Advances in Interventional Therapies for Painful Diabetic Neuropathy

A Systematic Review

Li Xu, MD, PhD; Zhuo Sun, MD; Elizabeth Casserly, PharmD; Christian Nasr, MD; Jianguo Cheng, MD, PhD; Jijun Xu, MD, PhD


Anesth Analg. 2022;134(6):1215-1228. 

In This Article

Abstract and Introduction


Background: Painful diabetic neuropathy (PDN) is one of the major complications of diabetes mellitus. It is often debilitating and refractory to pharmaceutical therapies. Our goal was to systematically review and evaluate the strength of evidence of interventional management options for PDN and make evidence-based recommendations for clinical practice.

Methods: We searched PubMed, Scopus, Google Scholar, and Cochrane Llibrary and systematically reviewed all types of clinical studies on interventional management modalities for PDN.

Results: We identified and analyzed 10 relevant randomized clinical trials (RCTs), 8 systematic reviews/meta-analyses, and 5 observational studies of interventional modalities for PDN using pain as primary outcome. We assessed the risk of bias in grading of evidence and found that there is moderate to strong evidence to support the use of dorsal column spinal cord stimulation (SCS) in treating PDN in the lower extremities (evidence level: 1B+), while studies investigating its efficacy in the upper extremities are lacking. Evidence exists that acupuncture and injection of botulinum toxin-A provide relief in pain or muscle cramps due to PDN with minimal side effects (2B+/1B+). Similar level of evidence supports surgical decompression of lower limb peripheral nerves in patients with intractable PDN and superimposed nerve compression (2B±/1B+). Evidence for sympathetic blocks or neurolysis and dorsal root ganglion (DRG) stimulation is limited to case series (2C+).

Conclusions: Moderate to strong evidence exists to support the use of SCS in managing lower extremity pain in patients who have failed conventional medical management for PDN. Acupuncture or injection of botulinum toxin-A can be considered as an adjunctive therapy for PDN. Surgical decompression of peripheral nerves may be considered in patients with PDN superimposed with nerve compression. High-quality studies are warranted to further evaluate the safety, efficacy, and cost-effectiveness of interventional therapies for PDN.


Diabetes mellitus affects about 425 million people worldwide[1] with an estimated annual cost of $327 billion in the United States alone.[2] Diabetic sensorimotor polyneuropathy (DSP) is the most common complication, which affects up to 50% of patients with diabetes.[3–5] Approximately 30% to 50% of patients with DSP develop painful diabetic neuropathy (PDN).[1,6] It is estimated that 5.8 to 7.6 million people in the United States suffer from PDN,[7] which is often debilitating.[1,6]

Pharmacological therapies have been the mainstay for symptom management in patients with PDN in addition to optimizing the management of diabetes.[5,8] The most current first-line pharmacotherapies include gabapentinoids, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants.[1,5,8,9] However, the efficacy of these medications is limited, and many patients respond poorly to these drugs.[9,10] Other drugs such as dextromethorphan,[11–13] lacosamide,[14–17] lidocaine infusion,[18,19] sustained release formulation of sodium nitrite,[20] and inhaled cannabinoids[21] were reported to be effective, but the evidence is far from being conclusive. Therefore, these drugs have not been recommended in practice guidelines by professional societies.[8]

With millions of people suffering from PDN and many of them not responding well to drugs, nonpharmacological interventions have been investigated in recent years. Interventional therapies such as spinal cord stimulation (SCS), acupuncture, botulinum toxin-A (BTX-A) injection, sympathetic nerve blocks, and surgical decompression of specific peripheral nerves have shown promise to improve clinical outcomes of PDN and to decrease the use of drugs and their associated adverse effects. In this systematic review, we seek to review the recent advances in interventional therapies for PDN, to evaluate the evidence (or lack of it) for the application of interventional treatments, to fill the knowledge gap in this emerging field, and to provide evidence-based recommendations in managing patients with refractory PDN.