A narrative review of pulsed radiofrequency for the treatment of carpal tunnel syndrome

Carpal tunnel syndrome (CTS), which is the most common peripheral nerve entrapment syndrome, can commonly persist despite conservative treatment modalities such as wrist splinting or medications. Pulsed radiofrequency represents a minimally invasive pain intervention technique to alleviate pain. The literature was reviewed to establish the effectiveness of PRF therapy for CTS.

7% and 25% and the requirement for repeat surgery in up to 12% of cases. 2 In addition, complications of the surgical release include painful neuromas, subluxation of flexor tendons, tender or hypertrophic scars, as well as wound infections, and complex regional pain syndrome. 3s such, it is prudent to ensure patients are being offered options that are minimally invasive with fewer risk of complications in the treatment of symptomatic CTS.
Pulsed radiofrequency (PRF) is the application of significant and extremely powerful electric fields without generating a significant thermal effect. 4Unlike continuous radiofrequency (CRF), PRF does not produce any anatomical lesions in the intended target.Given the pulsatile nature of PRF, the relatively long pauses between pulses allow for dissipation of the heat generated.As the heat is not able to accumulate, this prevents the development of a destructive lesion.The mechanisms underlying the therapeutic effects of PRF are not yet fully understood.
Though further research is needed to fully identify the treatment mechanism, PRF has been shown to have therapeutic benefit in a variety of chronic pain conditions.Currently, PRF is being explored for conditions not traditionally treated by CRF.The bulk of the evidence to support the use of CRF is in the treatment of facetogenic pain by ablating the medial branches of the primary dorsal ramus. 4CRF induces coagulative necrosis in targeted nervous tissue felt to be responsible for producing pain.However, many conditions may not be amenable to CRF, where it may not be desirable to create a destructive lesion of neural structures that subserve important neurological functions, such as motor innervation.As such, it is has been suggested that PRF, which does not result in a clear destructive lesion, may be beneficial in pain syndromes due to nerve injury.Carpal tunnel syndrome is one such entity.
Given the efficacy of PRF targeting the dorsal root ganglion and other targets, 4,5 it has been suggested that PRF may be a viable treatment modality for CTS.This is particularly relevant given PRF does not have the destructive element that would otherwise affect the motor function provided by the median nerve.Furthermore, given its lack of known long-term risks (such as with glucocorticosteroids), the intervention may be repeated safely to manage the patient's pain disorder.It also has the feature of being minimally invasive, and thus may represent an option in the subset of patients who may not be candidates for surgical release and those patients who have persistent pain following surgical management.Although the utility of PRF has been established for other pain disorders, this has not yet been done in CTS.Thus, this review aims to summarize the current literature analyzing the effect of PRF for patients with CTS.

M ET HOD
We performed a narrative review to examine the effect of PRF on patients with CTS.We searched the MEDLINE database, Cochrane Central Register of Controlled Trials, Embase, OVID Emcare, and Web of Science from inception to September 12, 2022, including published articles that described case reports.The following key phrases were used: "PRF" OR "pulsed radiofrequency" OR "radiofrequency" OR "Pulsed Radio Frequency Treatment" AND "carpal tunnel syndrome" OR "median nerve" OR "CTS".Inclusion criteria included: (a) available in English, (b) human participants in any study design (eg, case report, retrospective or prospective design, randomized control trial), (c) use of pulsed radiofrequency, (d) diagnosis of carpal tunnel syndrome.Review articles were excluded.
The titles and abstracts of all gathered articles were read by two authors independently (CV & HG).Any disagreement about the inclusion of a study was discussed with a third author (AS) until an agreement was met.This process was then repeated to review the articles' full texts, with independent data extraction being completed by two authors (CV & HG) using a structured format.
Upon completion of the data review, all included bibliographies were searched for additional relevant articles.

R E SU LT S
A total of 804 studies were found.After removing duplicates and those not meeting inclusion criteria, 20 remained and were advanced to full-text review.In total, 12 studies were further excluded as they had not yet been completed (n = 2), performed the wrong intervention (n = 2), had the wrong study design (n = 5), included the wrong patient population (n = 3), leaving a final number of eight studies for inclusion (Figure 1).Of the final included studies, one was a case report, 6 three studies were retrospective in nature, 1,7,8 and four were prospective [9][10][11][12] (with three being randomized trials [9][10][11] ).Six of the eight studies were available in full-text, 1,6,8,[10][11][12] whereas two were available in abstract-only form from the same conference. 7,9From a search of the reference sections of included studies, we found no additional studies that satisfied the inclusion criteria for this review.Studies are summarized in Table 1.

Case report
We found a single case report on the application of PRF for carpal tunnel syndrome. 6Haider et al. report of a man with two previous carpal tunnel surgeries experiencing refractory pain who was then advanced to a median nerve block at the elbow.The nerve block was performed at the elbow due to concerns about postsurgical scarring at the wrist.Given the efficacy of the nerve block, the patient subsequently received PRF of the median at three positions in the cubital fossa (ventral surface, medial aspect, and dorsal surface).He had 70% analgesic relief post-procedure, and graduate return to baseline pain after 12 weeks post-intervention.This is the index report on the utility of PRF in carpal tunnel syndrome, and although applied more proximal due to post-surgical scarring, it has provided proof of concept for subsequent research.Notably, they target the nerve from three angles to ensure adequate exposure.

Retrospective studies
We found three retrospective studies that report on the application of PRF in CTS. 1,7,8n an abstract, Ruiz-López 7 describes the application of bipolar PRF for 21 cases (n = 13 patients).The technical methods described the fluoroscopic-guided placement of two radiofrequency cannulas 3-4 cm, both distal and proximal to the carpal tunnel, which, following sensory and motor stimulation, underwent PRF simultaneously at both sites for 20 min. 13Then, steroid and local anesthetic were injected following PRF.The authors noted complete resolution of pain at 2 weeks in all patients, with approximately 50% (10/21 patients) having ongoing complete pain relief at 4-6 months.Interestingly, an even greater number of cases at the 1-year interval had complete resolution of their pain (13 of 20 available follow-ups).However, it is not clear how many patients may have underwent repeat intervention.Given the use of bipolar PRF (compared to the more conventional monopolar technique) and imaging guidance via fluoroscopy, and the lack of details regarding repeat intervention, findings from this study must be interpreted with caution.However, this is the only study reported to date with evidence of the combined effect of PRF with local steroid injection.Suslu et al. 8 reported on a retrospective case-control study whereby they identified patients with CTS that either underwent local steroid injection or PRF.Patients included in this study had CTS of mild severity, confirmed with electrodiagnostic studies.Patients underwent the procedure with sedation (intravenous midazolam and fentanyl) as well as local anesthesia with 20 mg of lidocaine.They noted that there was no difference in Visual Analogue Scale (VAS) or Neuropathic Pain Scale (NPS) scores pre-intervention, 1, and 3 months; however, there was a significant difference in the NPS at 6 months that favored steroid treatment.They also detected a statistical difference in the change in the VAS and NPS scores between the two treatment arms.This study suggests that there is no significant difference in analgesic benefits between steroid and PRF up to 3 months, though steroids appear to be more effective at the 6-month timepoint.
The most recent evidence arises from a retrospective, case-control study performed by Celenlioglu et al. 1 With similar demographic features across the two treatment arms (n = 45 each), they compared the results of steroid and local anesthetic injection with hydrodissection compared to PRF.Needles were guided under ultrasound.They found that both treatment arms significantly improved the Numerical Rating Scale (NRS) and functional scores on the Boston Carpal Tunnel Questionnaire (BCTQ) across their various time points (week 1, month 1, month 3), though differences across groups were not present.However, they did find an earlier onset of pain relief in the PRF group at 1.4 day post-procedure (vs.2.6 days in the steroid injection group).They did note the presence of a transient reaction resolving within one hour, where three patients undergoing the steroid injection experienced fullness in the thenar aspect of

T A B L E 1 (Continued)
their hand distal fingers due to compression of the injection agent.Although their study is retrospective in nature, it suggests that both treatment options are therapeutically effective for up to 3 months.However, it should be noted that this is the only study to also use hydrodissection during the steroid injection, which may have provided some additional benefit from a mechanical rationale. 14

Prospective studies
][11] One prospective, single-group observational study performed in Poland used bipolar PRF in the treatment of 15 patients with CTS. 12 This study, in addition to using the bipolar technique, is the only available study that used electrophysiological stimulation of motor and sory pathways to situate radiofrequency probes without imaging guidance.They noted statistically significant functional improvement post-PRF treatment, as measured by the BCTQ and functional strength.They did note subjective improvement in the patient's pain score as well, though this did not reach statistical significance.Finally, they noted a reduction in CTS severity for three cases and, on average, an increase in the sensory nerve conduction velocities, though these did not reach statistical significance.The overall findings in this paper suggest functional benefit with bipolar PRF, however, the study was limited by a small sample size, which likely impacted the statistical significance of improvements in their other outcomes of interest.It is possible that the insertion of two cannulas may have resulted in more peri-procedural pain that could have counteracted the therapeutic effect of the intervention.Furthermore, a lack of imaging guidance could potentially result in more tissue trauma, including the possibility of neurovascular injury.Conversely, the use of electrophysiological stimulation theoretically provides functional confirmation that the radiofrequency probe is at least peri-neural to the target of interest.With respect to the bipolar modality, only one other study 7 employed a similar PRF technology, and they also reported analgesic benefits.Overall, it is difficult to compare this non-image-guided approach with the other studies, though it may offer therapeutic benefits.
Chen et al. 10 conducted a randomized, controlled, single-blinded study, involving 36 adults with clinicoelectrophysiologically proved CTS.The intervention arm (n = 18) included PRF of the median nerve, in addition to the control group's (n = 18) standard of care (wrist splinting).They noted that there was at least a 40% reduction in the VAS within 2 days for the intervention group, compared to 14 days for the control group.Additionally, they found a continual reduction in VAS until 12 weeks, whereas the improvement in the control group had plateaued around weeks 4-8.Furthermore, they noted a reduction in the sonographic cross-sectional area of the median nerve (with higher values correlated with more severe CTS) and stronger finger pinch in both treatment groups (although no statistically significant difference between the two groups).This study, although lacking a sham-controlled interventional procedure group, provides support for the utility of PRF above and beyond the standard of care of wrist splinting.They further demonstrate that there is not only improvement on the usual primary outcomes employed in pain research, namely the VAS, but also functional benefit as measured by the BCTQ.
Ozyuvaci reports in an abstract the results of a randomized trial (n = 50) conducted in Turkey investigating steroid injections and PRF in the treatment of CTS. 9 In both treatment groups (n = 25), patients underwent ultrasound-guided steroid injection at the beginning of the study.After 3 weeks, the control group received a second injection of steroids, whereas the intervention group received PRF.They reported significant improvements in pain and disability scores for both interventions at follow-up compared to baseline, with no significant differences between groups.Given the lack of available methodology, it is difficult to further comment on the particular PRF parameters employed.However, this is the only study to have had a repeat steroid injection within 3 weeks of the initial injection.It is very likely that the steroid may have had an ongoing benefit at the time of the second injection, even up to 3 months (eg, Suslu et al., 2016), and thus masked any incremental benefit from repeat injection or PRF performed at 3 weeks.Furthermore, this report unfortunately does not provide much practical significance as it would be uncommon to offer repeat intervention, particularly with steroids, with such short intervals between treatments.
Yildiran et al. 11 completed the only randomized, controlled trial (n = 24) for the utility of PRF in patients undergoing CTS surgery.In both treatment arms (n = 12), patients underwent conventional carpal tunnel release under general anesthesia, with the interventional arm also receiving intra-operative PRF.They found that disability scores, measured on the 11-item QuickDASH, were significantly lower for the interventional group at 1-month post-operation, and although the benefit continued until 1 year, this difference between the two groups did not persist.Furthermore, they reported that VAS scores were significantly lower in the interventional arm at both the 1-and 3-month time assessments, but unfortunately, VAS scores at 12 months were not reported.This study suggests that the addition of PRF to conventional CTS surgery is significantly beneficial, improving post-operative pain and consequent functional status.The most recent American Academy of Orthopaedic Surgeons (AAOS) guidelines 15 do not comment the utility of PRF in addition to standard surgical management, and with additional research studies, this may warrant further discussion.

Synopsis
This review summarizes the findings of one case report, three retrospective cohorts, and four prospective studies of the effects of PRF in the treatment of CTS.The current evidence supports the analgesic and functional improvements with this treatment modality.All prospective studies demonstrated a reduction in pain scores and disability status following intervention with PRF, particularly in the short term.Retrospective cohort analyses were generally in agreement with the results from the prospective studies.It is unclear whether PRF provides longer-term benefits in the treatment of CTS as most studies did not evaluate the past 3 months, though the available evidence appears promising.It also appears likely that steroid injection may represent a comparable treatment modality to PRF.Notably, all studies differed in their methodology, making direct comparisons between studies challenging.
There are two ongoing randomized controlled trials underway registered in the Cochrane Central Register of Controlled Trials.These studies were excluded in screening for this review due to no results but will be valuable in the future for determining comparative efficacy to steroid 16 or platelet-rich plasma 17 injection.

Mechanisms of PRF in CTS
Carpal tunnel syndrome, typically idiopathic in etiology, is thought to occur due to compression of the median nerve at the wrist.Increased compartmental pressure is believed to be at the core in the pathogenesis of idiopathic CTS, which is associated with multiple pathophysiological sequela including ischemic vascular injury, breakdown of the blood-nerve barrier, and synovial tissue hypertrophy. 18Steroid injections have been shown to be safe and effective in the treatment of CTS, presumed historically to be via anti-inflammatory effects. 19However, more recent molecular genetic analyses have challenged this traditional view. 20 Yamanaka  et al. (2021) reported on the downregulation of fibrosisrelated genes Col1A1 (collagen type 1 alpha 1 chin), Col1A2, and Col3A1 in ten patients who underwent ultrasound-guided injection with triamcinolone acetonide.However, in these same patients, they did not find a significant reduction of proinflammatory genes (interleukin [IL]-6, cyclooxygenase-2 [COX-2], nuclear factor-kappa B [NF-κB]).This is consistent with findings that the serum levels of inflammatory cytokines (tumor necrosis factor-alpha [TNFα], IL-2, IL-4, IL-10) were not elevated in a group of 40 females with CTS relative to controls. 21As such, it remains unclear how steroid injections provide analgesic benefits, but it may be via its anti-fibrotic as opposed to anti-inflammatory properties.
Although effective, steroid injections have many known adverse local side effects, such as atrophy and hypopigmentation, as well as a host of various systemic side effects.Comparatively, PRF can be applied locally without any requirement for injecting medications, and thus presumably offer no systemic toxicity.Moreover, some patients may be receiving injection-based treatment with corticosteroids in other body regions, thus limiting the amount of steroid that could be given at each target and/or deciding not to treat certain pain regions if the steroid maximum has already been reached.Finally, the recent history of corticosteroid use may be contraindicated in patients who are planned for surgery, and thus, steroid injection may not be a feasible treatment option in the interim. 22This is especially relevant for healthcare jurisdictions where there is limited/delayed access to surgical care.
PRF involves the application of powerful electric fields in a pulsatile manner to the intended target, thereby allowing for dissipation of generated heat in between the pulses.This is particularly advantageous where the intended target subserves important neurological function (eg, motor), where a destructive lesion is not desirable.However, the mechanisms by which PRF appears to exhibit its therapeutic effects are unclear.It has been previously noted that PRF may selectively modulate small diameter Aδ and C-type fibers, which are involved in pain transmission. 23This could possibly be mediated via microscopic changes of the mitochondria, microfilaments, and microtubules in Aδ and C-type fibers. 24Nonetheless, histologic murine studies have demonstrated only transient changes in the sciatic nerve with PRF, suggesting there may also be non-structural changes in gene expression or cytokine upregulation that are eliciting positive effects. 25Indeed, PRF has been shown to be associated with downstream changes in gene and molecular expression, such as lower levels of proinflammatory cytokines IL-6 and TNFα, lower levels of intracellular proteins such as β-catenin that are correlated with neuropathic pain, and internalization of glutamate receptor subunits. 26The mechanism by which PRF appears to have its therapeutic effect in CTS is unclear.It may be that steroid injections provide analgesic benefit via their anti-fibrinolytic properties, and that PRF exerts its therapeutic effect via other, possibly multifactorial, mechanisms, such as via modulation of nociceptive Aδ and C fibers and changes in expression of mediators implicated in neuropathic pain.Further research is required to elucidate the mechanism by which PRF exerts its effects in CTS.

Limitations of review
There are several limitations to this review.There is heterogeneity in the methodology of every included study.Heterogeneity extended beyond the nature of the study design (eg, retrospective versus observational) to include the nature of the PRF treatment (eg, bipolar 7,12 and the use of sensory/motor stimulation 1,7,10,12 ).Notably, the technical parameters varied quite significantly across the studies.Radiofrequency probes ranged from 5 to 10 cm, active tip ranging from 4 to 10 mm, needle gauge ranging from 20 to 22 G, and the duration of treatment from 120 s to 20 min.Output voltage, although seldom reported in the reviewed studies, was at the standard output of 45 V.As such, these results may not reflect more recent studies employing high-voltage PRF at 60 V at other anatomical targets, for which the upcoming results of a meta-analysis will be of high clinical interest. 27That being said, most studies (except for two 7,8 ), appeared to have some consistency in a few of the PRF technical parameters (duration of 2 min, 42°C, 5 cm active tip, 22 Gauge needle) and all studies except one 12 utilized ultrasound guidance.Overall, the lack of standardization for PRF parameters makes it challenging to compare results across studies.
Another great source of heterogeneity in the comparison studies was the control group's treatment, which varied from steroid-only injection, 8,9 steroid with local anesthetic injection, 1 wrist splint alone, 10 and CTS surgery alone. 11dditionally, it appeared that most studies utilized electrodiagnostics as a means of confirmation for the diagnosis of CTS, though this was not always specified, 11 which is important given the high prevalence of nonspecific symptoms that may mimic CTS.Furthermore, there were two studies 7,9 that were not available in fulltext format.This raises the concern that there may have been methodological concerns pre-empting peer-review publication, despite reporting therapeutic benefit.

CONC LUSION
Our narrative review suggests that non-surgical treatment of CTS with ultrasound-guided PRF is therapeutically effective, and likely comparable to steroid injection, in a diverse spectrum of patients with CTS.Given the lack of systemic side effects associated with steroids and potential contraindications (eg, upcoming surgery), PRF could be a more favorable treatment option.However, further prospective, randomized, controlled trials are required with larger subject populations to investigate this.Future studies would benefit from sham-controlled treatment arms, standardized PRF protocols and longer follow-up periods.Furthermore, the mechanisms by which PRF exerts its therapeutic effects merit further research.

CON F L IC T OF I N T E R E ST STAT E M E N T
Each author certifies that they have no relevant conflicts of interest.

DATA AVA I L A BI L I T Y STAT E M E N T
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

R E F E R E NC E S
Cochrane Central Register of Controlled Trials, (3) Embase, (4) OVID Emcare and (5) Web of Science through September 12, 2022.Title and abstract screening of 804 records Full text screening of 20 records 784 records excluded because: (a) Duplicate records (n = 367) (b) Not meeting inclusion criteria (n = 417) 8 studies included in review 12 records excluded because: (a) Not yet completed (n = 2) (b) Wrong intervention (n = 2) (c) Wrong study design (n = 5) (d) Wrong patient population (n = 3) Reference sections of included studies yielded no additional relevant studies T A B L E 1 Application of pulsed radiofrequency for carpal tunnel syndrome.