Promising effects of donepezil when added to patients treated with gabapentin for neuropathic pain.

Aims The clinical relevance of adding the acetylcholinesterase inhibitor donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The two drugs have previously shown synergism following co-administration in nerve-injured rats [1,2]. Methods The study comprised two consecutive periods of minimum six weeks: (1) titration of gabapentin until highest tolerable dose or maximum 24GG 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 and analgesic rescue medication. Pain scores were also analyzed using mixed-effects analysis (i.e. incorporating inter-subject variability) with the software NONMEM. Results Eight patients commenced treatment with donepezil upon the gabapentin titration period, of which two withdrew due to adverse events. Addition of donepezil reduced pain by >35% in four of six patients compared to gabapentin monotherapy. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (p < 0.05 combination vs. monotherapy). Donepezil was well tolerated in combination with gabapentin. At the end of study, three patients wished to continue combination therapy with gabapentin and donepezil. Conclusions Donepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. Further confirmation in controlled clinical trials is justified. Mixed-effects analysis was sensitive enough to detect statistically significant effects, showing its usefulness in small-scale trials and/or when data is associated with high variability.