title: Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study.
abstract: BACKGROUND
  The first-line medication gabapentin and the acetylcholinesterase inhibitor donepezil represent a new promising combination to improve treatment outcomes for patients with severe neuropathic pain. The drugs have previously shown synergism following co-administration in nerve-injured rats.
  
  
  METHODS
  The clinical relevance of adding donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The study comprised two consecutive periods of minimum 6 weeks: (1) titration of gabapentin to the highest tolerable dose or maximum 2400 mg daily, and (2) addition of donepezil 5 mg once daily to the fixed gabapentin dose. Efficacy and tolerability were assessed by ratings of pain intensity, questionnaires for pain and health-related quality of life, and reporting of adverse events. Pain scores were also analysed using mixed-effects analysis with the software NONMEM to account for intersubject variability.
  
  
  RESULTS
  Eight patients commenced treatment with donepezil, of which two withdrew because of adverse events. Addition of donepezil resulted in clinically relevant reductions of pain (> 11 units on a 0-100 scale) and improved mental wellness in three of six patients. The remaining three patients had no obvious supplemental effect. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P < 0.0001 combination vs. monotherapy).
  
  
  CONCLUSIONS
  Donepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. The promising results support controlled clinical trials of the drug combination. The usefulness of mixed-effects analysis in small-scale trials and/or for data with high intersubject variability was also demonstrated.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Basnet
authors.forename: S
authors.initials: S
authors.lastname: Butler
authors.forename: P H
authors.initials: PH
authors.lastname: Honoré
authors.forename: M
authors.initials: M
authors.lastname: Butler
authors.forename: T E
authors.initials: TE
authors.lastname: Gordh
authors.forename: K
authors.initials: K
authors.lastname: Kristensen
authors.forename: O J
authors.initials: OJ
authors.lastname: Bjerrum
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000588:Amines / Q000009:adverse effects / Q000627:therapeutic use*; D000700:Analgesics / Q000009:adverse effects / Q000627:therapeutic use*; D003509:Cyclohexanecarboxylic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D003511:Cyclohexanols / Q000627:therapeutic use; D000077265:Donepezil; D004359:Drug Therapy, Combination; D005260:Female; D000077206:Gabapentin; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D018401:Sample Size; D000069470:Venlafaxine Hydrochloride; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D003511:Cyclohexanols; D007189:Indans; D018696:Neuroprotective Agents; D010880:Piperidines; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000069470:Venlafaxine Hydrochloride; D000077265:Donepezil