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Pregabalin add-on for drug-resistant partial epilepsy

  1. Jennifer Pulman1,*,
  2. Karla Hemming2,
  3. Anthony G Marson1

Editorial Group: Cochrane Epilepsy Group

Published Online: 12 MAR 2014

Assessed as up-to-date: 3 MAR 2014

DOI: 10.1002/14651858.CD005612.pub3


How to Cite

Pulman J, Hemming K, Marson AG. Pregabalin add-on for drug-resistant partial epilepsy. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD005612. DOI: 10.1002/14651858.CD005612.pub3.

Author Information

  1. 1

    Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK

  2. 2

    University of Birmingham, Public Health, Epidemiology and Biostatistics, Birmingham, UK

*Jennifer Pulman, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre for Research and Education, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK. jennifer.pulman@liv.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 12 MAR 2014

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Characteristics of included studies [ordered by study ID]
Arroyo 2004

MethodsRandomised double-blind PCB-controlled parallel multicentre (45 in Europe, Australia and South Africa) trial. 3 treatment arms: 1 PCB, 2 PGB. Patients randomised in blocks of 6, each allocated unique ID number. All patients received 2 capsules TDS but 2 capsule sizes were used (no further information available). Duration of baseline period: 8 weeks. 12-week treatment period included 4- to 8-day titration period


ParticipantsAdults aged 17 to 73 years (mean 37 years), 50.5% male, all with treatment-resistant partial epilepsy. Patients were on 1 to 4 baseline AEDs. 344 patients screened, 288 patients randomised: 97 patients to PCB (mean baseline 28-day seizure frequency: 23.5), 99 patients to 50 mg/day PGB TDS (mean baseline 28-day seizure frequency: 26.2) and 92 patients to 200 mg/day PGB TDS (mean baseline 28-day seizure frequency: 19.3)


InterventionsGroup 1: PCB
Group 2: PGB 50 mg TDS (4-day titration phase)
Group 3: PGB 200 mg TDS (8-day titration phase)


OutcomesPrimary outcome: reduction in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, seizure freedom, change in seizure frequency, adverse events


NotesStudy used capsules of 2 sizes, containing 25 mg PGB or PCB (size 1# = small capsules); and 100 mg PGB or PCB (size 4# = large capsules). It is stated that patients received 2 capsules TDS. One patient excluded from ITT in PCB arm, as failed to take study drugs


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom computer-generated code used stratified by centre using block size of 6

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
All outcomes
Low riskMedication presented in identical capsules

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis performed

Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes

Other biasHigh riskAs an EEG was not required to confirm the above, some of the 18 patients included who were stated to have 'generalised seizures' rather than secondary generalised, may have had primary generalised epilepsy

Sponsored by the same pharmaceutical company (Pfizer Ltd.) as with all the other included trials

Baulac 2010

MethodsRandomised double-blind PCB- and active drug-controlled parallel multicentre (97 in Europe, Canada and Australia) trial. 3 treatment arms: 1 PCB, 1 PGB and 1 LTG. Patients randomised to 1 of 3 treatment arms (no further information available). Duration of baseline period: 6 weeks. 12-week treatment period with 5-week titration phase before treatment (1 week of titration for PGB and 5 weeks of titration for LTG)


ParticipantsAdults aged 16 to 82 years (mean 39.4 years), 48.5% male, all with treatment-resistant partial epilepsy confirmed by history and recent EEG. Patients were on 1 to 3 baseline AEDs. 546 patients screened, 434 patients randomised: 141 patients to PCB (mean baseline 28-day seizure frequency: 16.38), 152 patients to 150 mg to 300 mg PGB BD (mean baseline 28-day seizure frequency: 21.32), and 141 patients to 150 mg to 300 mg LTG BD (mean baseline 28-day seizure frequency: 21.80)


InterventionsGroup 1: PCB

Group 2: PGB 150 mg to 300 mg BD (1-week titration phase)

Group 3: LTG 150 mg to 300 mg BD (5-week titration phase)


OutcomesPrimary outcome: change in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, seizure freedom, adverse events


NotesOne patient randomised to the PCB group failed to take > 1 dose of medication, and therefore was excluded from ITT analysis. No information provided on methods of randomisation, concealment or blinding


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details of method of randomisation

Allocation concealment (selection bias)Unclear riskNo details of concealment of allocation

Blinding (performance bias and detection bias)
All outcomes
Unclear riskSame number of capsules administered per study day per group. No further details provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed

Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes

Other biasHigh riskSponsored by same pharmaceutical company (Pfizer Ltd.) as with all the other included trials

Beydoun 2005

MethodsRandomised double-blind PCB-controlled parallel multicentre (43 in USA and Canada) trial. 3 treatment arms: 1 PCB, 2 PGB. Patients randomised in blocks of 6, each allocated unique ID number. All patients received TDS regimen of blinded capsules (no further information available). Duration of baseline period: 8 weeks. 1-week titration period and 11-week treatment period


ParticipantsAdults aged 17 to 82 years (mean 39.1 years), 50.2% male, all with treatment-resistant partial epilepsy confirmed by history and recent EEG. Patients were on 1 to 4 baseline AEDs. 378 patients screened, 313 patients randomised: 98 patients to PCB (mean baseline 28-day seizure frequency: 25.1), 104 patients to 300 mg PGB BD (mean baseline 28-day seizure frequency: 21.5), and 111 patients to 200 mg PGB TDS (mean baseline 28-day seizure frequency: 21.3)


InterventionsGroup 1: PCB
Group 2: 300 mg PGB BD (1-week titration phase)
Group 3: 200 mg PGB TDS (1-week titration phase)


OutcomesPrimary outcome: reduction in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, median percentage change in seizure frequency


NotesOne patient randomised to the 300 mg BD group failed to take tablets, and therefore was excluded from ITT analysis. Blinding was broken with 1 patient in the PCB arm when she became pregnant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients randomised in blocks of 6 and allocated unique ID number

Allocation concealment (selection bias)Unclear riskNo details provided

Blinding (performance bias and detection bias)
All outcomes
Low riskAll patients received identical capsules

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed

Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes

Other biasHigh riskSponsored by same pharmaceutical company (Pfizer Ltd.) as with all the other included trials

Elger 2005

MethodsRandomised double-blind PCB-controlled parallel multicentre (53 in Europe and Canada) trial. 3 treatment arms: 1 PCB, 2 PGB. Patients randomised in blocks of 5, each allocated unique ID number. All regimens mimicked control group using identical capsules (no further information available). Duration of baseline period: 6 weeks. 12-week treatment period


ParticipantsAdults aged 18 to 78 years (mean 40.5 years), 49.9% male, all with treatment-resistant partial epilepsy confirmed by personal and family history as well as recent EEG. Patients were on 1 to 5 baseline AEDs. 400 patients screened, 341 patients randomised: 73 patients to PCB (median baseline 28-day seizure frequency: 8.7), 137 patients to 300 mg PGB BD fixed (median baseline 28-day seizure frequency: 10), and 131 patients to PGB flexible dosing (median baseline 28-day seizure frequency: 9.33)


InterventionsGroup 1: PCB
Group 2: 300 mg PGB BD fixed dose
Group 3: 75 mg to 300 mg PGB BD flexible titration at physician's discretion


OutcomesPrimary outcome: reduction in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, median percentage change in seizure frequency and reduction of GTCS in those completing the study, adverse events


NotesIn PGB titration and PCB groups, patients were included with seizure frequency of over 120 a day. Documenting seizures at this frequency is difficult and may be unreliable. Medium length of follow-up not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients randomised using a 1:2:2 ratio and block sizes of 5

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
All outcomes
Low riskStudy medication presented in identical capsules

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed

Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes

Other biasHigh riskSponsored by same pharmaceutical company as with all the other included trials

French 2003

MethodsRandomised double-blind PCB-controlled parallel multicentre (71 in the USA and 5 in Canada) trial. 5 treatment arms: 1 PCB, 4 PGB. Patients randomised in blocks of 5, each allocated unique ID number. Capsule sizes varied (no further information available). Duration of baseline period: 8 weeks. There was no titration; 12-week treatment period


ParticipantsPatients 12 years and above (range 12 to 75 years, mean 38.4 years), 48.1% male, all with treatment-resistant partial epilepsy. Patients were on 1 to 4 baseline AEDs. 586 patients screened, 455 patients randomised: 100 patients to PCB (mean baseline seizure frequency: 22.3); 88 patients to 50 mg PGB (mean baseline seizure frequency: 27.4); 88 patients to 150 mg PGB (mean baseline 28-day seizure frequency: 23.1); 90 patients to 300 mg PGB (mean baseline 28-day seizure frequency: 19.1) and 89 patients to 600 mg PGB (mean baseline 28-day seizure frequency: 18.6)


InterventionsGroup 1: PCB
Group 2: 50 mg PGB daily
Group 3: 150 mg PGB
Group 4: 300 mg PGB
Group 5: 600 mg PGB daily


OutcomesPrimary outcome: reduction in seizure frequency compared to baseline (response ratio)

Secondary outcomes: responder rate, pair-wise comparisons with PCB, adverse events


NotesBlinding broken for interim analysis (data obtained were only known to committee who were not involved in further running of study) and for 1 patient who developed visual field defect. 2 patients were excluded from ITT analysis (1 withdrew consent, 1 had AEDs changed during baseline period). Seizure frequency and responder rate were calculated from data collected from seizure diaries and mean calculated over a 4-week period


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsed a computer-generated randomised schedule using block sizes of 5

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
All outcomes
Unclear riskStudy medication presented in identical capsules

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed

Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes

Other biasHigh riskPossibility of the inclusion of patients with primary generalised epilepsy

Sponsored by same pharmaceutical company as with all the other included trials

Lee 2009

MethodsRandomised double-blind PCB-controlled parallel multicentre (9 in Korea) trial. 2 treatment arms: 1 PCB, 1 PGB. Patients randomised to 1 of 2 treatment arms (no further information available). Duration of baseline period: 6 weeks. 12-week treatment period (no further details provided)


ParticipantsPatients 18 years and above (mean 34.2 years), 48.3% male, all with treatment-resistant partial epilepsy. Patients were on 1 to 3 baseline AEDs. 209 patients screened, 178 patients randomised: 59 patients to PCB (mean baseline 28-day seizure frequency: 13.2) and 119 patients to 150 mg to 600 mg PGB (mean baseline 28-day seizure frequency 13.2)


InterventionsGroup 1: PCB

Group 2: 150 mg/day to 600 mg/day


OutcomesPrimary outcome: change in seizure frequency (response ratio)

Secondary outcomes: responder rate, seizure freedom, anxiety/depression, sleep, quality of life, adverse events


NotesAll randomised patients included in ITT analysis. No information provided on methods of randomisation, concealment or blinding


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskPatients randomised using 2:1 ratio. No further information given

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported. ITT analysis employed

Selective reporting (reporting bias)Unclear riskAll outcomes stated in methods section of paper were reported in the results; however, there was no protocol available to check a priori outcomes

Other biasHigh riskSponsored by same pharmaceutical company (Pfizer Ltd.) as with all the other included trials

 
Characteristics of studies awaiting assessment [ordered by study ID]
Russi 2006

MethodsRandomised observational controlled study. 4 treatment arms: 1 LEV fast rate, 2 LEV slow rate, 3 PGB fast rate, 4 PGB slow rate dosage

Participants128 patients with refractory partial epilepsy (32 in each treatment arm)

InterventionsGroup 1: starting dose of 1000 mg BD LEV fast rate with weekly increments of 500 mg

Group 2: starting dose of 500 mg BD LEV slow rate with weekly increments of 250 mg

Group 3: starting dose of 300 mg BD PGB fast rate with weekly increments of 150 mg

Group 4: starting dose of 150 mg BD PGB slow rate with weekly increments of 75 mg

OutcomesRate of withdrawals and continuation to maximum dose

Incidence of adverse events

NotesStudy reported in abstract form only. Further details of study are unavailable

Tata 2007

MethodsRandomised cross-over trial consisting of 2 treatment arms: 1 PGB, 2 LEV. Patients randomised to groups using 1:1 ratio. Study was open-label. Long-term study duration of minimum 6 months

Participants28 adults aged 19 to 62 years, 54% male. Patients currently taking different AED without maintaining good seizure control, stabilised to therapeutic association of valproate and lamotrigine

InterventionsGroup 1: starting dose of 150 mg to target dose of 600 mg PGB

Group 2: starting dose of 1000 mg to target dose of 3000 mg LEV

OutcomesSeizure freedom

Seizure reduction

Withdrawals

Adverse events

NotesStudy reported in abstract only. Further details of study are unavailable

 
Characteristics of ongoing studies [ordered by study ID]
Bali 2012

Trial name or titleComparison of the effect of Zonisamide and Pregabalin as adjunctive therapy in control of intractable epilepsy in children

MethodsA single-blind parallel RCT comparing Zonisamide to Pregabalin. Duration: 6 months.

Participants96 children aged 1-18 years with drug-resistant epilepsy

InterventionsIntervention group 1 treated with Zonisamide orally with dose of 2-12 mg per kg daily and after one month and six months.

Intervention group 2 treated with Pregablin orally with dose of 5-15mg per kg daily and after one month and six months.

Outcomes1) > 50% seizure reduction.

2) Seizure severity.

Starting dateRecruitmanet start date: 01/04/2012.

Contact informationDr Mohammad Kazem Bakhshandeh Bali, Dr.MK.Bakhshandehbali@sbmu.ac.ir

NotesAuthor contacted, no response received.

 
Comparison 1. Pregabalin versus placebo: 50% seizure reduction - ITT

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

 1 50% responders, ITT6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.52, 2.12]

    1.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 95% CI)2.22 [1.36, 3.63]

    1.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 95% CI)2.86 [1.65, 4.94]

    1.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 95% CI)2.86 [2.32, 3.54]

    1.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 95% CI)2.86 [1.42, 5.76]

    1.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 95% CI)2.55 [2.06, 3.16]

 2 50% responders (Random-effects)61868Risk Ratio (M-H, Random, 95% CI)2.61 [1.70, 4.01]

 3 50% responders, Best-Case Analysis64206Risk Ratio (M-H, Fixed, 95% CI)3.72 [3.27, 4.23]

    3.1 50mg pregabalin
1188Risk Ratio (M-H, Fixed, 95% CI)1.87 [1.03, 3.40]

    3.2 150mg pregabalin
2384Risk Ratio (M-H, Fixed, 95% CI)2.61 [1.63, 4.19]

    3.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 95% CI)4.37 [2.61, 7.29]

    3.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 95% CI)4.09 [3.34, 5.01]

    3.5 Titrated dose of pregabalin (150-600mg)
1204Risk Ratio (M-H, Fixed, 95% CI)5.02 [2.56, 9.82]

    3.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 95% CI)3.60 [2.93, 4.43]

 4 50% responders, Best-Case Analysis Random-effects63240Risk Ratio (M-H, Random, 95% CI)1.50 [0.92, 2.45]

    4.1 600 mg pregabalin
61372Risk Ratio (M-H, Random, 95% CI)1.64 [0.78, 3.44]

    4.2 Any dose pregabalin
61868Risk Ratio (M-H, Random, 95% CI)1.40 [0.65, 3.00]

 5 50% responders, Worst-Case Analysis64206Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.96, 1.14]

    5.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.30, 0.99]

    5.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.88, 1.96]

    5.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.98, 2.23]

    5.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 95% CI)1.24 [1.08, 1.43]

    5.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.27, 0.46]

    5.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.94, 1.23]

 
Comparison 2. Pregabalin versus placebo: seizure freedom - ITT

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

 1 Seizure freedom post titration6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 95% CI)3.40 [0.14, 82.52]

    1.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.92]

    1.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 600 mg pregabalin
61880Risk Ratio (M-H, Fixed, 95% CI)2.45 [1.02, 5.91]

    1.5 Titrated dose of pregabalin (150-600mg)
1204Risk Ratio (M-H, Fixed, 95% CI)5.05 [0.28, 92.42]

    1.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 95% CI)2.59 [1.05, 6.36]

 
Comparison 3. Pregabalin versus placebo: treatment withdrawal (any reason) - ITT

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

 1 Treatment withdrawal any reason6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.40, 1.89]

    1.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.41, 1.28]

    1.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 95% CI)1.62 [0.85, 3.10]

    1.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 95% CI)1.65 [1.33, 2.04]

    1.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.61, 1.71]

    1.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 95% CI)1.39 [1.13, 1.72]

 
Comparison 4. Pregabalin versus placebo: treatment withdrawal (adverse events) - ITT

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

 1 Treatment withdrawal for adverse events6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.43, 4.31]

    1.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.45, 2.32]

    1.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 95% CI)2.89 [1.07, 7.78]

    1.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 95% CI)3.39 [2.36, 4.87]

    1.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 95% CI)1.78 [0.68, 4.67]

    1.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 95% CI)2.69 [1.88, 3.86]

 
Comparison 5. Pregabalin versus placebo: adverse effects

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

 1 Ataxia6Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    1.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 99% CI)1.14 [0.14, 9.00]

    1.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 99% CI)1.98 [0.56, 7.01]

    1.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 99% CI)3.33 [0.62, 17.81]

    1.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 99% CI)4.93 [2.56, 9.48]

    1.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 99% CI)2.23 [0.44, 11.26]

    1.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 99% CI)3.90 [2.05, 7.42]

 2 Fatigue6Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    2.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 99% CI)0.71 [0.17, 2.94]

    2.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 99% CI)1.09 [0.50, 2.39]

    2.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 99% CI)1.53 [0.49, 4.76]

    2.4 600 mg pregabalin
61503Risk Ratio (M-H, Fixed, 99% CI)1.32 [0.89, 1.95]

    2.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 99% CI)1.23 [0.49, 3.04]

    2.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 99% CI)1.28 [0.88, 1.86]

 3 Dizziness6Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    3.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 99% CI)1.01 [0.31, 3.33]

    3.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 99% CI)2.04 [0.99, 4.22]

    3.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 99% CI)3.46 [1.39, 8.62]

    3.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 99% CI)3.57 [2.50, 5.09]

    3.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 99% CI)2.97 [1.01, 8.77]

    3.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 99% CI)3.06 [2.16, 4.34]

 4 Nausea3Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    4.1 150 mg pregabalin
1196Risk Ratio (M-H, Fixed, 99% CI)1.31 [0.34, 5.00]

    4.2 600 mg pregabalin
3712Risk Ratio (M-H, Fixed, 99% CI)1.18 [0.51, 2.75]

    4.3 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 99% CI)1.11 [0.12, 10.05]

    4.4 Any dose pregabalin
3942Risk Ratio (M-H, Fixed, 99% CI)1.14 [0.51, 2.53]

 5 Somnolence6Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    5.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 99% CI)0.93 [0.31, 2.78]

    5.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 99% CI)1.26 [0.58, 2.74]

    5.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 99% CI)1.62 [0.63, 4.12]

    5.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 99% CI)2.42 [1.68, 3.50]

    5.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 99% CI)2.32 [0.77, 7.04]

    5.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 99% CI)2.08 [1.45, 2.99]

 6 Weight gain6Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    6.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 99% CI)3.40 [0.05, 224.69]

    6.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 99% CI)3.85 [0.64, 23.35]

    6.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 99% CI)14.43 [0.34, 620.87]

    6.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 99% CI)5.61 [2.74, 11.47]

    6.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 99% CI)2.79 [0.84, 9.29]

    6.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 99% CI)4.92 [2.41, 10.03]

 7 Headache6Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    7.1 50 mg pregabalin
1188Risk Ratio (M-H, Fixed, 99% CI)0.52 [0.16, 1.77]

    7.2 150 mg pregabalin
2384Risk Ratio (M-H, Fixed, 99% CI)0.53 [0.24, 1.17]

    7.3 300 mg pregabalin
1190Risk Ratio (M-H, Fixed, 99% CI)0.43 [0.12, 1.57]

    7.4 600 mg pregabalin
61372Risk Ratio (M-H, Fixed, 99% CI)0.77 [0.51, 1.15]

    7.5 Titrated dose of pregabalin (150-600 mg)
1204Risk Ratio (M-H, Fixed, 99% CI)1.25 [0.45, 3.50]

    7.6 Any dose pregabalin
61868Risk Ratio (M-H, Fixed, 99% CI)0.75 [0.52, 1.08]

 
Comparison 6. Pregabalin versus Lamotrigine

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

 1 50% responders, ITT1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 2 Seizure freedom1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 3 Treatment withdrawal (any reason)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 4 Treatment withdrawal (adverse events)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 5 Adverse events1Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    5.1 Ataxia
1293Risk Ratio (M-H, Fixed, 99% CI)1.72 [0.54, 5.55]

    5.2 Fatigue
1293Risk Ratio (M-H, Fixed, 99% CI)1.72 [0.77, 3.83]

    5.3 Dizziness
1293Risk Ratio (M-H, Fixed, 99% CI)2.94 [1.32, 6.52]

    5.4 Somnolence
1293Risk Ratio (M-H, Fixed, 99% CI)1.99 [0.91, 4.33]

    5.5 Weight gain
1293Risk Ratio (M-H, Fixed, 99% CI)4.33 [0.86, 21.68]

    5.6 Headache
1293Risk Ratio (M-H, Fixed, 99% CI)0.52 [0.26, 1.05]

 6 50% responders, Best- and Worst-Case Analysis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Best-Case
1293Risk Ratio (M-H, Fixed, 95% CI)2.73 [1.99, 3.74]

    6.2 Worst-Case
1293Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.52, 0.88]

 
Summary of findings for the main comparison. Pregabalin versus placebo: 50% seizure reduction - ITT for drug-resistant partial epilepsy

Pregabalin versus placebo: 50% seizure reduction - ITT for drug-resistant partial epilepsy

Patient or population: patients with drug-resistant partial epilepsy
Settings:
Intervention: Pregabalin versus placebo: 50% seizure reduction - ITT

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlPregabalin versus placebo: 50% seizure reduction - ITT

50% responders, ITT - any dose pregabalin15 per 10040 per 100
(26 to 61)
RR 2.61
(1.7 to 4.01)
1868
(6 studies)
⊕⊕⊕⊝
moderate1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; ITT: intention-to-treat; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 High heterogeneity statistic.
2 All studies sponsored by the same pharmaceutical company all reporting significant findings.