Emerging Therapeutic Modalities and Pharmacotherapies in Neuropathic Pain Management: A Systematic Review and Meta-Analysis of Parallel Randomized Controlled Trials

Abstract

Background: Neuropathic pain (NP) is a chronic condition caused by abnormal neuronal excitability in the nervous system. Current treatments for NP are often ineffective or poorly tolerated. Hence, we reviewed the efficacy and safety of novel drugs or devices that target neuronal excitability in NP patients compared with placebo, sham, or usual care interventions. Methods: Six databases were searched for parallel randomized controlled trials (RCTs) reporting novel devices (rTMS, SCS, and TENS) or drugs (EMA401, capsaicin 8% patch, and Sativex) for NP. Data were extracted and quality was assessed using the ROB2 tool. The random-effects inverse variance method was used for analysis. Results: In our review of 30 RCTs with 4251 participants, device-based interventions were found to be more effective in reducing pain scores than control interventions (SMD = -1.27, 95% CI: -1.92 to -0.62). However, high heterogeneity was seen (p < 0.01, I ² = 91%), attributable to the etiology of NP (R ² = 58.84%) and year of publication (R ² = 49.49%). Funding source and type of control comparator were ruled out as cause of heterogeneity. Although drug interventions did not differ from placebo interventions in absolute pain reduction (SMD = -1.21, 95% CI: -3.55 to 1.13), when comparing relative change in pain intensity from baseline, drug interventions were found to be effective (SMD = 0.29, 95% CI: 0.04-0.55). Asymmetry in the funnel plot was visualized, suggesting publication bias. Certainty of evidence was very low according to GRADE assessment. Conclusions: Our review indicates that device-based interventions are more effective than control interventions in reducing pain intensity in NP. Nevertheless, available evidence is limited due to heterogeneity and publication bias, prompting the need for more high-quality RCTs to confirm the efficacy and safety of these interventions.

Keywords: EMA401; Sativex; capsaicin; neuropathic pain; spinal cord stimulation; transcranial magnetic stimulation; transcutaneous electrical nerve stimulation.

Figure 1

PRISMA flowchart for the present review.

Figure 2

Risk of bias quality appraisal of the included publications according to the Cochrane ROB2 tool.

Figure 3

Comparison of the effectiveness of device and drug interventions for neuropathic pain (primary endpoint). The figure displays the SMD and 95% confidence intervals (CIs) of each study comparing an intervention with a comparator for reducing neuropathic pain. The zero line represents no effect of the intervention. The size of the blue squares reflects the study weight in the meta-analysis. The red diamonds show the pooled SMD and 95% CI for each intervention type. The red lines indicate the prediction intervals, which estimate the expected SMD and 95% CI for a new study within each intervention type.

Figure 4

Subgroup comparison of the effectiveness of different device types for neuropathic pain (primary endpoint). The figure displays the SMD and 95% confidence intervals (CIs) of each study that evaluated a device type (TENS, rTMS, and SCS) against a comparator for reducing neuropathic pain. The zero line represents no effect of the device type. The size of the blue squares reflects the study weight in the meta-analysis. The red diamonds show the pooled SMD and 95% CI for each device subtype. The red lines indicate the prediction intervals, which estimate the expected SMD and 95% CI for a new study within each device subtype.

Figure 5

Contour-enhanced funnel plots assessing publication bias in device intervention studies. Each round dot signifies an individual trial. (a) Standard funnel plot showing publication bias in 17 observations. (b) Contour-enhanced funnel plot for the 17 observations. (c) Trim-and-fill funnel plot illustrating bias after adding five hypothetical studies (white dots) to the original 17 observations (gray dots). (d) Limit meta-analysis funnel plot demonstrating increasing bias due to small-study effects as the standard error rises. The gray diamonds mark the adjusted average effect size when the standard error on the y-axis is zero.

Figure 6

Meta-analysis of the change from baseline in neuropathic pain, comparing the effects of drug interventions to placebo. The figure shows the standardized mean differences (SMDs) and their 95% confidence intervals (CIs) for each study, as well as the overall effect size under a random-effects model. The zero line represents no effect of the intervention. The dotted line that extends to the red diamond shows the position of the overall effect size on the x-axis. The size of the blue squares reflects the study weight in the meta-analysis. The red diamonds show the pooled SMD for each drug and its width depicts the 95% CI. The red lines indicate the prediction intervals, which estimate the expected SMD and 95% CI for a new study to the meta-analysis.

Figure 7

Forest plot of the risk ratio (RR) and 95% confidence interval (CI) for dizziness as an adverse event of drug and device interventions on neuropathic pain. The vertical line at RR = 1 represents no difference between the intervention and comparator groups. The size of the squares reflects the weight of each study in the meta-analysis. The horizontal lines represent the 95% CI for each study. The diamonds represent the pooled RR and 95% CI for each intervention type.

Figure 8

Forest plot of the risk ratio (RR) and 95% confidence interval (CI) for headache as an adverse event of drug and device interventions on neuropathic pain. The vertical line at RR = 1 represents no difference between the intervention and comparator groups. The size of the squares reflects the weight of each study in the meta-analysis. The horizontal lines represent the 95% CI for each study. The diamonds represent the pooled RR and 95% CI for each intervention type.

Figure 9

Forest plot of the risk ratio (RR) and 95% confidence interval (CI) for hypertension as an adverse event of drug interventions on neuropathic pain. The vertical line at RR = 1 represents no difference between the intervention and comparator groups. The size of the squares reflects the weight of each study in the meta-analysis. The horizontal lines represent the 95% CI for each study. The diamonds represent the pooled RR and 95% CI for each intervention type.

Figure 10

Forest plot of the risk ratio (RR) and 95% confidence interval (CI) for nausea as an adverse event of drug interventions on neuropathic pain. The vertical line at RR = 1 represents no difference between the intervention and comparator groups. The size of the squares reflects the weight of each study in the meta-analysis. The horizontal lines represent the 95% CI for each study. The diamonds represent the pooled RR and 95% CI for each intervention type.

Figure 11

Forest plot of the risk ratio (RR) and 95% confidence interval (CI) for diarrhea as an adverse event of drug interventions on neuropathic pain. The vertical line at RR = 1 represents no difference between the intervention and comparator groups. The size of the squares reflects the weight of each study in the meta-analysis. The horizontal lines represent the 95% CI for each study. The diamonds represent the pooled RR and 95% CI for each intervention type.

Figure 12

Forest plot of the risk ratio (RR) and 95% confidence interval (CI) for vomiting as an adverse event of drug interventions on neuropathic pain. The vertical line at RR = 1 represents no difference between the intervention and comparator groups. The size of the squares reflects the weight of each study in the meta-analysis. The horizontal lines represent the 95% CI for each study. The diamonds represent the pooled RR and 95% CI for each intervention type.