Effectiveness of Pulsed Electromagnetic Field Therapy on Neuropathic Pain: A Systematic Review and Meta-Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Effectiveness of pulsed electromagnetic field therapy on neuropathic pain: A systematic review and meta-analysis

Congratulations to the authors for the article, which we consider of interest to the scientific community. They have conducted an acceptable systematic review of PEMF in neuropathic pain, which had not been done to date. They have followed criteria of quality and rigour in the article, being cautious when presenting the results and conclusions drawn. The  article discusses the results of this treatment in neuropathic pain and breaks down the main differences depending on the frequency used or the type of neuropathic pain treated.

The following comments aim to clarify fundamental points and improve some important aspects of the work

Comments for author File: Comments.pdf

Author Response

We would like to express our sincere gratitude to the Reviewer for their thorough and insightful analysis of our manuscript. Your comments regarding the regulatory landscape, the methodological challenges of blinding, and the clinical nuances of neuropathic phenotypes have been instrumental in refining the quality and precision of this systematic review.

We have addressed each point below.

Point-by-point response:

 

Comment 1. Has PEMF been approved by the FDA or EMA? Please state this.

Response 1: We agree that stating the regulatory status provides essential context for the clinical applicability of the therapy. We have updated the Introduction to clarify that while agencies like the FDA have cleared specific PEMF devices for bone healing (non-union fractures) and post-operative edema, a dedicated approval specifically for "neuropathic pain" remains largely off-label or jurisdiction-dependent. We have included a recent reference (Flatscher et al., 2023) to document this regulatory distinction.

Change in manuscript (Introduction):

[…] From a regulatory perspective, these discrepancies are reflected in the current status of the technology; while the U.S. Food and Drug Administration (FDA) and European regulatory bodies have cleared specific PEMF devices for bone healing and post-operative pain or edema [18], their dedicated indication for neuropathic pain remains largely off-label or jurisdiction-dependent. This regulatory gap further emphasizes the necessity of a systematic synthesis to clarify the real clinical reach of the therapy. […]

 

Comment 2. ...and the difficulty in administering placebos with these devices.

Response 2: We appreciate the reviewer highlighting this critical methodological hurdle. We fully acknowledge that the physical nature of electromagnetic therapy (vibration, heat, or device interaction) makes creating a truly indistinguishable sham challenging, which can inadvertently unmask the active group. We have integrated this limitation into the Introduction, citing the relevant literature to explain how these sensory cues may compromise blinding.

Change in manuscript (Introduction):

[…] Furthermore, the technical challenge of administering a truly indistinguishable sham (placebo) is a recognized limitation in electromagnetic therapy trials; sensory or auditory cues can often compromise participant blinding, potentially inflating the placebo response [16, 21]. […]

 

Comment 3. Outcomes: The period of improvement in months or years has not been included.

Response 3: You raise a vital point regarding chronic pain management. Unfortunately, our systematic search revealed that the existing randomized controlled trials (RCTs) are limited to short- and medium-term interventions, with durations ranging from 10 days to a maximum of 18 weeks. No included study provided follow-up data extending into months or years. To address this, we have added a specific paragraph in the Limitations (Section 4.5) explicitly noting this duration gap.

Change in manuscript (Section 4.5. Limitations):

[…] A significant limitation of the current body of evidence is the lack of long-term follow-up data. The RCTs included in this synthesis primarily focused on immediate post-intervention outcomes, with treatment periods ranging from 10 days to 18 weeks. Consequently, there is a lack of evidence regarding the sustainability of the analgesic effect over several months or years. This duration gap represents a critical area for future research, as chronic neuropathic pain requires interventions with demonstrated long-term durability. […]

 

Comment 4. Interesting to know what previous analgesic medication they were on and whether these treatments were discontinued before the PEMF or administered concurrently with the study treatment.

Response 4: This is a pertinent clinical inquiry. In the studies we analyzed, PEMF was primarily evaluated as an adjunctive (add-on) therapy. While the protocols generally followed a "Treatment as Usual" (TAU) design—meaning participants continued their baseline analgesics—we found that the specific details regarding stabilization periods or discontinuation were not consistently reported across all trials. We have added a clarifying statement in Section 3.6 (Adjuvant Effectiveness) to be transparent about this limitation.

Change in manuscript (Section 3.6. Adjuvant Effectiveness and Safety):

[…] It is important to note that while these studies employed a TAU design, implying the continuation of baseline analgesics, the specific protocols regarding medication stabilization or discontinuation were not consistently detailed across all included trials. This lack of granular reporting limits the precision with which the add-on effect can be strictly isolated from potential pharmacological interactions. […]

 

Comment 5. We are also limited by the short period of time that patients have been treated with PEMF. In chronic pain, it is essential that devices be tested for more than one year.

Another important limitation when it comes to neuropathic pain is that it is not only the intensity or relief of pain that is assessed, but also the different specific symptoms of neuropathic pain: allodynia, hyperalgesia, paraesthesia, etc. It is important to be able to classify PEMF into one of the different neuropathic pain profiles, depending on the symptoms that can be best alleviated.

Response 5: We strongly concur with both observations. The lack of long-term data and the generic assessment of pain are indeed major barriers to precision medicine in this field. As mentioned in Comment 3, we have acknowledged the lack of long-term follow-up. Furthermore, regarding symptoms, we have expanded the Limitations (Section 4.5) to highlight that future research must move beyond global scales (VAS/NRS) and adopt phenotype-specific tools to determine if PEMF is differentially effective against specific mechanisms.

Change in Manuscript (Section 4.5. Limitations):

[…] Similarly, strict phenotypic characterization remains an unmet need in the field. The majority of included trials relied on global pain intensity scales (e.g., VAS, NRS) without stratifying outcomes by specific neuropathic symptoms. Consequently, it remains unclear whether PEMF is differentially effective against distinct sensory profiles, such as mechanical allodynia, thermal hyperalgesia, or paresthesia, which is information vital for phenotypic-based treatment selection. […]

 

Comment 6. A cost-benefit study is important... as self-application is not possible. However, it could be considered as an option for the future.

Response 6: We appreciate this forward-looking comment. We agree that cost-effectiveness is the next frontier for implementation. Inspired by your suggestion, we have added a paragraph in the Discussion (Section 4.3) regarding the future of technology. We respectfully note that the field is rapidly evolving towards miniaturized, wearable devices that do allow for safe home-based self-administration, which will be key for cost-efficiency.

Change in manuscript (Section 4.3. Secondary Outcomes and Implementation):

[…] Finally, regarding implementation, future research must address the cost-effectiveness of PEMF therapy. While traditional high-power systems often require professional administration in clinical settings, the rapid development of portable, user-friendly wearable devices is shifting the paradigm towards home-based self-administration. Validating the efficacy of these home-use systems will be crucial for reducing healthcare costs and improving accessibility for chronic pain patients. […]

Reviewer 2 Report

Comments and Suggestions for Authors

Despite its methodological accuracy, meta-analysis doesn't completely solve the fundamental problems of primary research:

1) Heterogeneity indicates the degree of inconsistency in the results of the included studies. The statistical indicator I² = 92.8% indicates extremely high heterogeneity, differences in effects between studies are caused not by random variation but by systematic factors. The analysis includes patients with different diagnoses (diabetic polyneuropathy, carpal tunnel syndrome, cervical radiculopathy, disc herniation pain). The pathophysiology, prognosis, and response to treatment for these conditions can vary significantly. In addition, there is methodological diversity (technical parameters of PEMF): the frequency varies from extremely low values (ELF, <100 Hz) to radio frequencies (27.12 MHz); magnetic induction also varies widely, treatment duration varies from 10 min to 2 h per session, and the total course varies from 10 days to 18 weeks; there are also differences in the types of coils and how they are applied (local vs. more general). Finally, the quality of blinding and the realism of sham devices could vary significantly between studies, affecting the magnitude of the placebo effect. High heterogeneity means that it is incorrect to calculate a single “average” effect (SMD: -1.01). This indicator masks fundamentally different response patterns in different patient subgroups. Doctors cannot use the overall result to make decisions, as it does not reflect whether PEMF will work for a specific patient with a specific diagnosis and specific treatment parameters. The random effects model used by the authors takes this heterogeneity into account but does not eliminate it. The wide prognostic interval (-4.26 to 2.25), which crosses zero, clearly indicates that in future studies, the effect of PEMF could be strongly positive, negative, or zero. It is precisely because of this high heterogeneity (combined with other factors) that the authors downgraded the quality of evidence on the GRADE scale to “low.” This means that further studies are likely to change the assessment of the effect.

2) As a rule, studies with “statistically significant” positive results are published more often, faster, and in more prestigious journals than studies with zero or negative results. 

The graph (Fig. 6A) shows a “gap” in the lower left corner for small studies with zero or negative effects.

Egger's test showed statistically significant asymmetry (p < 0.05).

After statistical correction, which simulates the addition of “missing” studies, the overall effect of PEMF ceased to be statistically significant (adjusted SMD: -0.35; 95% CI: -1.51 to 0.82).

The main conclusion of the meta-analysis turns out to be unstable. Most importantly, the “significant overall reduction in pain” (p=0.03) disappears after taking into account potentially unpublished data. This means that the claimed effectiveness of PEMF may be an artifact of the publication system rather than a true biological effect. It is likely that published studies show a greater effect than the average of all studies performed. This misleads clinicians and scientists about the real benefits of the intervention. The presence of significant publication bias indicates that the literature on PEMF and neuropathic pain is incomplete and systematically biased. Any conclusions drawn from it require extremely cautious interpretation. The authors rightly note that interventions using devices often cause a stronger placebo effect due to the complexity and “technological” nature of the procedure. Unpublished zero studies may have been better at controlling or measuring this effect. Their absence from the analysis may lead us to mistake an enhanced placebo response for a specific effect of PEMF.

Therefore, the article does not provide a definitive answer to the question “Does PEMF work for neuropathic pain?” Instead, it:

1. Demonstrates that the evidence base is highly fragmented and likely biased toward optimism.
2. Suggests that the effect may be significant for a subgroup with spinal/radicular pain.
3. Clearly indicates directions for improvement: future RCTs should use standardized high-frequency protocols, strictly stratify patients by etiology, and be sure to publish all results, including zero results.

Thus, the main value of this work lies not in its final verdict but in its high-quality diagnosis of problems in the entire field of PEMF research and in providing a methodological guideline for future work.

The structure and focus of the “Abstract” and ‘Conclusions’ need to be radically revised. In the abstract, it is better to start with the key conclusion right away: "The meta-analysis revealed significant heterogeneity and publication bias in the evidence base for PEMF. After accounting for these, the significant overall effect disappears, but subgroup analysis indicates a potentially large and clinically important effect for spinal/radicular pain, as opposed to peripheral neuropathy."

In the conclusions, focus should be placed not on “significance” but on diagnosing problems and developing a roadmap. The focus should be, first, to state that the existing evidence is highly fragmented and likely biased due to publication bias. These problems prevent us from drawing a clear conclusion about the overall effectiveness of PEMF, but they clearly signal the critical importance of pain etiology for treatment response. Emphasize that future studies should abandon a universal approach and become targeted: select patients with spinal/focal neuropathic pain; use high-frequency/PRF protocols; register studies in advance and publish all results to combat bias.

It is also necessary to strengthen the “Discussion” section by adding the following sections: 

1) Create a separate subsection that honestly explains what I² > 90% and a positive Egger test mean. Explain that the main result of this meta-analysis is not a specific SMD figure, but a demonstration of data inconsistency. This is not a weakness of the work, but its main discovery about the state of science in this field.

2) Justify that despite the overall heterogeneity, the difference found between the subgroups (spinal vs. peripheral) is a biologically and clinically plausible signal that is resistant to parameter variations.

3) Specifically propose the standardization of parameters - “candidates” for standard protocols based on trends in the analysis.

4) Insist on separate sets of patients with focal (radiculopathy, mononeuropathy) and diffuse (polyneuropathy) neuropathy.

5) Provide recommendations for improving the design of sham devices for similar interventions.

Author Response

We would like to express our sincere appreciation to the Reviewer for their exceptionally thorough and insightful critique. The Reviewer has accurately identified the core challenge of this field: the tension between methodological rigor in synthesis and the inherent messiness of the primary data.

We fully agree with the assessment that the value of this work lies in its diagnosis of the field rather than a simplistic endorsement of efficacy. We have embraced this perspective, moving away from a binary it works conclusion to a more nuanced roadmap that highlights the critical divergence between spinal and peripheral etiologies. We believe these changes have significantly strengthened the manuscript.

 

Point-by-point response:

 

Comment 1. Heterogeneity indicates the degree of inconsistency in the results of the included studies. The statistical indicator I² = 92.8% indicates extremely high heterogeneity… High heterogeneity means that it is incorrect to calculate a single “average” effect (SMD: -1.01). This indicator masks fundamentally different response patterns in different patient subgroups.

Response 1: We fully concur with the reviewer. The extreme heterogeneity (I² = 92.8%) is indeed the most important signal in the data, indicating that "neuropathic pain" is too broad a label to be treated as a monolithic entity. We agree that the global SMD of -1.01 is descriptive of the dataset but not prescriptive for individual clinical decision-making. To address this, we have added a dedicated subsection in the Discussion interpreting this heterogeneity not as statistical noise, but as a diagnostic finding of etiological divergence. We also updated the Results to explicitly mention the prediction interval and its implications for uncertainty.

Change in manuscript (Discussion - Section 4.1):

4.1. Interpreting the Heterogeneity: A Diagnostic Finding

A defining feature of this meta-analysis is the extreme statistical heterogeneity (I² = 92.8%) observed in the global comparison [16, 21]. While high heterogeneity is often viewed merely as a statistical limitation stemming from differences in stimulation parameters [9], we interpret this value as a structural diagnostic signal indicating that neuropathic pain is too broad a category to be treated as a monolithic entity in PEMF research. The variance in effect sizes is not attributable to random sampling error but is driven by systematic biological factors. Our analysis suggests that this heterogeneity is etiologically driven. The statistical "noise" in the global dataset resolves into a clear, coherent signal when stratified by lesion location. [...] Therefore, the high I² should be interpreted clinically as evidence of divergent response patterns: PEMF is not a generic analgesic for all neuropathy, but likely a specific intervention for focal, proximal lesions.

 

Comment 2. As a rule, studies with “statistically significant” positive results are published more often… The main conclusion of the meta-analysis turns out to be unstable. Most importantly, the “significant overall reduction in pain” (p=0.03) disappears after taking into account potentially unpublished data.

Response 2: This is a critical observation. We acknowledge that the disappearance of statistical significance after the Trim-and-Fill correction is a crucial finding that challenges the validity of a "general" recommendation. In response, we have added a specific subsection in the Discussion titled "The Illusion of Efficacy" to honestly address this instability. We explain that the published literature likely overestimates the true therapeutic benefit due to the "file drawer problem" and advise caution in interpreting global averages.

Change in manuscript (Discussion - Section 4.2):

4.2. The Illusion of Efficacy: Publication Bias and Stability

A major concern identified in this analysis is the presence of significant publication bias, confirmed by the asymmetry of the funnel plot and a positive Egger’s regression test (p < 0.05). [...] The implications of this bias are profound for the interpretation of our results. While our primary unadjusted analysis showed a significant pain reduction, the application of the Trim-and-Fill method, which simulates the inclusion of these missing negative studies, reduced the global effect size to non-significance (Adjusted SMD: -0.35). Clinically, this indicates that the "overall" effectiveness of PEMF reported in the broader literature is likely inflated. [...] This instability reinforces our conclusion that relying on global averages is misleading, and clinical utility is likely restricted to the specific, robust responders identified in the spinal subgroup...

 

Comment 3. The structure and focus of the “Abstract” and ‘Conclusions’ need to be radically revised. In the abstract, it is better to start with the key conclusion right away: "The meta-analysis revealed significant heterogeneity and publication bias..."

Response 3: We have accepted this suggestion entirely. It transforms the paper from a potentially biased efficacy claim into a rigorous methodological critique. We have rewritten the Abstract and Conclusions to mirror the reviewer's suggested flow: acknowledging the heterogeneity and bias first, and then highlighting the spinal subgroup as the area of genuine potential.

Change in manuscript (Abstract):

Results: Thirteen RCTs met the inclusion criteria (N = 688). While global analysis indicated a statistically significant pain reduction (SMD: -1.01; p = 0.03), it exhibited extreme statistical heterogeneity (I² = 92.8%) and instability. After adjusting for missing studies using the Trim-and-Fill method, global significance disappeared. However, subgroup analysis resolved this inconsistency, revealing a massive, clinically meaningful effect in Spinal/Radicular pain (SMD: -2.35; 95% CI: -4.42 to -0.29), whereas Peripheral Neuropathy showed no significant reduction (SMD: -0.38; 95% CI: -0.86 to 0.10).

Conclusions: The PEMF evidence base for neuropathic pain is currently highly fragmented. Extreme heterogeneity and publication bias render "one-size-fits-all" efficacy estimates invalid and potentially misleading. Instead, our data reveals a critical etiological divergence: PEMF appears highly effective for spinal/radicular pathology, likely due to the mechanical nature of the lesion, but demonstrates limited efficacy for diffuse peripheral neuropathy. Future research must abandon generic protocols in favor of etiology-specific trials, prioritizing high-frequency parameters and rigorous bias control.

Change in manuscript (Conclusions):

[...] The most clinically relevant discovery is the profound divergence in therapeutic response based on etiology. PEMF exhibited a massive analgesic effect in spinal and radicular pain, likely exceeding the Minimal Clinically Important Difference, whereas its efficacy in peripheral neuropathy was modest and statistically non-significant. [...]

 

Comment 4. It is also necessary to strengthen the “Discussion” section by adding the following sections: 1) Explain I²... 2) Justify biological plausibility... 3) Specifically propose standardization of parameters... 4) Insist on separate sets of patients... 5) Recommendations for sham devices.

Response 4: We have incorporated all these valuable suggestions. We created a "Roadmap" section in the Discussion to guide future research.

• Regarding Biological Plausibility: We expanded the discussion to contrast the focal/mechanical nature of spinal pain with the metabolic/diffuse nature of diabetic neuropathy (Section 4.1).
• Regarding Standardization & Design: We added Section 4.4 to explicitly recommend High-Frequency protocols, strict cohort separation, and sensory-matched active shams.

Change in manuscript (Discussion - Section 4.4):

4.4. Roadmap for Future Research: Standardization and Design

To advance the field beyond its current fragmented state and address the methodological flaws identified above, future clinical trials must abandon the trial-and-error approach and adopt a rigorous, standardized methodology. Based on the trends identified in this analysis, we propose the following guidelines for future investigation:

Parameter standardization (The High-Frequency shift): Researchers should prioritize High-Frequency or PRF parameters (>1 kHz) rather than generic ELF stimulation. [...]

Strict cohort separation: The practice of pooling heterogeneous "neuropathic pain" patients must end. Future trials should be designed to exclusively recruit either Focal/Compressive phenotypes (e.g., radiculopathy, mononeuropathy) or diffuse/metabolic phenotypes (e.g., diabetic polyneuropathy). [...]

Enhanced sham design: Device-based interventions are prone to high placebo response rates due to the sophisticated nature of the treatment ritual. Extensive interaction with medical technology may amplify patient expectations compared to pharmacological trials, contributing to the asymmetry observed in the funnel plot and making the detection of specific therapeutic effects more challenging [47]. Simple "device off" shams are no longer sufficient... Future studies should employ sensory-matched active shams... to ensure effective blinding and isolate the true electromagnetic effect from the ritual of therapy.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have taken into account all the critical comments and now the manuscript can be accepted for publication. Thanks to the authors for the revision of the manuscript.