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

Disclosures

Anesth Analg. 2022;134(6):1215-1228. 

In This Article

Results

Detailed search strategy and results are shown in Supplemental Digital Content 1, Appendix, https://links.lww.com/AA/D798. After removing duplicates, we identified 1505 articles. Among which 557 abstracts were screened, 315 full-text articles assessed after reading the abstracts. A total of 267 full articles were reviewed thoroughly, and 27 articles were included in qualitative synthesis and analysis (Figure). We summarized the findings in Table 2 and Table 3.

Figure.

PRISMA flow diagram of literature search and selection process. PRISMA indicates Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Risk of Bias Assessment

The risk of bias assessment is summarized in Table 4. Most of the studies were judged to have a high risk of bias due to open-label design, lack of placebo-control, small sample sizes, and/or subjective outcome measurement.

Botulinum Toxin-A Injections

BTX-A has been used to treat neuropathic pain as well as spasticity.[29] In a randomized clinical trial (RCT) of 18 patients with PDN, 9 patients received intradermal injection of 50 units of BTX-A over 12 spots in the foot and 9 patients received placebo injections.[30] After 12 weeks, patients were allowed to crossover to the other group. At 12 weeks postinjection, 44% (8 of 18) of patients in the study achieved a visual analog scale (VAS) reduction of >3. Patients reported no major complications.[30] In another RCT, 40 patients were randomized to receive intradermal injections of either 100 units of BTX-A or 0.9% saline in 12 spots in the foot.[31] At 3 weeks postinjection, 30% of patients in the BTX-A group reported no pain, compared to 0% of patients in the placebo group. No major adverse effects were reported.[31] A meta-analysis based on these 2 reports favored BTX-A but also cautioned that it might be best used as an adjunctive treatment for PDN because of the small effect size of the studies.[32] In a recent RCT, BTX-A was used to treat muscle cramps and its associated pain in the calf or foot in patients with PDN. A total of 50 patients were randomized to intramuscular injection of saline or BTX-A into the gastrocnemius (100 units) or flexor muscles of the foot (30 units).[33] The intensity and frequency of muscles cramps were significantly improved in the BTX-A group, compared with placebo control. Improvements started at 1 week and maintained up to 14 weeks.

In summary, BTX-A injections showed moderate level of evidence (2B+/1B+) in managing PDN (50 or 100 units intradermal injection for pain; 100 or 30 units intramuscular for pain and muscle cramping).

Acupuncture

Acupuncture has become a part of pragmatic and integrative treatment for PDN. Chen et al[34] reviewed 25 RCTs (1649 subjects) of manual acupuncture for PDN. The majority of the trials (23 of 25) reported improvement in global symptoms, but these trials have high risk of bias (methodology or publication). A meta-analysis of 15 studies (among which, 4 RCTs studied PDN) on peripheral neuropathy showed an overall benefit of acupuncture for PDN over sham control.[35] The benefit remains after study heterogeneity was corrected. In a recently published RCT, 40 patients with PDN were randomized to receive usual care only, usual care with acupuncture once or twice weekly for 12 weeks.[36] At week 12, the weekly average pain intensity was significantly reduced from baseline in those receiving acupuncture, compared with those receiving usual care only, but the pain intensity returned to baseline levels by week 18. Quality-of-life scores and physical functioning improved in the acupuncture groups by week 18. No significant differences were observed between the once/week versus twice/week acupuncture groups. The effects of electroacupuncture for PDN was evaluated in a multicenter, randomized, assessor-blinded, and controlled trial.[37] Patients in the electroacupuncture treatment group showed significantly improvement in pain intensity (on 0–10 numerical rating scale [NRS]) than those in the control group. While these results are promising, the authors recognize the methodological problems with standardization, control, blinding, and outcome measures.

In summary, multiple RCTs showed beneficial effects of acupuncture on PDN management. Acupuncture can be considered an adjunctive therapy with minimal side effects for patients with PDN based on moderate level of evidence (2B+ or 1B+), mainly due to methodological and blinding concerns.

Lumbar Sympathetic Ganglion Block and Neurolysis

The sympathetic nervous system may contribute to PDN. Cheng et al[38] reported a 37-year-old man with PDN which was diagnosed by clinical presentations and skin biopsy. The patient failed multiple conservative therapies. A series of 9 lumbar sympathetic blocks over a 26-month period provided sustained pain relief and improved quality of life over a period of more than 2 years. Lumbar sympathetic neurolysis has also been reported to treat PDN. In a retrospective comparative study, 90 patients with PDN were treated with anhydrous ethanol (AE) chemical blockade, radiofrequency thermocoagulation (RF), or combined AE and RF of the lumbar sympathetic ganglion (AE + RF).[39] Postoperative VAS were significantly decreased from preoperative baseline. Pain started to return at 3 months after AE chemical blockade, 6 months after RF, 1 year after combined AE and RF. The complete remission rates for AE, RF, and AE + RF groups at 1 year were 66.7%, 73.3%, and 93.3%, respectively. No severe complications were observed. The authors concluded that RF combined with AE chemical blockade of the lumbar sympathetic ganglion was safe and effective in managing PDN.

In summary, there is week evidence (2C+) to support application of lumbar sympathetic ganglion block and neurolysis in selected patients with PDN, who have failed pharmacological and other therapies (see later).

Spinal Cord Stimulation

SCS has emerged as a cutting-edge treatment for chronic refractory neuropathic pain.[40,41] In a case series of SCS implants in 276 patients with peripheral neuropathy, 4 patients with PDN had excellent early pain relief and 3 achieved long-term success with an average of 87-month follow-up.[42] Another case series reports that 8 of 10 patients with refractory PDN had significant pain relief during SCS trial and after permanent implant at 3, 6, and 14 months.[43] By the end of the study (14 months), 6 patients continued to use SCS as the sole treatment for PDN with significant pain relief. SCS used in this small sample size study was paresthesia-based thus blinding was impossible; however, the authors argued against placebo effects by pointing out that the pain relief was lost immediately when there was a lead displacement. The authors speculated that 2 of the patients did not respond to SCS due to loss or gross dysfunction of the inhibitory A-beta fibers. A study with extended follow-ups of up to 7 years after implantation revealed that the pain relief was maintained with few associated complications.[44] In an open-label, prospective study, 11 patients with refractory PDN in the lower extremities received thoracic SCS implantation and 9 patients had significant pain relief.[45] Average VAS pain score decreased from 77 mm at baseline to 34 mm at 6 months after implantation. At the end of the study at 6 months, 8 of the 9 patients significantly reduced pain medication use and 6 patients used SCS as the sole treatment for the PDN.[45] A systematic review of the above-mentioned 4 studies with a total of 25 patients summarized that, at 1 year postimplantation, SCS resulted in ≥50% pain relief in 63% of patients with PDN.[46] Also, analgesics usage was reduced in most SCS-treated patients in the same time. The authors then reported a pilot study in 15 patients with refractory PDN.[47] Eleven patients achieved clinically significant pain reduction, defined as ≥50% decrease of pain intensity, during a 2-week SCS trial, and 10 patients achieved the treatment objective at 12 months after the SCS implant. Quality-of-life and neuropathic pain scores were significantly improved at in follow-up visits at 2 weeks and 3 to 12 months.[47] The effects of SCS were maintained at 12, 24, and 36 months, with 91%, 55%, and 64% patients continued to have ≥50% pain reduction, respectively. Improvement in quality of life at 12, 24, and 36 months was reported in 64%, 55%, and 64% of the patients.[48]

The first multicenter RCT of SCS for refractory PDN was reported in 2014.[49] Sixty patients were randomized to best medical treatment with or without SCS and followed up for 6 months. The average VAS pain score decreased from 73 mm at baseline to 31 mm in the SCS group, whereas there were no changes in the non-SCS group. Patients in the SCS group also had improved quality of life measured with the EuroQoL 5D questionnaires.[49,50] Later in 2014, another RCT studied SCS for PDN in 36 patients and reported a trial success rate of 77%.[51] Treatment success at 6 months, defined as ≥50% pain relief, was reported in 59% of patients in the SCS group and 7% in the best medical treatment only group. Pain and sleep were "very much improved" in 55% and 36%, respectively, in the SCS group, whereas there were no changes in the medical treatment only group.[51] After 6 months, 93% of patients in the medical treatment only group crossed over to SCS treatment with success rates of 65% patients at 24-month[52] and 55% at 5-year follow-ups.[53] About 80% of patients continued to use the SCS treatment after 5 years.[53] Recent systematic reviews and meta-analyses of these studies demonstrated that SCS is an effective therapy in reducing PDN pain.[54,55]

All of the above-mentioned studies used conventional, paresthesia-based SCS, which makes blinding of the treatments questionable. Some patients may also complaint about discomfort of paresthesia associated with the stimulation. Recently, burst stimulation using 5 high-frequency pulses at 500 Hz running 40 bursts a second was tested and paresthesia was barely present.[56] In a study of 12 patients with refractory PDN, conventional tonic SCS was switched to burst SCS for 2 weeks.[57] It was found that tonic stimulation reduced the average VAS score from 70 to 28 mm while the burst stimulation further decreased the pain score to 16 mm. Eight of the 12 patients (67%) had additional pain reduction with burst stimulation as compared with tonic stimulation.[57]

Completely paresthesia-free, high-frequency SCS (HF-10, 10 kHz) was implanted in 8 patients with PDN in a pilot study. Among the 7 patients who attended the 12-month follow-up, 6 had at least 50% pain relief and 5 demonstrated improvements in sensory and reflex testing.[58] Petersen et al[59] recently reported a multicenter RCT study of HF-10 SCS for refractory PDN mainly in the lower extremities. A total of 216 patients were enrolled; 103 were randomized to conventional medical management (CMM) and 113 to HF-10 SCS plus CMM group. Patients were followed up at 3, 6, 12, and 24 months. At 6 months, patients could opt to crossover to the other treatment arm if they had insufficient (<50%) pain relief. As high as 82% (76 of 93) of patients in the CMM group elected to crossover while no patients in the SCS group did. The proportion of responders with ≥50% pain reduction from baseline was 5% (5 of 93) in the CMM group and 85% (74 of 87) in the SCS group at 6 months. Neurological assessments, including motor, sensory, and reflex testing, were improved in 60% (52 of 87) of patients in the SCS group, in contrast to 3% (3 of 93) in the CMM group. Sleep quality and the Global Assessment of Functioning were also improved in the SCS group but not the CMM group. HbA1c level increased in both groups at 6 months. Study-related adverse events included infection in 3 patients, wound dehiscence in 2 patients, impaired healing in 1 patient, among a total of 90 subjects; 2 of 90 implants required explant. The study is limited by nonblinding and potential placebo effects, which may be mitigated through the ongoing long-term follow-up.

In summary, these studies provide moderate to strong evidence to support the use of SCS in treating PDN in the lower extremities (evidence level: 1B+) while the efficacy and safety of SCS for upper extremity PDN remains to be investigated.

Dorsal Root Ganglion Stimulation

In a retrospective case series, dorsal root ganglion (DRG) stimulation with up to 4 quadripolar percutaneous leads between L2 and L5 were used in 10 patients with refractory PDN in the lower extremities.[60] Seven patients received permanent implant after successful trials. Four of 5 patients at 12-month follow-up had an average pain reduction of 64%. In a multicenter retrospective case series using DRG stimulation to treat peripheral neuropathy, 75% to 100% VAS improvement was reported in 2 patients with PDN at 6-week follow-up.[61] One patient completely discontinued the use of gabapentin while there was no change in drug use in the other patient. Interestingly, unilateral DRG leads placed at T12 and S1 significantly improved pain, disability, quality of life in a patient with refractory PDN in both lower extremities. The patient had significant relief of PDN-related symptoms of both feet.[62] Overall, the evidence of use DRG stimulation for PDN is limited to small sample size case series (2C+).

Surgical Decompression of the Peripheral Nerves

The metabolic derangement in PDN may render peripheral nerves susceptible to compression. Surgical decompression may help relieve pain in select cases.[63] In a multicenter prospective study, 628 subjects with diabetes underwent tarsal tunnel release and neurolysis of the medial and lateral plantar and calcaneal tunnels.[64] The procedures resulted in a significant decrease in mean VAS score from 8.5 to 2.0 at 6-month follow-up. The effects were maintained at 3.5 years after the surgery. However, interpretation of these results of this study is compromised due to lack of a control group. A single center prospective study compared a surgical group (214 patients) with a nonsurgical group (92 patients) and reported significant improvements in VAS pain score, Brief Pain Inventory Short Form for diabetic peripheral neuropathy questionnaire, 2-point discrimination, nerve conduction velocity, and high-resolution ultrasonography (cross-sectional area).[65] Pain relief was better in patients with "focal" than "diffuse" pain pattern.

A single-center RCT in 42 patients with PDN evaluated unilateral surgical decompression of the tibial, superficial, deep, and common peroneal nerves while using the contralateral limb as control (within-patient comparison).[66] The VAS scores improved significantly in 73.7% patients from a mean of 6.1 preoperatively to 3.5 postoperatively at 12 months, of which 35.7% patients had a decrease of more than 5 points. In a related article, the authors reported 42.5% of the study subjects achieved clinically important difference in VAS at 12 months.[67] But the surgery did not improve health-related quality-of-life scores[67] or the results of nerve conduction studies.[68] In another randomized single-blind study, 12 patients underwent lower extremity decompression surgery of the common peroneal, tibial, and deep peroneal nerves and 10 patients received usual care for 1 year.[69] Patients in the surgery group had significant VAS reduction at 3 and 6 months compared to the control groups. Although this benefit waned at 12 months, NeuroQol pain item sensitivity analysis demonstrated a statistically significant change of more than 3 points in VAS pain scores at 12 months compared to baseline. No statistically significant differences in quality of life were detected within or between groups. Patients in the surgical group had over 3 times the odds of rating their pain as "better" compared those in the control group at 12 months. A recent retrospective study in 36 patients with PDN reported that the mean NRS score decreased significantly at 6 days, 6 months, and 12 months after nerve decompression surgery.[70] At 12 months, 64.7% of patients had at least 50% reduction in NRS score from preoperative baseline.

A systematic review identified 8 prospective and 4 retrospective studies with a total of 1825 patients.[71] Meta-analysis showed that surgical decompression achieved clinically and statistically significant improvements in VAS and 2-point discrimination in the lower extremities. In contrast, a structured review concluded that the literature is insufficient to recommend surgical decompression of peripheral nerves for PDN, due to questionable definition of PDN, methodological design, issue of blindness, lack of specific controls/sham surgeries, and unexpected similar positive effect of sham surgery (reported only in an abstract and through the personal communications between the authors).[72] This conclusion is consistent with the recommendations based on studies published before 2006 by the American Academy of Neurology (AAN) Practice Advisory.[73] A RCT to assess cost-effectiveness of surgical decompression of peripheral nerves in the lower extremity compared to nonsurgical care is underway.[74]

In summary, large observational studies and small-sample sized RCTs provide moderate to strong evidence (2B± to 1B+) for surgical decompression of peripheral nerves to manage PDN. Well-designed high-quality RCTs are needed to overcome the limitations of published studies and to ascertain the role of surgical decompression in the management of PDN.

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