Although clinical trials have shown that gabapentin is an effective treatment for various forms of neuropathic pain, the authors of a recent study on the use of gabapentin for this purpose noted that “monotherapy is seldom sufficient for the management of the more severe neuropathic pain conditions.” They also noted that although combination therapy in these patients “may be a rational strategy to reach more favourable results at lower doses and with fewer unwanted side effects,” currently “little evidence is available for optimal drug combinations.”

Based on encouraging results from previous studies that used combination treatment with gabapentin and the acetylcholinesterase inhibitor donepezil on nerve-injured rats, the authors of “Donepezil Provides Positive Effects to Patients Treated with Gabapentin for Neuropathic Pain: An Exploratory Study, published in the January 2014 issue of Acta Anaesthesiologica Scandinavica, looked at the effect of combination treatment with gabapentin and donepezil on post-traumatic neuropathic pain in a small cohort of patients.

For the study, patients with neuropathic pain caused by surgery or trauma underwent an initial screening visit, followed by “two consecutive treatment periods of a minimum of 6 weeks, which were accompanied by evaluation visits at the end of each period.”

During the screening visit, patients received a physical and neurological exam, and were tested for baseline levels of serum creatinine and aspartate aminotransferase/alanine aminotransferase (AST/ALT). Patients also completed several pain and quality of life tests: McGill Pain Questionnaire, numeric rating scale for pain severity, visual analogue scale (VAS), and the SF-36 health-related quality of life questionnaire. Patients also received a diary in which to record adverse events and the use of rescue medication.

The authors reported that patients were permitted to use paracetamol as rescue analgesic during the study, but were restricted in their use of non-steroidal anti-inflammatory drugs (NSAIDs) “to occasional use for other types of pain.” The authors wrote that “Benzodiazepines, zolpidem or zopiclon for insomnia were allowed only if prescribed before screening. Opioids, tramadol and drugs that might affect neuropathic pain (including antidepressants, centrally acting muscle relaxants, anticonvulsants, capsaicin and anxiolytics) were prohibited. Antacids containing aluminium or magnesium were not allowed as concomitant intake reduces the bioavailability of gabapentin.”

For first treatment phase, patients received 300 mg gabapentin monotherapy on the evening of the first day after the screening visit. Gabapentin dose was titrated up over the course of 3-4 weeks to “either the highest tolerable dose or the maximum dose of 2400 mg daily (divided in three separate doses).” Participants had to be on a stable gabapentin dose for at least two weeks before the treatment effects of the drug were evaluated.

During the second treatment phase, no further titration of the gabapentin dose was permitted. Patients were also given daily 5 mg donepezil (in the evening). Investigators evaluated the effect of combination therapy after a minimum of 6 weeks of treatment.

For the study, 28 patients were screened for inclusion, 10 of whom started gabapentin treatment in the first treatment phase. Two patients withdrew before beginning gabapentin-donepezil combination treatment during the second treatment phase. Six patients completed treatment during the study. According to the authors, three patients withdrew due to adverse events (“subjects reported somnolence, dizziness and muscle cramp as being intolerable”) and one patient withdrew from the study due to non-compliance.

The initial study group of 10 patients included six men and four women, with a median age of 48.5 (38—66) years. Patients had been experiencing severe neuropathic pain for a median of three years prior to study enrollment.

At the end of treatment with gabapentin monotherapy (first treatment phase), patients reported a median drop in pain score of 29.5 units on VAS (range 6—75 units) compared with baseline. At the conclusion of the combination gabapentin-donepezil treatment phase, patients reported “a further reduction of the VAS scores, with a median drop of 9.5 units (range −1 to 63 units).”

Patients also reported reduction in pain severity using several other pain scales. Three of the six patients who completed treatment experienced improved mental wellness scores. The authors also reported that “Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P < 0.0001 combination vs. monotherapy).”

In their discussion of these results, the authors noted that this was the first time donepezil had been evaluated for its pain-relieving effects in neuropathic pain patients.

Although analysis of data “showed a trend in favour for combination therapy,” the authors wrote that “the distinct reduction in pain scores following gabapentin treatment in the first period of the study may have compromised the possibilities for exploring the full potential of co-administered donepezil, as only a small window was open for additional analgesia.” They also wondered whether switching the dose order (ie, initiate treatment with donepezil until achieving a stable dose, then add gabapentin) might be “an easier strategy for finding optimal drug doses for combination.”

Based on their findings, the authors concluded that “donepezil may provide additional analgesia to neuropathic pain patients who do not receive sufficient pain relief from gabapentin as monotherapy. The addition of donepezil may also be beneficial for patients who experience troublesome adverse effects from gabapentin treatment, enabling a reduction of the gabapentin dose.”