title: The effect of a combination of gabapentin and donepezil in an experimental pain model in healthy volunteers: Results of a randomized controlled trial.
abstract: This double-blind, placebo-controlled, 3-period cross-over, 4-treatment option, incomplete block study (ClinicalTrials.gov number NCT01485185), with an adaptive design for sample size re-estimation, was designed to evaluate gabapentin plus donepezil in an established experimental model of electrical hyperalgesia. Thirty healthy male subjects aged 18-55 years were randomized to receive gabapentin 900 mg or gabapentin 900 mg+donepezil 5mg for 2 of the 3 treatment periods, with 50% of subjects randomized to receive placebo (negative control) and 50% to gabapentin 1800 mg (positive control) for the remaining period. Each treatment period was 14 days. Gabapentin or corresponding placebo was administered on Day 13 and the morning of Day 14. Donepezil or corresponding placebo was administered nocturnally from Day 1-13 and the morning of Day 14. Co-primary endpoints were the area of pinprick hyperalgesia (260 mN von Frey filament) and allodynia (stroking by cotton bud) evoked by electrical hyperalgesia on Day 14. Gabapentin 1800 mg (n=14) significantly reduced the area of allodynia vs placebo (n=14; -12.83 cm(2); 95% confidence interval [CI] -23.14 to -2.53; P=0.015) with supportive results for hyperalgesia (-14.04 cm(2); 95% CI -28.49-0.41; P=0.057), validating the electrical hyperalgesia model. Gabapentin+donepezil (n=30) significantly reduced the area of hyperalgesia vs gabapentin 900 mg (n=30; -11.73 cm(2); 95% CI -21.04 to -2.42; P=0.014), with supportive results for allodynia (-6.62 cm(2); 95% CI -13.29-0.04; P=0.052). The adverse event profile for gabapentin+donepezil was similar to the same dose of gabapentin. Data are supportive of further clinical investigation of a gabapentin-and-donepezil combination in patients with an inadequate response to gabapentin.
authors.affiliation: GlaxoSmithKline Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK GlaxoSmithKline, Brentford, UK GlaxoSmithKline, Stevenage, UK GlaxoSmithKline, Verona, Italy.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Boyle
authors.forename: Disala
authors.initials: D
authors.lastname: Fernando
authors.forename: Hazel
authors.initials: H
authors.lastname: Kurz
authors.forename: Sam R
authors.initials: SR
authors.lastname: Miller
authors.forename: Mauro
authors.initials: M
authors.lastname: Zucchetto
authors.forename: James
authors.initials: J
authors.lastname: Storey
mesh_terms: D000293:Adolescent; D000328:Adult; D000588:Amines / Q000627:therapeutic use*; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D000077265:Donepezil; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004558:Electric Stimulation / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D000077206:Gabapentin; D064368:Healthy Volunteers; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018697:Nootropic Agents / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D010147:Pain Measurement; D010880:Piperidines / Q000627:therapeutic use*; D012867:Skin / Q000294:innervation; D013497:Sural Nerve / Q000502:physiology; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
chemical_list: D000588:Amines; D018712:Analgesics, Non-Narcotic; D003509:Cyclohexanecarboxylic Acids; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000077265:Donepezil
keywords: Donepezil; Electric stimulation; Gabapentin; Humans; Hyperalgesia; Models, biological; Randomized controlled trial