Diabetic peripheral neuropathy and neuromodulation techniques: a systematic review of progress and prospects

Abstract

Neuromodulation for diabetic peripheral neuropathy represents a significant area of interest in the management of chronic pain associated with this condition. Diabetic peripheral neuropathy, a common complication of diabetes, is characterized by nerve damage due to high blood sugar levels that lead to symptoms, such as pain, tingling, and numbness, primarily in the hands and feet. The aim of this systematic review was to evaluate the efficacy of neuromodulatory techniques as potential therapeutic interventions for patients with diabetic peripheral neuropathy, while also examining recent developments in this domain. The investigation encompassed an array of neuromodulation methods, including frequency rhythmic electrical modulated systems, dorsal root ganglion stimulation, and spinal cord stimulation. This systematic review suggests that neuromodulatory techniques may be useful in the treatment of diabetic peripheral neuropathy. Understanding the advantages of these treatments will enable physicians and other healthcare providers to offer additional options for patients with symptoms refractory to standard pharmacologic treatments. Through these efforts, we may improve quality of life and increase functional capacity in patients suffering from complications related to diabetic neuropathy.

Introduction

Diabetes poses a major healthcare challenge, with its global prevalence escalating rapidly (GBD 2021 Diabetes Collaborators, 2023; Arshad et al., 2024; Chillo et al., 2024; Mittal et al., 2024a; Núñez-Baila et al., 2024). In 2009, it was estimated that around 285 million individuals were living with diabetes worldwide (Saeedi et al., 2019). By 2019, this number had risen to 463 million, accounting for approximately 9.3% of the world’s population (Hyun et al., 2021). Projections indicate a further increase to 578 million by 2030 and possibly over 700 million by 2045 worldwide. Alarmingly, half of those with diabetes (50.1%) are unaware of their condition (Saeedi et al., 2019). Diabetes is associated with various comorbidities (Geng et al., 2023; Lu et al., 2023; Meir et al., 2024). One of the most frequent complications of diabetes is diabetic peripheral neuropathy (DPN) (Anandhanarayanan et al., 2022; D’Souza et al., 2022; Roikjer and Ejskjaer, 2022; Smith et al., 2022; Elafros and Callaghan, 2023; Jadhao et al., 2024; Mekuria Negussie and Tilahun Bekele, 2024). DPN is characterized by a range of symptoms primarily affecting the limbs (Figure 1; Røikjer et al., 2022; Bodman and Varacallo, 2024; Zhu et al., 2024). Patients often experience a tingling sensation, numbness, or burning pain, particularly in their feet and hands (Dillon et al., 2024). These sensations can start off mild and gradually worsen over time. In some cases, individuals may report sharp pains or cramps, and increased sensitivity to touch. As the condition progresses, it can lead to a loss of feeling in the affected areas, which poses a risk of unnoticed injuries (Zhu et al., 2024). Additionally, muscle weakness and coordination problems may occur, making it difficult to perform certain tasks (Chang and Yang, 2023). In severe cases, diabetic peripheral neuropathy can also cause changes in foot shape, leading to joint and bone disorders (Selvarajah et al., 2019; Galiero et al., 2023; Figure 1). It is important to recognize that the severity and impact of these symptoms can differ greatly among individuals.

Figure 1.

A comprehensive overview of the common symptoms associated with diabetic peripheral neuropathy.

Key symptoms depicted include pain, tingling, and numbness, primarily affecting the extremities such as the feet and hands. The figure also highlights other less common but significant symptoms such as muscle weakness, loss of balance, and sensitivity to touch. Created with BioRender.com.

Distal symmetric polyneuropathy (DSPN) is the most common type of DPN observed in individuals with diabetes (Callaghan et al., 2020; Vági et al., 2023). DSPN affects roughly 50% of individuals with type 2 diabetes (T2D) within 10 years (Newlin et al., 2022; Smith et al., 2022), and over 20% of those with type 1 diabetes (T1D) after 20 years (Martin et al., 2014). Notably, 10%–25% of people newly diagnosed with T2D already show signs of DSPN (Kisozi et al., 2017; Gylfadottir et al., 2020). DSPN typically manifests as a “glove-and-sock” sensation in the hands and feet, but in severe cases, it can coincide with peripheral vascular disease (Chang and Yang, 2023; Eid et al., 2023; Galiero et al., 2023). This can lead to additional serious problems such as diabetic foot ulcers, which may escalate to gangrene or amputation (Jeyam et al., 2020; Wukich et al., 2022; Deng et al., 2023; McDermott et al., 2023; Murphy-Lavoie et al., 2023; Russo et al., 2023;).

A significant challenge in managing DPN is due to the limited efficacy of current therapeutic strategies (Jensen et al., 2021; Hagedorn et al., 2022; Rafiullah and Siddiqui, 2022; Shinu et al., 2022; Sloan et al., 2022). A previous study indicates that while glycemic control plays a role in modulating DPN progression in T1D, its relationship with DPN in T2D is more intricate and not as straightforward (Callaghan et al., 2012). The current pharmacological interventions primarily target symptom management, as no current drugs have been shown to fundamentally alter the underlying pathophysiology of DPN (Preston et al., 2023). Furthermore, there is evidence of frequent discontinuation of initial pharmacological treatments, possibly indicating inadequate efficacy or patient dissatisfaction (Yang et al., 2015).

Consequently, there is growing interest in exploring non-pharmacological approaches, such as neuromodulation, for the treatment of neuropathic pain associated with DPN (Jones et al., 2016; Snyder et al., 2016; Wang and Chen, 2019; Staudt et al., 2022; Basem et al., 2023; Burkey et al., 2023; Zheng et al., 2023). Neuromodulation is defined as medical technologies that temporarily augment or inhibit neural activity with the ultimate goal of disease treatment (Legon et al., 2018; Brinker et al., 2020; Reznik et al., 2020; Arulpragasam et al., 2022; Rajabalee et al., 2022). This field encompasses both implantable and non-implantable devices that deliver electrical, chemical, or other forms of intervention (Gupta et al., 2021; Armstrong and Grunberger, 2023; Jang and Oh, 2023). The most common neuromodulation therapies for DPN include spinal cord stimulation, frequency rhythmic electrical modulated systems, and dorsal root ganglia stimulation (Yeung et al., 2024a, b). These modalities offer promising alternative pathways for addressing the complex challenges of DPN management.

Since its inception in 1967 by physicians at Case Western, who were the first to apply tonic spinal cord stimulation (SCS) for unmanageable cancer pain (Shealy et al., 1967), the understanding and application of SCS have evolved. Initially, it was believed that tonic SCS worked by electrically stimulating amyloid-β fibers in the dorsal columns to inhibit pain signals carried by smaller Aδ and C fibers in the dorsal horn (Vallejo et al., 2017; Joosten and Franken, 2020). Subsequent research revealed that stimulating these amyloid-β fibers also induced paresthesia in their innervation zones. This discovery became instrumental during SCS lead implantation, allowing physicians to align the paresthesia with the patient’s pain area (Barolat et al., 1993; Joosten and Franken, 2020).

Despite years of advancement in tonic SCS, its efficacy remains limited, providing over 50% pain relief in only 50%–70% of patients (de Vos et al., 2014; Joosten and Franken, 2020). This limitation has spurred the development of alternative SCS methods, notably high-frequency SCS and burst SCS (Edinoff et al., 2022; London and Mogilner, 2022; Tapia Perez, 2022). These newer approaches are less well-understood than traditional tonic SCS and are distinct in that they do not produce paresthesia, as they operate below the sensory threshold (Joosten and Franken, 2020). All three forms of SCS, despite their differences, have received Food and Drug Administration approval for treating various conditions, including neuropathic pain, complex regional pain syndrome, failed back surgery syndrome, and intractable low back or leg pain (Rock et al., 2019; Schmidt, 2019; Heijmans and Joosten, 2020; Ferraro et al., 2022; Kurt et al., 2022; Strand Burkey, 2022; Petersen, 2023; Traeger et al., 2023).

The frequency rhythmic electrical modulated system (FREMS) represents an advanced transcutaneous therapeutic modality, utilizing frequency-modulated electromagnetic neural stimulation (Crasto et al., 2022; Gorczyca-Siudak and Dziemidok, 2022; Contardi et al., 2023; Imholz et al., 2023). This technique delivers short bursts of high-intensity, biphasic electrical stimuli, characterized by variable frequencies, pulse durations, and amplitudes. The primary objective of FREMS is to facilitate the maintenance of electrical homeostasis in tissues (Barrella et al., 2006). Beyond its fundamental mechanism, alternative hypotheses propose that FREMS may contribute to the liberation of vascular growth factors (Bevilacqua et al., 2007), augmentation of microvascular blood flow (Conti et al., 2008), and enhancement of oxygen delivery to neuronal cells, thereby mitigating pain (Hange et al., 2022). Despite its potential, the research surrounding FREMS is relatively constrained, possibly due to the high costs associated with the treatment (Hange et al., 2022).

Since its introduction in 2013, dorsal root ganglia stimulation (DRGS) has emerged as an effective therapeutic intervention for various neuropathic pain conditions, including chemotherapy-induced neuropathy, discogenic lower back pain, chronic regional pain syndromes, postamputation pain, and diabetic peripheral neuropathy (Joosten and Franken, 2020; Grabnar and Kim, 2021; Ege et al., 2023; Koetsier et al., 2023). Although initially presumed to share a similar mechanism with tonic SCS, subsequent research indicates that DRGS may exert its effects independently of gamma-aminobutyric acid (GABA) release. Instead, it is postulated that DRGS predominantly dampens the excitability of slow-conducting, nociceptive C-fibers (Koopmeiners et al., 2013; Kent et al., 2018; Koetsier et al., 2020). Conversely, a study in 2017 posited that dorsal root ganglia are involved in GABA synthesis and release, suggesting a potential role for GABA in DRG depolarization (Du et al., 2017). These findings highlight the necessity for further investigation to comprehensively elucidate the underlying mechanisms by which DRGS modulates neuropathic pain.

The objective of this systematic review article is to critically appraise the current literature to better understand the efficacy of these therapies in the treatment of diabetic peripheral neuropathy. The review seeks to highlight the strengths and limitations of the current research landscape, identify potential gaps in knowledge, and suggest directions for future studies.

Methods

Search strategy and selection criteria

This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al., 2021) and was further enhanced by following the recommendations provided in the Cochrane Collaboration Handbook. A protocol for this systematic review was designed a priori and was registered in the PROSPERO database (registration number: CRD42023490688). As narrative or systematic review articles were available covering studies up to 2017, searches were performed between January 1, 2018 and October 1, 2023 in the following databases: PubMed (MEDLINE), Science Direct, Scopus, and EMBASE databases using the following MeSH terms: (“Neuromodulation”[Mesh]) AND (“Diabetic Neuropathy”[Mesh]); (“Pain Management”[MeSH]) AND (“Diabetes Complications”[MeSH]); (“Electrical Stimulation Therapy”[MeSH]) AND (“Diabetic Neuropathies”[MeSH]) where MeSH search was not available the following Boolean terms were used (“Neuromodulation”) AND (“Diabetic Neuropathy”); (“Pain Management”) AND (“Diabetes Complications”); (“Electrical Stimulation Therapy”) AND (“Diabetic Neuropathies”).

Study selection

All studies with a confirmed diagnosis of T1D or T2D in human subjects with a confirmed diagnosis of neuropathy using well-established measures such as reduced vibration sensation to tuning fork, abnormal pressure sensation on monofilament testing, reduced reflexes, and decreased pinprick sensation were included. Studies were excluded based on the following exclusion criteria: studies with no confirmed diagnosis of T1D or T2D, diabetes-induced animal models, review articles, meta-analyses, abstracts only, conference proceedings, editorials/letters, case reports, or articles published before January 1, 2018. Additionally, studies performed in vitro, or ex vivo were excluded. All searched titles, abstracts, and full-text articles were independently reviewed by at least two trained reviewers (KM, GK, EM, and RM). Disagreements on inclusion and exclusion were resolved by consensus among the reviewers or through discussions with other researchers involved in this study. Articles were initially screened based on title and abstract before proceeding to full-text analysis.

Data extraction

The data were extracted by at least two trained reviewers (the authors KM, GK, EM, and RM). Results were grouped based on the neuromodulation technique.

Quality assessment

The Joanna Briggs Institute (JBI) Critical Appraisal Tools for randomized controlled trials (RCTs) and case series were used to perform a quality assessment on eligible studies (Munn et al., 2020; Barker et al., 2023; Mittal et al., 2024; Tolstrup et al., 2024). For the RCTs, 13 questions were evaluated: (1) was true randomization used for assignment of participants to treatment groups; (2) was allocation to groups concealed; (3) were treatment groups similar at baseline; (4) were participants blind to treatment assignment; (5) were those delivering the treatment blind to treatment assignment; (6) were treatment groups treated identically other than the intervention of interest; (7) were outcome assessors blind to treatment assignment; (8) were outcomes measured in the same way for treatment groups; (9) were outcomes measured in a reliable way; (10) was follow up complete and, if not, were the differences between groups adequately described; (11) were participants analyzed in the group to which they were randomized; (12) were appropriate statistical analyses used; and (13) was the trial design appropriate and any deviations accounted for in the analysis. For the case series, ten questions were evaluated: (1) were there clear criteria for inclusion; (2) was the condition measured in a standard/reliable way for all participants; (3) were valid methods used for identification of the condition for all participants included; (4) did the case series have consecutive inclusion of participants; (5) did the case series have complete inclusion of participants; (6) was there clear reporting of the demographics of the participants; (7) was there clear reporting of clinical information of the participants; (8) were the outcome or follow up results of cases clearly reported; (9) was there clear reporting of the presenting site(s)/clinic(s) demographic information; and (10) was statistical analysis appropriate. The questions were answered using “Yes,” “No,” and “Unclear.” At least two reviewers independently conducted this assessment (the authors KM, GK, EM, and RM) and any disagreements were resolved by consensus between the reviewers or discussion with other investigators of this study.

Results

A total of 534 studies were retrieved using the predefined search algorithm as described in the Methods section. After removing duplicates, 505 studies were included for title and abstract screening. After screening, 424 studies were excluded based on irrelevance and 81 articles were included for whole-text analysis. A total of 69 articles were then excluded as 22 did not discuss a treatment, 34 did not discuss diabetic neuropathy, 11 were performed on diabetes-induced animal models, 1 was an incomplete study, and 1 was performed in vitro. Finally, 12 articles remained for inclusion in the literature review and qualitative analysis.

A total of 12 articles were included in this systematic review. Across the 12 articles included in the analysis, 822 human subjects were collectively evaluated. Out of these studies, 3 evaluated frequency rhythmic electrical modulated system (FREMS), 2 evaluated DRGS, 4 evaluated SCS, and 3 evaluated other unique techniques. Most of the studies were RCTs where subjects had a diagnosis of diabetes mellitus, or were diabetes-induced, and were randomized to receive neuromodulatory treatment. A few studies were case series. The search strategy employed for the studies included is shown in the PRISMA diagram in Figure 2. Risk of bias for RCT and case series is outlined in Figures 3 and 4, respectively. It was observed that 8 of the 12 studies have a low risk of bias, 4 a moderate risk of bias, and 0 a high risk of bias. Bias was mostly introduced in these studies due to a lack of appropriate information on randomization and blinding. Overall, however, the studies were determined to be of appropriate quality to be included in the review. A summary of each study design, patient grouping, and included results is presented in Additional Table 1.

Figure 2.

A PRISMA (preferred reporting items for systematic reviews and meta-analyses) flow diagram, illustrating the process of literature selection and inclusion in this systematic review.

Figure 3.

Risk of bias for randomized clinical trials.

This figure provides a detailed visual representation of the risk of bias analysis for randomized clinical trials. Color coding is used to easily distinguish between the levels of risk, enhancing the readability and interpretation of the data. Created using the Robvis visualization tool.

Figure 4.

Risk of bias for case control series.

This figure provides a detailed visual representation of the risk of bias analysis for case-control studies. Color coding is used to easily distinguish between the levels of risk, enhancing the readability and interpretation of the data. Created using the Robvis visualization tool.

Additional Table 1.

A comprehensive summary of all the studies included in this systematic review

Reference	Study	Population	Exposure	Comparison	Outcomes
Crasto et al., 2022	Randomized controlled trial	25 participants aged 18-75 years with inadequately controlled painful diabetic peripheral neuropathy from either type 1 or type 2 diabetes	12 weeks of Frequency Rhythmic Electrical Modulated System (FREMS) + usual care (n = 13)	12 weeks of usual care (n = 12)	• Reduction in perceived pain (median = -4 on a scale from 0-10), not significant between groups [r = - 0.34, P = 0.087]. • Significant decrease in sensory and affective questionnaire SF-MPQ [r = -0.58, P = 0.042]. • Significant decrease in neuropathic pain questionnaire DN4 [r = -0.58, P = 0.042]. • Significant increase in a number of participants who experienced a greater than a 30% reduction in pain perception (P = 0.042).
Gorczyca- Siudak and Dziemidok, 2022	Randomized controlled trial	44 participants aged 18 or older with symptomatic diabetic polyneuropathy from either type 1 or type 2 diabetes	5 days of IV alpha- lipoic acid + FREMS (n = 24)	5 days of IV alpha- lipoic acid + sham treatment (n = 20)	• Significant reduction in pain perception utilizing the visual analog scale (VAS) across both groups at the end of the 5 days (P < 0.001). • No statistically significant difference in VAS scores between the groups at the end of the 5 days. • Significant difference in VAS scores between the groups 8 weeks after treatment completed, with FREMS treatment group having a larger reduction in perceived pain (P < 0.05). • No statistically significant difference in Clinical Global Improvement (CGI) ratings between the groups at the end ofthe 5 days. • Significant difference in CGI ratings between the groups 8 weeks after treatment completed, with FREMS treatment group having a larger reduction in perceived pain (P < 0.05).
Imholz et al., 2023	Case series	248 participants with a diagnosis of painful diabetic peripheral neuropathy that was refractory to 2 different pharmacologic therapies	5 sessions of FREMS per week for 2 weeks, repeated every 4 months for 12 months	Baseline scores of both the neuropathic pain symptom inventory (NPSI) and quality of life (QOL) via EQ-5D.	• Significant reduction in pain scores via the NSPI at 1, 3, and 12 months (P < 0.001). • A clinically relevant (defined as 33.3%) decrease in pain found in 44.8% of participants at 1 month and 49.6% at 3 months. • Significant improvement in quality of life at 1 and 3 months (P < 0.001). • Decrease in self-reported use of medication throughout treatment.
Eldabe et al., 2018	Case series	10 male participants with painful diabetic peripheral neuropathy	Dorsal Root Ganglion Stimulation at L2-L5 levels for 12 months (n = 5)	Baseline scores of the visual analog scale (VAS)	• Statistically significant reduction in VAS at 12 months compared to post-implantation (P < 0.001).
Falowski et al., 2019	Case series	8 participants with symptomatic peripheral neuropathy in the lower extremities with a successful response to previous dorsal root ganglion stimulation trial between L4-S1 spinal levels	Dorsal Root Ganglion Stimulation for 6 weeks	Baseline scores of the visual analog scale (VAS)	• Statistically significant reduction in VAS ratings from 7.4 at baseline to 1.5 at the 6 week follow-up.
Kissoon et al., 2023	Case series	9 participants aged 18 or older with type 2 diabetes, lower extremity neuropathic pain for > 1 year, and failed medication management.	12 months of treatment with implanted high- frequency spinal cord stimulation	Baseline scores at the time of implantation	• Statistically significant improvement in VAS ratings (P < 0.001), Oswestry Disability Index (P = 0.026), Neuropathy Symptoms and Change total severity (P = 0.006), and Neuropathy Impairment Score (P = 0.016).
Petersen et al., 2021	Randomized controlled trial	216 adult participants with painful diabetic peripheral neuropathy refractory to gabapentin/pregabalin and at least 1 other analgesic for 1 year	Conventional medical management (CMM) plus 10 kHz spinal cord stimulation (SCS) for 6 months	Conventional medical management for 6 months	• Significantly more participants in the CMM + SCS group achieved 50% pain relief via VAS (P < 0.001). • Significantly fewer participants in the CMM + SCS group reported worsening pain via VAS (P < 0.001). • Significant improvement in neurologic function and QOL in the CMM + SCS group compared to the CMM control group at 3 and 6 months (P < 0.001)
Petersen et al., 2023	Randomized controlled trial (RCT)	142 adult participants with painful diabetic peripheral neuropathy refractory to gabapentin/pregabalin and at least 1 other analgesic for 1 year	Conventional medical management plus 10 kHz spinal cord stimulation for 24 months (n = 84 from original CMM+SCS group, n = 54 crossed over from CMM only group at 6 months)	Baseline neuropathic pain, neurologic function, and QOL scores prior to starting SCS either at month 0 (original randomized group) or month 6 (crossover group)	• Significant decrease in pain intensity via VAS score and neuropathic pain using DN4 questionnaire (P < 0.001). • Significant improvement in neurologic function, including clinically meaningful improvement in sensory, motor, and reflex function. • Significant improvement in health-related QOL (P < 0.001) and sleep via PSQ-3 (P < 0.001).
Zuidema et al., 2023	Case series	19 adults who had a spinal cord stimulation device implanted > 8 years, followed up on from an original RCT for diabetic peripheral neuropathy	Spinal cord stimulation for > 8 years	Baseline pain intensity scores and patient reported outcome measures (PROMs) at different time points throughout the day and night	• Significant decrease in pain intensity during the day (P = 0.001) and night (P = 0.003) from baseline to long-term follow-up. • No significant change in PROMs, including QOL, sleep quality, and depression symptoms from baseline to follow up.
Anju et al., 2020	Case series	50 participants aged 30-60 with a diagnosis of type 2 DM and painful diabetic peripheral neuropathy	Treatment with both EC laser and Thor laser for 9 minutes on the dorsal and plantar aspects of the feet for 10 days.	Baseline vibration perception threshold (VPT), numeric pain rating scale (NRPS), monofilament tests, and serum neuron specific enolase (NSE) levels.	At 4 weeks compared to baseline: • Significant decrease in both VPT (P = 0.003) and NRPS (P = 0.002). • Significant improvement in monofilament sensation (P = 0.001). • Significant reduction in serum NSE level (P = 0.006).
Thakkar et al., 2023	Randomized controlled trial	42 participants with type 2 diabetes and painful diabetic peripheral neuropathy.	Treatment with a single session of prolonged continuous theta burst stimulation (pcTBS) at the primary motor cortex (M1) or the dorsolateral prefrontal cortex (DLPFC)	Sham treatment prior to active treatment.	• Significant improvement in pain ratings post-test compared to pre-test (P = 0.03). • M1 treatment: no significant decrease in motor evoked potential (MEP) from baseline to post-sham, but a significant increase in MEP from post-sham to post-active. • DLPFC treatment: significant increase in MEP from baseline to post-active and from post-sham to post-active. • Short intracortical inhibition (SICI) showed a significant effect for time at 4ms(P <0.001) and for brain region (P = 0.024). For both groups, there was a significant increase from baseline to post-active • Long intracortical inhibition (LICI), there was found to be a significant effect at 100 ms for time (P < 0.001) and brain region (P = 0.024). For the M1 group, there was a significant increase from baseline to post-active. There was no difference found for DLPFC.
Yoo et al., 2023	Case series	9 adult patients with painful diabetic peripheral neuropathy	10 consecutive scrambler therapy (ST) for 45 minutes every 1 to 2 days	VAS measurements at baseline	• Significant improvement in VAS scores at 8th, 9th, and 10th sessions, as well as 1 month post treatment. • Significant decrease in self-reported Michigan Neuropathy Screening Instrument (MNSI) at 1 month post treatment. • No significant changes at 2, 3, or 6 months post treatment.

CGI: Clinical global improvement; DLPFC: dorsolateral prefrontal cortex; FREMS: frequency rhythmic electrical modulated system; LICI: long intracortical inhibition; MEP: motor evoked potential; MNSI: Michigan neuropathy screening instrument; NPSI: neuropathic pain symptom inventory; NRPS: numeric pain rating scale; NSE: neuron specific enolase; PROMs: patient reported outcome measures; QOL: quality of life; RCT: randomized controlled trial; SCS: spinal cord stimulation; SICI: short intracortical inhibition; ST: scrambler therapy; VAS: visual analog scale; VPT: vibration perception threshold

The management of DPN in human subjects is an emerging and rapidly evolving area of medical science. A number of studies have evaluated the efficacy of various neuromodulation techniques as a treatment modality for DPN as discussed in the following sections:

Frequency rhythmic electrical modulated system

Crasto et al. (2022) performed a study on FREMS and its effectiveness for treating painful diabetic peripheral neuropathy (PDPN). The primary purpose of the trial was to assess the change from baseline in perceived pain between the different groups after 12 weeks. The secondary objective of the trial was to assess the proportion of individuals achieving a 30% and 50% reduction in pain, with 30% seen as significant and 50% seen as ideal. The trial lasted for 12 weeks and consisted of 25 participants that were aged between 18 and 75 years old who possessed either T1D or T2D. It was also mandatory for the participants to have symptoms of PDPN for a minimum of 6 months and possess at least two abnormalities that determined sensory loss. Twenty-five participants were randomized: 13 participants were placed with FREMS intervention and the other 12 were controls. The treatment was administered to the participants through a series of biphasic asymmetrical electrical sequences of electrical pulses with double modulation. The electrical pulses were delivered to the patients through electrode pads, along the path of the peripheral nerves, of both lower limbs. The voltage was administered stepwise for each participant until the participant deemed the voltage to not be painful or uncomfortable. Each treatment cycle was 10 treatment sessions that lasted 35 minutes and occurred every day, except weekends. The results of the participants were recorded on an 11-point scale ranging from 0 to 10. Pain scores for each patient were taken at baseline, 2 days, 4 weeks, 8 weeks, and 12 weeks. The sensory and affective pain descriptors from the Short-Form McGill Pain Questionnaire were rated with an intensity scale that ranged from 0 to 3. The Douleur Neuropathique 4 questionnaire was used for neuropathic pain, and a total score of 4 out of 10, or higher, suggested neuropathic pain. Effect sizes for each participant (r value) were calculated individually and were characterized as small (0.1–0.299), medium (0.3–0.499), or large (greater than 0.5). When the primary outcome was evaluated at 12 weeks, FREMS showed a reduction in perceived pain (median = –4), but it was not significant between the treatment groups (r = –0.34 and P = 0.087). In the secondary outcomes, significant changes were found from baseline, Short-Form McGill Pain Questionnaire (r = –0.58, P = 0.042) and Douleur Neuropathique 4 questionnaire (r = –0.58, P = 0.042). The FREMS group showed greater than 30% reduction in pain perception in 7 of the 13 participants; by comparison, the control group was 0 out of 12 (P = 0.042). These findings suggest that FREMS therapy is a viable option for individuals afflicted with PDPN. Despite lacking statistical significance, the study observed enhancements in sleep quality, reduced symptoms of depression, decreased reliance on pain medication, and an overall improved quality of life (QOL) among participants undergoing FREMS intervention. The results of this study could lay the foundation for designing broader, more conclusive trials aimed at evaluating the efficacy of FREMS therapy in individuals with PDPN (Crasto et al., 2022).

Gorczyca-Siudak and Dziemidok (2022) also conducted a study to evaluate if FREMS is a useful add-on treatment for diabetic peripheral polyneuropathy. Participants were 18 years or older, had a diagnosis of T1D or T2D, and had symptomatic diabetic polyneuropathy. Forty-four patients were randomized: 24 patients to the FREMS group and 20 patients to the sham group. The intervention included 5 days of intravenous alpha-lipoic acid (standard treatment), plus FREMS or sham treatment depending on assignment. Alpha-lipoic acid (ALA) possesses potent antioxidant properties and has been studied in the context of DPN (Papanas and Zieglar, 2014; Salehi et al., 2019; Skibska et al., 2023). Clinical trials have shown that ALA can improve symptoms such as pain, burning, and numbness in the legs and arms of diabetic patients (Reljanovic et al., 1999; Zieglar et al., 2006; Agathos et al., 2018; El-Nahas et al., 2020). It is thought to enhance glucose uptake by promoting insulin sensitivity, thereby potentially slowing the progression of neuropathy (Nguyen and Takemoto, 2018; Capece et al., 2022). ALA represents a promising therapy for managing the symptoms of DPN that can be combined with neuromodulation techniques such as FREMS. Patients were assessed at the end of the 5-day treatment and at 8 weeks post-treatment. Utilizing the visual analog scale (VAS), researchers found there was a significant reduction in pain perception across both groups at the end of the 5-day treatment (P < 0.001). There was no statistical significance between the groups after 5 days; however, after 8 weeks, a significant difference was found in VAS scores between the groups, with the FREMS group having a larger reduction (P < 0.05). Similarly, there was no difference in symptom improvement, assessed by the Clinical Global Improvement rating scale, at 5 days, but there was a significant difference at 8 weeks (P < 0.05). The study also evaluated QOL using the EQ-5D-5L questionnaire. No significant differences were found between the two groups. However, the FREMS group had a statistically significant improvement in the vertical VAS component of the questionnaire (P < 0.01), which persisted at 8 weeks. This study demonstrated that FREMS may be a useful treatment for DPN and may last longer than standard ALA treatment (Gorczyca-Siudak and Dziemidok, 2022).

Additionally, Imholz et al. (2023) performed a study to assess the efficacy of FREMS in patients with PDPN. They performed an uncontrolled prospective study that included 248 patients who had a diagnosis of PDPN and were refractory to treatment with two different pharmacologic therapies. FREMS was applied to both legs below the knees. The patients received five sessions per week over 2 weeks. The sessions lasted 35 minutes. This was repeated every 4 months for 12 months. The neuropathic pain symptom inventory and QOL measurements from the EQ-5D were utilized to assess pain throughout the experiment. In terms of the neuropathic pain symptom inventory, there was found to be a significant reduction in pain scores at 1 and 3 months (P < 0.001). Evaluation of all measures showed a significant decrease over the full 12-month period (P < 0.001). The researchers defined a 33.3% decrease in pain as a clinically relevant change, which was found in 44.8% of patients at 1 month and 49.6% of patients at 3 months. QOL was also significantly improved at 1 and 3 months (P < 0.001). The study also evaluated self-reported use of medication, which showed a decrease throughout treatment. These results show that FREMS may play a useful role in the treatment of PDPN (Imholz et al., 2023).

Dorsal root ganglion stimulation

Another potential therapy option, DRGS, was studied by Eldabe et al. (2018) in a retrospective case study with patients suffering from PDPN. Patients received electrical stimulation of the DRGS and reported changes in their perceived pain and complication rates. The study lasted for 12 months and consisted of 10 males, averaging 65.2 years old. These 10 males were each tested with up to four quadripolar percutaneous DRGS stimulation leads, between the L2 and L5 spinal levels. The patients were able to control their level of paresthesia using a wireless remote that was connected to the implanted stimulation leads. Each patient’s perceived pain level was reported within a week of implantation, and then repeatedly at 1, 3, 6, and 12 months after implantation. Of the 10 patients who participated in the trial, seven received permanent implants after they went through successful initial trials. Five patients were ultimately evaluated during the 12 months. Baseline VAS was reduced by an average of 63.90% (SD 21.39; P < 0.001) post-implantation. Four of these five patients had a 64.16% reduction in overall perceived pain (SD 35.8; P < 0.001). This small retrospective case study suggests that DRGS is a safe and effective option for improving painful symptoms in PDPN patients. Future trials of DRGS are required to further investigate the effectiveness of this style of treatment (Eldabe et al., 2018).

Falowski et al. (2019) also performed a retrospective analysis of DRGS in the treatment of PDPN. The analysis consisted of eight patients, seven males and one female, with an average age of 64.8 ± 10.2 years. These patients were included in the analysis because they possessed peripheral neuropathy symptoms in their legs and/or feet and had a successful response (greater than 50% pain relief) to a previous DRGS trial with stimulation leads located between L4–S1 spinal levels. Six of the eight patients possessed bilateral neuropathy, while the other two possessed unilateral neuropathy. At the baseline visit, usage of pain medication and VAS pain scores were recorded for each patient, and then again after 6 weeks of treatment. At the baseline visit, pain was rated at 7.4 ± 0.7, with a range of 6–8. After 6 weeks of treatment, pain levels were recorded at 1.5 ± 1.3, with a range of 0–4. This reduction was statistically significant. After 6 weeks of treatment, the average pain reduction was (79.5 ± 18.8)%, with a range of 43%–100%. There were two patients who reported they had 100% pain reduction, two who reported greater than 80%, and three more patients who reported greater than 50% pain reduction. This was a small case series with only eight patients, but the results provide preliminary evidence that DRGS can be effective in managing peripheral neuropathy in the lower extremities. Future treatments using DRGS are still necessary to further investigate the effectiveness of this style of treatment (Falowski et al., 2019).

Spinal cord stimulation

SCS is another potential treatment option to improve lower-extremity peripheral nerve function in patients with PDPN, which was studied by Kissoon et al. (2023). The participants were over the age of 18 years, had a diagnosis of T2D, lower-extremity neuropathic pain for greater than 1 year, and failed medication management. They were implanted with high-frequency SCS. Leads were placed in the posterior spinal epidural space, with one lead placed at the top of the T8 vertebral body and one lead at the mid-T9 vertebral level. Clinical assessments were performed at baseline, 6 months, and 12 months. Nine patients in total made it to the full 12-month follow-up. At 12 months, there was a significant improvement in VAS (P < 0.001), Oswestry Disability Index (P = 0.026), Neuropathy Symptoms and Change total severity (P = 0.006), and Neuropathy Impairment Score (P = 0.016). Additionally, two patients who were taking opioids demonstrated a reduction in the daily oral morphine equivalents utilized over the 12 months. The researchers also evaluated autonomic nerve functioning using the quantitative sudomotor axon reflex test. This looks at small-fiber nerve function related to sweating, with a reduction in sweat production correlating with reduced autonomic functioning. A reduction in sweat volume in the proximal leg was noted (P = 0.004), but this was insignificant in other areas. No significant differences were found in laser Doppler flowmetry. This demonstrates that high-frequency SCS may provide pain relief and improve neuropathy symptoms (Kissoon et al., 2023).

Petersen et al. (2021) also studied the effects of SCS. They performed an RCT to assess whether 10 kHz SCS is effective in improving outcomes for patients with PDPN. Participants were adult patients (mean age = 60.8) with PDPN refractory to gabapentin or pregabalin and at least one other analgesic for at least 1 year. These patients were taken from multiple academic centers and pain clinics across the United States. Treatment groups included conventional medical management (CMM) or CMM plus 10 kHz SCS. At 6 months, those with insufficient pain relief could cross over to the other treatment group. The study randomized 216 participants, and 187 patients were ultimately evaluated at 6 months. At the end of the trial, it was discovered that 5 of the 94 patients in the CMM group had 50% or more pain relief using the VAS, compared to 75 of the 95 in the combination group (P < 0.001). When evaluated at 3- and 6-month intervals, the combination group had a significant reduction in VAS scores at both time points compared to CMM alone. Additionally, the CMM group reported worsening pain in 48 of 93 patients, whereas only 2 out of 87 had worsening pain in the combined group (P < 0.001). Remission of pain was achieved in 53 of 88 patients in the combined group, while only 1 of 95 achieved remission in the CMM group (P < 0.001). They also assessed neurologic function at 3 and 6 months, which demonstrated a significant improvement in the combined group compared to the CMM group (P < 0.001). This was mostly an improvement in sensory function. Finally, they evaluated health-related QOL using the EQ-5D-5L. The combined group demonstrated a significant improvement in QOL compared to the CMM group (P < 0.001). However, 14 patients in the combined group experienced adverse events due to their implant, including infection and wound dehiscence. Overall, this trial demonstrates that 10 kHz SCS is successful in relieving pain and improving health-related QOL in patients with PDPN (Petersen et al., 2021).

Peterson et al. (2023) performed a subsequent analysis on these patients at 24 months to understand the long-term efficacy of the 10 kHz treatment regimen. They followed 142 patients for 24 months: 84 patients from the initial randomization and 58 crossovers from the CMM only group. The assessment included pain intensity, health-related QOL, sleep, and neurologic function. Pain was seen to decrease on the VAS score from a mean of 7.6 cm to 1.5 cm (P < 0.001). Neuropathic pain was assessed using the Douleur Neuropathique 4 questionnaire, which demonstrated a decrease in scores from 6.6 to 3.5 (P < 0.001). In terms of neurologic function, 92 of the 142 patients exhibited clinically meaningful improvement in sensory, motor, and reflex function. The original randomized group showed even higher improvements that reached statistical significance (P = 0.048). Additionally, the mean EQ-5D-5L index value increased by 0.146 (P < 0.001), which showed a significant improvement in health-related QOL. There was also a significant improvement in sleep, with a decrease in the Pain and Sleep Questionnaire 3-Item Index from 6.5 cm to 1.9 cm (P < 0.001). These results were consistent across both the original randomized group and crossovers. This demonstrates that 10 kHz SCS is a durable and highly effective way to treat PDPN (Petersen et al., 2023).

Additionally, Zuidema et al. (2023) focused on evaluating the impact of SCS treatment after 8–10 years of follow-up in a cohort of patients with PDPN. This was a follow-up of a previously performed pilot and RCT, with the cohort consisting of patients who had an SCS device implanted for greater than 8 years (n = 19). They utilized their original inclusion criteria: insufficient pain relief and/or unacceptable side effects with drug treatment and the presence of pain in the lower limbs for greater than 1 year, with a mean numeric rating scale (NRS) score for pain of 5 or greater. Additionally, the eligible patients were screened for exclusion criteria, including neuropathic pain from an origin other than DM and pain more prevalent in upper limbs compared to lower limbs. The original treatment included a 14-day trial of an octopolar lead, paresthesia-based SCS. If the patients received benefit from the stimulation, indicated by a pain reduction of greater than 50% on their NRS score or a score of 6 or higher on their Global Impression of Change rating, a permanent implantable pulse generator was placed into the left lower abdominal wall or buttock in surgery, which was then connected to the stimulator lead. Device settings were then programmed individually to create optimal relief, and the patients were followed. If they no longer benefitted from the SCS, it was explanted. In terms of measurements, the researchers collected NRS pain intensities via a pain diary at baseline and follow-up. Patients provided pain intensity scores at different time points throughout the day (9 a.m., 2 p.m., and 8 p.m.), as well as an additional score to summarize the average pain during the night. Additionally, patient-reported outcome measures were collected to evaluate parameters such as QOL, sleep, and depression. The study found that the mean NRS scores for pain intensity during the day and night significantly decreased by 2.3 ± 2.5 (P = 0.001) and 2.2 ± 2.4 (P = 0.003), respectively, from baseline to long-term follow-up. For more than half the cohort, the reduction in pain intensity for both day and night was > 30% and was thus considered clinically meaningful. The secondary parameters, including QOL, sleep quality, and depression symptoms, did not have a statistically significant difference between baseline and follow-up. Overall, the results indicate that SCS can remain effective in reducing pain intensity long-term for patients with PDPN in the lower legs (Zuidema et al., 2023).

Other neuromodulation techniques

Anju et al. (2020) performed an experiment to assess whether low-level laser therapy (LLLT) is an effective way to improve symptoms and decrease serum neuron specific enolase, associated with neuropathy, in patients with PDPN. Neuron-specific enolase (NSE), also known as enolase 2, is a glycolytic enzyme that is predominantly found in neuronal and neuroendocrine cells (Isgro et al., 2015). Functioning as a part of the glycolytic pathway, NSE catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate. Due to its high concentration in neurons and cells of the neuroendocrine system, NSE is widely used as a clinical marker for neuronal damage. Elevated levels of NSE in the blood or cerebrospinal fluid often indicate acute brain damage, such as that resulting from stroke, head injury, or neurodegenerative disorders such as Alzheimer’s disease (Echeverria-Palacio et al., 2019; Metallinou et al., 2024; Mochetti et al., 2024). It has been suggested that NSE may serve as a potential biomarker for the diagnosis and progression of DPN (Li et al., 2013). Fifty patients were included who were aged 30–60 years, and had a diagnosis of T2D, and PDPN. Participants were treated with both an EC laser and Thor laser for 9 minutes on the plantar and dorsal aspects of the foot for 10 days. Effects were evaluated using the vibration perception threshold, numeric pain rating scale, and serum NSE levels. After 4 weeks, there was a significant decrease in vibration perception threshold (P = 0.003), a significant reduction in the numeric pain rating scale (P = 0.002), and improved sensation in the foot based on the monofilament test (P = 0.001). Additionally, there was a significant reduction in serum NSE levels in 42 of the 50 patients at 4 weeks (P = 0.006). This shows that LLLT is a potential treatment option to reduce symptomatology in patients suffering from PDPN (Anju et al., 2020).

Thakkar et al. (2023) performed an RCT to assess if prolonged continuous theta burst stimulation (pcTBS), which is a new form of transcranial magnetic stimulation, is a viable treatment option for neuropathic pain in patients with T2D. The study consisted of 42 patients with PDPN. They were randomized to receive a single session of pcTBS at the primary motor cortex (M1) or the dorsolateral prefrontal cortex (DLPFC). Both groups received a sham treatment followed by active treatment within their respective groups, and both were blinded to the sequence. Data was collected using the Brief Pain Inventory for patients with diabetic neuropathy (BPI-DN), psychophysical pain protocol, motor corticospinal excitability measures, and intracortical inhibition. No significant interaction effects were found for either of the stimulation groups when analyzing the BPI-DN pain severity subscale or BPI-DN interface subscale (P = 0.963 and P = 0.100, respectively). However, when asking patients to acutely rate their pain pre- and post-test, there was an average improvement of 13.53% post-test (P = 0.03). No significant changes were found when analyzing the psychophysical pain protocol. In terms of motor corticospinal excitability, it was found that the M1 group showed no significant decrease in motor evoked potential (MEP) from baseline to post-sham, but a significant increase in MEP from post-sham to post-active. For DLPFC, there was a significant increase in MEP from baseline to post-active and from post-sham to post-active. It was also found that short intracortical inhibition (SICI) showed a significant effect for time at 4 ms (P < 0.001) and for brain regions (P = 0.024). For both groups, there was a significant increase from baseline to post-active; the other measures of SICI were insignificant. For long intracortical inhibition (LICI), there was found to be a significant; the other measures of SICI were insignificant. For LICI, there was found to be a significant increase in the M1 group (P = 0.024) at 100 ms (P < 0.001) from baseline to post-active. For the M1 group, there was a significant increase from baseline to post-active. There was no difference found for DLPFC. There was also a significant effect for time at 155 ms (P = 0.001) in the DLPFC group, with a significant increase in LICI from baseline to post-active. Further analysis of all the results revealed that MEP, SICI, and LICI did not predict any of the scores on the BPI-DN. Only current pain significantly predicted scores on the BPI-DN (P = 0.017). Overall, pcTBS modulated the systems related to motor corticospinal excitability and those linked to GABA activity, but it did not modulate ascending or descending modulatory systems. However, there was a decrease in acute pain intensity. Additional studies are needed to further elucidate these underlying mechanisms (Thakkar et al., 2023).

Finally, Yoo et al. (2023) performed a prospective trial to investigate the long-term effects of scrambler therapy (ST) in managing PDPN. In this trial, nine adult patients with PDPN were evaluated. The study participants received 10 consecutive STs for 45 minutes every 1 to 2 days. VAS measurements were evaluated at baseline, during ST, immediately after ST, and at 1-, 2-, 3-, and 6-month post-treatment. VAS scores showed significant improvement at the 8th, 9th, and 10th sessions during treatment and 1 month after treatment. They secondarily evaluated the Michigan Neuropathy Screening Instrument, Semmes-Weinstein monofilament test, and Leeds Assessment of Neuropathic Symptoms and Signs pain scores, which were measured at similar time points to VAS, except during treatment. The Michigan Neuropathy Screening Instrument self-report component decreased at 1-month post-treatment. No significant differences were found in the other measures. These results suggest that ST may demonstrate short-term effects but has limited long-term effects in the treatment of PDPN (Yoo et al., 2023).

Discussion

Neuromodulation techniques help treat DPN through a variety of mechanisms (Krames, 2015; van Beek et al., 2018). These include modulation of pain pathways as well as stimulating specific nerve fibers to inhibit pain signals transmitted to the brain. Neuromodulation also reduces the inflammatory response by altering the release of pro-inflammatory cytokines and stimulating anti-inflammatory molecules (Sokal et al., 2021; Tynan et al., 2022), thereby reducing nerve damage and pain. In addition, neuromodulation improves blood flow to the affected nerves, causing vasodilation, improving nutrient and oxygen delivery, promoting recovery, and reducing neuropathic pain (Visocchi, 2008). Furthermore, neuromodulation promotes neuroplasticity and nerve regeneration, allowing the nervous system to reorganize and form new nerve connections (Zhang et al., 2021; Martin, 2022; Jin et al., 2023), improving nerve function and reducing pain. It also affects the levels of neurotransmitters such as serotonin, norepinephrine, and GABA, which are important in regulating pain perception (Nadim and Bucher, 2014). Neuromodulation can prevent nerve damage by reducing oxidative stress by increasing the activity of antioxidant enzymes and reducing the production of reactive oxygen species (Lu et al, 2015). Neuromodulation targeting specific nerve pathways improves peripheral nerve function by enhancing sensory and motor nerve transmission (Ong Sio et al., 2023), thereby improving sensory and muscle control in patients with DPN. These combined mechanisms contribute to the treatment of DPN by reducing pain, promoting nerve repair, and improving overall nerve function.

The findings from the studies included in this review on neuromodulation techniques for DPN were mostly encouraging. The positive trend in the results highlights the potential of neuromodulation as a promising therapeutic avenue for managing DPN. For FREMS treatment, all three studies observed a significant reduction in pain across multiple measures post-treatment (Crasto et al., 2022; Gorcyza-Siudak and Dziemidok, 2022; Imholz et al., 2023). One study also found a significant improvement in QOL (Imholz et al., 2023). The other two studies found improvements in sleep, depression symptoms, and QOL, with a reduction in the use of pain medications, but these results were insignificant (Crasto et al., 2022; Gorcyza-Siudak and Dziemidok, 2022).

In terms of DRGS, both of the studies evaluating this modality found a significant reduction in scores on the VAS (Eldabe et al., 2018; Falwoski et al., 2019). In one of the studies, some of the patients even reported 100% pain reduction (Falwoski et al., 2019).

For SCS, four studies evaluated its efficacy and all four found a significant improvement in pain across multiple measures, including VAS, Oswestry Disability Index, neuropathy symptoms, change in total severity, and neuropathy impairment score (Petersen et al., 2021, 2023; Kissoon et al., 2023; Zuidema et al., 2023). Additionally, two studies saw clinically meaningful improvement in neurologic function (Petersen et al., 2021, 2023). One study also found a reduction in the number of opioids the patients were requiring (Kissoon et al., 2023), and one even found a significant worsening in the control group, which was not found in the treatment group (Petersen et al., 2021). However, one study found there was no significant difference in QOL, sleep, or depression symptoms (Zuidema et al., 2023).

LLLT was found to produce a significant decrease in vibration perception threshold and numeric pain rating scale, with a significant improvement in the monofilament test (Anju et al., 2020). pcTBS and ST were both found to have significant improvements in the short term, but this improvement decreased over time.

It is important to acknowledge that implantable devices used in treatments are not completely devoid of risks and complications. While a majority of patients have shown good tolerance towards these devices, there have been instances of adverse events such as infections and wound dehiscence (Petersen et al., 2021). These complications, notably absent in control groups, underscore the need for careful monitoring and management when using such implantable technologies. It is also crucial to conduct thorough pre-implantation evaluations and follow stringent post-implantation care protocols to minimize these risks. Additionally, further research to refine device design and improve surgical techniques may help reduce the incidence of these adverse events, thereby enhancing the overall safety and efficacy of implantable treatment modalities.

Overall, these studies demonstrate that FREMS, DRGS, SCS, and LLLT could be viable and successful options for the treatment of PDPN, including reduction in pain and increase in QOL. pcTBS and ST do not seem to demonstrate the longer-term benefits seen with these other treatment options. This distinction highlights the potential of FREMS, DRGS, SCS, and LLLT in offering sustained relief and enhanced life quality, making them valuable considerations in the treatment of PDPN. These findings advocate for a more nuanced approach to treatment selection, focusing on long-term efficacy and patient QOL as key factors.

Limitations

The included studies in this systematic review have a few limitations. Primarily, many of the studies have small sample sizes and short follow-up periods, which limit the generalizability and long-term applicability of the findings. There is also a notable lack of standardization in the methodologies, including variations in neuromodulation techniques, stimulation parameters, and outcome measures, making it challenging to compare results across studies. Furthermore, the majority of these studies focus predominantly on pain relief as the primary outcome, often overlooking other critical aspects such as functional improvements, QOL, and psychosocial impacts. Another significant limitation is the scarcity of RCTs, which are essential for establishing causality and understanding the true efficacy of neuromodulation therapies. Additionally, many studies do not adequately account for placebo effects, which are particularly relevant in pain-related interventions. The heterogeneity of the patient populations studied, including variability in the duration and severity of DPN, further complicates the interpretation of results. Lastly, there is a need for more comprehensive reporting on the side effects and long-term safety of these interventions. Addressing these limitations in future studies is crucial for advancing our understanding of the role of neuromodulation in the management of DPN and for optimizing treatment strategies.

Conclusions and Future Directions

The studies included in this systematic review suggest that neuromodulatory approaches, particularly FREMS, DRGS, and SCS, hold a significant potential in the management of DPN. This potential is demonstrated by observed reductions in pain and improvements in QOL. Healthcare professionals, including physicians, should consider these neuromodulatory techniques, especially for patients with DPN who show resistance to conventional pharmacological therapies. To further validate and expand upon these findings, additional RCTs with larger patient cohorts are essential.

While the outcomes of neuromodulatory approaches are encouraging, they are associated with potential risks. The necessity of device implantation means that patients must be appropriate candidates for surgery. Additionally, there is an elevated risk of post-surgical complications, including wound dehiscence and infection. It is imperative that patients are thoroughly informed about these potential side effects, ensuring that the decision to proceed with such treatments is made collaboratively between the patient and the healthcare provider. In addition, technological innovations, such as more sophisticated implantable devices, wireless technology, and closed-loop systems that adjust stimulation in real time based on feedback from the nervous system, are expected to enhance the effectiveness and comfort of neuromodulation therapies. Continued research into the biological mechanisms underlying the effectiveness of neuromodulation will help in refining these therapies and may lead to the development of new effective treatment modalities for DPN.

A key area of future research will involve unraveling the precise underlying mechanisms of action to better tailor neuromodulation therapies to individual patient profiles. This will likely include genetic, molecular, and imaging studies to identify biomarkers predictive of treatment response. Additionally, advancing technology in neuromodulation devices offers the potential for more refined and targeted interventions, potentially improving efficacy and reducing side effects. There is also a growing interest in exploring the synergistic effects of combining neuromodulation with other treatments, such as pharmacotherapy, physical therapy, and lifestyle modifications. This integrative approach could offer a more comprehensive management strategy for DPN, addressing not just pain relief but also functional and QOL improvements. Furthermore, cost-effectiveness and accessibility will be key considerations, aiming to make these advanced treatments available to a broader range of patients. Finally, early intervention studies are crucial, as there is potential for neuromodulation therapies to prevent or slow the progression of neuropathy if applied in the initial stages of the disease. By addressing these areas, the field of neuromodulation for DPN is poised to make significant strides, offering hope for improved patient outcomes and quality of life.

Additional file:

Additional Table 1: A comprehensive summary of all the studies included in this systematic review.

Data availability statement:

All relevant data are within the manuscript and its Additional files.