgi*)
#3 #1 or #2
#4 MeSH descriptor: [Anticonvulsants] explode all trees
#5 (anticonvulsant* or antiepileptic* or acetazolamide or carbamazepine or chlormethiazole or clobazam or clonazepam or clorazepate or diazepam or divalproex or ethosuximide or felbamate or fosphenytoin or gabapentin or lamotrigine or levetiracetam or lidocaine or lignocaine or lorazepam or mephobarbital or methsuximide or midazolam or nitrazepam or oxcarbazepine or paraldehyde or pentobarbital or phenobarbital or phenytoin or primidone or valproate or tiagabine or topiramate or valproic or vigabatrin or zonisamide or eslicarbazepine or lacosamide or perampanel or phenobarbitone or pregabalin or retigabine or rufinamide or stiripentol or *barbit*)
#6 #4 or #5
#7 #3 and #6
(search limited to years 2005-2012)

 

MEDLINE and MEDLINE In-Progress (via Ovid)

  1. exp Migraine Disorders/
  2. (migrain* or cephalgi* or cephalalgi*).tw.
  3. or/1-2
  4. exp Anticonvulsants/
  5. (anticonvulsant* or antiepileptic* or acetazolamide or carbamazepine or chlormethiazole or clobazam or clonazepam or clorazepate or diazepam or divalproex or ethosuximide or felbamate or fosphenytoin or gabapentin or lamotrigine or levetiracetam or lidocaine or lignocaine or lorazepam or mephobarbital or methsuximide or midazolam or nitrazepam or oxcarbazepine or paraldehyde or pentobarbital or phenobarbital or phenytoin or primidone or valproate or tiagabine or topiramate or valproic or vigabatrin or zonisamide or eslicarbazepine or lacosamide or perampanel or phenobarbitone or pregabalin or retigabine or rufinamide or stiripentol or $barbit$).tw.
  6. or/4-5
  7. 3 and 6
  8. randomized controlled trial.pt.
  9. controlled clinical trial.pt.
  10. randomized.ab.
  11. placebo.ab.
  12. clinical trials as topic.sh.
  13. randomly.ab.
  14. trial.ti.
  15. or/8-14
  16. exp animals/ not humans.sh.
  17. 15 not 16
  18. 7 and 17

For MEDLINE: limited 18 to yr="2005 -Current"
For MEDLINE In-Process: searched current week on 15 January 2013

 

EMBASE (via Ovid)

  1. exp Migraine/
  2. (migrain* or cephalgi* or cephalalgi*).tw.
  3. or/1-2
  4. exp Anticonvulsants/
  5. (anticonvulsant* or antiepileptic* or acetazolamide or carbamazepine or chlormethiazole or clobazam or clonazepam or clorazepate or diazepam or divalproex or ethosuximide or felbamate or fosphenytoin or gabapentin or lamotrigine or levetiracetam or lidocaine or lignocaine or lorazepam or mephobarbital or methsuximide or midazolam or nitrazepam or oxcarbazepine or paraldehyde or pentobarbital or phenobarbital or phenytoin or primidone or valproate or tiagabine or topiramate or valproic or vigabatrin or zonisamide or eslicarbazepine or lacosamide or perampanel or phenobarbitone or pregabalin or retigabine or rufinamide or stiripentol or $barbit$).tw.
  6. or/4-5
  7. 3 and 6
  8. random$.tw.
  9. factorial$.tw.
  10. crossover$.tw.
  11. cross over$.tw.
  12. cross-over$.tw.
  13. placebo$.tw.
  14. (doubl$ adj blind$).tw.
  15. (singl$ adj blind$).tw.
  16. assign$.tw.
  17. allocat$.tw.
  18. volunteer$.tw.
  19. Crossover Procedure/
  20. double-blind procedure.tw.
  21. Randomized Controlled Trial/
  22. Single Blind Procedure/
  23. or/8-22
  24. (animal/ or nonhuman/) not human/
  25. 23 not 24
  26. 7 and 25
  27. limit 26 to yr="2005 -Current"

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 15 January 2013.


DateEventDescription

8 May 2014AmendedMinor edit made to numbers reported in Results of the search.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Review first published: Issue 6, 2013


DateEventDescription

20 June 2013New citation required and conclusions have changedThe pooled evidence derived from trials of gabapentin suggests that it is not efficacious for the prophylaxis of episodic migraine in adults. This contrasts with the findings of our previous review (Chronicle 2004; Mulleners 2008). Gabapentin enacarbil (considered for the first time in this update) is not efficacious for the prophylaxis of episodic migraine in adults.

20 June 2013New search has been performedSearches updated on 15 January 2013. Four new trial reports included (RR 4301-00066; RR 995-00074; RR 995-00085; Silberstein 2013), including three previously confidential research reports (RR 4301-00066; RR 995-00074; RR 995-00085). One previously included trial report now excluded (Mathew 2001, describing a post hoc subgroup analysis of RR 995-00074).

26 August 2008AmendedConverted to new review format.

11 May 2007New search has been performedMay 2007 (Issue 3, 2007):

  • Electronic searches updated through December 2005
  • Handsearches updated through April 2006
  • Review revised to incorporate eight new included trials
  • Dr WM Mulleners took over as guarantor of the review



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Prof Linde: Designing the review. Co-ordinating the review. Data collection for the review. Screening search results. Organising retrieval of papers. Screening retrieved papers against eligibility criteria. Appraising quality of papers. Extracting data from papers. Writing to authors of papers for additional information. Providing additional data about papers. Data management for the review. Entering data into RevMan. Analysis of data. Interpretation of data. Providing a clinical perspective. Writing the review.

Dr Mulleners: Conceiving the review. Designing the review. Data collection for the review. Screening search results. Organising retrieval of papers. Screening retrieved papers against eligibility criteria. Appraising quality of papers. Extracting data from papers. Interpretation of data. Providing a clinical perspective.

Prof Chronicle: Performing previous work that was the foundation of the current review.

Assoc Prof McCrory: Analysis of data. Interpretation of data. Providing a methodological perspective. Providing general advice on the review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Prof Linde: During the process of preparing this review the author received a travel grant from Allergan in Sweden and was involved as an investigator in a clinical trial in Norway sponsored by AstraZeneca and comparing candesartan, propranolol, and placebo in the prophylaxis of migraine.

Dr Mulleners: The author was a paid consultant for the Merck Dutch Migraine Advisory Board and received a speaker's fee from Merck Sharp & Dohme Corp.

Prof Chronicle: Author deceased. During the process of preparing the original review the author was a paid consultant for Johnson & Johnson and NPS Pharmaceuticals in the USA.

Assoc Prof McCrory: During 2008, the author was a paid expert witness for the plaintiffs in a legal action against the manufacturer of Neurontin (gabapentin). In this capacity, he prepared a systematic review examining previously confidential research reports obtained from the manufacturer (through discovery), along with published trial reports of gabapentin for migraine prophylaxis, and testified at trial.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • International Headache Society, UK.
    Funding for administrative costs associated with editorial and peer review of the original and updated reviews
  • Lifting The Burden: the Global Campaign against Headache, UK.
    Funding for administrative costs associated with editorial and peer review of the updated review

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

After reviewing the variety of methods used for calculating headache index, we decided that no systematic analysis of headache index data would be undertaken, for two principal reasons. First, rarely was sufficient information given to allow a clear understanding of how the index was calculated, and second, even when indexes were clearly described, they were not always useful — for example, because they confounded severity scores with frequency scores. Avoiding the use of headache index measures is consistent with the recommendations of the International Headache Society (Tfelt-Hansen 2012).

After publication of the protocol, we decided not to extract trial data on pain intensity, duration of attacks, or associated symptoms of migraine (nausea, vomiting, photophobia, phonophobia). The reasons were that such information was rarely given, and that the methods used were not standardised.

Our methods for assessing and dealing with heterogeneity have evolved over time in line with changing Cochrane methods. The protocol for the original review specified that we would test estimates of efficacy for homogeneity, use a fixed-effect model to combine homogenous estimates, and use a random-effects model to combine estimates when a group of studies with statistically heterogeneous results appeared to be clinically similar. In the original review itself, and in the 2007 update (Chronicle 2004; Mulleners 2008), we in fact used a random-effects model throughout for pooled analyses. In the present review, we again use a random-effects model for pooling, but we have added a possible fixed-effect sensitivity analysis in select cases; see Assessment of heterogeneity for details.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Di Trapani 2000 {published and unpublished data}
  • Di Trapani G, Mei D, Marra C, Mazza S, Capuano A. Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study. Clinica Terapeutica 2000;151(3):145-8. [MEDLINE: 10958046]
Jimenez 2002 {published data only}
  • Jimenez-Hernandez MD, Torrecillas-Narvaez MD, Friera-Acebal G. Effectiveness and safety of gabapentin in the preventive treatment of migraine [Eficacia y seguridad de la gabapentina en el tratamiento preventivo de la migrana]. Revista de Neurologia 2002;35(7):603-6. [MEDLINE: 12389143]
RR 4301-00066 {unpublished data only}
  • Feuerstein T, Quebe-Fehling E. A double-blind, placebo-controlled, parallel-group, multicenter study of the safety and efficacy of gabapentin (CI-945) as a prophylactic interval therapy in patients with common migraine (Protocols 879-201, -205, -206, -207, -209). Research Report No. RR 4301-00066. Freiburg: Goedecke AG Research and Development; June 25, 1990. Available at: http://dida.library.ucsf.edu/pdf/crr13j10.
RR 995-00074 {published data only}
  • Magnus-Miller L, Bernstein P, Caswell K. Double-blind, randomized, placebo-controlled, multicenter trial to determine the efficacy and safety of Neurontin® (gabapentin) in migraine prophylaxis administered in doses divided three times a day (TID) (Protocol 945-220). Research Report No. RR 995-00074. Morris Plains, NJ: Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company Medical and Scientific Affairs Department; August 24, 1999. Available at: http://dida.library.ucsf.edu/pdf/arr13j10.
RR 995-00085 {unpublished data only}
  • Magnus-Miller L, Bernstein P, Caswell K. Double-blind, randomized, placebo-controlled, multicenter trial to determine the efficacy and safety of Neurontin® (gabapentin) in migraine prophylaxis (Protocol 945-217). Research Report No. RR 995-00085. Morris Plains, NJ: Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company Medical and Scientific Affairs Department; January 20, 2000. Available at: http://dida.library.ucsf.edu/pdf/brr13j10.
Silberstein 2013 {published data only (unpublished sought but not used)}
  • Silberstein S, Goode-Sellers S, Twomey C, Saiers J, Ascher J. Randomized, double-blind, placebo-controlled, phase II trial of gabapentin enacarbil for migraine prophylaxis. Cephalagia 2013;33(2):101-11. [MEDLINE: 23165696]

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Cutrer 2001 {published data only}
Jimenez 1999 {published data only}
  • Jimenez MD, Freira G, Morales A, Cuartero F, Morralla C, Sol JM, et al. Gabapentine in the prophylaxis of migraine. A pilot study [Gabapentina en la profilaxis de la migrana. Estudio piloto]. Neurologia 1999;14(10):478.
Mathew 2001 {published data only}
Merren 1998 {published data only}
  • Merren MD. Gabapentin for treatment of pain and tremor: a large case series. Southern Medical Journal 1998;91(8):739-44. [MEDLINE: 9715219]
Spira 2003 {published data only}
  • Spira PJ, Beran RG, Australian Gabapentin Chronic Daily Headache Group. Gabapentin in the prophylaxis of chronic daily headache: a randomized, placebo-controlled study. Neurology 2003;61(12):1753-9. [MEDLINE: 14694042]
Wessely 1987 {published data only}
  • Wessely P, Baumgartner C, Klingler D, Kreczi J, Meyerson N, Sailer L, et al. Preliminary results of a double blind study with the new migraine prophylactic drug gabapentin. Cephalalgia 1987;7 Suppl 6:476-7.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Ad Hoc Cttee 1962
  • Ad Hoc Committee on the Classification of Headache of the National Institute of Neurological Diseases and Blindness. Classification of headache. JAMA 1962;179(9):717-8.
Alderson 2004
  • Alderson P, Green S, Higgins JPT, editors. Highly sensitive search strategies for identifying reports of randomized controlled trials in MEDLINE. Cochrane Reviewers' Handbook 4.2.2 [updated December 2003]; Appendix 5b. In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.
Clarke 1996
  • Clarke CE, MacMillan L, Sondhi S, Wells NE. Economic and social impact of migraine. QJM 1996;89(1):77-84. [MEDLINE: 8730346]
Dalkara 2012
  • Dalkara S, Karakurt A. Recent progress in anticonvulsant drug research: strategies for anticonvulsant drug development and applications of antiepileptic drugs for non-epileptic central nervous system disorders. Current Topics in Medicinal Chemistry 2012;12(9):1033-71. [MEDLINE: 22352861]
Drugs.com 2013
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Edmeads 1993
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Evers 2009
GBD 2010 Study
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Hollis 1999
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IHS Cttee 1988
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Jadad 1996
Landefeld 2009
Linde 2012
Linde 2013a
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Linde 2013b
Linde 2013c
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Linde 2013d
  • Linde M, Mulleners WM, Chronicle EP, McCrory DC. Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 10.1002/14651858.CD010608]
Mayo Clinic Staff 2011
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McCrory 2008
  • McCrory DC. Report on gabapentin (Neurontin) for migraine prophylaxis: evaluation of efficacy, effectiveness and marketing. Expert consultant’s report. August 11, 2008. Available at: http://dida.library.ucsf.edu/pdf/oxx18q10.
McQuay 1998
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Mehuys 2012
Olesen 2006
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Porter 1992
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Pringsheim 2012
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Saris 2010
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Silberstein 2008
Silberstein 2012
  • Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E, Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78(17):1337-45. [MEDLINE: 22529202]
Tfelt-Hansen 2012
  • Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, D'Amico D, Diener HC, et al. International Headache Society Clinical Trials Subcommittee. Guidelines for controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia 2012;32(1):6-38. [MEDLINE: 22384463]
Vedula 2009
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  • Victor S, Ryan S. Drugs for preventing migraine headaches in children. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/14651858.CD002761]
Wiffen 2010