Description
Peripheral subcutaneous field stimulation (PSFS) is a form of neuromodulation intended to treat chronic neuropathic pain. Applications of PSFS being evaluated are craniofacial stimulation for headache/migraine, craniofacial pain, or occipital neuralgia. PSFS is also being investigated for low back pain, neck and shoulder pain, inguinal and pelvic pain, thoracic pain, abdominal pain, fibromyalgia, and postherpetic neuralgia.

For individuals who have chronic neuropathic pain who receive PSFS, the evidence includes 1 randomized controlled trial (RCT), 1 nonrandomized comparative study, and case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. The single RCT, which used a crossover design, did not compare PSFS to alternatives. Rather, it compared different methods of PSFS. Among trial participants, 24 (80%) of 30 patients had at least a 50% reduction in pain with any type of PSFS. However, because the RCT did not include a sham group or comparator with a different active intervention, this trial offers little evidence for efficacy beyond that of a prospective, uncontrolled study. Case series are insufficient to evaluate patient outcomes due to the variable nature of pain and the subjective nature of pain outcome measures. Prospective controlled trials comparing PSFS with placebo or alternative treatment modalities are needed to determine the efficacy of PSFS for chronic pain. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
CHRONIC PAIN
Chronic, noncancer pain is responsible for a high burden of illness. Common types of chronic pain are lumbar and cervical back pain, chronic headaches, and abdominal pain. All of these conditions can be challenging to treat.

Treatment
Pharmacologic agents are typically the first-line treatment for chronic pain, and several classes of medications are available. They include analgesics (opioid and nonopioid), antidepressants, anticonvulsants, and muscle relaxants. A variety of nonpharmacologic treatments also exist, including physical therapy, exercise, cognitive-behavioral interventions, acupuncture, chiropractic, and therapeutic massage.

Neuromodulation, a form of nonpharmacologic therapy, is usually targeted toward patients with chronic pain refractory to other modalities. Some forms of neuromodulation, such as transcutaneous electrical nerve stimulation and spinal cord stimulation (SCS), are established methods of chronic pain treatment. Peripheral nerve stimulation, which involves placement of an electrical stimulator on a peripheral nerve, is also used for neuropathic pain originating from peripheral nerves.

Peripheral Subcutaneous Field Stimulation
Peripheral subcutaneous field stimulation (PSFS) is a modification of peripheral nerve stimulation. In PSFS, leads are placed subcutaneously within the area of maximal pain. The objective of PSFS is to stimulate the region of affected nerves, cutaneous afferents, or the dermatomal distribution of the nerves, which then converge back on the spinal cord. Combination SCS plus PSFS is also being evaluated.

Similar to SCS or peripheral nerve stimulation, permanent implantation is preceded by a trial of percutaneous stimulation with at least 50% pain reduction. Currently, there is no consensus on the indications for PSFS. Criteria for a trial of PSFS may include a clearly defined, discrete focal area of pain with a neuropathic or combined somatic/neuropathic pain component with characteristics of burning and increased sensitivity, and failure to respond to other conservative treatments including medications, psychological therapies, physical therapies, surgery, and pain management programs.

The mechanism of action in PSFS is unknown. Theories include an increase in endogenous endorphins and other opiate-like substances; modulation of smaller A delta and C nerve fibers by stimulated largediameter A beta fibers; local stimulation of nerve endings in the skin; local anti-inflammatory and membrane-depolarizing effect; or a central action via antegrade activation of A beta nerve fibers. Complications of PSFS include lead migration or breakage and infection of the lead or neurostimulator.

Regulatory Status
In July 2018, the SPRINT Peripheral Nerve Stimulation System  (SPR Therapeutics, Inc) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process (K181422). FDA determined that this device was substantially equivalent to existing devices for use in pain management. PSFS is alsoan off-label use of spinal cord stimulation devices that have been approved by the Food and Drug Administration for the treatment of chronic pain (see evidence review 7.01.25).

Related Policies
70125 Spinal Cord Stimulation

Policy
Peripheral subcutaneous field stimulation is investigational and/ or unproven and therefore considered NOT MEDICALLY NECESSARY. 

Policy Guidelines
Please see the Codes table for details.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all U.S. Food and Drug Administration (FDA)-approved devices, drugs or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale  
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the 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 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 technology, 2 domains are examined: the relevance, and the quality and credibility. To be relevant, studies must represent 1 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 (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs 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.

Chronic neuropathic pain
Clinical Context and Therapy Purpose
The purpose of peripheral subcutaneous field stimulation in patients who have chronic neuropathic pain is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does peripheral subcutaneous field stimulation improve the net health outcome in patients with chronic neuropathic pain?

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

Populations
The relevant population of interest is individuals with chronic neuropathic pain.

Interventions
The therapy being considered is peripheral subcutaneous field stimulation. Peripheral subcutaneous field stimulation is a modification of peripheral nerve stimulation. In peripheral subcutaneous field stimulation, leads are placed subcutaneously within the area of maximal pain. The objective of peripheral subcutaneous field stimulation is to stimulate the region of affected nerves, cutaneous afferents, or the dermatomal distribution of the nerves, which then converge back on the spinal cord.

Comparators
The following therapies are currently being used to make decisions about peripheral subcutaneous field stimulation: pharmacotherapy, exercise or physical therapy, and cognitive-behavioral therapy.

Outcomes
The general outcomes of interest are symptoms, functional outcomes, quality of life, and treatment-related morbidity.

As a chronic condition, follow-up of at least 6 weeks to 12 months would be desirable to assess outcomes in chronic neuropathic 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.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
One crossover RCT compared levels of peripheral subcutaneous field stimulation. McRoberts et al. (2013) reported on a randomized, crossover trial of different types of peripheral subcutaneous field stimulation in 44 patients with chronic back pain. In the first phase of the trial, patients rotated through 4 levels of peripheral subcutaneous field stimulation: minimal, subthreshold, low frequency, and standard stimulation.¹ Of 30 patients who completed the first phase, 24 reported that pain was significantly reduced by at least 50% in all of the stimulation groups and were considered responders. In phase 2, a permanent peripheral subcutaneous field stimulation system was placed in 23 responders. During the 52 weeks over which these patients were followed, reported mean visual analog scale scores, present pain index, and total scores on the Short-Form McGill Pain Questionnaire were significantly improved from baseline at all follow-up visits (p < 0.001). Because this trial did not include a control group, the methodologic strength of these results is similar to that of an uncontrolled study.

Johnson et al. (2021) conducted a 2-part study comprised of a double-blind, sham controlled RCT followed by an open-label mechanistic study to determine the impact of external non-invasive peripheral electrical nerve stimulation (ENPENS) in adults with chronic moderate to severe peripheral nerve injury pain.[Johnson S, Marshall A, Hughes D, et al. Mechanisti.... 021; 19(1): 458. PMID 34742297] Patients were randomized to either active ENPENS or sham for 3 months (minimum 10 minutes daily). The primary outcome was change in average pain intensity (on a 0 to 10 Likert scale) after ENPENS or sham. Seventy-six patients were randomized (38 per group), with 65 (31 active, 34 sham) included in the intention-to-treat analysis. After adjusting for baseline scores, pain scores were 0.3 units lower in the active group, but not significantly different from the sham group (p = .30). Nineteen patients continued on to the open-label ENPENS mechanistic study after the RCT. In the open-label phase, primary outcomes of mechanical pain sensitivity (p = .006) and mechanical allodynia (p = .043) significantly improved, indicating reduced sensitivity to pain with low-frequency nerve stimulation. Results from the RCT failed to reach significance and the results from the open-label portion were limited by the small sample size and lack of a comparator group.

Nonrandomized Comparative Study
In another comparative study, Mironer et al. (2011) used a 2-part evaluation of combined use of spinal cord stimulation and peripheral subcutaneous field stimulation in patients with low back pain.³ In the first part of the study, 20 patients with failed back surgery syndrome or spinal stenosis underwent a trial with both spinal cord stimulation and peripheral subcutaneous field stimulation and selected the type of stimulation they found most efficacious (program 1: spinal cord stimulation alone; program 2: peripheral subcutaneous field stimulation alone; program 3: combined spinal cord stimulation plus peripheral subcutaneous field stimulation). Patients were blinded to the differences among the programs (randomized order of presentation) and were encouraged to try each program for at least 8 hours; 79% of patients preferred the combined use of spinal cord stimulation plus peripheral subcutaneous field stimulation. In the second part of the study, 20 patients were implanted with spinal cord stimulation and peripheral subcutaneous field stimulation electrodes and selected which program they preferred (spinal cord stimulation and peripheral subcutaneous field stimulation used simultaneously, spinal cord stimulation as anode and peripheral subcutaneous field stimulation as cathode, spinal cord stimulation as cathode and peripheral subcutaneous field stimulation as anode). The programs were presented in a random order, and patients were blinded to the differences among the programs offered. Communication between spinal cord stimulation and peripheral subcutaneous field stimulation was reported to provide wider coverage of axial pain, with an overall success rate (> 50% pain relief) of 90%. The most effective program was spinal cord stimulation as cathode and peripheral subcutaneous field stimulation as anode.

Case Series
In addition to the controlled studies, a number of case series have been published, several of which included 50 or more patients. Kloimstein et al. (2014) reported on a prospective multicenter study of 118 patients treated with peripheral subcutaneous field stimulation for chronic low back pain.⁴  Before patients were implanted with the permanent peripheral subcutaneous field stimulation system, trial stimulation was given for at least 7 days. The permanent stimulation system was implanted in 105 patients. Significant improvements occurred at the 1-, 3-, and 6-month postimplantation follow-ups in average visual analog score pain, Oswestry Disability Questionnaire, Beck Depression Inventory, and 12-Item Short-Form Health Survey scores. Significant reductions in use of opioids, nonsteroidal anti-inflammatory, and anticonvulsant medications were also reported.

Sator-Katzenschlager et al. (2010) reported on a retrospective multicenter study of peripheral subcutaneous field stimulation.⁵ A total of 111 patients with chronic focal noncancer pain were treated, including 29 patients with low back pain, 37 with failed back surgery syndrome, 15 with cervical neck pain, and 12 patients with postherpetic neuralgia. The median duration of chronic pain was 13 years, and the median number of previous surgeries was 2.7. For permanent implantation of the leads, patients had to have achieved at least 50% reduction in pain on a numeric rating scale during the trial period. After permanent implantation, pain intensity decreased in 102 (92%) patients. Mean pain intensity decreased from 8.2 at baseline to 4.0 at follow-up, with a concomitant reduction in consumption for analgesics and antidepressants. Lead dislocation or fracture occurred in 20 (18%) patients.

Verrills et al. (2011) reported on a series of 100 patients treated with peripheral subcutaneous field stimulation for chronic neuropathic pain. Indications included chronic pain occurring among varying regions: occipital/craniofacial (n = 40), lumbosacral (n = 44), thoracic (n = 8), groin/pelvis (n = 5), or abdominal (n = 3).⁶ Selection criteria included a clearly defined, discrete focal area of pain with a neuropathic component or combined somatic/neuropathic pain component with characteristics of burning and increased sensitivity, and failure to respond to other conservative treatments, including medications, psychological therapies, physical therapies, surgery, and pain management programs. Outcomes, assessed at a mean of 8.1 months after implantation (range, 1- to 23 months), included a combination of numeric pain scores, self-report questionnaires, and patient medical histories. For the entire cohort, pain decreased from 7.4 at baseline to 4.2 at follow-up. Pain scores improved by 75% or more in 34% of patients and by 50% or more in 69% of patients. Analgesia use decreased in 40% of patients after peripheral subcutaneous field stimulation. Adverse events were reported in 14% of patients and included unpleasant sensations, lead erosions, and lead or battery migration.

Verrills et al. (2014) also reported on peripheral subcutaneous field stimulation for chronic headache conditions.⁷ After a trial stimulation period, 60 patients underwent permanent implantation of the peripheral subcutaneous field stimulation system and were followed for an average of 12.9 months (range, 3 to 42 months). Ten patients required revision of the implant system. Significant reductions in pain from baseline were reported (p ≤ 0.001). Additionally, use of analgesics or prophylactic medications was reduced in 83% of patients, and reductions in degree of disability and depression were noted.

A retrospective case series by Warner et al. (2020) reported on adults undergoing peripheral nerve stimulation implantation at an academic medical center.[Warner NS, Schaefer KK, Eldrige JS, et al. Periphe ... 21(4): 411-418. PMID 33222402] The primary outcomes were changes in numeric rating scale pain scores, opioid use in oral morphine milligram equivalent (MME), and self-reported patient functioning at 6 months post-implantation. A total of 72 patients underwent peripheral nerve stimulation implantation. The most common indication for stimulation was occipital neuralgia (47.3%) followed by lower-extremity neuropathies (16.5%). Peripheral nerve stimulation implantation was associated with a 6-month reduction in pain scores (median baseline score 7 vs median score 4 at 6 months; p < .001) and opioid utilization (median 60 MME at baseline vs median 18 MME among those with baseline opioid use [n = 25]; p < .001). All patients reported improvement in daily functioning, with median improvement of 73% post-implantation.

Summary of Evidence
For individuals who have chronic neuropathic pain who receive peripheral subcutaneous field stimulation, the evidence includes a 2 RCTs, a nonrandomized comparative study, and case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. One RCT, McRoberts et al. (2013), which used a crossover design, did not compare peripheral subcutaneous field stimulation with alternatives. Rather, it compared different methods of peripheral subcutaneous field stimulation. Among trial participants, 24 (80%) of 30 patients had at least a 50% reduction in pain with any type of peripheral subcutaneous field stimulation. However, because the RCT did not include a sham group or comparator with a different active intervention, this trial offers little evidence for efficacy beyond that of a prospective, uncontrolled study. Another RCT by Johnson et al. (2021) compared sham to external non-invasive peripheral electrical nerve stimulation, but found no significant differences in pain scores between groups after intervention. Case series are insufficient to evaluate patient outcomes due to the variable nature of pain and the subjective nature of pain outcome measures. Prospective controlled trials comparing peripheral subcutaneous field stimulation with placebo or alternative treatment modalities are needed to determine the efficacy of peripheral subcutaneous field stimulation for chronic pain. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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.

National Institute for Health and Care Excellence
In 2013, issued guidance on peripheral subcutaneous field stimulation for chronic low back pain, which stated:⁹

“Current evidence on the efficacy of peripheral nerve-field stimulation for chronic low back pain is limited in both quantity and quality, and duration of follow-up is limited. Evidence on safety is also limited and there is a risk of complications from any implanted device.”

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

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

References   

1. McRoberts WP, Wolkowitz R, Meyer DJ, et al. Peripheral nerve field stimulation for the management of localized chronic intractable back pain: results from a randomized controlled study. Neuromodulation. Nov-Dec 2013; 16(6): 565-74; discussion 574-5. PMID 23577773
2. Johnson S, Marshall A, Hughes D, et al. Mechanistically informed non-invasive peripheral nerve stimulation for peripheral neuropathic pain: a randomised double-blind sham-controlled trial. J Transl Med. Nov 06 2021; 19(1): 458. PMID 34742297
3. Mironer YE, Hutcheson JK, Satterthwaite JR, et al. Prospective, two-part study of the interaction between spinal cord stimulation and peripheral nerve field stimulation in patients with low back pain: development of a new spinal-peripheral neurostimulation method. Neuromodulation. Mar-Apr 2011; 14(2): 151-4; discussion 155. PMID 21992203
4. Kloimstein H, Likar R, Kern M, et al. Peripheral nerve field stimulation (PNFS) in chronic low back pain: a prospective multicenter study. Neuromodulation. Feb 2014; 17(2): 180-7. PMID 24320718
5. Sator-Katzenschlager S, Fiala K, Kress HG, et al. Subcutaneous target stimulation (STS) in chronic noncancer pain: a nationwide retrospective study. Pain Pract. Jul-Aug 2010; 10(4): 279-86. PMID 20230450
6. Verrills P, Vivian D, Mitchell B, et al. Peripheral nerve field stimulation for chronic pain: 100 cases and review of the literature. Pain Med. Sep 2011; 12(9): 1395-405. PMID 21812906
7. Verrills P, Rose R, Mitchell B, et al. Peripheral nerve field stimulation for chronic headache: 60 cases and long-term follow-up. Neuromodulation. Jan 2014; 17(1): 54-9. PMID 24165152
8. Warner NS, Schaefer KK, Eldrige JS, et al. Peripheral Nerve Stimulation and Clinical Outcomes: A Retrospective Case Series. Pain Pract. Apr 2021; 21(4): 411-418. PMID 33222402
9. National Institute for Health and Care Excellence (NICE). Peripheral nerve-field stimulation for chronic low back pain [IPG451]. 2013; https://www.nice.org.uk/guidance/ipg451. Accessed March 1, 2022.

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, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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