Interventional Therapies for Painful Diabetic Neuropathy

Table 1. Summary of Evidence Scores and Implications for Recommendation
Score	Description	Implication
1 A+	One or more RCTs of good methodological quality demonstrate effectiveness. The benefits clearly outweigh risk and burdens	Positive recommendation
1 B+	One or more RCTs with methodological weaknesses, demonstrate effectiveness. The benefits clearly outweigh risk and burdens
2 B+	One or more RCTs with methodological weaknesses, demonstrate effectiveness. Benefits closely balanced with risk and burdens
2 B±	Different RCTs or observational studies yield contradictory results better or no better than the control treatment. Benefits closely balanced with risk and burdens, or uncertainty in the estimates of benefits, risk and burdens	Considered, preferably study-related
2 C+	Effectiveness only demonstrated in observational studies. Given that there is no conclusive evidence of the effect, benefits closely balanced with risk and burdens
0	There is no literature or there are case reports available, but these are insufficient to suggest effectiveness and/or safety. These treatments should only be applied in relation to studies	Only study-related
2 C−	Observational studies indicate no or too short-lived effectiveness. Given that there is no positive clinical effect, risk and burdens outweigh the benefit	Negative recommendation
2 B−	One or more RCTs with methodological weaknesses, or large observational studies that do not indicate any superiority to the control treatment. Given that there is no positive clinical effect, risk and burdens outweigh the benefit
2 A−	RCT of a good quality which does not exhibit any clinical effect. Given that there is no positive clinical effect, risk and burdens outweigh the benefit

Abbreviation: RCTs, randomized controlled trials.

Table 2. Advancements in the Pain Management of Refractory PDN
	Level of evidence	Reference	Type of study	N (size)	Results	Side effects
Botox - A	2B+	Yuan et al (2009)³⁰	RCT	18	Forty-four percent (8/18) of patients in the study achieved a VAS reduction of >3 within 3 mo of the injections	Pain at injection site
	2B+	Ghasemi et al (2014)³¹	RCT	18	Thirty percent of patients in the onabotunlinumtoxin A group report no pain after receiving the injections compared to 0% of the placebo group	Pain at injection site
	1B+	Lakhan et al (2015)³²	Meta-analysis	36	Meta-analysis of the above 2 RCTs favors botulinum toxin A in PDN	Infection at injection site was not statistically significant
	2B+	Restivo et al (2018)³³	RCT	50	BTX-A (100 or 30 units) significantly improved calf or foot cramp in patients with PDN. Improvements started at 1 wk and maintained up to 14 wk	Mild pain in the injection site
Acupuncture	1B+	Chen et al (2013)³⁴	Meta-analysis	1649	23 of 25 trials reported global improvement by manual acupuncture but there were high risk of bias	No trials reported adverse effects
	1B+	Dimitrova et al (2017)³⁵	Meta-analysis	322	Four trials of PDN. Meta-analysis showed an overall benefit of acupuncture for PDN over control. The benefit remains after study heterogeneity was corrected	No acupuncture-related serious adverse events reported
	1B+	Chao et al (2019)³⁶	RCT	40	Acupuncture (once or twice a week) significantly reduced the average weekly pain score compared with usual care at week 12 but pain returns to baseline by week 18. Quality of life and physical functioning improved in the acupuncture group by week 18	15 mild side effects in 263 treatments. No serious adverse events were reported
	1B+	Shin et al (2018)³⁷	RCT	98	The EA treatment group showed significantly greater improvement on the short form McGill Pain Questionnaire, sleep interference scores, and the EuroQol-5 Dimensions questionnaire. The percentage of patients reporting improvement in the Patient Global Impression of Change was greater in the EA group	No significant difference in the incidence of adverse events (AEs) and SAEs between groups
Surgical decompression of peripheral nerve	2B±	Dellon et al (2012)⁶⁴	Multicenter prospective	628	Tarsal tunnel release and neurolysis of the medial and lateral plantar and calcaneal tunnels reduced mean VAS from 8.5 to 2.0 at 6 mo and remained for 3.5 y after the surgery. No control groups (nonsurgical or a negative Tinel sign) were included	Not discussed
	2B+	Liao et al (2014)⁶⁵	Comparative	306	VAS, BPI-DPN, and NCV were all improved in the surgical group (214 patients) compared to nonsurgical group (92 patients). Pain relief was better achieved in patients with "focal" than "diffuse" pain pattern. No patients in the surgical group developed new ulcer or required amputation during the 2-y follow-up	Two patients had wound dehiscence and 1 had subcutaneous hemorrhage in surgical group. Ten patients developed lower extremity skin ulcer and 2 underwent amputation
	1B+	van Maurik et al (2014)⁶⁶	RCT	42	Surgical decompression of peripheral nerves provided significant limb pain relief in 73.7 % patients at 12 mo compared to contralateral nondecompressed limb. Surgery did not change health-related quality-of-life score	Anticoagulants cause hematoma in 1 patient, wound infection happened in 2 patients at the ankle site
	1B+	Best et al (2019)⁶⁹	RCT	22	Surgery provided significant McGill pain VAS reduction at 3 and 6 mo but not at 12 mo compared to control groups. NeuroQol pain item sensitivity analysis demonstrated a statistically significant change of more than 3 points in pain scores at study end (12 mo) compared to baseline	Postoperative surgical site infection at the tarsal tunnel decompression site happened in 1 patient
	1B+	Tu et al (2017)⁷¹	Meta-analysis	1825	Meta-analysis showed surgical patients achieved clinically and statistically significant improvement in VAS and 2-point discrimination in lower extremities	Superficial wound infection, dehiscence, hematoma, ulcer
	1B+	Albers and Jacobson ^(2018)72	Systematic review	N/A	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, the literature is insufficient to recommend surgical decompression of peripheral nerves for PDN	Not discussed
Sympathetic nerve block or neurolysis	2C+	Cheng et al (2012)³⁸	Case report	1	A series of 9 lumbar sympathetic blocks over a 26-mo period provided sustained pain relief and improved quality of life over a period of more than 2 y	Not reported
	2C+	Ding et al (2018)³⁹	Retrospective	90	90 patients were randomly assigned to anhydrous ethanol (AE) neurolysis, RF, or AE + RF group. Pain starts to return at 3 mo after AE chemical blockade, 6 mo after RF, 1 y after combined AE and RF. Total remission rates in AE, RF, and AE + RF group at 1 year was 66.7%, 73.3%, and 93.3%, respectively	No severe complications were observed

Abbreviations: BPI-DPN, Brief Pain Inventory - Diabetic Painful Neuropathy; BTX-A, botulinum toxin-A; EA, electroacupuncture; N/A, not available; NCV, nerve conduction velocity; PDN, painful diabetic neuropathy; RCT, randomized clinical trial; RF, radiofrequency thermocoagulation; SAEs, serious adverse events; VAS, visual analog scale.

Table 3. Advancements in the Pain Management of Refractory PDN-SCS
2C+	Kumar et al (1996)⁴²	Retrospective study	4	Long-term pain relief in 3 of the 4 PDN patients on an average of 87-mo follow-up (not clear whether the 4 PDN followed such long)	Infection, fractured electrode, hardware malfunction, electrode displacements: not specifically for PDN
2C+	Tesfaye et al (1996)⁴³Daousi et al (2005)⁴⁴	Observational	10	Neuropathic pain and exercise tolerance improved in 6 patients at 14 mo. Prolonged pain relief up to 7 y	Superficial wound infection
2C+	de Vos et al (2009)⁴⁵	Open-label, prospective	11	Nine patients had significant pain relief and 8 reduced pain medication use at 6 mo	Mild infection in 1 patient resolved with antibiotics. Lead revision in 2 patients
2C+	Pluijms et al (2011)⁴⁶	Systematic review	25 total	SCS resulted in ≥50% pain relief reduced or withdrew analgesics usage in 60% patients at 1 y	Infection (14%), technical complications (24%), death from unrelated cause (19%) and remaining complications (10%)
2C+	Pluijms et al (2012)⁴⁷ Slangen et al (2013)⁴⁸	Prospective open-label cohort	15	Overall success rates of SCS on pain relief were 91% at 12 mo, 55% at 24 mo, and 64% at 36 mo. Improvement in QoL was seen in 64% of the patients at 12 mo, 55% at 24 mo, and 64% at 36 mo	No serious adverse events were encountered
1B+	de Vos et al (2014)⁴⁹; Duarte et al (2016)⁵⁰	Multicenter RCT	60	Significant reduction in average VAS pain score and improvement in health-related quality of life at 6 mo in SCS group compared to best medical treatment	2 infections, 1 femur fracture, and 1 cardiac arrest in the SCS group
1B+	Slangen et al (2014)⁵¹; van Beek et al⁵²; van Beek et al⁵³	Multicenter RCT	36	At 6 mo, 59% of patients in SCS group (vs 7% in best medical treatment group) had at least 50% pain reduction. 65% and 55% of patients in SCS group had ≥50% pain relief at 24 mo and 5 y, respectively. About 80% of patients still use the SCS treatment after 5 y	Postdural puncture headache and subdural hematoma in 1 case, infection and autonomic neuropathy in 1 case
1B+	Petersen et al (2021)⁵⁹	Multicenter RCT	216	High-frequency SCS was compared to SCS plus conventional medical management in refractory PDN. Responder rate, defined as at least 50% pain reduction from baseline, was 5% (5 of 93) in the CMM group and 85% (74 of 87) in the HF-10 SCS plus CMM group at 6 m. Neurological assessment including motor, sensory, and reflex testing were improved in 60% (52 of 87) in SCS plus CMM group (vs 3%, 3 of 93 in CMM group). 12 and 24 mo results coming soon	3 study-related adverse events for infection, 2 for wound dehiscence, and 1 for impaired healing among 5 of 90 subjects. Two of 90 implants required explant
1B+	Duarte et al (2021)⁵⁴	Meta-analysis	93	Meta-analysis showed significant pain reductions in patients received SCS compared with best medical therapy alone at the 6-mo follow-up. The proportion of patients achieved at least a 50% reduction in pain intensity was significantly higher in SCS compared with best medical therapy. SCS also improved health-related quality of life	Infection in 2 patients, pain from implanted IPG in 2 patients, 1 coagulopathy; 1 postdural puncture headache and subdural hematoma
1B+	Raghu et al (2021)⁵⁵	Meta-analysis	102	RCTs showed that tonic spinal cord stimulation provided greater pain relief than the best medical therapy at 6 mo	Not analyzed
2C+	de Vos et al (2014)⁵⁷	Evaluation studies	12	Patients who had at least 6 mo of conventional tonic SCS underwent burst stimulation for 2 wk. Burst SCS stimulation yielded significantly more pain reduction in 44% patients with little or no paresthesia	Headaches, dizziness, and the sensation of "heavy legs," "warm feet"

Abbreviations: CMM, conventional medical management; HF-10, high frequency 10 kHz; IPG, implantable pulse generator; PDN, painful diabetic neuropathy; QoL, quality of life; RCT, randomized clinical trial; SCS, spinal cord stimulation; VAS, visual analog scale.

Table 4. Risk of Bias Assessment in Included Studies
Study	Risk of bias arising from the randomization process	Risk of bias due to deviations from the intended interventions	Risk of bias in missing outcome data	Risk of bias in measurement of the outcome	Risk of bias in selection of the reported results	Overall risk of bias
Yuan et al (2009)³⁰	Low	Low	High	High	Some concerns	High
Ghasemi et al (2014)³¹	Low	Low	High	High	High	High
Lakhan et al (2015)³²	Low	Low	High	Some concerns	Some concerns	Some concerns
Restivo et al (2018)³³	Low	Low	Some concerns	High	Some concerns	High
Chen et al (2013)³⁴	Low	Some concerns	High	High	Some concerns	High
Dimitrova et al (2017)³⁵	Low	Some concerns	High	High	Some concerns	High
Chao et al (2019)³⁶	Some concerns	High	High	High	Some concerns	High
Shin et al (2018)³⁷	Low	Some concerns	High	High	Some concerns	High
Kumar et al (1996)⁴²	High	Some concerns	High	High	Some concerns	High
Tesfaye et al (1996)⁴³Daousi et al (2005)⁴⁴	High	Some concerns	High	High	High	High
de Vos et al (2009)⁴⁵	High	Some concerns	High	High	High	High
Pluijms et al (2011)⁴⁶	High	Some concerns	High	High	High	High
Pluijms et al (2012)⁴⁷Slangen et al (2013)⁴⁸	High	Some concerns	High	High	Some concerns	High
de Vos et al (2014)⁴⁹; Duarte et al (2016)⁵⁰	Low	Low	Some concerns	High	Some concerns	Some concerns
Slangen et al (2014)⁵¹; van Beek et al⁵²; van Beek et al⁵³	Low	Low	Some concerns	High	Some concerns	Some concerns
Petersen et al (2021)⁵⁹	Low	Low	Some concerns	High	Some concerns	Some concerns
Duarte et al (2021)⁵⁴	Low	Low	Some concerns	High	Some concerns	Some concerns
Raghu et al (2021)⁵⁵	Low	Low	Some concerns	High	Some concerns	Some concerns
de Vos et al (2014)⁵⁷	High	Some concerns	Some concerns	High	High	High
Dellon et al (2012)⁶⁴	High	Some concerns	High	High	High	High
Liao et al (2014)⁶⁵	High	Some concerns	Some concerns	High	High	High
van Maurik et al (2014)⁶⁶	Low	Some concerns	Some concerns	High	High	High
Best et al (2019)⁶⁹	Low	Some concerns	Some concerns	High	High	High
Tu et al (2017)⁷¹	High	Some concerns	Some concerns	High	High	High
Albers and Jacobson (2018)⁷²	High	Some concerns	Some concerns	High	High	High
Cheng et al (2012)³⁸	High	Low	High	High	Some concerns	High
Ding et al (2018)³⁹	Some concerns	Low	High	High	Some concerns	High

Authors and Disclosures

Li Xu, MD, PhD*, Zhuo Sun, MD†, Elizabeth Casserly, PharmD‡, Christian Nasr, MD§, Jianguo Cheng, MD, PhD||¶ and Jijun Xu, MD, PhD||#**

*Department of Anesthesiology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, China; †Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia; Departments of ‡Pharmacy, §Endocrinology, ||Pain Management, Anesthesiology Institute, ¶Neuroscience, Lerner Research Institute, and #Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; and **Department of Anesthesiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.

Address correspondence to
Jijun Xu, MD, PhD, 9500 Euclid Ave, Cleveland, OH 44195. Address e-mail to xuj3@ccf.org.

The authors declare no conflicts of interest.

Disclosures
Name: Li Xu, MD, PhD.
Contribution: This author helped write the manuscript, extract the data, interpret the results, and approve the final manuscript.
Name: Zhuo Sun, MD.
Contribution: This author helped write the manuscript, extract the data, interpret the results, and approve the final manuscript.
Name: Elizabeth Casserly, PharmD.
Contribution: This author helped write the manuscript, extract the data, interpret the results, and approve the final manuscript.
Name: Christian Nasr, MD.
Contribution: This author helped write the manuscript, extract the data, interpret the results, and approve the final manuscript.
Name: Jianguo Cheng, MD, PhD.
Contribution: This author helped design the study, write the manuscript, extract the data, interpret the results, and approve the final manuscript.
Name: Jijun Xu, MD, PhD.
Contribution: This author helped design the study, write the manuscript, extract the data, interpret the results, and approve the final manuscript.
This manuscript was handled by: Honorio T. Benzon, MD.

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