Description
Peripheral nerve stimulation (PNS) is a percutaneous system consisting of leads, electrodes, and a pulse transmitter that delivers electrical impulses to peripheral nerves. Leads are placed using ultrasound guidance and can be placed for temporary or permanent use in an outpatient procedure.

Summary of Evidence
For individuals who have peripheral, neuropathic, chronic pain who receive peripheral nerve stimulation (PNS), the evidence includes 1 randomized controlled trial (RCT). Relevant outcomes are symptoms, medication use, and quality of life. The RCT reported a statistically significant difference between the treatment group and control group at 90 days in mean reduction in average pain from baseline (27.2% vs. 2.3%; p < .0001) and reported 38% responders, defined as having at least a 30% decrease in the numerical rating scale (NRS) with no upward titration in pain medications, in the treatment group. The RCT had a sample size of 94 with broad descriptions of pain diagnoses, including diagnoses beyond the labeled indications, and a lack of sample population diversity that is not generalizable to the US. There was 51% missing follow-up data at 12 months. Additional evidence from RCTs with larger sample sizes and longer durations of comparative data are necessary to assess the efficacy and durability of PNS. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Background
Peripheral Neuropathic Chronic Pain
Chronic, noncancer pain is responsible for a high burden of illness and can be defined as persistent pain that lasts for more than 3 months.¹ Chronic pain of peripheral origin may be caused by damage to peripheral nerves impacting the upper and lower extremities.

Peripheral Nerve Stimulation
Peripheral nerve stimulation (PNS) has been used to treat chronic pain. It is a percutaneous system consisting of leads, electrodes, and a pulse transmitter that delivers electrical impulses to peripheral nerves. Leads are placed using ultrasound guidance and can be placed for temporary or permanent use in an outpatient procedure.

Regulatory Status
A number of PNS devices have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. These are listed in Table 1.

Two PNS devices by Stimwave Technologies Inc., the StimQ Peripheral Nerve Stimulator (PNS) System and the Receiver Kit, Trial Kit, Spare Lead Kit, Sterile Revision Kit, SWAG Kit, SWAG Accessory Kit, Charger Kit, were recalled in Sept 2020 for the product containing a non-functional component not referenced in product labeling.

Table 1. FDA-Cleared Peripheral Nerve Stimulation Devices (FDA Product Code: GZF)

Policy
Peripheral nerve stimulation as a treatment for chronic pain is investigational/unproven therefore considered NOT MEDICALLY NECESSARY.

Policy Guidelines
Spinal cord and dorsal root ganglion stimulation are covered in policy 70125 and are not reviewed herein.

The Nalu Medical Inc. and Neuspera Medical Inc. device indications state "trial devices are solely for trial stimulation (no longer than 30 days) to determine efficacy before recommendation for a permanent (long term) device."

Coding
See the Codes table for details.

Benefit Application

State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration‒approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African American, Asian, Black, Latino and Native American]; LGBTQIA [lesbian, gay, bisexual, transgender, queer, intersex, asexual]; women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Peripheral Nerve Stimulation for Chronic Neuropathic Pain
Clinical Context and Therapy Purpose
The purpose of PNS in individuals who have peripheral neuropathic chronic pain is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are individuals with peripheral neuropathic chronic pain which may be caused by damage to peripheral nerves impacting the upper and lower extremities that is persistent for longer than 3 months. This population does not include individuals with chronic pain such as craniofacial, migraine, low back and trunk, amputation, or post-traumatic pain.

Interventions
The therapy being considered is PNS. It is a percutaneous system consisting of leads, electrodes, and a pulse transmitter that delivers electrical impulses to peripheral nerves. Leads are placed using ultrasound guidance and can be placed for temporary or permanent use in an outpatient procedure.

Comparators
The following therapies are currently being used to make decisions about PNS: pharmacologic and nonpharmacologic treatments.

Outcomes
The general outcomes of interest are symptoms, medication use, and quality of life.

As a chronic condition, follow-up of at least 6 weeks to 12 months would be desirable to assess outcomes in chronic neuropathic pain.

The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommends that chronic pain trials should consider assessing outcomes representing 6 core domains: pain, physical functioning, emotional functioning, participant ratings of improvement and satisfaction with treatment, symptoms and adverse events, and participant disposition.² Table 2 summarizes provisional benchmarks for interpreting changes in chronic pain clinical trial outcome measures per IMMPACT.³

Table 2. Health Outcome Measures Relevant to Individuals with Chronic Pain

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A systematic review has been published.⁴ The only relevant RCT from the systematic review is discussed in the following section and the systematic review will not be discussed further here.

Randomized Controlled Trials
Deer et al. (2016) conducted an RCT to assess the safety and efficacy of PNS using the StimRouter Neuromodulation System to treat individuals with chronic pain of peripheral nerve origin.⁵ Participants (N = 94) were randomized 1:1 into the treatment (n = 45) or control (n = 49) group. The treatment group received PNS and a stable dose of pain medications, and the control group received no PNS and a stable dose of pain medications for 90 days. After 90 days, crossover from the control group to the treatment group was offered. Study visits were planned at 30, 60, and 90 days after randomization, with follow-up at 6 and 12 months. The primary outcomes were pain relief and safety. Average pain at rest was measured by a numerical rating scale (NRS) over 3 months and safety was assessed by adverse events reported during the 1-year study period. A responder was defined as having at least a 30% decrease in the NRS with no upward titration in pain medications. Secondary outcomes included changes in medication, quality of life, patient global impression of change scale (PGIC), and change in worst pain using the NRS. At 90 days, there was a statistically significant difference between the treatment group and control group in the mean reduction in average pain from baseline (27.2% vs. 2.3%; p < .0001). There were statistically significantly more responders in the treatment group compared to the control group (38% vs. 10%; p = .0048). At 90 days, the treatment group compared to the control group had a significantly better improvement in quality of life (change from baseline [mean ± SD]: 1.4 ± 5.9 vs. -0.2 ± 3.4; p = .037) and PGIC (mean ± SD: 4.8 ± 1.5 vs. 2.5 ± 1.9; p < .0001). There were no device related serious adverse events through follow-up (mean duration: 320 days). Study characteristics and results are summarized in Tables 3 and 4. Study limitations are summarized in Tables 5 and 6.

Table 3. Summary of Key RCT Characteristics

NR: not reported; RCT: randomized controlled trial

Table 4. Summary of Key RCT Results

PGIC: patient global impression of change; RCT: randomized controlled trial; SD: standard deviation.

Table 5. Study Relevance Limitations

US: United States.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 6. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Nonrandomized Studies
Nonrandomized studies have been published^6,7,8 but do not provide additional information on safety, efficacy, or subgroups beyond what is available in the RCT and will not be reviewed in detail here.

Section Summary: Peripheral Nerve Stimulation for Chronic Neuropathic Pain
The evidence includes 1 RCT. Relevant outcomes are symptoms, medication use, and quality of life. The RCT reported a statistically significant difference between the treatment group and control group in mean reduction in average pain from baseline at 90 days (27.2% vs. 2.3%; p < .0001) and reported 38% responders, defined as having at least a 30% decrease in the numerical rating scale (NRS) with no upward titration in pain medications, in the treatment group. The RCT had a sample size of 94 with broad descriptions of pain diagnoses, including diagnoses beyond the labeled indications, and a lack of sample population diversity that is not generalizable to the U.S. There was 51% missing follow-up data at 12 months. Additional evidence from RCTs with larger sample sizes and longer durations of comparative data are necessary to assess the efficacy and durability of PNS.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Pain and Neuroscience
In 2022, the American Society of Pain and Neuroscience published consensus clinical guidelines for the use of implantable peripheral nerve stimulation in the treatment of chronic pain based on a review of the literature through March 2021.⁹ Relevant recommendations for best practices pertinent to this review are listed below in Table 7.

Table 7. American Society of Pain and Neuroscience Best Practices Peripheral Nerve Stimulation Guidelines

DOR: degree of recommendation; LOE: level of evidence; PNS: peripheral nerve stimulation.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing trials that might influence this review are listed in Table 8.

Table 8. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References:

1. Hardt J, Jacobsen C, Goldberg J, et al. Prevalence of chronic pain in a representative sample in the United States. Pain Med. Oct 2008; 9(7): 803-12. PMID 18346058
2. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. Jan 2005; 113(1-2): 9-19. PMID 15621359
3. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. Feb 2008; 9(2): 105-21. PMID 18055266
4. Char S, Jin MY, Francio VT, et al. Implantable Peripheral Nerve Stimulation for Peripheral Neuropathic Pain: A Systematic Review of Prospective Studies. Biomedicines. Oct 17 2022; 10(10). PMID 36289867
5. Deer T, Pope J, Benyamin R, et al. Prospective, Multicenter, Randomized, Double-Blinded, Partial Crossover Study to Assess the Safety and Efficacy of the Novel Neuromodulation System in the Treatment of Patients With Chronic Pain of Peripheral Nerve Origin. Neuromodulation. Jan 2016; 19(1): 91-100. PMID 26799373
6. Langford B, D'Souza RS, Pingree M, et al. Treatment of Ulnar Neuropathic Pain with Peripheral Nerve Stimulation: Two Case Reports. Pain Med. May 02 2023; 24(5): 566-569. PMID 36271859
7. Oswald J, Shahi V, Chakravarthy KV. Prospective case series on the use of peripheral nerve stimulation for focal mononeuropathy treatment. Pain Manag. Nov 2019; 9(6): 551-558. PMID 31686589
8. Deer TR, Levy RM, Rosenfeld EL. Prospective clinical study of a new implantable peripheral nerve stimulation device to treat chronic pain. Clin J Pain. Jun 2010; 26(5): 359-72. PMID 20473041
9. Strand N, D'Souza RS, Hagedorn JM, et al. Evidence-Based Clinical Guidelines from the American Society of Pain and Neuroscience for the Use of Implantable Peripheral Nerve Stimulation in the Treatment of Chronic Pain. J Pain Res. 2022; 15: 2483-2504. PMID 36039168
10. Centers for Medicare & Medicaid. National Coverage Determination (NCD) for Peripheral Nerve Stimulation (L34328). 2019; https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?LCDId=34328. Accessed May 7, 2024.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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