In addition to the histological and ultrastructural axonal findings in PRF, and the animal studies demonstrating PRF effects, there are also convincing biochemical basis for PRF effects. Higuchi et al. [27
] demonstrated that pulsed but not continuous RF applied at 38°C to the rat cervical DRG resulted in increased c-Fos immunoreactivity in the laminae I & II of the dorsal horn 3 h after treatment. These effects were not seen in animals treated with continuous RF at 38°C. Although not specific for nociceptive pathways, the expression of c-Fos is an indirect marker of neuronal activity as c-Fos is often expressed when neurons fire actions potentials [5
]. Its presence indicates that nerve fibers have been activated by high electric fields, and that these changes are detectable up to the dorsal horn of the spinal cord. Lending further evidence to the definite biological effects of PRF, an upregulation of ATF-3 (activating transcription factor-3), another marker of “cellular stress” was observed in the DRG neuronal bodies in animal models with PRF applied to the L4 DRG compared to sham-operated and L4 axotomised controls [26
]. In addition, Hagiwara et al. [24
] more recently demonstrated that PRF may actually enhance the descending noradrenergic and serotonergic inhibitory pathways, which are intimately involved in the modulation of neuropathic pain. From the available evidence, PRF appears to have genuine biological effects in cell morphology, synaptic transmission, and pain signaling, which are likely to be temperature independent.
Translated into patient management, some well-conducted trials have substantiated its use in conditions, such as cervical radicular pain [65
]. In conditions whereby conventional RF had already been established as an effective treatment, such as in facet denervation, PRF would prove to be of little benefit. In fact, van Boxem et al. [61
] estimate RF lesioning of the facet joint to be effective with a NNT between 1.1 and 1.5. In conditions where the efficacy of conventional RF had been demonstrated but with significant complications, such as in TN [31
], and to a lesser extent, sphenopalatine ganglion treatment of cluster headaches [47
], PRF application would appear to be attractive. The evidence at the current moment, however, does not support this. In our opinion, one of the main reasons for this is the insufficient “PRF dose” applied in some of the above-mentioned studies. In a recent study on the effects of PRF on Resiniferatoxin-induced neuropathic pain in an animal model, the anti-allodynic effects of PRF was significantly greater when PRF exposure was increased from 2 to 6 min [55
]. This dose effect of PRF has not been evaluated formally in human studies.
As Cohen et al. [9
] aptly put it, “PRF is a treatment in search for a cause”. Even though more substantiated evidence is required, PRF has repeatedly been demonstrated to be a safe and effective procedure, even in instances where other treatment modalities have failed [25
]. Its use in a variety of conditions demonstrates the attractiveness of PRF as a less invasive alternative to surgical intervention that may involve significant morbidity.
There had also been some anecdotal reports and retrospective studies on the intra-articular application of PRF [25
]. Given the paucity of evidence for intra-articular PRF, we cannot even begin to imagine how this might work. The authors suggest that the current is actually deflected by the bony surfaces of the joint, forcing it to remain inside the joint space, and thus, resulting in a more localized effect [52
]. There may, in fact, be a plausible explanation for this: Electric fields have demonstrated effects on immune modulation, as there are studies that show proinflammatory cytokines, such as interleukin (IL)-1b, TNFa and IL-6 are attenuated by electric fields [29
]. Upregulation of adenosine A2A receptor density has also been observed in human neutrophils treated with generated electric fields [66
], and this appeared to be associated with inhibition of the catabolic cytokines, such as TNFa, IL-6, and IL-8 [4
]. Another hypothesis on the mode of action of intra-articular PRF is a possible cartilage-protective or regenerative mechanism. In vitro studies have demonstrated that chondrocyte proliferation and matrix synthesis were found to be significantly enhanced by electric field exposure [15
]. Fini et al. [21
] suggest that pulsed electric field delivery combines an anabolic effect on chondrocytes, a catabolic cytokine blockage, a stimulatory effect on anabolic cytokine production, and a counteraction of the inflammatory process in osteoarthritis. However, these effects are at the moment restricted to observations that will need to be reproduced in vivo [52
] in a more systematic manner. Future research may involve changing our focus from pain transmission and neural tissue effects, and broaden the evaluation of PRF to different cell lines and tissue types.