The effect of a combination of gabapentin and donepezil in an experimental pain model in healthy volunteers: Results of a randomized controlled trial |
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| Affiliation: | 1. GlaxoSmithKline Clinical Unit Cambridge, Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, Cambridge, UK;2. GlaxoSmithKline, Brentford, UK;3. GlaxoSmithKline, Stevenage, UK;4. GlaxoSmithKline, Verona, Italy;1. National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark;2. Multidisciplinary Pain Centre, Department of Neuroanaesthesiology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark;3. Section of Palliative Medicine, Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark;4. Department of Clinical Medicine, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark;1. Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA;2. Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA;3. Geriatric Research, Education and Clinical Center, James J. Peters VAMC, Bronx, NY, USA;4. Medical University of South Carolina, Charleston, SC, USA;5. Department of Emergency Medicine, Oregon Health & Science University, Portland, SC, USA;6. Department of Emergency Medicine, George Washington University Medical Center, Washington, DC, USA;7. Department of Emergency Medicine, University of Colorado, Aurora, CO, USA;8. Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;9. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;1. Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St Louis, MO 63104, USA;2. Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina 98122, Italy;3. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA;1. Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA;2. The Synthetic Neurobiology Group, Media Lab, Massachusetts Institute of Technology, Cambridge, MA, USA;1. Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway;2. Department of Community Medicine, Institute of Health and Society, University of Oslo, Norway;3. Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway |
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| 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 5 mg 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 cm2; 95% confidence interval [CI] −23.14 to −2.53; P = 0.015) with supportive results for hyperalgesia (−14.04 cm2; 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 cm2; 95% CI −21.04 to −2.42; P = 0.014), with supportive results for allodynia (−6.62 cm2; 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. |
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| Keywords: | Randomized controlled trial Models, biological Electric stimulation Hyperalgesia Gabapentin Donepezil Humans |
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