In this issue of the Scandinavian Journal of Pain Akural et al. [1] publish an important study on pulsed radiofrequency, a high quality randomized controlled, double blind study with unfortunately, negative outcome. Their study necessitates a review of the background and history of this fairly recent addition to the tools of interventional pain medicine.
Thermal radiofrequency neurotomy or continuous radiofrequency (CRF) has been widely used for chronic pain. Pulsed radiofrequency (PRF) was introduced in 1998 as a non-destructive alternative, and since then it has gained high popularity among pain physicians. Via a thin needle high voltage radiofrequency current is delivered in short 20ms bursts, two per second, to the target [2]. The long pause between each burst prevents heat accumulating, and the temperature can be kept below 42 °C.
1 Mechanism of action?
There is still an ongoing debate on how PRF works. In the early 1960s researchers observed that continuous radiofrequency (CRF), giving a rise to 40 °C, temporarily blocks the nerve conduction [3]. However, a similar effect was observed after exposure to heated water, suggesting that heat itself, and not the RF current, is responsible.
1.1 Ablative procedure?
It has been speculated whether the effect of PRF reflects a minimal ablation. In the study by Cahana et al. both PRF and CRF was found to produce tissue damage, but only very close to the electrode (<0.5mm) [4], and at a distance 0.5–1mmchanges were only observed in tissue subjected to CRF. In dorsal root ganglia (DRG), subjected to either PRF or CRF at 42 °C [5], cellular edema was observed after 2 days, but the changes resolved within 21 days. Electron microscopy of PRF treated nerves has visualized enlargements of the endoplasmic reticulum cistern along with vacuole groups, but in sum the morphology of the nerves was intact [6]. Thus, there is no clear evidence for long-lasting structural effects of PRF.
1.2 Effects on the dorsal horn?
A long-term depression in the spinal cord has been suggested a possible mechanism of action. In hippocampal tissue slices, subjected to either continuous or pulsed RF at 42 °C, researchers observed a 50% reduction of the excitatory postsynaptic potentials, but the effect lasted for only a few minutes [4]. Other researchers have suggested altered gene expression in the dorsal ganglia. PRF at 38 °C, adjacent to the DRG, but not 38 °C CRF, was found to rapidly increase the c-fos levels in the dorsal horn of rats [7]. Van Zundert et al. measured a more delayed increase of c-fos after both PRF and CRF [8], while Hamann et al. demonstrated an upregulation of ATF-3 (activating transcription factor-3) in PRF treated DRGs [9]. It should be born in mind that c-fos and ATF-3 respectively are markers of metabolic activity and cellular stress, and whether they are linked to pain perception has not been shown. It is therefore highly interesting when Hagiwara et al. show how PRF interacts with the descending noradrenergic and serotonergic inhibitory pathways [10]. In a controlled animal study with an inflammatory model PRF of the sciatic nerve was found to reverse the hyperalgesia. The antihyperalgetic effect of PRF was subsequently inhibited by intrathecal administration of the alpha2-adrenoceptor antagonist (yohimbine), selective 5-HT3 serotonin receptor antagonist (MDL72222), and non-selective serotonin receptor antagonist (methysergide).
2 Clinical evidence
2.1 PRF applied to DRGs
Sluiter et al. were the first to report clinical effect of PRF. In a study with patients suffering from radiculopathy a lumbar or cervical DRG was either treated with PRF or CRP. At the 6-week follow-up 56% of the PRF treated patients reported more than75% effect versus 4% in the CRF group [11]. In another study, including patients with leg pain after back surgery, eight out of 15 obtained a satisfactory effect after PRF to lumbar DRGs. Six months after treatment the patients still reported more than two-point improvement on the pain scale [11]. The two studies, however, had no control group, and were not designed to assess the efficacy of PRF.
A randomized controlled trial (RCT), including 76 patients suffering from chronic lumbosacral radicular pain, found PRF of the lumbar DRGs to provide short-term pain relief [12], and addition of CRF did not offer any advantage.
A small (n: 23), but high quality RCT found PRF of cervical DRGs found superior to sham for highly selected patients with cervicobrachialgia [13]. After 3months the PRF group reported significantly better outcome with >50% global improvement and 20 point pain reduction on VAS. The need for pain medication was still lower 6 months after treatment.
2.2 PRF applied to medial branches
PRF, applied to the medial branches, has been tested in patients with facet joint pain. In a non-controlled study, including 114 low back patients, 60% of the patients obtained at least 50% pain reduction [14]. In a more recent, three arm RCT (n: 60), both CRF and PRF were found superior to local anesthetics [15], but the pain rating, satisfaction rate, need of analgesics, and duration of pain relief were in favor of CRF. The next RCT (n: 50) found no significant difference between CRF and PRF, and only the CRF group showed significant change from baseline [16]. Thus, CRF is the recommended RF modality for facet joint pain.
2.3 PRF applied to peripheral non-spinal nerves
Small and non-controlled case series and an observational study have reported effect of PRF on peripheral non-spinal nerves and encouraged clinicians to perform PRF for post-thoracotomy pain [2], ilioinguinal neuralgia [17], shoulder pain, post-tonsillectomy pain [18], and postherpetic neuralgia [19]. However, the results from recent RCTs are less impressive.
In patients with shoulder pain (n: 40) PRF was not found superior to TENS [20], and PRF of the suprascapular nerve (n: 50) was less effective than one intraarticular steroid injection [21]. Erdine et al. demonstrated that CRF of the ganglion Gasseri is highly superior to PRF [22]. Only two of the 20 PRF treated patients with idiopathic trigeminal neuralgia reported pain relief. In only one study PRF was found superior to the comparator. Among patients with cervicogenic headache (n: 30) both PRF and steroid injection of the great occipital nerve was effective, but only PRF provided pain relief for 9 months [23].
3 PRF – a treatment option for peripheral neuropathic pain?
PRF is suggested as a potential treatment modality for neuropathic pain, and two experimental in vivo studies have addressed this question. In rats Ozsoylar et al. [24] found PRF, applied to the rear paw, after tight ligation of the L5 and L6 nerves to reduce the mechanical allodynia. In a controlled study on rabbits, subjected to tight ligation of the sciatic nerve, Aksu et al. [25], studied the effect of PRF on heat and mechanical hyperalgesia. Eight minutes with PRF to the L5 and L6 DRG returned mechanical and thermal hyperalgesia to baseline for 4 weeks.
In this issue of the Scandinavian Journal of Pain, Akural et al. [1] present the first properly designed double-blind comparison of PRF and sham therapy for peripheral neuropathic pain. A heterogeneous group of patients (n: 43) with amoderate to severe peripheral posttraumatic neuropathic pain were either subjected to PRF or sham treatment and followed for a 3 month time interval. PRF was not found superior to sham treatment; out of seven patients who achieved more than 30% pain relief, four were sham treated! Considering that all patients had been suffering from mechanical allodynia or pinprick hyperalgesia in the painful area, it should not surprise that about one third reported adverse effects (transient pain and local irritation).On the other hand, there was no difference between the treatment groups, and the reactions did not necessitate any treatment. These results are in line with other RCTs: PRF is generally well tolerated, but the technique seems ineffective on peripheral nerves. It should, however, be emphasized that PRF adjacent to DRGs may act via other mechanisms than PRF to the axonal part of peripheral nerves. This could explain why PRF adjacent to a DRG seems effective for radicular pain.
Given the completely negative results of the study by Akural et al., the reader may question if the study was optimally performed. First, it should be noted that the inclusion of patients was based on single test blocks and a cut-off level at 50% pain relief. For medial branch blocks a single block has been associated with rather high false-positive responses (30%) [26]. If the authors had added a confirmatory and comparative block, this would probably have reduced this risk [26,27]. Second, the PRF procedure was not strictly standardized and varied from 1 to 4 times at each treatment point. These two factors might have an impact on the result. Given the large heterogeneity of pain conditions, a beneficial effect in subgroups of the sample cannot be excluded (as the authors correctly comment). On the other hand, such a heterogeneous population has increased the external validity of the study.
4 Conclusion
From the data, discussed above, it may be surprising that PRF has gained such a high popularity in the treatment of chronic pain. There are two reasons that make PRF attractive: first, the technique is simpler and therefore faster than thermal CRF. Second, as a non-destructive technique the risk of side effects and complications is low. Considering the conflicting evidence, however, PRF can so far not be recommended for routine treatment of patients with a peripheral neuropathic pain disorder. More research is needed to define which pain conditions, that effectively can be treated with PRF, and which dose that is required.
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2012.04.004
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