Effects of Ultrasound-Guided Nerve Stimulation Targeting Peripheral Nerve Tissue on Pain and Function: A Scoping Review

This paper assesses the effects of percutaneous electrical nerve stimulation (PENS) on pain- and function-related outcomes by means of a scoping review of studies with single cases, case-series, quasi-experimental, and randomized or non-randomized trial designs. We consulted the PubMed, MEDLINE and EMBASE databases. Data were extracted by two reviewers. The methodological quality of studies was assessed using the Physiotherapy Evidence Database (PEDro) scale for experimental studies and the Joanna Briggs Institute (JBI) tool for case reports or cases series. Mapping of the results included: (1), description of included studies; (2), summary of results; and, (3), identification of gaps in the existing literature. Eighteen articles (five randomized controlled trials, one trial protocol, nine case series and three case reports) were included. The methodological quality of the papers was moderate to high. The conditions included in the studies were heterogeneous: chronic low back pain, lower limb pain after lumbar surgery, chronic post-amputation pain, rotator cuff repair, foot surgery, knee arthroplasty, knee pain, brachial plexus injury, elbow pain and ankle instability. In addition, one study included a healthy athletic population. Interventions were also highly heterogeneous in terms of sessions, electrical current parameters, or time of treatment. Most studies observed positive effects of PENS targeting nerve tissue against the control group; however, due to the heterogeneity in the populations, interventions, and follow-up periods, pooling analyses were not possible. Based on the available literature, PENS interventions targeting peripheral nerves might be considered as a potential therapeutic strategy for improving pain-related and functional outcomes. Nevertheless, further research considering important methodological quality issues (e.g., inclusion of control groups, larger sample sizes and comparatives between electric current parameters) are needed prior to recommending its use in clinical practice.


Introduction
Percutaneous electrical nerve stimulation (PENS) consists of the application of electric current through a solid filiform needle. The needle is inserted and ultrasound-guided until the tip of the needle is placed into musculoskeletal structures, but also nearby peripheral nerves to induce sensitive or motor stimulation with different therapeutic objectives [1]. This intervention is defined as a minimally invasive treatment and the US-guided use ensures patient safety with regard to avoiding adverse events derived from needling punctures of sensible tissues. Thus, it is a cost-effective intervention compared with pharmacological treatments or infiltrations [2]. The electrical current most commonly

Study Design
This scoping review will provide the readers with a broad overview of the existent literature on PENS targeting peripheral nerves, where the heterogeneity of methods and populations could be comprised. As recommended by Arksey and O'Malley [28], we first identified the research question, identified relevant studies on this topic, selected the studies, charted the data and, finally, collated, summarized and reported the results extracted from the studies. We followed the guidelines reported on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) [29]. This scoping review was prospectively registered on 17 May 2022 in the Open Science Framework (registration DOI: 10.17605/OSF.IO/64RVM).

Identifying the Research Question
The research question aimed to analyze the potential clinical utility of PENS interventions aimed peripheral nerves for improving pain or functional outcomes. Therefore, the research question was: "Is Percutaneous Electrical Nerve Stimulation that targeting peripheral nerves an effective intervention for improving pain and related-functions?"

Identifying the Relevant Studies
A literature search was conducted on three databases as recommended by Dhammi and Haq [30] up to 31 May 2022 in the PubMed, MEDLINE and EMBASE databases. After a first scanning, we also revised those articles referenced in the identified papers. Since not all journals are indexed in those databases, we manually screened the articles published in specific key journals. The search was conducted by two members of the research group with the assistance of an experienced health science librarian. Articles were filtered to those published in the English or Spanish languages, conducted in humans and including single case studies, case-series, quasi-experimental, and randomized or non-randomized clinical trials.
The search strategy combined the following terms using Boolean operators follows for all databases as follows (Table 1). Stimulation" OR "Nerve Tissue Stimulation" #2 "Pain" OR "Related-disability" OR "Function" OR "Mobility" #3 #1 AND #2

Selecting the Studies
The PCC (Participants, Concept, Context) framework was followed to identify the main concepts: Participants: Healthy participants or clinical populations with musculoskeletal pain. Concept: Use of PENS targeting peripheral nerves. Context: Evaluation of functional and pain-related changes after intervention After a first screening, consisting of a first title and abstract reading, a full-text read of the remaining studies was conducted. In case of discrepancies between both reviewers, a third author would be asked to make a determination.

Charting the Data
Data extraction was conducted with a data charting form as recommended by Arkesy and O'Malley [28], providing a standardized summary of the results for each article included in the scoping review. All data were extracted by two authors including the authors' information, year of publication, population, sample size, intervention details and pain or functional outcomes assessed [31]. Again, both authors had to achieve consensus on each item and in case of disagreement, a third author would provide a final decision.

Mapping the Data
After data extraction, we mapped the literature thematically, providing a description of the identified and included studies, a summary of the results and, finally, identifying gaps in the existing literature.

Methodological Quality Assessment
The methodological quality of all studies was assessed by both authors using the Physiotherapy Evidence Database (PEDro) scale [32] for experimental studies and the Joanna Briggs Institute (JBI) tool for case reports [33].
The PEDro scale is widely used to assess the methodological quality of experimental trials and includes 11 items. The first item, although is not included in the score, is related to external validity. The following 10 items are used to calculate the final score (ranging from 0 to 10 points), evaluating the random allocation, concealed allocation, similarity at baseline, subject blinding, therapist blinding, assessor blinding, lost follow-up, intention-to-treat analysis, between-group statistical comparison, and point/variability measures for at least one key outcome. Total scores between 0 and 3 are considered "poor", 4 and 5 as "fair", 6 and 8 are considered "good", and 9 and 10 are "excellent" for this scale [32].
The methodological quality of case series and case reports was assessed using the JBI tool [33,34]. The critical appraisal of case reports assesses whether the studies describe the patient's demographic characteristics, the patient's history, the clinical condition of the patient, the diagnostic tests and results, the interventions, post-clinical conditions and adverse events, and if there is any key lesson learned from the exposed case, in an eight-item scale with Yes/No/Unclear possible answers for each item [33]. On the other hand, the JBI tool used for assessing the methodological quality of case series considers whether the studies described the inclusion criteria, if measurement tools were standard, valid and reliable, consecutive inclusion, completed inclusion of participants, reported the demographics and clinical information of participants, described the outcomes, presented the sites and clinics demographic information and statistical analyses were appropriate on a 10-point scale [34].
to external validity. The following 10 items are used to calculate the final score (ranging from 0 to 10 points), evaluating the random allocation, concealed allocation, similarity at baseline, subject blinding, therapist blinding, assessor blinding, lost follow-up, intentionto-treat analysis, between-group statistical comparison, and point/variability measures for at least one key outcome. Total scores between 0 and 3 are considered "poor", 4 and 5 as "fair", 6 and 8 are considered "good", and 9 and 10 are "excellent" for this scale [32].
The methodological quality of case series and case reports was assessed using the JBI tool [33,34]. The critical appraisal of case reports assesses whether the studies describe the patient's demographic characteristics, the patient's history, the clinical condition of the patient, the diagnostic tests and results, the interventions, post-clinical conditions and adverse events, and if there is any key lesson learned from the exposed case, in an eightitem scale with Yes/No/Unclear possible answers for each item [33]. On the other hand, the JBI tool used for assessing the methodological quality of case series considers whether the studies described the inclusion criteria, if measurement tools were standard, valid and reliable, consecutive inclusion, completed inclusion of participants, reported the demographics and clinical information of participants, described the outcomes, presented the sites and clinics demographic information and statistical analyses were appropriate on a 10-point scale [34].

Methodological Quality
The methodological quality assessment of the experimental studies is reported in Table 2. Scores ranged from 4 to 8 with a mean value of 6.5 ± 1.5 points. The most repeated flaw was the lack of intention to treat analysis [11,12,36,37,49]. On the other hand, all the studies considered a random allocation.  [12] RCT-P + The methodological quality assessment of case reports is reported in Table 3. The only three case reports found during the review had a methodological quality score of 7 out of 8 points, this being the lack of adverse events description, which was the only flaw found in all of the studies [38,40,44,45]. Table 3. JIB tool for assessing the methodological quality of case reports. Finally, the methodological quality assessment of case series is summarized in Table 4. All studies assessed the conditions with standard and reliable tools, used valid methods for identifying the condition, clearly reported the outcomes during the follow-up period and clearly reported the sites' demographic information. The most constant flaw was the absence of consecutive inclusion of participants. In fact, only one study provided this information [43].

Summarizing Findings
The characteristics of the participants in the included studies are reported in Table 5. The total sample consisted of 257 patients (139 men, 128 women) with recruited samples ranging from single case reports [38,44] to clinical trials including 80 subjects [36].

Discussion
Although a previous meta-analysis analyzing the efficacy of PENS in pain-related outcomes has been published [5], this is the first scoping review focusing on pain and functional changes when PENS is specifically applied targeting the peripheral nerves.

Literature Mapping
Despite the short lifetime of this novel therapeutic approach, multiple pain conditions benefited from the use of PENS targeting peripheral nerve tissue. The most widely assessed conditions were chronic low back pain (three articles, all of them with a case series design [10,43,46]) and unilateral anterior knee pain (two articles, a randomized clinical trial [37] and a case series [42]). Even though one of the most important discussions is currently whether the frequency, duration, intensity and pulse width may induce different effects, none of the studies compared two different modalities of PENS in the same article.
Although previous studies have reported the mechanisms behind high-frequency and low-frequency currents (regarding the activation of endogenous opioid receptors) supporting the different peripheral antinociceptive responses depending on the stimulation received [5], three studies reported similar improvements in low back pain intensity and disability in the mid-term [43] and long-term [10,46]. However, it should be noted that previous studies analyzing the effects of electric current parameters on sensory variables were mostly focused on mechano-sensitivity indicators (e.g., pressure pain thresholds) instead of clinical self-reported pain intensity. While pain experience is highly subjective and a complex experience influenced by several factors [50], local responses dependent of electrical current parameters may produce changes in primary or secondary hyperalgesic areas [5].
Regarding the efficacy of PENS targeting peripheral nerves in populations with unilateral anterior knee pain, both studies used similar current parameters [37,42] and assessed pain-related (in the study conducted by García-Bermejo et al. [37]) and physical conditioning (in the study conducted by Álvarez-Prats et al. [42]) outcomes. In both cases, the studies showed significant changes compared with the baseline in terms of maximal isometric strength of the quadriceps, range of movement, pain intensity and disability in the short term.
Comparison between studies for the rest of the conditions including lower limb pain after lumbar surgery [38], chronic post-amputation pain [11], musculoskeletal impairments after unilateral rotator cuff repair [35], foot surgery [39] and knee arthroplasty [48], reduced hamstring flexibility [36], brachial plexus injury [40], lateral elbow pain [44] and ankle instability [45] was not possible as only one study was found for each condition. However, in general all studies reported good results in the short, middle and long term after PENS interventions targeting peripheral nerves.
Finally, the experimental studies including a comparative group were also heterogeneous. For instance, Garcia-Bermejo et al., [36] compared the effects of a single PENS intervention between clinical and healthy populations (with comparable effects between groups) while Gallego-Sendarrubias et al., [47] compared the inclusion of PENS as a complementary intervention to a training program in a sample of semiprofessional soccer players without symptoms. While the effects of PENS seem to be similar in both the clinical and healthy populations, the inclusion of this technique demonstrated additional improvements in the short-term regarding sports performance. However, in the mid-term these differences are not significant.

Strengths and Limitations of the Review
The results from this scoping review should be interpreted according to its potential strengths and limitations. Strengths of this scoping review include a comprehensive literature search, methodological rigor, data extraction, and the inclusion of studies (experimental studies, case reports and case series) of moderate to high methodological quality. However, some potential limitations are also present. First, despite the high number of studies initially identified, only a relatively small number (n = 17) were finally included in the review, since the remaining paper was a proposed protocol. The most important issue was the heterogeneity in the conditions, nerves targeted, outcomes and populations included. Second, most studies are from the same research teams. Third, most of the studies had a design with no control groups and limited samples, which limits the clinical application or the real effectiveness of this intervention. As has been previously stated, studies investigating the efficacy of PENS targeting different peripheral nerves, in different clinical conditions and assessing different outcomes (i.e., pain intensity, function, sports performance, muscle strength, muscle stiffness, range of movement or balance, for mentioning some), should be conducted to further elucidate whether this intervention could be recommended in specific conditions. In addition, further studies should consider the comparison between different current modalities in the short-, middle-and long-term in order to provide clinicians with guidelines based on adequate scientific evidence.

Conclusions
This scoping review analyzed the efficacy of PENS intervention targeting peripheral nerves on pain-related and functional outcomes in both clinical and asymptomatic populations. The results were highly heterogeneous in terms of conditions assessed, outcomes measured, follow-up periods, study designs, electric current parameters, samples, intervention programs, number of sessions and nerves targeted. Based on the available literature, PENS interventions targeting peripheral nerves might be considered as a potential therapeutic strategy for improving pain-related and functional outcomes. Nevertheless, further research considering important methodological quality issues (e.g., inclusion of control groups, larger sample sizes and comparatives between electric current parameters) are needed prior to recommending its use in clinical practice.