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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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Characteristics of included studies [ordered by study ID]
Di Trapani 2000

MethodsProspective, randomised, double-blind, parallel-group trial. 1-month baseline period. Duration of treatment: 4 weeks titration then 8 weeks stable dosage

Discontinuation rate: dropout 0%

Compliance (adherence) data: no compliance data reported

Rule for use of acute medication: analgesics were permitted

Methodological quality score: 3


ParticipantsInclusion: IHS migraine criteria; migraine frequency of 4 to 7 attacks per month for the previous year. No mixed or combination headaches included

Exclusion: secondary headaches were adequately excluded. Neither daily headache nor analgesic overuse headache was adequately excluded. Other exclusions: participants with cardiac, hepatic, or renal disease; pregnancy or reproductive intentions; or who had used migraine prophylactic medication in the last 3 months

Setting: single headache clinic

Country: Italy

63 migraine patients participated; 31 with aura and 32 without. 33 females, 30 males; age range 18 to 65. 35 received active treatment and 28 received placebo


InterventionsGabapentin (12 weeks) versus placebo (12 weeks). Dosage titrated up to 1200 mg/day and maintained for 8 weeks


OutcomesNumber of migraine attacks per month. Self reported attack intensity

Time point(s) considered in the review: last (third) month of treatment phase


NotesSenior author confirmed that statistical variance data were SEMs, not SDs (as supposed in our previous review (Chronicle 2004; Mulleners 2008)), and provided data on headache frequency for combined migraine with and without aura groups

Funders of the trial: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom allocation of participants reported as performed but method not described

Allocation concealment (selection bias)Unclear riskNo information

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThe study was reported as double-blind but method not described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo patients withdrew

Selective reporting (reporting bias)Low riskResults are given for both efficacy measures

Jimenez 2002

MethodsProspective, randomised, open-label, parallel-group, dose-comparison trial. Duration of treatment: 1- or 2-week titration, then 16 weeks stable dosage

Discontinuation rate: dropout 18% over entire period of study

Compliance (adherence) data: method of assessing compliance not reported

Rule for use of acute medication: not reported

Methodological quality score: 2


ParticipantsInclusion: IHS migraine criteria; migraine frequency of 3 or more per month, 1 month or more since discontinuation of any previous migraine prophylaxis; adequate contraception
Exclusion: secondary, daily, and analgesic abuse headaches were adequately excluded. Other exclusions: lactation; other severe medical illness, history of alcohol or drug abuse, previous treatment with gabapentin, contraindications to gabapentin

Setting: multicentre

Country: Spain

164 patients recruited. 81% migraine without aura; 19% migraine with aura. 74% females, 26% males; mean age 35 years. Complete case analysis of 135 patients. 95 received 1200 mg/day and 40 received 2000 mg/day


InterventionsGabapentin 1200 mg/day versus gabapentin 2000 mg/day (16 weeks). Dosage started at 400 mg/day and incremented over 1 week to reach 1200 mg/day or over 2 weeks to reach 2000 mg/day


OutcomesHeadache frequency per month, pain intensity and duration, global satisfaction of the patient

Time point(s) considered in the review: last (fourth) month of treatment phase


NotesPatient numbers in table V do not appear to be internally consistent

Funders of the trial: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskRandom allocation of participants reported as performed but method not described. Very unequal numbers of patients in each dosage group unlikely to be achieved by strict randomisation

Allocation concealment (selection bias)Unclear riskNo information

Blinding of participants and personnel (performance bias)
All outcomes
High riskStudy not blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concern among the review authors over incomplete outcome data

Selective reporting (reporting bias)High riskGlobal satisfaction with treatment measured but not reported. AEs are not reported separately for each group

RR 4301-00066

MethodsProspective, randomised, double-blind, parallel-group trial. The study, which applied a retrospective baseline (3 months), consisted of a 12-week, double-blind treatment period

Discontinuation rate: gabapentin 15%, placebo 16%

Compliance (adherence) data: no compliance (adherence) data reported

Rule for use of acute medication: analgesics were allowed for acute treatment but no more than 20 tablets per month

Methodological quality score: 4


ParticipantsInclusion: migraine without aura according to the Ad Hoc criteria (Ad Hoc Cttee 1962); therapy-resistant (not adequately defined) to standard migraine treatment; migraine frequency minimum 8 episodes per month for the primary study centre and minimum 2 episodes per month for the other study centres. Above 18 years of age. Females of child-bearing potential must utilise an adequate method of contraception

Exclusion: chronic daily headache or medication overuse not excluded. Unclear if other secondary headaches were adequately excluded. Other exclusion: use of prophylactic intervention; pregnant or nursing females; severe liver or kidney insufficiency; Parkinson's disease; severe progressive accompanying diseases, eg, diabetes

Setting: 5 centres

Country: Austria (4 centres) and (West) Germany (1 centre)

The SES included all randomised patients: 89; all had migraine without aura; 21/89 also had migraine with aura; 68 were females and 21 males; mean age in gabapentin group 42 (range 20 to 68); mean age in placebo group 42 (range 23 to 68). 46 allocated to receive gabapentin and 43 allocated to receive placebo. The efficacy evaluable population comprised 53 participants. Among them, the proportion with migraine with aura is not reported; 42 were females and 11 males; mean age in gabapentin group 43 (range 20 to 68); mean age in placebo group 40 (range 24 to 59). 22 allocated to gabapentin and 31 to placebo


InterventionsGabapentin 900 mg/day versus placebo (12 weeks). No information on titration. Capsules of gabapentin (300 mg) or placebo were given 3 times a day


OutcomesMigraine attack frequency calculated on a 28-day basis. Response ratio defined as difference in attack frequency from baseline to treatment period divided by the sum of attacks during baseline and treatment. Subjective evaluation of improvement of migraine. Duration of attacks (hours) under treatment and the percent reduction in duration relative to baseline. Average pain. Maximal pain during attacks. Change in patients with aura symptoms. The relation between response ratio and dose per kilogram body weight. AEs

Time point(s) considered in the review: entire 12-week treatment phase


NotesSince the baseline was retrospective, change scores from baseline were excluded from the analyses of the present review. This report reveals essential limitations in design and conduct of the study. There are differences between the original protocol (appendix) and the study protocol that is discussed in the main body of the report. Initially it was intended that dropouts (eg, for lack of efficacy) would be replaced with newly randomised subjects, but this does not appear in the final description. Also, all centres were initially to include migraineurs with at least 8 attacks per month, but it is clear that sometime during the conduct of the study this criterion was relaxed to at least 2 attacks per month for most centres. This implies that the design may have changed during the execution of the study. This may have influenced outcomes

Funders of the trial: Goedecke AG – Research and Development, Freiburg


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation per centre in permuted blocks of 10. No information found on method used for sequence generation

Allocation concealment (selection bias)Unclear riskNo information

Blinding of participants and personnel (performance bias)
All outcomes
High riskBoth participants and clinicians were blinded. Medications were given as identical capsules distributed in bottles. Bottle labels contained medication number only. It is not specified how subject number was linked to medication number on bottle. Given that the number of gabapentin subjects erroneously receiving other prophylaxis was nearly 3 times higher in the gabapentin group than in the placebo group, it is likely that the blinding was inadequate

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh number of protocol violators due to the initiation or continuation of other prophylactics (19 of those allocated to gabapentin; 7 of those allocated to placebo). 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 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 are included in this review

Selective reporting (reporting bias)Unclear riskThe research report was never published and results would have remained unobtainable had it not been for the discovery process in a legal case. The response ratio measure was not mentioned in the original protocol (appendix A.2)

RR 995-00074

MethodsProspective, 2:1 randomised, double-blind, parallel-group trial. 3-week washout period for previous migraine prophylactic medication. 4-week single-blind, placebo-only baseline period. Duration of treatment: 4 weeks titration, then 8 weeks stable dosage

Discontinuation rate: dropout 24.5% for active treatment; 20.0% for placebo

Compliance (adherence) data: no compliance data reported

Rule for use of acute medication: not explicitly reported, but see notes

Methodological quality score: 5


ParticipantsInclusion: IHS migraine criteria; migraine frequency of 3 to 8 attacks per month for the previous 3 months; no more than 2 previous migraine prophylactic medications. Mixed headaches were included if tension-type headache attacks occurred on 10 or fewer days per month; subgroups cannot be distinguished

Exclusion: secondary headaches, daily headaches, and analgesic overuse headache were adequately excluded. Other exclusions: migraine aura without headache, cluster headache, significant CNS disorder, other serious medical or psychological problems, confounding medication

Setting: multicentre

Country: 7 sites in the USA

Of 145 randomised patients (gabapentin 99; placebo 46), 143 received study medication and comprise the SES. 61 of the SES had migraine with aura; 116 were females and 27 males; mean age 39.9 ± 11.3 (range 16 to 71). 98 received active treatment and 45 received placebo. Demographic data for mITT population (77 active; 36 placebo): 50 with aura and 63 without, 92 females and 21 males; mean age 39.9 ± 11.2 (range 16 to 67)


InterventionsGabapentin (12 weeks) versus placebo (12 weeks). Dosage titrated up to 1800 to 2400 mg/day and maintained for 8 weeks. We estimate the proportion of patients on 1800 mg versus 2400 mg as 19% (15/78)


OutcomesNumber of migraine attacks per 28 days. Number of migraine days per 28 days. Treatment success. Peak intensity. Attack duration. Functional ability at peak intensity. Aura severity

Time point(s) considered in the review: last (third) month of treatment phase


NotesErgotamine use up to 2 days per week permitted. NSAIDs, analgesics, benzodiazepines, cyproheptadine, baclofen, SSRIs up to 3 days per week permitted. mITT does not conform to recent recommendations
Funders of the trial: Warner-Lambert Company, New Jersey


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation schedule, 2:1 ratio

Allocation concealment (selection bias)Low riskEach investigator was provided with "blinded" medication

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo capsules matched active treatment. During the double-blind phase, investigators, patients, study monitors, and observers were blinded to codes until after the clinical database was locked

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concerns over incomplete outcome data

Selective reporting (reporting bias)Unclear riskThe research report was never published and results would have remained unobtainable had it not been for the discovery process in a legal case

RR 995-00085

MethodsProspective, randomised, double-blind, parallel-group trial. The 16-week study consisted of a 4-week, single-blind baseline period and a 12-week, double-blind treatment period (divided into a 4-week titration period and an 8-week stable dosing period (the first 4 weeks called Stabilization Period 1 and the second 4 weeks called Stabilization Period 2))

Discontinuation rate: gabapentin 25%, placebo 24%

Compliance (adherence) data: compliance was to be measured by counting unused medication and confirming lack of gabapentin in blood drawn from placebo group, but results not summarised in the research report

Rule for use of acute medication: symptomatic medications (eg, aspirin, acetaminophen, NSAIDs, tramadol, codeine and codeine derivatives, dihydroergotamine, and ergotamine (< 10 mg/week or ≤ 5 mg/day), sumatriptan, Midrin, antiemetics) were permitted on an "as needed" basis for treatment of individual headaches and were to have been taken 1 hour following initial onset of an attack. These medications were to have been taken for less than 3 days each week on average. Narcotics were not to have been used as a first-line treatment

Methodological quality score: 4


ParticipantsInclusion: migraine with or without aura according to IHS criteria; migraine frequency 3 to 8 episodes per month for each of the 3 months prior to screening and during the 4-week baseline period; history of migraine at least 6 months prior to screening. Ages 16 to 75. Other inclusion criteria: capability of compliance and ability to understand and follow the instructions of the investigator; understanding and capability of completing the study diaries as described in the protocol; informed consent obtained from the patient or legal guardian

Exclusion: chronic daily headache or TTH occurring > 10 days/month, medication overuse headache and other secondary headaches were adequately excluded. Other exclusions: if sexually active, female patients must have been practicing a reliable method of contraception and must have had a negative serum pregnancy test; female patients who were using oral contraceptives were to have been using the same product for at least 3 months prior to study entry; previously untreated for migraine prophylaxis or having failed an adequate trial (eg, at least 1 month of treatment at a full therapeutic dose) on no more than 2 prophylactic anti-migraine medications; pregnant or nursing; having received prophylactic anti-migraine medication for a period equal to or greater than 5 half-lives of that medication before entering the baseline phase; previous treatment with gabapentin; migraine aura without headache only; serious neurological, psychiatric, or other medical disorder

Setting: 11 centres

Country: USA

Among the 157 randomised patients (gabapentin 102; placebo 55), 150 received study medication and comprise the SES. Of the SES, 57 had migraine with aura and 93 migraine without aura; 123 were females and 27 males; mean age 39.1 ± 11.0; age range 16 to 64. 95 received gabapentin and 55 received placebo. mITT analysis of 122 patients: 48 had migraine with aura; 97 were females and 25 males; mean age 39.2 ± 11.0 (range 16 to 64). 76 received gabapentin and 45 received placebo


InterventionsGabapentin 1800 mg/day versus placebo (12 weeks). Gabapentin 300 mg capsule starting with 1 at night-time and then titrated up to 1800 mg/day divided into BID dosing during a 4-week period. Thereafter stable dosing. 94/95 SES patients treated with active treatment received 1800 mg/day as the final stable dose. Placebo capsules were titrated in the same manner as active treatment


OutcomesHeadache frequency per 28 days. Proportion of responders (≥ 50% reduction in migraine attacks). Average severity at peak intensity. Average duration of migraine headache. Average functional ability at the time of peak intensity. Aura severity. Number of days per 4 weeks with a migraine headache. SF-36 quality of life. AEs. Vital signs. Physical examinations. Laboratory assessments

Time point(s) considered in the review: Stabilization Period 2, ie, third month of treatment


NotesFunders of the trial: Warner-Lambert Company, New Jersey


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation in a 2:1 ratio was performed by the Clinical Pharmaceutical Operations (CPO) Department of Parke-Davis. No information on method used for randomisation found

Allocation concealment (selection bias)Low riskBlinded medication provided by CPO or other designated facility based on the randomisation code

Blinding of participants and personnel (performance bias)
All outcomes
Low riskClinicians and patients were blinded. Gabapentin and placebo were provided as capsules identical in size and colour by Parke-Davis, packaged in patient-specific bottles and shipped to investigators

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concerns over incomplete outcome data

Selective reporting (reporting bias)Unclear riskThe research report was never published and results would have remained unobtainable had it not been for the discovery process in a legal case

Silberstein 2013

MethodsProspective, randomised, double-blind, parallel-group trial. The 30-week study consisted of a 2-week screening period, a 6-week baseline period, a 5-week flexible titration period, a 12-week maintenance period, a 3-week tapering out period, and a 2-week post-treatment AE monitoring period

Discontinuation rate: GEn 1200 mg 27%, GEn 1800 mg 34%, GEn 2400 mg 28%, GEn 3000 mg 40%, placebo 26%

Compliance (adherence) data: no compliance (adherence) data reported

Rule for use of acute medication: use of acute migraine medication was permitted for breakthrough migraine attacks Methodological quality score: 4


ParticipantsInclusion: migraine with or without aura according to ICHD-II; migraine frequency ≥ 3 attacks and ≥ 4 calendar days per month during each of the 3 months prior to screening and during baseline; migraines consistent in incidence and severity over time; history of migraine at least 1 year prior to screening; onset of migraine before age 50. Ages 18 and above. Other inclusion criteria: written informed consent

Exclusion: chronic daily headache (≥ 15 migraine or non-migraine headache days per month); history of ergotamine, triptan, opioid, or combination analgesic intake ≥ 10 days per month or simple analgesic intake ≥ 15 days per month, for ≥ 3 months. Secondary headaches were adequately excluded. Other exclusions: pregnancy; child-bearing potential and inadequate contraception; unable to discontinue beta-blockers, TCAs, Ca-blockers, antiepileptic drugs, bupropion, SNRIs during screening and study duration (fluoxetine, riboflavin, Mg and feverfew allowed); previous use of gabapentin or pregabalin for migraine prophylaxis; lack of efficacy  of ≥ 2 trials of migraine prophylaxis for ≥ 8 weeks; uncontrolled hypertension (> 160 mmHg systolic or > 90 mmHg diastolic in sitting position)

Setting: 51 centres

Countries: USA and Canada

ITT analysis of 523 patients. No information on how many had migraine with aura; 429 were females and 94 males; mean ages: GEn 1200 mg 39.4 ± 9.74, GEn 1800 mg 37.7 ± 11.75; GEn 2400 mg 39.0 ± 12.04; GEn 3000 mg 39.1 ± 11.78, placebo 41.1 ± 11.72; allocation of randomised subjects: GEn 1200 mg 67; GEn 1800 mg 134; GEn 2400 mg 134; GEn 3000 mg 62, placebo 129


InterventionsGabapentin enacarbil (GEn) 1200 mg/day versus GEn 1800 mg/day versus GEn 2400 mg/day versus GEn 3000 mg/day versus placebo (20 weeks). GEn given BID, orally and titrated within 5 weeks to target dose or the maximum tolerated dose


OutcomesMigraine attacks per 4 weeks. Migraine days (calendar days with any occurrence of migraine head pain ≥ 30 min duration). Migraine headache periods (24-hour segment with migraine). Proportion with ≥ 50% reduction in migraine attacks, migraine days, migraine periods. Attack duration. Peak migraine pain severity. Acute migraine medication use. Occurrence of aura, nausea, vomiting, photophobia, phonophobia. AEs

Time point(s) considered in the review: last (third) month of maintenance period


NotesFunder of the trial: GlaxoSmithKline


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskBlocks of randomisation codes were assigned to each centre. Information on block size and code generation not provided. Randomisation ratio: 2 placebo : 1 GEn 1200 mg : 2 GEn 1800 mg : 2 GEn 2400 mg : 1 GEn 3000 mg

Allocation concealment (selection bias)Low riskInteractive voice recognition system (IVRS)

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskIt is assumed from the term 'double-blind' that participants and clinicians were blinded. No information on method used. Potential unblinding by AEs (notably dizziness)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
High riskSubjects have been randomised despite missing baseline values. Missing values in secondary outcomes not accounted for

Selective reporting (reporting bias)High riskWithin-group changes (with standard deviations) from baseline in mean migraine frequencies during the double-blind period lacking. Only differences in changes (with 95% CIs) from placebo given in publication. Supplementary information requested corresponding author, but no reply

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Cutrer 2001Basic science paper

Jimenez 1999Abstract only

Mathew 2001Post hoc subgroup analysis of RR 995-00074 (included). "Modified intention-to-treat" (mITT) population described in Mathew 2001 (n = 87; gabapentin 56, placebo 31) is smaller and more select than the mITT population described in RR 995-00074 (n = 113; gabapentin 77, placebo 36). This is due to the exclusion in Mathew 2001 of participants who did not maintain a stable dose of 2400 mg/day of study medication during the last (third) month of the treatment phase. By focusing on this narrower population, Mathew 2001 overstates the efficacy of gabapentin when compared with the results as reported in RR 995-00074 (McCrory 2008; Saris 2010; Vedula 2009)

Merren 1998Reports case studies only

Spira 2003Reports data on chronic daily headache only

Wessely 1987Extended abstract only; insufficient information provided. Close similarities in the design of the trial and the fact that there are several names in common between the authors of this abstract and the outside investigators listed in RR 4301-00066 lead us to conclude that this abstract reports an interim analysis of RR 4301-00066 (included). Some differences between this abstract and RR 4301-00066 in the results and numbers of patients are likely explained by this abstract being an interim report (before completion) while RR 4301-00066 represents a final report (after completion)

 
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]

 
Table 1. Numbers (percentages) of adverse events (AEs) in placebo-controlled studies of gabapentin

StudyType of AE*Active treatmentControl

RR 4301-00066Gabapentin 900 mg (n = 46)Placebo (n = 43)

Any AE11 (24)9 (21)

Dizziness6 (13)2 (5)

Nausea/vomiting4 (9)3 (7)

Fatigue1 (2)2 (5)

Withdrawal due to AE5 (11)1 (2)


Di Trapani 2000Gabapentin 1200 mg (n = 35)Placebo (n = 28)

Somnolence

Dizziness

TremorTotal of 13 eventsNot reported

Fatigue

Ataxia

Withdrawal due to AE00


RR 995-00085Gabapentin 1800 mg (n = 95)Placebo (n = 55)

Any AE70 (74)37 (67)

Dizziness23 (24)2 (4)

Somnolence14 (15)3 (5)

Asthenia8 (8)6 (11)

Flu syndrome7 (7)2 (4)

Abnormal thinking7 (7)0

Back pain6 (6)0

Pharyngitis5 (5)1 (2)

Dry mouth5 (5)0

Pain4 (4)4 (7)

Headache2 (2)4 (7)

Withdrawal due to AE16 (17)7 (13)


RR 995-00074Gabapentin 2400 mg (n = 98)Placebo (n = 45)

Any AE81 (83)35 (78)

Dizziness25 (26)5 (11)

Somnolence24 (24)5 (11)

Asthenia22 (22)12 (27)

Infection11 (11)11 (24)

Flu syndrome9 (9)4 (9)

Sinusitis8 (8)3 (7)

Nausea6 (6)4 (9)

Diarrhoea6 (6)2 (4)

Pain6 (6)1 (2)

Confusion6 (6)0

Flatulence6 (6)0

Abnormal thinking5 (5)1 (2)

Nervousness5 (5)0

Withdrawal due to AE14 (14)4 (9)

 *For RR 4301-00066, RR 995-00085, and RR 995-00074, only AEs reported by ≥ 5% participants in at least 1 group are included in the table.
Abbreviation: AE = adverse event
 
Table 2. Numbers (percentages) of adverse events (AEs) in placebo-controlled studies of gabapentin enacarbil (GEn)

StudyType of AE*Active treatmentControl




Silberstein 2013GEn 1200 mg

(n = 66)
GEn 1800 mg

(n = 134)
GEn 2400 mg

(n = 133)
GEn 3000 mg

(n = 62)
Placebo

(n = 128)

Any AE44 (67)99 (74)101 (76)49 (79)87 (68)

Dizziness16 (24)43 (32)35 (26)11 (18)8 (6)

Fatigue10 (15)12 (9)14 (11)3 (5)9 (7)

Nausea3 (5)15 (11)12 (9)6 (10)12 (9)

Somnolence6 (9)7 (5)14 (11)9 (15)6 (5)

Weight increase4 (6)8 (6)9 (7)4 (6)7 (5)

Upper respiratory

tract infection
4 (6)4 (3)9 (7)5 (8)9 (7)

Constipation4 (6)7 (5)8 (6)5 (8)3 (2)

Dry mouth4 (6)6 (4)5 (4)3 (5)3 (2)

Nasopharyngitis3 (5)4 (3)4 (3)2 (3)8 (6)

Diarrhoea1 (2)1 (< 1)7 (5)1 (2)8 (6)

Vomiting1 (2)3 (2)7 (5)2 (3)5 (4)

Influenza1 (2)3 (2)4 (3)3 (5)4 (3)

Insomnia4 (6)1 (< 1)6 (5)2 (3)1 (< 1)

Peripheral edema4 (6)1 (< 1)3 (2)2 (3)4 (3)

Sinusitis4 (6)3 (2)3 (2)1 (2)3 (2)

Balance disorder2 (3)2 (1)6 (5)1 (2)1 (< 1)

Abdominal pain2 (3)2 (1)3 (2)3 (5)1 (< 1)

Back pain1 (2)6 (4)1 (< 1)3 (5)0

Cough3 (5)1 (< 1)000

Withdrawal due to AE4 (6)17 (13)16 (12)13 (21)11 (9)

 *Only AEs reported by ≥ 5% participants in at least 1 group are included in the table.
Abbreviations: AE = adverse event; GEn = gabapentin enacarbil