Pulsed Radiofrequency Neuromodulation of Peripheral Nerve Injury

Pulsed-radiofrequency neuromodulation (PRF) is a pain management technique that involves placing a needle electrode near nerves and generating electrical current pulses in order to modulate the transduction of somatosensory information through those nerves. This technique evolved from a similar radiofrequency (RF) procedure in which constant current is distributed to a nerve or neural structure. RF interrupts nerve conduction and prevents somatosensory information from reaching the brain. In the case of continuous radiofrequency, however, the destructive lesion can cause further complications and unwanted side effects. According to research, PRF, unlike RF, is non-destructive yet still induces analgesia and consequently represents a more advantageous technique. Only a handful of previous studies have attempted to determine the neural effects of PRF. The current study seeks to develop an animal model of PRF using the spared nerve injury model (SNI) and, through molecular analysis of neurological tissues harvested from rats, examines mechanisms by which PRF causes analgesia. The study found that there was a significant difference between the SNI lesion model groups and the groups that did not receive the SNI lesion model. However, for the rats with SNI lesions, the analgesic effects of PRF appear to be inconclusive. Pulsed Radiofrequency 3 Pulsed Radiofrequency Neuromodulation of Peripheral Nerve Injury Pain is a universal sensation that is unavoidable in the course of a lifetime. Acute pain is a term which applies to the immediate experience of pain. However, if a specific pain is experienced for more than three months, then it is known as chronic pain (Turk and Okifuji, 2001). A type of chronic pain known as neuropathic pain is a debilitating condition which seriously impacts a patient’s quality of life. Neuropathic pain is the result of injury to the peripheral or central nervous system, and the resulting barrage of pain messages makes the condition overwhelming and difficult to manage (Bonica, 1992; Millan 1999). As a result of the enhanced transmission of pain signals, noxious stimuli are perceived as even more painful—a condition known as hyperalgesia—and normally harmless stimuli, such as brushing up against clothing, elicit pain—a circumstance known as allodynia (Luongo, 2009). Neuropathic pain has been a subject of study for many years and numerous methods to relieve a patient’s suffering have been investigated. One discovery was the surgical technique of radiofrequency (RF) which lessens the experience of pain by damaging the nerve and preventing transmission of stimuli. However, further research discovered that pulsed radiofrequency (PRF) has been found to be an alternative technique that reduces pain with moderately high voltages near the nerve and it does not produce any significant lesion (Wu and Groner, 2007). The purpose of this study is to test whether PRF will significantly reduce chronic pain. Pain has a purpose: it is fundamental for protecting the body and preventing further tissue damage. Signals sent to the brain and spinal cord indicate when damage is taking place so the person or animal can react appropriately to the situation. Sharp, immediate pain, known as acute pain, encourages the body to avoid the injurious stimulus. Pain travels through C-fibers in the ascending neural pathways through the spinal cord into the brain (Casals-Diaz, Vivo and Pulsed Radiofrequency 4 Navarro, 2009). Sometimes pain is persistent until the damaged tissue is healed; this continued pain results because of activity-dependent functional plasticity in the spinal dorsal horn that persists beyond the stimulus to remind the person or animal to protect the wounded area (Woolf and Decosterd, 1999). However, there are times when the injured area continues to experience pain even though the damaged tissue has healed. This continuing, chronic pain renders a person dysfunctional and debilitated and can make daily activities nearly impossible for those suffering from it (Sah, Ossipov, and Porreca, 2003). The study of chronic pain has largely focused on how to treat its effects or, at the very least, lessen its severity. Historically, one of the first techniques used to treat the condition was the use of drugs such as opiates. These drugs are effective in lessening the perception of pain, yet they often leave the patient with many significant negative side effects such as drowsiness and addiction (Rosenblum, Marsch and Joseph, 2008). Subsequently, surgery became a viable solution to improving chronic pain. Physicians attempted to resolve the pain by surgically locating a problem and attending to its dysfunction. As surgical techniques and knowledge of the functions and interactions of physical structures improved, increasingly sophisticated procedures were developed. One promising category of procedures involved applying electrical and thermal stimulation to interfere with the transmission of pain signals. The first of these procedures to be developed that met with some success is radiofrequency (RF), which involves inserting a small needle with an electrically active tip into a nerve and activating the tip continuously for short intervals at high temperatures approximately 75 o C or higher (Ruiz-Lopez and Erdine, 2002). This procedure was first used as a neuroablative technique and the heat produced by the needle was administered until the cells of the nerve that were causing the chronic pain were destroyed Pulsed Radiofrequency 5 (Ischia, Luzzani, Ischia and Maffezzoli, 1984; Bogduk, 2006). Slappendel et al. (1997) demonstrated that the use of radiofrequency was shown to reduce pain significantly. Thus, the success of this technique allowed patients to have a new treatment option for their pain. Nevertheless, although this procedure lessened pain, it did have some complications. Radiofrequency uses high temperatures on the tissues which produce thermal lesions on the nerve and result in both neuroablation and deafferenation (Abejon and Reig, 2003). For this reason, radiofrequency has been shown to work, and work well, when larger lesions are desired (Kapural, et al., 2008). Nevertheless, changes were made to the procedure to improve upon its technique. Researchers subsequently discovered that the nerve did not need to be completely destroyed for subjects to get relief from the pain. By changing the procedure so that the temperature was 67 o C instead of 80-90 o C at the tip of the needle, they were able to prevent total destruction of the nerve (Bogduk, 2006). In 1997, there was a fundamental shift in the approach to radiofrequency, and new insight into the way radiofrequency was thought to produce its therapeutic effect. Slappendel et al. (1997) demonstrated that patients receiving radiofrequency at 40 o C and 67 o C had no significant difference between their levels of pain relief. This experimental result indicated that another mechanism was responsible for radiofrequency’s previous success and it was not a consequence of the thermal lesion. Thus, it was inferred that the electrical current was the source of the therapeutic effects and the approach to radiofrequency was significantly changed. The new hypothesis was that using bursts of electrical current and allowing time between each burst, so that the heat produced would have time to dissipate through the tissue and not damage the nerve, would still provide the electrical field that would result in pain relief (Bogduk, 2006). This Pulsed Radiofrequency 6 theoretical supposition gave rise to the method of treatment known as pulsed radiofrequency neuromodulation. Pulse radiofrequency neuromodulation (PRF) was a modification of the older radiofrequency technique. The method of action of PRF is identical to that of conventional radiofrequency therapy. Both treatments employ an insulated needle that is only activated at the tip, and in both techniques heat and an electric current pass through the needle tip. The resulting electric field is the movement of the electrons within the tissues when they are exposed to the charge produced by the needle’s tip. However, one of the crucial differences between the two approaches involves the temperature required to create a reversible lesion: lesions created by temperatures above 45 o C produce irreversible injury, whereas lesions produced between 42 o C and 44 o C are reversible (Abejon and Reig, 2003). It is the “pulsed” component of PRF that prevents the heat of the insulated needle from reaching temperatures that would destroy the nerve. Because the pulses are administered with a pause between each one, the heat can dissipate by thermal conductance into the surrounding area, and therefore only mild lesions are created, making PRF safer and consequently preferable to radiofrequency (Abejon and Reig, 2003; van Boxem et al., 2008; Tun et al., 2009; Liliang et al., 2009). There is a tremendous advantage to PRF because of the remarkable decrease in aversive side effects; there is no indication of significant damage done to the motor and sensory nerves after the application of PRF (Slappendel et al., 1997). The reason for this improvement is that PRF provides treatment to the C-fibers and spares large, myelinated fibers, keeping them intact and preventing deafferentation syndromes (Abejon and Reig, 2003). By definition, neuropathic pain results from a lesion of the nervous system (Campbell and Meyer, 2006). Peripheral neuropathic pain is produced by the interaction of multiple Pulsed Radiofrequency 7 physiological mechanisms which operate at different times and in diverse sites. PRF has significantly reduced chronic pain for patients in a clinical setting (Wu and Groner, 2007), yet clinical studies cannot always provide the same level of control and continued participation as experimental, empirical studies. In the attempt to create an animal model of such pain, most experimental investigations use a combination of injured and uninjured nerves (Decosterd and Woolf, 2000). Partial sciatic nerve injury (SNI) was designed to produce a sensation in the rat that is similar to the sensation of pain experienced by human beings (Kim and Chung, 1992; Decosterd and Woolf, 2000). In the SNI model, the tibial and common peroneal nerves, which are two of the three terminal branches of the sciatic nerve, are severed (lesioned), but the third branch of the nerve, the sural nerve, is left intact (Chiasson, R.B., 1958). The result of SNI is the production of consistent, enduring hypersensitivity in the area surrounding the spared sural nerve (Bourquin et al., 2005). An experimental SNI model performed on mice suggests that injuring only the tibial nerve results in mechanical hypersensitivity, yet injuring both the peroneal and sural nerves does not result in hypersensitivity to areas surrounding the uninjured tibial nerve (Bourquin et al., 2005). Therefore, the SNI model seems to show the most promise for future experimental investigation. Several experimental studies have demonstrated that SNI alters the sensitivity to thermal and mechanical stimuli (Casals-Diaz, Vivo and Navarro, 2009; Baliki, Calvo, Chialvo and Apicarian, 2005). A range of mechanical stimuli, such as Von Frey probes and pinpricks, and a variety of thermal applications, both hot (hot plates) and cold (cold plates and the application of acetone) have been tested on rats (Dowdall, Robinson and Meert, 2004; Baliki, Calvo, Chialvo and Apicarian, 2005). These experiments were designed to elicit escape behaviors in the rat, such as lifting the injured paw and moving away from the thermal plate, since such actions are Pulsed Radiofrequency 8 evidence of a reduced pain threshold (Baliki, Calvo, Chialvo and Apicarian, 2005). Further investigations of mechanical and thermal sensitivity should provide evidence from which a model of peripheral neuropathic pain in rats could be constructed. One way to observe the neurological effects of chronic pain is to examine and analyze tissues of rats for altered gene expression. Similar to the process in people, when a rat experiences chronic pain, glial activation marker cells alter their gene expression and release tumor necrosis factor-α, interleukin-1β, and interleukin-6 at the injured area; each of these cytokines plays an important role in chronic pain (Cunha, Poole, Lorenzetti, and Ferreira, 1992). There is substantial support for the relationship of tumor necrosis factor-α and neuropathic pain, as evidenced by a correlation between the expression level of tumor necrosis factor-α and the development of allodynia or hyperalgesia in neuropathic pain models (DeLeo, Sorkin and Watkins, 2007). Interleukin-6 is also expressed during chronic pain and elevated serum levels have been identified in patients who have disorders associated with hypersensitivity and tenderness in the tissues, such as neuropathies, burn injuries, and autoimmune and chronic inflammatory conditions (DeLeo, Sorkin and Watkins, 2007). Additionally, interleukin-1β, is a potent proinflammatory cytokine which is apparently involved in neuropathic pain (Sommer et al., 1999; Schafers et al., 2001). Interleukin-1β is secreted in circumstances that are linked to medical conditions that are accompanied by increased pain and hyperalgesia (Watkins et al., 1999). Interestingly, for the purposes of experimental research, studies have shown that gene expression of interleukin-1β is increased in the sciatic nerve 7 days after nerve injury, timing which coincides with peak thermal hyperalgesia (DeLeo, Sorkin and Watkins, 2007). This peak in interleukin-1β provides an ideal time frame for behavioral testing in experiments on rats. Pulsed Radiofrequency 9 The tissues which are most likely to reveal higher levels of gene expression associated with the experience of chronic pain are located near the injury site. For the purposes of this study, those are the sciatic nerve, left and right dorsal root ganglion as well as the spinal cord. The altered expression of the genes will further indicate that the rat was in a state of chronic pain. Empirical studies conducted on PRF have found significant results for its analgesic properties. However, there has not been a study that has observed PRF’s beneficial effects with a SNI lesion model on rats. Thus, the current study will enhance the knowledge of PRF and contribute to the present literature. The present study tested PRF on the sciatic nerve of rats using the SNI model (Decosterd and Woolf, 2000) to observe their responses to pressure exerted on the plantar surface of each hind paw using a Specialized Force Transducer. Acetone was also used on the hind paws to test for indications of thermal hypersensitivity. Rats in the experimental group had an initial surgery to create the SNI model and a second surgery with PRF stimulation. After the initial surgery the rats had behavioral testing done on days 1, 3 and 7. On the 7 th day after the behavioral testing the rats had their second surgery. The rats had behavioral testing on days 8, 10 and 14 after the initial surgery (see Figure 1). On day 14 the tissues of the rats were harvested to test for interleukin-1β, interleukin-6, and tumor necrosis factor-α as further evidence of pain. A repeated measure ANOVA was used to statistically test for significant results. This study attempted to demonstrate that rats receiving PRF stimulation had a significant increase in pain relief as compared to the group not receiving PRF stimulation. Method