Although there are guidelines for the management of NeP, very few head-to-head comparisons of pharmacotherapies exist. The present study suggests that venlafaxine as monotherapy or adjuvant treatment for NeP has similar benefits on pain severity, sleep, anxiety/depression and functioning compared to gabapentin. Based on our open-label results, venlafaxine adjuvant or monotherapy should be considered in NeP patients. Modulation of multiple NeP pathogenic pathways (“rational polytherapy”) may be beneficial in numerous patients with NeP, as demonstrated by the efficacy of adjuvant therapy with either therapy of interest in this study.
We decided to use gabapentin as a comparator given its widespread use, reasonable adverse event profile, therapeutic benefits at sub-maximal dosing (1800 mg/day), low cost and acceptance as beneficial NeP therapy.13
It was expected that all treatment groups would fare better than the untreated, or control, group. Although the control group had lower VAS pain scores that changed little over time, there were similar improvements for both therapy groups that were not witnessed in the control group. Both venlafaxine and gabapentin, with proven efficacy in the treatment of NeP,12
demonstrated improvement in VAS pain scores, but also were associated with some improvements in sleep, pain-associated psychiatric difficulties, and functional abilities. Previous studies examining low dose venlafaxine asserted a number needed to treat (NNT) of 5.5 (3.4–13.5),22
while higher dosing of venlafaxine provides a NNT of 4.6 (2.9–10.6)22
– thus, venlafaxine is suggested to be provided at a minimum of ≥150 mg daily23
in order to manage pain. In comparison, gabapentin for management of NeP due to a peripheral nervous system disease is associated with an NNT of 4.3 (2.8–8.6).12
Therefore, the expected therapeutic benefit for both groups is similar. In our study, the two pharmacotherapies were quite comparable for most parameters, although venlafaxine had possibly better efficacy in management of anxiety/depression and sleep dysfunction than gabapentin. Our results suggest that venlafaxine is also an effective medication in NeP therapy, with benefits that are comparable to those of gabapentin.
The most common adverse event with the use of either venlafaxine or gabapentin was sedation, although the numbers of adverse events did not differ between the two therapies assessed. Sedation, lightheadedness/dizziness and fatigue were the most common adverse events to lead to discontinuation of therapy in all intervention groups. Inefficacy also occurred in 13% to 16% of patients with either pharmacotherapy. Global benefit assessed with the PGIC found overall beneficial effects within any of the four intervention groups compared to that of the control group receiving no pharmacotherapy.
Another SNRI, duloxetine, also reduces pain in patients with major depressive disorder.38
Interestingly, a post-hoc analysis of two independent, randomized, controlled trials in patients with major depressive disorder comparing duloxetine with placebo identified that approximately 50% of duloxetine’s total effect on overall pain was independent of responses in depression, suggesting an independent analgesic effect of duloxetine which may contribute to efficacy in diabetic peripheral NeP20
The reuptake inhibition of both serotonin and norepinephrine has remained the proposed mechanism by which SNRIs alleviates pain and improves mood through increased availability of serotonin and norepinephrine, important neurotransmitters in descending pain inhibitory pathways in the central nervous system.42
There are a number of limitations associated with our results. The greatest limitation was a lack of randomization and blinding. The flexible dosing and variability in overall dosing performed was analogous to everyday clinical therapy, but may certainly limit the direct comparison of the agents considered. Selection bias may have occurred based upon the physician and patient choosing the desired therapy – in particular, it is possible, but unintended, that patients with history of psychiatric illness may have been more likely to start on venlafaxine. Flexible dosing, although commonly used in routine management, may have contributed to variability in efficacy or adverse events. There is no optimal control group for comparison – we selected a cohort group who chose to receive no pharmacotherapy, but these patients may have expectations of no improvement over time, and had lower baseline VAS scores. It is extremely difficult to control for such variables without performing a randomized, double-blinded, controlled study, although the expense of such a study with an assumed very large sample size is likely prohibitive. Although all patients were encouraged to use conservative measure to assist with NeP relief, including aerobic forms of exercise, there was no means of controlling for non-pharmaceutical interventions, nor was there any means of controlling for patients who also used over-the-counter medications for pain relief. Patients referred to our tertiary care clinic may have not been representative of the general population of patients with PN and PN-mediated NeP.
NeP is a significant debilitating sequelae of PN that usually demands pharmacotheapy. We advocate for future randomized, blinded, head-to-head studies of pharmacotherapies in the management of NeP. Future studies examining combination therapy using agents with distinct mechanisms of action, such as venlafaxine and gabapentin, will be of benefit to determine possible additive effects. Our results suggest that therapies for NeP modulate parameters of sleep and mood/anxiety, and enhance functional abilities in addition to modifying pain severity. We suggest that both venlafaxine and gabapentin are appropriate and comparable adjuvant therapies and monotherapies in the management of NeP.