Painful diabetic peripheral neuropathy (PDPN) affects roughly one in five people with diabetes and is among the most disabling long-term complications of the disease. Pharmacologic therapy — typically gabapentinoids, serotonin–norepinephrine reuptake inhibitors, or tricyclic antidepressants — remains first-line, but many patients experience inadequate relief, intolerable side effects, or both. That treatment gap has fueled renewed interest in non-pharmacologic neuromodulation, including a transcutaneous modality called the Frequency Rhythmic Electrical Modulation System (FREMS). Over the past several years, randomized trials and a 2025 systematic review have clarified what FREMS can and cannot do, and how it fits alongside other neuromodulation options.
What FREMS Is and How It Differs From TENS
FREMS delivers brief, biphasic, asymmetric electrical pulses through surface electrodes placed on the lower limb. Unlike conventional transcutaneous electrical nerve stimulation (TENS), which relies on relatively fixed pulse parameters, FREMS continuously varies pulse frequency, duration, and voltage during each session. Proponents argue that this variability reduces nerve accommodation and may stimulate microcirculatory and trophic responses in addition to gate-control analgesia. Treatments are typically delivered in cycles of 8–10 sessions over two to three weeks, with each session lasting roughly 30 minutes.
Evidence for Pain Reduction
Randomized Trials
Early signals of efficacy came from a double-blind, randomized, multicenter, placebo-controlled trial by Bocchi and colleagues, which reported reductions in daytime and nighttime pain scores compared with sham stimulation in patients with symptomatic diabetic neuropathy. The 2022 FREMSTOP pilot RCT, published in Diabetic Medicine, extended that work to a particularly difficult-to-treat population: patients with PDPN inadequately controlled on at least two classes of neuropathic pain medication. Although the trial was small (25 randomized), the FREMS arm demonstrated improvements in pain severity and in patient-reported impact of treatment relative to usual care, supporting its role as an add-on rather than a replacement therapy.
A separate 8-week open-label evaluation by Conti and colleagues in 2022 examined FREMS as an add-on therapy for symptomatic diabetic polyneuropathy and reported reductions in pain intensity and improvements in neuropathy-related symptom scores during the treatment cycle.
Systematic Review and Meta-Analysis
The most rigorous synthesis to date is the 2025 systematic review and meta-analysis by Bashir and colleagues, published in Diabetes & Metabolic Syndrome: Clinical Research & Reviews. Five RCTs comprising 333 participants met inclusion criteria. Pooled analysis showed that FREMS significantly reduced daytime visual analogue scale (VAS) pain scores compared with control (standardized mean difference −0.56; 95% confidence interval −0.82 to −0.29), with low between-study heterogeneity (I² = 4%). Adverse events were uncommon and generally mild, consistent with the non-invasive nature of the intervention.
How FREMS Compares With Other Neuromodulation Options
A 2024 network meta-analysis of neuromodulation therapies for PDPN evaluated seven modalities — including TENS, FREMS, spinal cord stimulation (SCS), and high-frequency electrical nerve stimulation — against sham. All active modalities outperformed sham for pain intensity, but the ranking placed TENS and SCS ahead of FREMS for analgesic effect size. SCS in particular has the strongest evidence base for refractory PDPN, although it is invasive, costly, and not appropriate for many patients. FREMS occupies a middle ground: better tolerated and more accessible than implanted neurostimulation, with effect sizes that are modest but consistent in the populations studied.
Practical Considerations and Limitations
Several caveats temper the enthusiasm. The total RCT evidence base for FREMS remains small, with most trials enrolling fewer than 100 participants and follow-up rarely extending beyond a few months. Long-term durability of pain relief, optimal session frequency, and effects on objective measures of nerve function — such as nerve conduction velocity and intra-epidermal nerve fibre density — are incompletely characterized. Most trials enrolled patients already on stable analgesic regimens, so FREMS is best understood as an adjunct to, rather than a substitute for, comprehensive neuropathy care that includes glycemic optimization, foot protection, and screening for treatable contributors such as vitamin B12 deficiency or thyroid disease.
Contraindications include the presence of implanted cardiac devices, pregnancy, active malignancy in the treated region, and broken skin or active infection at electrode sites. The IWGDF 2023 wound-healing and prevention guidelines do not currently make a specific recommendation for or against FREMS in PDPN, reflecting the still-developing evidence base.
Clinical Summary
FREMS is a non-invasive, well-tolerated form of neuromodulation that produces statistically significant reductions in pain intensity in patients with painful diabetic peripheral neuropathy, including those refractory to standard pharmacologic therapy. Effect sizes are moderate and the evidence base remains limited in size and duration, but the favourable safety profile makes FREMS a reasonable adjunctive option for selected patients who cannot tolerate or do not respond adequately to first-line medications. Ongoing trials and larger pragmatic studies will be needed to define its place relative to TENS, SCS, and emerging pharmacologic agents.
References
Bashir A, et al. Efficacy of Frequency Rhythmic Electrical Modulated System (FREMS) in the treatment of diabetic neuropathy: a systematic review and meta-analysis of randomized controlled trials. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2025.
Crasto W, et al. Frequency rhythmic electrical modulation system (FREMS) to alleviate painful diabetic peripheral neuropathy: a pilot, randomised controlled trial (the FREMSTOP study). Diabetic Medicine. 2022;39(2):e14710.
Conti M, et al. The 8-week efficacy of Frequency Rhythmic Electrical Modulated System (FREMS) as an add-on therapy in the treatment of symptomatic diabetic peripheral polyneuropathy. Journal of Clinical Medicine. 2022;12(1):103.
Bocchi L, et al. Frequency-modulated electromagnetic neural stimulation (FREMS) as a treatment for symptomatic diabetic neuropathy: results from a double-blind, randomised, multicentre, long-term, placebo-controlled clinical trial. Diabetologia. 2013;56(3):467–475.
Network meta-analysis of randomized controlled trials assessing neuromodulation therapies for painful diabetic neuropathy. Neuromodulation. 2025.
Chen P, et al. Guidelines on interventions to enhance healing of foot ulcers in people with diabetes (IWGDF 2023 update). Diabetes/Metabolism Research and Reviews. 2024;40(3):e3644.
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