Pulsed radiofrequency differs from CRF in that pulsed radiofrequency does not lead to a neurodestructive process [3, 4]. This theoretical benefit is important for sensitive nerves such as peripheral nerves in the head and neck, dorsal root ganglia, trigeminal ganglia, and peripheral nerves in the abdominal and inguinal regions [12, 13], and the lower extremity.

During the developmental phases of what is now known to be pulsed radiofrequency, interest was sought for the possible beneficial role of the magnetic field in treatment. Cosman et al. [14] determined that the magnetic component was an incidental vector that would have negligible effects toward clinical benefit [7]. It was then proposed to deliver energy in waves or pulses with a short rest period between generator activation. This rest period would allow the dispersal of the heat that was generated (as in CRF). This interrupted treatment would theoretically deliver electrical energy to elicit a clinical response, but not lead to the side effects of denervation and its resultant complications. In the initial description by Sluijter et al. [14], the pulses were for 20 ms separated by 0.5 s. This separation allowed for a rest period whereby heat that is generated by oscillatory motion would be allowed to dissipate via vascular runoff. Still, this treatment should not be thought of as a “nonthermal” lesion as there is increased temperature at the thermocouple. Consequently, as the pulse duration is a fraction of total pulse time (pulse duration + interpulse duration), voltage utilized during PRF is higher without risking increased temperature change with the higher energy.

PRF technology, however, may also lead to lesion injury. Heavner et al. [15] however showed that when PRF is utilized (10 ms duration at 2 Hz), coagulation begins to occur in egg-white media at a temperature of 60 °C. Therefore, regardless of technology, PRF vs. CRF, increased temperature at the tip can lead to coagulation and tissue injury. In essence, PRF as is currently used is a neuromodulatory treatment option as opposed to the ablative CRF.

The exact mechanism of PRF’s clinical benefit is unclear; initially, PRF was believed to play a role in causing neuronal plasticity with upregulating of c-Fos [16] in rat DRG. c-Fos is a proto-oncogene that is expressed in response to neuronal activity and may have a role in nociceptive transmission. Animals were exposed to RF at the C6 dorsal root ganglion, via CRF at or PRF, at 38 °C for 120 s. Immunohistochemical assays for c-Fos were performed, and animals with PRF had an increased expression of the protein in laminae I and II of the spinal cord; this expression was not seen in animals exposed to CRF.

Additionally, c-Fos staining cells were found ipsilateral and contralateral to the side of PRF treatment. The implication of this finding is that PRF activates the dorsal horn laminae I and II neurons and could be a possible explanation for the clinical benefit of PRF, as both CRF and PRF animals were subject to the same temperature. This choice to have the temperatures of both CRF and PRF by the authors in the experimental design of this study leads to the possibility of deducing that a factor intrinsic to PRF not seen in CRF would lead to c-Fos expression.

This c-Fos selectivity for PRF-treated animals was subsequently refuted in a study by Van Zundert et al. [17] where sham, PRF, and continuous RF were applied adjacent to the cervical DRG of rats. All three groups had induction of c-Fos with staining that was noted 7 days after treatment study. Additional research is warranted regarding the genetic changes that may result and be responsible for the clinical effect of PRF.

Cahana et al. [18] evaluated in vitro neuronal preparations to determine tissue effects of CRF at 42 ° C versus PRF at 38 and 42 °C. The electrical energy required in CRF was less than that in PRF, yet CRF was found to be a destructive lesion in which heat was generated, with PRF specimens showing less tissue injury [18].

Cosman and Cosman [6] have opined that the heat produced with the pulsed energy may be responsible for the clinical benefit of PRF. This heat is subsequently removed during the rest phase, however. Additionally, they suggest that electroporation may be a factor in leading to the clinical effect of PRF. This concept is the alteration in electrical conductance and membrane permeability of a cell membrane in response to an applied electrical field, theoretically leading to analgesic benefit after PRF.

Hagiwara et al. [19] have opined that the analgesic action of PRF involves the action of the accessory adrenergic pain pathways. Hamann et al. [20] have looked at the possible mechanism of PRF and suggest that PRF targets neurons with small diameter axons by evaluating the role of activating transcription factor 3 (ATF-3), a marker of cellular stress, in rats. DRG application of PRF led to an increased presence of ATF-3 in neurons. The authors suggest that PRF can lead to increased cell stress in the absence of direct thermal lesioning. The role of this factor and others in regards to PRF is yet to be fully elucidated.

A proteomic study [21] has also been performed in rats to look at protein expression in animals treated with PRF. L5 dorsal root ganglia were exposed to PRF and sham therapy. Western blotting of samples showed increased levels of gamma-aminobutyric acid (GABA) and decreased 4-aminobutyrate aminotransferase (enzyme involved in production of GABA) in animals treated with PRF. GABA is a neurotransmitter regulating neuronal excitability. Further studies are warranted in exploring the role of PRF on GABA [22, 23].

Animal studies have been performed evaluating the histological effects of CRF therapy. In a study involving CRF of goat (DRG), de Louw et al. [24] found that a temperature of 67 °C at the DRG can lead to hemorrhagic loss of myelinated fibers. This neural destruction is absent if the CRF is performed adjacent to the DRG. Consequently, the heat lesion leads to neuronal injury after a radiofrequency procedure. Animal research has led to the theory that CRF was a selective lesioning modality, preferentially targeting C and A-δ fibers occurred before affecting the larger myelinated A-α and A-β fibers. Other studies have contradicted this result, and CRF is now widely thought of as leading to heat-induced equal destruction of all nerve fibers. Dreyfuss et al. [25] showed that RF neurotomy is a nonselective treatment that affects and coagulates all nerves as a result of EMG studies [26].

Vatansever et al. [27] compared the effects on the sciatic nerve of male Wistar rats. Five groups were studied: no procedure, sham procedure, 40 °C CRF for 90 s, CRF 80 °C for 90 s, and PRF for 240 s. CRF 40 °C showed the presence of endoneurial edema in the subperineurial and perivascular areas of the nerve. Light microscopy specimen evaluation demonstrated transverse myelin fibers damaged along with separation of the axoplasma. This separation would lead to impaired nerve transmission. Electron microscopy also confirmed alteration of myelin configuration. Additionally, lamellous separation with protrusion of myelin and accumulation of neurofilaments was found, pointing to a diagnosis of neurodegeneration.

CRF 80 °C showed significant endoneurial edema and evidence of Wallerian degeneration. Electron microscopy showed evidence of neurodegeneration, including epineurial thickening, lamellous separation, intra-axonal vacuolization, increased intracellular endoplasmic reticulum, and Schwann cell damage.

PRF demonstrated changes similar to CRF 40, but the severity of lesions was less.

Podhajsky et al. [28] observed effects of 80 °C CRF and 42 °C PRF lesions on rat DRG and sciatic nerves for 2, 7, and 21 days after initial treatment and found similar results. Massive edema in specimens was seen on day 2 with 80 °C treatment. Wallerian degeneration and tissue coagulation were observed on the 7th day after treatment. With 42 °C, edema was also seen on the 2nd day of treatment, but regressed and resolved by the 7th day.

Animal studies were also performed in rabbits [29] to evaluate PRF vs. CRF current on the DRG. Animals were in a PRF, CRF, control, or sham grouping. No changes noted at 2 weeks after treatment under light microscopy. By electron microscopic sections, CRF-DRG specimens showed degenerative changes including evidence of cytoplasmic vacuoles, a large endoplasmic reticulum, mitochondrial degeneration, and the loss of nuclear membrane material. PRF did not show the intensity of these changes, with just the presence of large vacuoles throughout the cytoplasm.

Slappendel et al. [39] published a report of the results of a randomized, double-blinded multicenter trial on the effect of CRF of the cervical DRG to treat cervicobrachial pain. This study evaluated the difference in temperature between two groups: one population was treated with CRF at 67 °C and the other group at 40 °C. Both patient groups developed a decrease in VAS scores; however, the 40 °C group maintained their decrease at 3-month follow-up. Van Zundert et al. [40] have evaluated PRF in the treatment of cervical radicular pain adjacent to the cervical DRG and found the technique be satisfactory at reducing discomfort for a mean duration of 9 months.

The concept of cervicogenic headache is a controversial topic in pain management circles. Difference of opinion exists between physicians as to whether this entity deserves a diagnosis or not [41].

Multiple papers [41–43] have provided a description of this unilateral headache that is present in the occipital or neck region, radiating to the temporal and/or frontal aspect of the cranium. Stovner et al. [44] have evaluated the use of radiofrequency denervation of facet joints for cervicogenic headache via a double-blinded, sham-controlled randomized double-blinded study. Twelve patients with unilateral cervicogenic headache were evaluated with half randomized to receive C2–C6 neurotomy and the others to receive sham therapy. Patients were followed for 2 years, with improvement noted at 3 months in the treated group. The authors followed patients for 2 years after the initial treatment and found no significant benefit for the use of this technology. Haspeslagh et al. [45] compared the use of radiofrequency of the medial branches supplying the z-joints, the dorsal root ganglion against an injection of local anesthetic at the greater occipital nerve with subsequent application of transcutaneous electrical nerve stimulation. There was no evidence that cervical z-joint radiofrequency was superior to injection of the greater occipital nerve and TENS application. The results of this study may be questioned, however, because of the small sample size (15 patients) and a relatively large number of patient dropouts. Govind et al. [46] have evaluated radiofrequency denervation for headache pain by targeting the third occipital nerve a particularly tenacious nerve. Multiple lesions, larger electrode (greater than 22 G), were utilized for best clinical effect. Untoward side effects such as ataxia, paresthesia, numbness, and dysesthesia may result from this procedure.

Navani et al. [47] presented their report of the use of PRF in a patient with occipital neuralgia. The patient underwent PRF at the medial branches of C1 and C2 dorsal rami with three cycles of 42 °C for 120 s. The patient subsequently underwent another PRF treatment 4 months after initial therapy with improvement of symptoms. As with PRF in other cervical applications, the benefits of treatment as compared to CRF here are evident with less potential risk of neuritis pain induced by heat lesions. Further research is warranted for the use of PRF for this indication.