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


PDN is often debilitating and refractory to conventional pharmacological therapies including anticonvulsants and antidepressants. For patients who do not respond or unable to tolerate medications, several interventional therapies have been investigated. SCS has been shown to be an effective treatment for neuropathic pain based on numerous clinical trials.[40,41,75] However, not all patients with neuropathic pain respond to SCS. Therefore, a trial stimulation is usually performed before a permanent implant of the stimulator. The success rate of achieving ≥50% pain reduction during a SCS trial is higher in patients with PDN (up to 77% or 84%)[46,51] compared to those with other neuropathic pain syndromes such as postherpetic neuralgia and complex regional pain syndrome (roughly 50%).[40] The reason for this difference is unclear and could be due to predominantly sensory involvement in PDN. Factors that predict SCS treatment success have not been clearly identified. Preoperative clinical sensory testing failed to identify responders to SCS,[47] even though modulation of A-beta fiber is thought to be one of the major mechanisms underlying SCS effect and the loss of A-beta (eg, complete absence of vibration and joint-position) is considered to predict unresponsiveness to SCS.[43] There is no difference in baseline severity of neuropathy measured with the Michigan Diabetic Neuropathy Score (MDNS) between responders and nonresponders.[47] However, higher baseline MDNS was associated with higher rate of long-term treatment failure and subsequent removal of the SCS system. In contrast, a higher baseline night NRS pain score was associated with a lower risk of treatment failure in a 5-year follow-up study.[53] In a small-size pilot study (15 patients with PDN), the forearm contact heat-evoked potential (CHEP, to test small-diameter nerve fiber function) latencies are increased in patients who responded to SCS treatment (10 of 15 patients) as compared to nonresponders (5 of 15 patients).[76]

Conventional SCS induces paresthesia to map the painful area and to determine the placement of electrodes. Compared to paresthesia-based conventional SCS, burst SCS or DRG stimulation (both with little or no paresthesia) appears to be more attractive to PDN patients who often suffer from tingling and numbness.[57] However, evidence supporting the use of burst or DRG stimulation in PDN is limited to case series. The recent multicenter trial using paresthesia-free (HF-10) SCS in 90 patients confirmed its efficacy for PDN.[59] To date, all SCS studies selected patients with refractory PDN in the lower extremities. It remains to be determined whether SCS could help relieve refractory PDN pain in the upper extremities.

Diabetes is an independent risk factor for surgical site infection for multiple surgical procedures, higher in cardiac than other surgeries.[77] Although diabetes did not independently increase the rate of infection in patients received SCS,[78] earlier studies reported that the incidence of infection after SCS in PDN patients (14%)[46] was much higher than that in the general population receiving SCS (2.45%–4.5%).[78,79] However, the recent HF-10 SCS trial in PDN patients reported 3 study-related infections out of 90 SCS implants (3%).[59] This low rate of infection might be due to a relatively tight inclusion criteria (HbA1c ≤ 10%, body mass index [BMI] < 45) in this cohort, although patient BMI was not associated with surgical site infection in a meta-analysis.[77] It is difficult to make specific recommendations in preventing surgical site infection in PDN patients undergoing SCS procedure since few studies addressed the causes of surgical site infection in patients with diabetes. Nevertheless, general guidelines to prevent surgical site infection should be strictly followed.[80]

The AAN did not recommend surgical decompression for PDN in its practice advisory published in 2006.[73] Since then, large observational studies and small RCTs have provided evidence to suggest that surgical decompression of peripheral nerves in the lower extremity can be considered in patients with PDN and superimposed compression of specific peripheral nerves.[66,69] Surgical decompression significantly improved pain[66,69] but data on whether it would also improve quality of life are conflicting.[67,69]

PDN pain might be sympathetically maintained in some patients,[81] so that lumbar sympathetic block or neurolysis may provide pain relief in the lower extremities.[38] The sympathetic block could be a viable option for patients with refractory PDN. It can be considered for patients who are waiting for SCS or surgical decompression of peripheral nerves. Lumbar sympathetic neurolysis should be used with great caution as it may cause severe adverse effects.[82]

Acupuncture has been reported to be beneficial and cost-effective in help manage chronic pain including myofascial pain, fibromyalgia, and neuropathic pain.[83] Acupuncture may modulate the endogenous opioid system, desensitize peripheral nociceptors, suppress release of proinflammatory cytokines, and inhibit spinal glial activation.[84–86] Both neuropathic symptoms and nerve conduction study parameters have been shown to be affected by acupuncture.[35] In this review, we identified multiple RCTs and meta-analyses that reported clinical efficacy of acupuncture for PDN. Studies on acupuncture for PDN, as for other pain conditions, are often challenged by concerns for methodology, blindness, standardization, and placebo effects. Nevertheless, acupuncture can be considered an adjunctive therapy for patients with PDN without causing significant complications.

A few RCTs of small sample sizes reported that intradermal[30,31] or intramuscular[33] injections of BTX-A provided better relief in pain and muscle cramp in the lower limbs as compared to saline injection in patients with PDN. Botulinum toxin may relieve neuropathic pain via different mechanisms such as by inhibiting the release of pain mediators (eg, substance P, calcitonin gene–related gene) from the nerve endings and DRG, deactivating sodium channels, and reducing inflammation.[87] Botulinum toxin also acts at the presynaptic membrane of the neuromuscular junction to prevent calcium-dependent release of acetylcholine, leading to biochemical denervation and muscle weakness.[88] The efficacy and safety of intradermal and intramuscular BTX-A injection have been compared and the maximum improvement of wrinkles were similar in both groups but the intramuscular group reported more muscle weakness–related side effects.[89] Besides its peripheral effect, recently, studies indicate that botulinum toxin may also cause changes in the central nervous system to modulate sensory inputs.[88] It has been reported that BTX-A injection significantly reduced the tactile threshold and mechanical pain threshold in patients with PDN.[90] In addition to PDN, botulinum toxin has been used to treat other types of neuropathic pain with minimal side effects and could reduce the use of invasive or surgical procedures.[91]