Indian Journal of Pain

REVIEW ARTICLE
Year
: 2022  |  Volume : 36  |  Issue : 2  |  Page : 75--83

Pulsed radiofrequency treatment of the dorsal root ganglion in patients with chronic neuropathic pain: A narrative review


Sarah Waicus1, Nishaant Bhambra2,  
1 Faculty of Medicine, Trinity College Dublin, Dublin, Ireland
2 Faculty of Medicine, McGill University, Montreal, Québec, Canada

Correspondence Address:
Dr. Nishaant Bhambra
Faculty of Medicine, McGill University, Montreal, Québec
Canada

Abstract

Background: Chronic neuropathic pain (CNP) is a complex condition that has profound impacts on quality of life. Pulsed radiofrequency (PRF) on the dorsal root ganglia (DRGs) is a novel treatment that has shown clinical efficacy in pain relief, however, its mechanism remains unknown. Objectives: The objective of this review is to synthesize the literature on inflammatory markers and clinical pain outcomes in CNP patients treated with PRF. Study Design: A narrative review was conducted. Setting: Eligibility criteria included human trials on adults diagnosed with CNP. Monopolar and bipolar PRF treatments on the DRG were included. Methods: Four peer reviewed electronic databases (Medline, EMBASE, PubMed, and Cochrane) were systematically searched for studies on PRF on the DRG to treat CNP. The primary outcome measures included pain scores and cerebrospinal fluid samples taken pre- and posttreatment measuring inflammatory markers. Results: Thirty-three articles were identified in the database searches. Titles, abstracts, and full-text articles were evaluated, and eight articles met the inclusion criteria. The study designs included five randomized-controlled trials and three quasi-experimental studies. Patients: There were 311 patients pooled with an age range of 35–76 years. Types of CNP included chronic radicular pain, postmastectomy pain syndrome, chronic lumbosacral pain, and postherpetic neuralgia. Intervention: Treatments in included studies included monopolar and bipolar PRF stimulation ranging from 120 s at 2 Hz to 360 s with 5 Hz pulses. Measurement: The main findings revealed that PRF treatment provided significant pain relief (P < 0.05), with the greatest pain reduction at 3 months. Pro-inflammatory markers were found to decrease, whereas anti-inflammatory markers increased post-PRF intervention. Limitations: There were differing PRF procedure standards, and it is uncertain whether a higher frequency or duration is correlated with better outcomes. Studies had small sample sizes increasing the margin of error. Longer duration randomized-controlled trials are needed to understand the optimal therapeutic duration using PRF.



How to cite this article:
Waicus S, Bhambra N. Pulsed radiofrequency treatment of the dorsal root ganglion in patients with chronic neuropathic pain: A narrative review.Indian J Pain 2022;36:75-83


How to cite this URL:
Waicus S, Bhambra N. Pulsed radiofrequency treatment of the dorsal root ganglion in patients with chronic neuropathic pain: A narrative review. Indian J Pain [serial online] 2022 [cited 2022 Sep 29 ];36:75-83
Available from: https://www.indianjpain.org/text.asp?2022/36/2/75/354725


Full Text



 Introduction



Chronic pain is an extensive and complex problem that has worldwide implications. Approximately 10% of the world's population – 60 million people – are estimated to have some form of pain lasting longer than 7 months.[1] It is estimated that 19.3% of the Indian population suffers from chronic pain.[2] Pain is an unpleasant sensory and emotional experience, associated with actual or potential damage to tissues.[2] Neuropathic pain is caused by lesions or disease affecting the somatosensory system.[3] The somatosensory system is involved in sensory transmission to the brain, where modalities such as pain touch and temperature can be perceived. Damage to this pathway results in abnormal transmission and dysfunctional pain perception. Common clinical symptoms include hyperalgesia, a heightened response to a painful stimulus, and allodynia, the sensation of pain in the absence of a painful stimulus.[3]

Neuropathic pain can be divided into central and peripheral pain. Central neuropathic pain is caused by a lesion or disease of the brain or spinal cord caused by neurodegenerative diseases, stroke, spinal cord injuries, or demyelinating diseases.[3] In contrast, peripheral neuropathic pain involves damage to the peripheral nerve fibers, predominantly C and Aδ.[3] C-fibers are unmyelinated and respond to heat and noxious stimuli that produce a long-lasting burning sensation. In comparison, Aδ-fibers are lightly myelinated and respond to cold, pressure, and pain, producing an acute sharp painful sensation.[4] When chronic or peripheral neuropathic pain persists, it is termed chronic neuropathic pain (CNP).

CNP is difficult to treat as patients often are unresponsive to traditional pharmacological treatment. First-line therapy includes anticonvulsants or antidepressants followed by topical creams and stronger opioids as second-line therapy.[5] These treatments are accompanied by a plethora of adverse side effects ranging from lethargy, nausea, vertigo, constipation, ataxia, and seizures.[5] Additionally, opioids have high risks of addiction and tolerance which escalate with dosage, at which point they have more harm than benefit in treating neuropathic pain.[6] Consequently, alternative interventions are required when pharmacological treatments fall short.

Pulsed radiofrequency treatment of the dorsal root ganglia

A novel therapeutic target for CNP is the dorsal root ganglia (DRGs). The DRG is found bilaterally at the intervertebral level, formed by the dorsal roots of the spinal cord.[7] The DRG is composed of afferent somatic and visceral nerve cell bodies that relay sensory information from the periphery.[7] The DRG can be described as a gatekeeper of pain in congruence with the gate control theory. Melzack and Wall (1965) proposed the gate control theory where Aβ afferent touch fibers can inhibit the transmission of pain at second-order neurons in the substantia gelatinosa at the dorsal spinal cord.[8] Pulsed radiofrequency (PRF) treatment takes advantage of pain modulation by applying radiofrequency current in 20 ms, high-voltage bursts directly on the DRG.[9] PRF treatment is given in cycles for 2–10 min that heats the tissue under 42°C to avoid lesioning. PRF can be performed via monopolar or bipolar stimulation, which is treatment with a single cannula or two parallel cannulae, respectively.[10] Clinical outcomes following PRF treatment have indicated long-term pain relief >50% lasting for up to 6 months.[11] Despite its high clinical efficacy, the mechanism behind PRF's pain modulation remains unclear. However, a temperature-dependent pathway that influences the neural-immune response has been proposed as a mechanism.[9]

Pulsed radiofrequency immunomodulation

There is growing evidence that CNP is driven by abnormal immune responses to the nerves. Individuals with CNP have shown increased levels of inflammatory mediators such as cytokines (i.e., interleukin-1, tumor necrosis factor-alpha, and interferon-gamma [IFN-γ]), lymphocytes (i.e., T-cells and natural killer cells [NKCs]), and neurotrophic growth factors (i.e., brain-derived neurotrophic factor [BDNF]).[12] In human studies, patients with painful inflammatory diseases such as multiple sclerosis have higher CD4+:CD8+ T-cell ratios and NKC counts in the cerebrospinal fluid (CSF) compared to healthy individuals.[13] CD4+ T-cells and NKCs have been implicated in mediating inflammation by promoting the production of cytokines such as IFN-γ.[14] This suggests that pro-inflammatory mediators play a significant role in the establishment and maintenance of neuropathic pain.

PRF specifically targets the DRG. The cell bodies in the DRG are separated by layers of satellite glial cells that influence sensory transmission.[15] Activated glial cells contribute to the release of inflammatory mediators and growth factors surrounding the DRG, which have been associated with allodynia.[16] Corticosteroid treatments of the DRG have attenuated mechanical sensitivity and have shown decreased satellite glia activation at the DRG.[17] This suggests that PRF is immunomodulating the surrounding DRG closer to homeostasis.

PRF immunomodulation has been examined in animal randomized controlled trials (RCTs). In an induced rat model of neuropathic pain, Park et al. found a significant reduction in mechanical hypersensitivity and immunoreactivity with microglial markers after PRF treatment.[18] A similar rat model conducted by Fang et al. found that PRF treatment inhibited the expression of interferon-8 and BDNF, which correlated with a reduction in allodynia and depression-like behaviors.[19] Further, an electrophysiological study conducted by Huang et al. investigated the conduction velocity of Aδ- and C-fibers in neuropathic rat models of pain.[20] It was found that PRF treatment induced long-term depression of C-fiber neuronal excitatory potentials, which correlated with reduction in mechanical allodynia and thermal hyperalgesia. These studies support the idea that PRF on the DRG has an immunomodulatory effect associated with a reduction of pain and depression-related behaviors and may have a preferential effect on burning pain mediated by C-fibers.

Objectives

The mechanism behind PRF remains unclear. The objective of this thematic review is to synthesize the literature on immunological and clinical pain outcomes in patients with CNP treated with PRF. This may aid pain specialists in providing a concise summary of the current PRF landscape, highlighting the potential immunomodulatory mechanism behind clinical outcomes.

 Methods



Search strategy and data collection

A systematic search strategy was conducted in the following electronic bibliographic databases: Medline, EMBASE, and PubMed, from January 2010 to July 2021. The medical subject heading terms used included “pulsed radiofrequency treatment,” “dorsal root ganglia,” and “neuropathic pain.” The performed search combined the abovementioned terms in all databases. The search was conducted by two independent reviewers, and search results were exported to Excel. Discrepancies when including studies were resolved by a third reviewer. Titles and abstracts were independently evaluated based on the inclusion criteria, followed by an analysis of the full-text articles by both reviewers. All articles identified, screened, and included are summarized in [Figure 1]. Short-term pain relief was defined as significant pain relief (P < 0.05) for <3 months. Long-term pain relief was defined as significant pain relief (P < 0.05) for >3 months.{Figure 1}

Eligibility criteria

The reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The inclusion criteria were guided by a Population, Intervention, Control, and Outcome model. The patient population included adults aged 18 years and older with a diagnosis of CNP. Neuropathic pain was defined as a lesion or disease of the somatosensory system, including peripheral fibers and central neurons.[3] The intervention included bipolar and monopolar PRF treatment on the DRG. The primary outcome measure was a change in pain, quantified by pain score questionnaires administered pre- and postintervention. The secondary outcome measure was a change in inflammatory marker levels measured in the CSF. These included T-cell co-receptors, interferons, NKCs, and cytokine concentrations pre- and postintervention. The study design included human RCTs and prospective experimental studies written in English.

Evidence grading

For RCTs, quality of evidence was assessed using the Cochrane risk-of-bias tool (RoB 2).[21] The risk of bias for the remaining five nonrandomized studies was assessed using the risk of bias in nonstandardized studies of intervention tools.[22] The overall risk of bias and individual domains of biases are shown in [Figure 2].{Figure 2}

 Results



Search results

Thirty-three records were identified in the electronic databases: 7 in Medline, 7 in EMBASE, 5 in PubMed, and 14 in Cochrane Database. All 33 records underwent tile and abstract screening. Four were excluded due to being nonhuman trials, six were review articles, and one was a case report, leaving 22 articles for full-text screening. During full-text evaluation, eight were excluded as duplicates and six were excluded as they did not primarily assess CNP. A total of eight studies were included in the analysis, of which five were RCTs and three were quasi-experimental studies. There were 311 patients pooled in the 8 studies with an age range of 35–76 years. Types of CNP included chronic radicular pain, postmastectomy pain syndrome, chronic lumbosacral pain, chronic lumbar pain, and postherpetic neuralgia. Relevant information including patient demographics, CNP classification, sample size, PRF protocol, pain scores, and inflammatory marker results are compiled in [Table 1].{Table 1}

Evidence for pain reduction using pulsed radiofrequency treatment

The most common type of CNP treated by PRF in the included studies was radicular pain. Moore et al. conducted a triple-blinded RCT on ten patients with unilateral radicular, cervical, or lumbosacral pain.[23] Half of the patients received PRF on the DRG, while the other half received no PRF as a sham group. Pain scores were measured before the procedure and 1 h, 1 month, 3 months, and 6 months postprocedure using the 0–10 Numerical Rating Scale (NRS). There was a significant (P < 0.05) reduction in NRS pain scores on average from 6.8 to 2.6, 3 months posttreatment, which suggested that PRF on cervical and lumbosacral DRG regions provided short-term pain relief.

Vigneri et al. conducted a double-blind RCT on 41 patients with chronic lumbar or sacral neuropathic pain.[24] Twenty-one patients were randomized to receive two cycles of bipolar PRF on the lumbar DRG followed by the injection of local anesthetics including hyaluronidase and betamethasone; twenty patients underwent sham treatment followed by the same local anesthetics. Significant NRS pain scores after 1 month were significantly different between the two groups (P = 0.031) and 6 months (P = 0.005). At 1 month, 57% of patients in the PRF group experienced pain reduction >50% compared to 25% of patients in the sham group (P = 0.037). Pain reduction decreased to 48% in the treatment group and 10% in the sham group at 6 months (P = 0.008). The results in this suggest that PRF provides long-term lumbosacral pain relief.

Das et al. conducted a quasi-experimental study examining PRF treatment on 10 patients with chronic lumbosacral radicular pain.[25] Pain change was measured pretreatment and 3 months posttreatment using the Brief Pain Inventory (BPI) Scale. Nine out of ten patients reported a significant decrease in pain severity (P = 0.0007) and increase in pain relief >50% at 3 months (P = 0.0015). These results suggest that PRF provides short-term lumbosacral radicular pain relief for up to 3 months. Similarly, Lee et al. conducted a quasi-experimental study that treated lumbosacral radicular pain with bipolar PRF on 23 patients that were unresponsive to monopolar PRF.[26] Pain intensities were assessed pretreatment at 1-, 2-, and 3-month intervals using the NRS. Pain reduction significantly changed over time (P < 0.001) and 12 patients reported pain relief >50% 3 months posttreatment. These results suggest that bipolar PRF provides short-term pain relief for chronic lumbosacral radiculopathy.

Chang et al. conducted an RCT on 50 patients with chronic lumbosacral pain.[10] Twenty-five patients were treated with bipolar PRF treatment, and 25 were treated with monopolar PRF treatment. NRS pain scores were measured pretreatment and monthly until 3 months posttreatment. Reductions in NRS pain scores were significantly larger in the bipolar PRF group (P = 0.037). Furthermore, faster rates of analgesia were achieved after bipolar PRF treatment (P = 0.041) compared to monopolar PRF treatment. For both monopolar and bipolar groups, NRS scores were significantly reduced at 1, 2, and 3 months (P = 0.000). The results suggest that both bipolar and monopolar PRFs produce short-term pain relief for chronic lumbosacral pain, however, bipolar PRF treatment produced higher levels and rates of pain relief.

PRF was also found to be efficacious in disc herniation pain. Marliana et al. conducted a quasi-experimental study on fifty patients with lumbar disc herniation.[27] Twenty-five patients received PRF treatment of the DRG, and 25 control patients received sodium diclofenac analgesic three times daily. The Visual Analog Scale (VAS) was used to assess patients' pain pretreatment and 1, 2, and 4 weeks post-PRF treatment. Four weeks posttreatment, the VAS score reported was significantly reduced compared to those of individuals in the pharmacological control group (P < 0.001). The results suggest that PRF is more efficacious in producing short-term lumbar radicular pain relief than analgesic pharmacological therapy.

For chronic postmastectomy pain, PRF was also found to be effective in reducing pain. Hetta et al. conducted a double-blinded RCT on 64 patients with postmastectomy pain syndrome, with 32 receiving PRF on the thoracic paravertebral nerves (PVN) and 32 receiving PRF on the DRG.[28] Pain scores were measured pre- and posttreatment at 4 and 6 months using the NRS. Pain reduction was higher for PRF on the DRG compared to PVN after 4 months (P = 0.007) and 6 months (P < 0.001). Furthermore, at the 6-month follow-up period, the number of patients who discontinued their analgesics was higher when PRF was on the DRG compared to the PVN. Results suggested that PRF on the DRG provided long-term pain when compared to PVN stimulation.

PRF treatment was found to be effective for patients with chronic postherpetic neuralgia. An RCT conducted by Liu et al. examined the effects of spinal cord stimulation and PRF on 63 older patients with zoster-related chronic pain.[29] Patients were randomized into two treatment groups. 31 patients received bipolar PRF on the thoracic DRG and 31 patients received spinal cord stimulation. Electrodes were placed on the spinal ganglion segment for spinal cord stimulation, whereas the radiofrequency needle punctured the DRG for PRF. The NRS pain score decreased significantly in both groups 1 week and 24 weeks postoperation (P < 0.001), however, there was no significant difference between the two groups. The number of analgesics after operation was significantly less compared to preoperation for both groups (P < 0.001). This suggests that PRF may be provided long-term pain relief and transferable to older populations.

Evidence against pain reduction using pulsed radiofrequency treatment

While PRF is effective, there is a limited short-term duration of pain reduction after treatment, lasting <3 months. Moore et al. found that pain reduction was significant at 3 months (P < 0.05), but not 6 months.[23] Similarly, Vigneri et al. found pain reduction significant at 1 month (P = 0.031) and progressively decreased to nonsignificant at 6 months.[24] Hetta et al. found that 82.8% of patients experienced significant pain relief at 3 months compared to 75.9% pain relief at 6 months.[28] These studies had a longer follow-up period compared to other studies, which were limited to 4 weeks,[27] 3 months,[10],[25],[26] and 5 months[29] posttreatment. The results suggest that pain relief after PRF treatment peaks at 3 months and begins to taper after.

Even though pain scores were significantly reduced compared to preintervention, there was limited success in functional pain relief. Lee et al. reported an overall improvement in NRS pain scores (P < 0.001), however, only 12 out of 23 patients reported pain relief over 50% at this time.[26] While it was rare that adverse effects were provoked by PRF treatment, it was reported one patient complaining of temporary aggravated radicular pain 14 days after PRF treatment.[26] Furthermore, Hetta et al. reported a specific case of dye delineated injection through the paravertebral network of blood vessels, which was an unintended consequence of treatment.[28]

Pulsed radiofrequency immunomodulation

Moore et al. measured CSF neuropeptide and lymphocyte levels in addition to pain scores.[23] Two milliliters of CSF was extracted pretreatment and 3 months posttreatment for flow cytometric analysis of lymphocytes and neuropeptides. There was a significant reduction in CD3+ lymphocyte (P = 0.0317) and tumor neurotrophic factor-alpha (TNF-α) neuropeptide levels (P = 0.0159), 3 months posttreatment. The majority of CD3+ cells in patients activated effector memory cells (80%) compared to surveillance central memory cells (85%) in healthy controls.

Das et al. examined lymphocyte frequencies and inflammatory markers in the CSF.[25] Cytokines, chemokines, and growth factors were quantified using flow cytometry and ELISA. There were significant reductions in CD56+, CD3−, NK cell frequencies and IFN-γ levels (P = 0.03). CD8+ T-cell frequencies (P = 0.02) and IL-6 levels were increased (P = 0.05). IL-17 levels were inversely correlated with posttreatment pain severity score (P = 0.01). The results of both studies suggest that PRF treatment is immunomodulatory in chronic radicular pain.

Risk of bias

Deviations from the intended intervention could have been influenced by medications that were concurrently given for other medical conditions.[24],[28] As a result, the analgesic effect may not be entirely due to PRF. There were studies where participants were not randomized into control and PRF treatment groups.[25],[26],[27] Patients were either retrospectively selected or referred to the pain clinic. For this reason, the influence of either known or unknown prognostic factors such as severity of illness may have affected the assignment of individual patients to groups. In these nonrandomized studies, participants and investigators were aware of their assigned intervention which may have led to performance bias or confirmation bias. Chang et al. did not report their randomization protocol.[10] Furthermore, even though Liu et al. randomized patients, patients and investigators were not blinded.[29] Knowledge of the assigned intervention may have unconsciously influenced the investigator's behavior, leading to bias in the patients' responses. The risk of bias for all studies is represented in [Figure 2].

 Discussion



This review evaluated the literature on CNP scores and the associated immune-inflammatory markers in patients who were treated with PRF. The thematic analysis brought out several important insights. There were three main themes found regarding pain relief after PRF treatment. Firstly, all eight studies reported statistically significant pain relief post-PRF treatment. Secondly, the greatest reduction in pain was observed at 3 months postintervention and tapered off after.[23],[24],[25],[26],[28],[29] Lastly, bipolar PRF stimulation had higher levels of pain reduction and was achieved at a faster rate compared to monopolar stimulation.[10],[26] These findings suggest that PRF on the DRG is an effective pain treatment in comparison to no treatment[23], PRF directed to the PVN[28], or to analgesic drugs.[27]

There were two major themes found when reviewing inflammatory markers. Pro-inflammatory markers decreased, and anti-inflammatory markers increased post-PRF treatment. These findings were limited as only two out of the eight studies measured inflammatory markers after PRF treatment. Nevertheless, both studies found a reduction of CD3+ lymphocytes.[23],[25] CD3+ is a T-cell co-receptor that is involved in activating effector memory cells that produce inflammatory cytokines.[23] This is congruent with current animal models, where CD3+ T-cells have been associated with driving and maintaining allodynia.[30] Further, PRF reduced pro-inflammatory markers including CD56+, CD3−, NKC, IFN-γ, and TNF-α.[25] Current literature suggests that CD56+ NKCs drive the secretion of cytokines such as IFN-γ and TNF-α, which have been associated with peripheral neuropathy.[31]

However, post-PRF treatment anti-inflammatory CD8+ T-cell and IL-6 levels were increased.[25] CD8+ T-cells have been shown to play a key role in resolving chemotherapy-induced neuropathic pain.[29] However, it was unexpected that IL-6 levels were raised after PRF treatment, as it has been shown to be a nonspecific marker of inflammation in neuropathic pain.[32] IL-6 levels have both pro-inflammatory and anti-inflammatory properties in local and systemic responses.[33] This suggests that through an unknown mechanism, PRF is selectively or predominantly influencing anti-inflammatory IL-6 cytokines.

Limitations

In general, it is difficult to quantify and measure pain because it is a subjective and multifaceted outcome. The studies reviewed used a variety of questionnaires to analyze pain: visually with the VAS or numerically with the NRS or BPI. However, patients may have trouble expressing their pain as a number or a visual value. One-dimensional scales have been suggested as inadequate for neuropathic pain assessment.[34] Specialized questionnaires that are multidimensional such as the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale or the McGill Pain Questionnaire may more accurately capture components of a patient's pain.

There were differing PRF procedure standards in the reviewed articles. Most studies delivered PRF for 120 s with 2 Hz pulses,[10],[23],[25],[27],[28] 240 s with 2 Hz pulses,[24] or 360 s with 5 Hz pulses.[10],[26],[29] It is uncertain whether a higher frequency or duration is correlated with better outcomes. A consistent PRF treatment procedure with the same frequency and duration is needed to allow replicability in pain clinics and generalization to the CNP populations.

Most of the studies examined radicular pain.[10],[24],[25],[26],[27] Radicular pain was not limited to a specific spinal region, as different patients had pain in cervical, lumbar, and/or sacral regions. The size of DRG depends on the vertebral level, and the spinal level correlates with the number of sensory neurons.[7] This suggests that a DRG with more or less sensory neurons may have a different threshold to achieve analgesia with the same PRF stimulation. PRF stimulation on the same DRG vertebral level may reveal clinical differences in pain relief that are related to the anatomical size and number of the sensory neurons.

All studies had small sample sizes below 50 patients, reducing the power of the studies and increasing the margin of error. Larger sample sizes are needed to have generalizability and transferability for individuals with CNP. Further, only four studies extended past 3-month follow-up periods.[24],[25],[28],[29] Longer duration RCTs are needed to understand the optimal therapeutic duration of pain relief. Further examination of the interaction between analgesic drugs and PRF treatment is warranted. A synergistic combination of pharmacological and PRF treatments could lengthen the duration of pain relief. Subsequently, hospital resources and cost could be reduced by less frequent interventions.

 Conclusion



Clinical pain relief can be achieved for patients with various types of CNP with using PRF on the DRG. All the reviewed studies revealed significant analgesic improvements. However, a limited number of studies attempted to understand the mechanism behind PRF treatment by measuring immunomodulatory samples. Future research is needed to bridge positive clinical outcomes with the inflammatory markers that may be driving and maintaining CNP.

Acknowledgments

We express sincere gratitude to the principal investigator Dr. Deborah Galvin for the opportunity to conduct this research project providing technical help for the drafting of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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