Review of Multimodal Therapies for the Treatment of Neuropathic Pain: Clinical Implications

Review of Multimodal Therapies for the Treatment of Neuropathic Pain: Clinical Implications

Background:

Neuropathic pain is secondary to many different underlying conditions and has a population prevalence of 7-10%. (Treede RD, et al.  Neurology 2007, 70, 1630–1635). With limited choices available, the treatment of neuropathic pain is effective in only 50% of patients (Afonso AS, et al. J Clin Med 2021;10:3533). This is due in part to suboptimal efficacy and/or dose-limiting adverse effects (AEs).  In addition, there has been a decrease in drug effect from recent randomized trials with progressively increasing NNTs. (Finnerup NB, et al. Pain 2018;159:2339-2346). Combination therapy is thus becoming more common in clinical practice.  It is perceived that combination therapy can be beneficial when medications are chosen based on differing mechanisms of action, which can often lead to additive or synergistic therapeutic benefits at lower doses and lower toxicity.

Purpose/Objectives:

We summarize the safety and efficacy data from three gabapentinoid combinations: gabapentinoid + opioid; gabapentinoid + antidepressants; and gabapentinoid + topical lidocaine and evaluate the benefit risk from each combination.

Method:

Using a recently published systematic review (Balanaser M, et al. Pain 2022;00:1-22), we identified combination studies of neuropathic pain.  In addition, we reviewed publications of gabapentinoid + topical lidocaine (Rehm S, et al.  Curr Med Res Opin 2010;26(7):1607-1619 and White WT, et al. Pain Medicine 2003;4(4): 321-330).

Results:

Gabapentinoid + opioid: We reviewed 6 studies evaluating the combination of an opioid with a gabapentinoid (931 total participants).  Efficacy results were mixed in this combination. Combination therapy was shown to be superior to monotherapy in some studies, but not in all.  Significant AEs were noted with this combination treatment.  There were also higher rates of dropouts related to AEs in the combination arm compared to monotherapy. Gabapentinoid + antidepressant: We reviewed 3 studies evaluating the combination of gabapentinoid and antidepressant (472 participants).  Efficacy results were mixed in this combination, with combination therapy shown to be superior to monotherapy in some studies.  There were no differences in dropouts due to AEs between combination and monotherapy arms. Gabapentinoid + topical lidocaine: We reviewed 2 studies evaluating the combination of gabapentinoid and topical lidocaine (205 participants).  Combination therapy was shown to be efficacious in reducing pain from baseline; however, both studies were limited in that both were open-label. The incidence of treatment-related adverse events was low and typically mild to moderate in severity.

Conclusions: Achieving meaningful pain relief in patients suffering from neuropathic pain can be challenging. There are limited effective options available to treat neuropathic pain and the majority of them are administered systemically resulting in adverse events that primarily affect the CNS, leading to functional limitations and discontinuation of drugs. Combinations of two systemic agents (gabapentinoid + opioid, gabapentinoid + antidepressants) have resulted in significant AEs and dropouts in clinical studies. On the other hand, combinations of a systemic agent and a topical agent (gabapentinoid + topical lidocaine) can confer improved efficacy with minimal additional adverse effects.

Topical medications with minimal systemic AEs such as lidocaine patch, which has shown to be beneficial in many neuropathic pain conditions can be of benefit to achieve meaningful pain relief in more patients as adjuvant therapy.

References: Treede RD, et al. Neurology 2007, 70, 1630–1635
Afonso AS, et al. J Clin Med 2021;10:3533
Finnerup NB, et al. Pain 2018;159:2339-2346
Balanaser M, et al. Pain 2022;00:1-22
Rehm S, et al. Curr Med Res Opin 2010;26(7):1607-1619
White WT, et al. Pain Medicine 2003;4(4): 321-330