Study ID | Design | Sample size | Duration | Setting | Population | Duration of neuropathic pain | Outcome measures | Interventions | ||
PGB | PLA | Cointerventions | ||||||||
Arezzo et al 18 | Parallel group | PGB 82; PLA 85. | 13 weeks | 23 centres; USA. | Men or women with T1DM or T2DM. | ≥3 months | Primary: mean pain score (MPS); proportion of responders; adverse events ≥3%; secondary: sleep interference (11 point NRS), Present Pain Intensity (PPI) index; SF-MPQ VAS; CGIC; PGIC. | 600 mg/day fixed. | Not described. | Aspirin (up to 325 mg/day for cardiac and stroke prophylaxis), acetaminophen (up to 4 g/day), SSRIs, and benzodiazepines such as lorazepam (dosed at bedtime with stable (>30 days) regimen for sleep problems) were allowed. |
Cardenas et al 19 | Parallel group | PGB 112; PLA 108. | 16 weeks | 60 centres; Chile, China, Columbia, Czech Republic, Hong Kong, India, Japan, Philippines, Russia and USA. | Patients aged ≥18 years with C2-T12 complete/incomplete SCI. | ≥12 months | Primary: duration-adjusted average change in pain (DAAC); secondary: change in MPS (from baseline to endpoint); percentage of patients with ≥30% reduction in MPS at endpoint; PGIC scores at endpoint; change in mean pain-related sleep interference score; change from baseline in mean pain at each study week; change from baseline in pain-related sleep interference scores at each week; Medical Outcomes Study-Sleep Scale (MOS-SS); HADS scores (at baseline and endpoint). | 150–600 mg/day flexible phase followed by maintenance phase. | Matching grey capsule. | NSAIDs, cyclo-oxygenase-2 inhibitors (COX-2) and acetaminophen (≤1.5 g/day in Japan, ≤4 g/day in all other countries) were permitted as rescue therapy. Antidepressants were permitted if the patient was on a stable dose within 30 days before the first visit. |
Dworkin et al 20 | Parallel group | PGB 89; PLA 84. | 8 weeks | 29 centres; USA. | Men or women ≥18 years old with PHN. | ≥3 months | Primary: pain reduction in last 24 hours; safety and adverse events; secondary: SF-MPQ at baseline, weeks 1, 3, 5 and 8; daily sleep interference score; MOS-SS; SF-36; PGIC; CGIC. | 300 mg/day, 600 mg/day fixed. | Identical in appearance; administered one capsule three times daily. | Permitted medications included narcotic and non-narcotic analgesics, acetaminophen (not to exceed 4 g/day), NSAIDs, aspirin and antidepressants, including SSRIs (provided that dosing had been stable for at least 30 days before baseline). |
Freynhagen et al 21 | Parallel group | PGB 273; PLA 65. | 12 weeks | 60 centres; 9 European countries that were not specified. | Men or women ≥18 years old with primary diagnosis of painful DPN or PHN. | ≥3 months PHN, ≥6 months DPN. | Primary: MPS; adverse events; secondary: daily sleep interference diary; MOS-SS; PGIC. | 150–600 mg/day flexible. 300 mg/day, 600 mg/day fixed. | Matching capsules; matching twice daily dosing schedule. | SSRIs for treatment of depression, aspirin for myocardial infarction and stroke prophylaxis, short-acting benzodiazepines for insomnia and paracetamol as rescue medication were allowable medications during the study period. |
Guan et al 22 | Parallel group | PGB 206; PLA 102. | 8 weeks | 11 centres; China | Males or females 18–75 years with primary diagnosis of painful DPN or PHN. | ≥3 months PHN, ≥1 year, <5 years DPN. | Primary: MPS (DPRS) during preceding 24 hours; DAAC score; secondary: daily sleep interference scale; SF-MPQ; PGIC; CGIC; safety and adverse events. | 150–600 mg/day flexible. | Flexible dose PLA in matching capsules; doses titrated using same regimen. | NSAIDs and SSRIs allowed to be continued on stable dose. |
Holbech et al 23 | Cross-over | PGB 18; PLA 19. | 5 weeks | e centres; Denmark. | Males or females 20–85 years with polyneuropathy due to DPN. | ≥6 months | Primary: total pain intensity on NRS; adverse events; secondary: pain-related sleep disturbances; pain relief on six-point verbal scale; other: specific pain symptoms on the NRS; number of paracetamol tablets used as escape medication; SF-36 (health-related QoL); Major Depression Inventory; QST tests. | 150 mg/day, 300 mg/day fixed. | Matched PLAs of identical appearance to the two trial drugs were dosed similarly using double-dummy technique. | Up to 6 tablets of 500 mg paracetamol could be used daily as escape medication. |
Huffman et al 24 | Cross-over | PGB 101; PLA 102. | 6 weeks | 36 centres; USA (25), Sweden (4), South Africa (4) and Czech Republic (3). | Men or women ≥18 years old with painful DPN and with pain on walking. | Not described. | Primary: NRS; DPN pain on walking (NRS); secondary: 30%, 50% responders; Brief Pain Inventory-Short Form (BPI-sf); daytime total activity counts per day; steps per day; Walk 12 questionnaire; Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Total Quality of Life Score; EuroQoL-5 Dimensions (EQ-5D); Mean Sleep Interference Rating Score; HADS. | 150–300 mg/day fixed. | Matching PLA also administered in three divided doses. | Not described. |
Kanodia and Singhal25 | Parallel group | PGB 23; PLA 22. | 4 weeks | 1 centre; India. | Patients with acute HZ presenting within 72 hours of onset. | <3 days. | Primary: pain on linear VAS; adverse events. | 150 mg/day fixed. | Not described. | Oral acyclovir 800 mg was given five times per day for 7 days. |
Kim et al 26 | Parallel group | PGB 110; PLA 109. | 12 weeks | 32 centres; Asia-Pacific. | Males or females ≥18 years with diagnosis of central poststroke pain. | ≥3 months | Primary: mean pain score; secondary: daily Sleep Interference Scale (DSIS); weekly MPS; proportion of 30%, 50% responders; Quantitative Assessment of Neuropathic Pain; Neuropathic Pain Symptom Inventory; weekly mean sleep interference scores; MOS-SS; HADS; SF-MPQ VAS – Part B; EQ-5D; PGIC; CGIC; safety and tolerability. | 300 or 600 mg/day dose adjustment followed by fixed maintenance phase. | Matching PLA. | Stable medications for pain or insomnia if used normally >30 days before screening. |
Krcevski Skvarc and Kamenik27 | Parallel group | PGB 14; PLA 15. | 3 weeks | 1 centre; Slovenia. | Men or women 30–80 years with HZ pain. | Primary: assessment of pain severity (11-point Likert scale); secondary: patients’ ratings of the severity of allodynia, hyperalgesia, and burning, prickling and tingling sensations; rating of quality of sleep and physical activity; consumption of analgesics; occurrence of adverse events; SHN; PHN. | 150 or 300 mg/day fixed. | PLA also administered twice daily. | Oxycodone, naproxen and/or tramadol, morphine and diclofenac. | |
Lesser et al 28 | Parallel group | PGB 240; PLA 97. | 5 weeks | 45 centres; USA. | Men or women ≥18 years old who were diagnosed with diabetes mellitus (type 1 or 2) and had distal symmetric sensorimotor polyneuropathy. | 1–5 years | Primary: pain (11-point NRS); secondary: daily sleep interference diary; SF-MPQ; CGIC; PGIC; SF-36; Profile of Mood States (POMS); safety outcomes. | 75, 300, 600 mg/day fixed. | PLA administered three times daily. | Acetaminophen and SSRIs permitted. |
Liu et al 29 | Parallel group | PGB 112; PLA 110. | 8 weeks | 22 centres; China. | Male and female ethnically Chinese patients aged ≥18, diagnosed with PHN. | Symptoms persisting ≥3 months after the healing of HZ lesions. | Primary: mean score of Daily Pain Rating Score; secondary: change from baseline on pain VAS; change from baseline on PPI of the SF-MPQ; 30% pain responders at endpoint; change from baseline in weekly MPS; change from baseline in sleep interference score (11-point NRS); CGIC; PGIC; MOS-SS; adverse events. | 150 mg/day, 300 mg/day fixed. | Matched PLA capsules on the same dosing schedule. | Concomitant use of medications permitted except antidepressants, epileptics, analgesics or corticosteroids, skeletal muscle relaxants, mexelitine and dextromethorphan as well as electrotherapy, transcutaneous electrical nerve stimulation, acupuncture and neurosurgical therapy. |
Mathieson et al 30 | Parallel group | PGB 108; PLA 101. | 8 weeks | Number not specified; Australia. | Patients with sciatica. | ≥1 week, <1 year. | Primary: average leg pain intensity score over the course of previous 24 hours as assessed at 8 weeks and 52 weeks; secondary: extent of disability (Roland Disability Questionnaire for sciatica); back pain intensity; global perceived effect; quality of life as measured on Short-Form Health Survey 12; adverse events. | 150–600 mg/day flexible. | Matching PLA capsules were packaged in white, opaque, sealed containers at a central pharmacy. | Concomitant therapies included physical therapies as well as other analgesic medications (except for adjuvant analgesic agents), which would ideally be prescribed in accordance with the WHO pain ladder. Trial clinicians were asked not to prescribe certain medicines (antiepileptic medications, SSRIs, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, topical lidocaine and benzodiazepines) or to schedule interventional procedures. |
Moon et al 31 | Parallel group | PGB 162; PLA 78. | 10 weeks | Multicentre (number not specified); Korea. | Korean patients aged 18 years with neuropathic pain (DPN, PHN or post-traumatic neuropathic pain). | Mean duration of pain PGB patients: 3 years, PLA patients: 3.2 years. | Primary: endpoint mean DPRS score, Secondary: weekly mean DPRS score, DAAC of adjusted mean DPRS from baseline to endpoint, proportion of responders (whose scores reduced by 30% or 50%), DSIS, Euro Quality of Life assessment (EQ-5D): utility and VAS score; MOS-SS; HADS; PGIC; CGIC; Tolerability evaluation of adverse events and vital signs | 150–600 mg/day flexible. | Matching PLA capsules provided by Pfizer. | Most patients were taking drug therapy at baseline, and the majority (83.8%) remained on concomitant drug therapy during the study, including one-third who received tricyclic antidepressants. |
Rauck et al 32 | Parallel group | PGB 56; PLA 112. | 20 weeks | 85 centres; USA. | Men or women ≥18 years old who were diagnosed with diabetes mellitus (type 1 or 2) and had pain attributed to DPN, defined as painful distal symmetric sensorimotor polyneuropathy. | ≥6 months, <5 years. | Primary: change from baseline in pain intensity score (11 point PI-NRS); secondary: change from baseline in mean 24 hours average pain intensity score, daytime average pain intensity score, night-time average pain intensity score, current pain intensity score, daytime worst pain intensity score, night-time worst pain intensity score, sleep interference score and rescue analgesia consumption (mg); Neuropathic Pain Scale; SF-MPQ; pre-50-foot and post-50-foot (15 m) walk pain scores; PGIC; CGIC; proportion of subjects achieving various levels of reduction in the 24 hours average pain intensity score; time to onset of sustained improvement in the 24 hours average pain intensity score; POMS; SF-36 health-related quality of life questionnaire; safety assessments. | 300 mg/day fixed. | Matching PLA in blister card. | Acetaminophen, up to 3 g/day was allowed as rescue medication for pain throughout the trial but was not allowed within 24 hours of any site visit for assessments. |
Richter et al 33 | Parallel group | PGB 161; PLA 85. | 6 weeks | Multicentre; not specified. | Patients with diabetes and painful distal symmetrical sensorimotor polyneuropathy. | 1–5 years | Primary: pain; adverse events; secondary: pain characteristics (SF-MPQ and PPI); sleep interference (11-point NRS: 0–10); health status (SF-36); psychological state (POMS); global improvement (PGIC and CGIC). | 150 mg/day and 600 mg/day fixed. | Matching dose and schedule. | Aspirin (for prophylaxis of myocardial infarction and transient ischaemic attacks), acetaminophen (3 g/day) and stable doses of serotonin reuptake inhibitors were allowed. |
Rosenstock et al 34 | Parallel group | PGB 76; PLA 70. | 8 weeks | 25 centres | Men or women ≥18 years old with type 1 or 2 diabetes mellitus who reported symmetrical painful symptoms in distal extremities for a period of 1–5 years prior to study. | 1–5 years | Primary: endpoint mean score; secondary: SF-MPQ – sensory, affective and total score; daily sleep interference score; PGIC; CGIC; SF-36; POMS; safety. | 300 mg/day fixed. | Lactose USP, one capsule three times daily. | Acetaminophen (up to 4 g/day), aspirin (up to 325 mg/day for myocardial infarction or transient ischaemic attack prophylaxis), and serotonin reuptake inhibitors provided no dose changes occurred within 30 days prior to randomisation or during the study). |
Sabatowski et al 35 | Parallel group | PGB 157; PLA 81. | 8 weeks | 53 centres; Europe and Australia. | Men or women ≥18 years old with PHN. | ≥6 months | Primary: endpoint mean score; secondary: mean sleep interference scores, PGIC, CGIC, SF-36 health survey, Zung Self-Rating Depression Scale, VAS of the SF-MPQ, adverse events. | 150 mg/day, 300 mg/day fixed. | Identical in appearance. | Patients allowed to continue acetaminophen (up to 3 g/day), NSAIDs, opioid or non-opioid analgesics or antidepressants. |
Satoh et al 36 | Parallel group | PGB 179; PLA 90. | 13 weeks **intervention period. | 62 centres; Japan. | Men or women ≥18 years old with DPN. | ≥1 year. | Primary: change from baseline in mean weekly pain score at week 13 using a 11-point NRS; secondary: weekly MPS, responder rates, SF-MPQ score, weekly mean sleep interference scores using 11-point NRS; MOS-Sleep Scale, SF-36, PGIC, CGIC, safety: adverse events. | 300 mg/day, 600 mg/day fixed. | Not described, same schedule. | Not described. |
Shabbir et al 37 | Parallel group | PGB 70; PLA 70. | 6 weeks | 2 centres; Mayo Hospital and Services Hospital, Lahore. | Men or women ≥18 years old with DPN. | ≥6 months. | Primary: reduction in pain (measured with NRS); responders who experienced 50% or more reduction in baseline pain score on NRS. | 150–600 mg/day flexible. | Not described. | Not described. |
Siddall et al 38 | Parallel group | PGB 70; PLA 67. | 12 weeks | 8 centres; Australia. | Patients with central neuropathic pain in spinal cord injury. | Persisted continuously for at least 3 months or with relapses and remission for at least 6 months. | Primary: endpoint MPS, Sleep-interference scores, SF-MPQ Total, sensory and affective scores, from which VAS and PPI score was derived. MOS-SS and HADS, PGIC; tolerability and safety. | 150–600 mg/day flexible. | PLA also administered twice daily. | 70% of patients taking other medications too: opiates, tricyclics, AEDs, NSAIDs/COX-2, Benzos, SSRI/SSNI and muscle relaxants. |
Simpson et al 39 | Parallel group | PGB 151; PLA 151. | 14 weeks | 44 centres; USA and Puerto Rico. | Men or women ≥18 years old with painful HIV-DSP. | ≥3 months | Primary: change from baseline in mean NPRS score; secondary: change in sleep interference scores; MOS-SS; PGIC; Pain- modified Brief Pain Inventory; Gracely Pain Scale; safety: adverse events. | 150–600 mg/day flexible. | PLA also administered twice daily. | Neurotoxic antiretroviral (ARV) drugs known to cause sensory neuropathy clinically similar to HIV-DSP must have been on stable doses for ≥3 months before screening. Doses of other pain medications had to be stable for ≥1 month before treatment and throughout the study. |
Simpson et al 40 | Parallel group | PGB 183; PLA 194. | 16 weeks | 45 centres; South Africa, USA, India, Columbia, Thailand, Peru, Puerto Rico and Poland. | Men and women ≥18 years of age with HIV neuropathy. | ≥3 months | Primary: change in pain scores (NRS); secondary: PGIC/CGIC; Brief Pain Symptom Inventory short form (BPI-sf); MOS-SS; pain-related sleep interference and overall sleep disturbance (NRS-Sleep scale); safety. | 150–600 mg/day flexible. | Matching PLA delivered through system for randomisation and drug dispensing. | NSAIDs, if taken at stable dose for ≥4 weeks before study, antidepressants without efficacy for neuropathic pain if taken at stable dose for ≥30 days before study (SSRIs, bupropion and trazodone), non-benzodiazepine hypnotics no more than once/week for sleep disturbance if clinically essential, rescue therapy of oral acetaminophen (max 3 g/day), low dose (≤650 mg/day) aspirin and stable ARV treatment >8 weeks before study. |
Stacey et al 41 | Parallel group | PGB 179; PLA 90. | 4 weeks | 42 centres; USA, Germany, Italy, Spain and UK. | Men or women ≥18 years old with PHN. | ≥3 months. | Primary: pain reduction; time to onset of meaningful pain relief; secondary: daily sleep interference score; PGIC; VAS of the SF-MPQ; VAS anxiety; VAS allodynia; safety evaluation. | 150–600 mg/day flexible dose; 300 mg/day fixed dose. | PLA also administered twice daily. | Concomitant pain treatments permitted given that it must be stable for at least 30 days. |
Tölle et al 42 | Parallel group | PGB 299; PLA 96. | 12 weeks | 58 centres; Germany, Hungary, Poland, UK, Australia, and South Africa. | Men or women ≥18 years old with painful symmetrical sensorimotor polyneuropathy due to diabetes. | ≥1 year. | Primary: pain reduction (according to 11-point NRS) from baseline; treatment responders; secondary: PGIC; CGIC; EuroQoL Health Utilities Index; daily pain-related sleep interference scores; EQ-5D (VAS); safety evaluation. | 150, 300, 300/600 mg/d fixed. | PLA also administered twice daily. | SSRIs for depression or anxiety given in a stable dose for >30 days. |
van Seventer et al 43 | Parallel group | PGB 275; PLA 93. | 13 weeks | 76 centres. | Men or women ≥18 years old with PHN. | >3 months | Primary: endpoint MPS; patients with ≥50% and ≥30% reduction in pain score from baseline; weekly MPS; secondary: endpoint mean sleep interference scores, weekly mean sleep interference scores and PGIC. | 150, 300, 600 mg/day fixed. | PLA also administered twice daily. | Non-narcotic analgesics, for example, noramidopyrine and paracetamol, and stable regimens of opioids, anti-inflammatories and antidepressants. |
van Seventer et al 44 | Parallel group | PGB 127; PLA 127. | 8 weeks | 44 centres; Belgium, Canada, Denmark, Finland, Italy, Netherlands, Portugal, Romania, Sweden, Switzerland and UK. | Men or women aged 18–80 years with post-traumatic peripheral neuropathic pain. | ≥3 months | Primary: endpoint MP; secondary: rating of extent to which pain interfered with sleep; MOS-SS; HADS; mBPI-sf; PGIC; tolerability and safety assessment. | 150–600 mg/day flexible. | PLA also administered twice daily. | NSAIDs, COX-2 inhibitors, opioid and non-opioid analgesics, anti-epileptic drugs, antidepressant medications, other concomitant medications if they had been stable for at least 1 month before the study and would remain stable throughout the study |
Vranken et al 45 | Parallel group | PGB 20; PLA 20. | 4 weeks | 1 centre; the Netherlands. | Men and women ≥18 years old with central neuropathic pain. | ≥6 months | Primary: pain intensity score (VAS); mean endpoint pain score; Pain Disability Index; EQ-5D; Medical Outcomes Short-Form Health Survey Questionnaire 36 (SF-36); safety. | 150–600 mg/day flexible. | Flexible dose PLA (1–4 capsules per day); matching capsules; on same dosing schedule. | Adjuvant analgesics. |
CGIC, Clinician Global Impression of Change; DAAC, duration-adjusted average change; DPN, diabetic peripheral neuropathy; HADS, Hospital Anxiety and Depression Scale; NRS, numerical rating scale; NSAIDs, non-steroidal anti-inflammatory drugs; HZ, herpes zoster; PGB, pregabalin; PGIC, Patient Global Impression of Change; PHN, postherpetic neuralgia; PLA, placebo; SF-MPQ PPI, Short-Form McGill Pain Questionnaire personal pain intensity; SF-MPQ VAS, Short-Form McGill Pain Questionnaire visual assessment scale; SSRIs, selective serotonin reuptake inhibitors; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; VAS, visual assessment scale.