Radicular pain resulting from spinal degeneration is a prevalent type of degenerative musculoskeletal pain. Depending on pain severity, a range of non-operative treatments, such as rest, analgesic medications, and epidural steroid injections, have been utilized. Exposure of the nucleus pulposus to the epidural space can provoke an immune response, leading to inflammation that irritates surrounding nerves and causes radicular pain.¹ Steroids are effective agents that modulate the immune system to achieve sustained inflammation reduction.² Thus, epidural steroid injections are widely established as a standard treatment to alleviate such inflammation effectively.³

Persistent inflammation can lead to central sensitization in the nervous system, which reduces the pain threshold, leading to pain from even minor stimuli and, in some cases, spontaneous pain without external triggers.⁴ In acute-phase, steroid use can prevent or mitigate central sensitization; however, once central sensitization has developed in the subacute or chronic phases, steroids may have limited efficacy in controlling pain.⁵ Therefore, managing chronic or neuropathic pain associated with central sensitization may require alternative treatments beyond standard epidural steroid injections for radicular pain.

Neuromodulation, defined as the regulation of pain and neural function through electrical stimulation targeting central or peripheral nerves, presents a viable alternative.⁶ Pulsed radiofrequency (PRF) stimulation is a neuromodulation technique that employs alternating currents at 500 kHz to manage pain in peripheral nerves. Traditionally, continuous radiofrequency (CRF) stimulation involves generating intense electrical energy within 2∼3 mm of the needle tip, producing high temperatures that can ablate the target nerve. CRF is typically used to manage facet joint pain by ablating the medial branch nerve.⁷ However, when targeting the dorsal root ganglion in radicular pain, CRF may lead to sensory nerve damage in the extremities, resulting in severe neuropathic pain.

In contrast, PRF is specifically designed to avoid thermal elevation above 42°C, allowing for effective electrical stimulation by electrical field without significant heat generation. This makes PRF suitable for targeting the dorsal root ganglion in radicular pain and applicable to various peripheral nerve entrapment syndromes. This review article aims to provide a comprehensive summary of the procedural techniques and clinical efficacy of PRF.

1. Mechanism of PRF for radicular pain

PRF is a procedure that stimulates nerves through the electrical field generated at the needle tip. The intensity of the electrical field differs between the needle shaft and the needle tip. Typically, the electrical field generated at the needle tip is stronger than that at the shaft, and beyond 0.5 mm, the field strength is relatively consistent. Therefore, if the end of the needle tip is within 0.1∼0.2 mm of the target nerve, the stimulation may be intense enough to risk nerve injury, which should be taken into consideration during the procedure. The 20 ms burst stimulation at 500 kHz alternating current is generally not sufficient to polarize the transmembrane potential of nerve cells.⁸ However, in clinical practice, patients sometimes report severe pain with sensory nerve stimulation as low as 0.2 V, suggesting that nerve stimulation can occur. In such cases, it is advisable to recognize this and slightly withdraw the needle to reduce post-procedural pain.

In neuromodulation, the mechanism of reduced nerve function is generally explained by long-term depression through α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-Methyl-D-Aspartate (NMDA) receptors.⁹ Sub-threshold stimulation induces intracellular trafficking of AMPA receptors in the postsynaptic membrane, which raises the threshold of the postsynaptic nerve in response to presynaptic stimulation. In other words, PRF triggers the intracellular movement of AMPA receptors, leading to a reduction in synaptic strength.¹⁰ Reduced synaptic strength in pain pathways decreases central sensitization, lowering pain intensity and sensitivity.

PRF induces a nerve block at the stimulation site while preserving nerve function outside the stimulated area.¹¹ When alternating currents above 10 kHz are applied to the nerve, a nerve block localized to the stimulation site occurs. If nerve stimulation is applied distal to the stimulation site during 10 kHz stimulation, nerve conduction continues in the distal direction. In other words, alternating currents above 10 kHz create a local nerve block without propagating along the nerve.

Although PRF does not cause propagation, it induces long-term depression at the distal synapse of the nerve. Typical electrical stimulation causes nerve conduction, which leads to neurotransmitter depletion at the pre-synapse of the stimulated nerve terminal. However, with PRF, no significant depletion of neurotransmitters at the nerve terminal is observed. At the same time, PRF stimulation is associated with increased expression of C-FOS in nerve cells.¹² C-FOS is an immediate early gene commonly used as a marker of neuronal activation, as its expression is rapidly induced in response to various stimuli.¹³ This increase in C-FOS indicates that PRF triggers intracellular signaling pathways without causing substantial nerve depolarization, suggesting that PRF influences postsynaptic neurons and may contribute to changes in synaptic plasticity and long-term depression at the synapse.

The response of AMPA and NMDA receptors to PRF is an immediate reaction to stimulation. This immediate response is thought to regulate central sensitization through a homeostatic mechanism that is not yet fully understood. Additionally, this effect can be observed through changes in gliosis. Inflammatory-induced gliosis in the spinal dorsal horn appears to decrease significantly following PRF, with a corresponding reduction in pain sensitivity observed post-PRF.

2. Arts of pulsed radiofrequency stimulation: C-arm guided procedure

In PRF, the needle tip targets the dorsal root ganglion. The goal of TFESI is to avoid contact with nerves like the dorsal root ganglion and spinal root, delivering steroids around the epidural space and nerve root. In TFESI, the needle’s trajectory and tip are directed toward a ‘safety zone’ defined by the facet joint, posterior vertebral body, and an imaginary nerve root line. However, unlike TFESI, PRF directly targets the spinal nerve root and dorsal root ganglion.

The patient is positioned in the prone position on the bed. The C-arm is adjusted with a cephalic tilt to align the upper vertebral body of the target spinal level horizontally. The C-arm is then rotated ipsilaterally by 25 to 30 degrees to clearly visualize the spinal foramen. The degree of tilting and rotation can be adjusted based on the patient’s degenerative changes. For example, in cases of significant disc height reduction, the C-arm rotation may exceed 30 degrees to provide a clearer view of the foramen. When targeting the L5 nerve root at the L5-S1 level, additional cephalic tilting may be necessary due to the height of the iliac crest, allowing for a more distinct view of the L5-S1 foramen. By increasing the cephalic tilt, the iliac crest can be moved caudally, enhancing the visibility of the L5-S1 foramen.

Unlike ultrasound-guided procedures, C-arm-guided procedures do not provide direct visualization of the target nerve. Instead, the approximate location is determined using anatomical landmarks, and the needle tip is positioned accordingly. Generally, the dorsal root ganglion is located at the foramen or along the mid-pedicle line, making it optimal to place the needle tip within the foramen in the anteroposterior (AP) and lateral views on the C-arm. However, the location of the dorsal root ganglion within the spinal foramen may vary, so it is recommended to confirm its position using magnetic resonance imaging.

Following skin anesthesia, the C-arm-guided needle approach is carried out as previously described. Once the patient experiences a tingling sensation in the leg, or the needle tip is confirmed to be positioned in the mid-foramen on AP and lateral C-arm views, sensory and motor stimulation are applied using the radiofrequency generator. This step ensures that the needle tip is adequately close to the dorsal root ganglion to deliver effective electrical stimulation.

The needle is correctly positioned if sensory nerve stimulation occurs below 0.5 V and motor nerve stimulation below 0.8 V. However, for optimal stimulation, it is preferable if sensory nerve activation occurs at a threshold below 0.3 V. In cases where severe nerve damage from inflammation is present, the patient may not perceive sensory stimulation even when the needle is in the appropriate position. In such instances, motor nerve stimulation can be utilized to observe muscle contractions, thus confirming the needle’s placement.

The stimulation parameters typically include a 2 Hz pulsed frequency, 20ms pulse width, 45 V, and a 120-second stimulation duration. However, pulse width and duration can vary depending on the treatment center. In some cases, the pulse width is reduced from 20 ms to 5 ms or 10 ms to allow for longer stimulation times. Reducing the burst width minimizes heat generation, enabling the electrical field to target the nerve effectively. Compared to CRF, PRF includes intervals between bursts without stimulation, which enables tissue cooling. Because the temperature is limited below 42°C, shortening the pulse width allows for sustained stimulation intensity. If the temperature rises or the resistance increases, the current of stimulation decreases, consequently reducing the intensity of the electrical field.

3. Adverse effect of PRF

Protein denaturation can occur at temperatures above 45°C.¹⁴ Therefore, PRF, performed at temperatures below 42°C, is considered relatively safer than CRF, which operates at around 80°C. However, some patients experience severe radicular pain for several days to weeks after PRF, suggesting that the electrical field generated by PRF may cause nerve damage. Experimental studies have demonstrated that PRF stimulation can damage mitochondrial and intracellular structures within nerve cells, including C-fibers.¹⁵ In other words, nerve damage can occur due to the electrical field, even in the absence of heat-induced injury. As previously noted, the needle tip produces a stronger electrical field at its end than at the shaft. Thus, depending on the anatomical proximity of the nerve to the tip, post-procedural pain from nerve injury may occur, and this risk should be carefully considered.

4. Clinical outcome of PRF

TFESI is commonly considered the initial treatment for radicular pain. Consequently, studies have primarily focused on the therapeutic potential of PRF in patients who continue to experience pain after TFESI. In patients with refractory radicular pain who have persistent pain despite repeated TFESI, PRF has been shown to reduce pain and decrease medication use.^16,17 In cases of refractory radicular pain, repeated TFESI likely reduces inflammation adequately. However, residual pain may persist due to mechanical factors or central sensitization. For patients where mechanical factors are the primary issue, surgery may be required for effective pain control. Conversely, PRF may be beneficial for reducing pain associated with central sensitization. However, it is challenging to clearly distinguish the contributions of mechanical factors and central sensitization to pain in refractory radicular pain patients. Therefore, PRF can be considered as a treatment option for pain reduction prior to surgery.

There are considerations regarding the effect size of PRF in refractory radicular pain. In a study involving patients with cervical radicular pain who continued to experience pain after two TFESI treatments, PRF was reported to have a success rate of 68%. Treatment success was defined as a reduction in NRS (Numeric Rating Scale) pain scores by 50% or more.¹⁸ However, most patients continued to report persistent pain at NRS levels of 2∼3 following treatment. This realistic success rate of PRF in pain reduction should be considered.

The pain control effect of PRF is achieved through nerve stimulation by an electrical field. Therefore, it might be assumed that higher voltage would result in better pain control. However, when comparing 45 V and 60 V, 45 V showed more effective pain control.¹⁹ Since the primary mechanism of PRF is long-term depression induced by subthreshold stimulation, stronger stimulation does not necessarily yield better results.

The PRF with TFESI group and the sham stimulation with TFESI group showed similar short-term effects.²⁰ However, after 2 to 3 months, the group receiving both PRF and TFESI demonstrated a statistically significant reduction in pain compared to the sham group. Additionally, when comparing a PRF with 1 ml of 0.5% bupivacaine group to a bupivacaine-only group, the PRF with bupivacaine group showed more effective pain control lasting up to 6 months.²¹ This suggests that PRF may inhibit the development of central sensitization, resulting in prolonged pain relief.

In another study, patients with radicular pain initially received TFESI, and subsequently patients were divided into groups that received either PRF or TFESI alone.²² The effects were observed over 3 months, and both groups showed significant pain reduction. Additionally, the degree of pain reduction was similar between the two groups, with no statistically significant difference. Early TFESI is more effective than later TFESI.²³ Persistent intense stimulation can lead to long-term potentiation.²⁴ So, early inflammation control is thought to help manage the development of pain memory more effectively. Considering that PRF does not have a direct anti-inflammatory effect, this suggests that a single TFESI may effectively control inflammation caused by disc herniation, while persistent pain may be due to central sensitization. Further studies are needed to develop treatment strategies for inflammation and central sensitization following disc herniation.

Inflammation is a primary cause of radicular pain, making early steroid use essential to reduce inflammation in the acute phase. However, central sensitization is also a critical factor in the persistence of chronic pain. While measuring the exact contribution of central sensitization to radicular pain remains challenging, PRF offers a way to modulate this process. Thus, incorporating PRF as an adjunctive treatment may be clinically valuable for managing chronic radicular pain.