Percutaneous Pulsed Radiofrequency Reduces Mechanical Allodynia in a Neuropathic Pain Model ¨ zgu¨r O ¨ zsoylar, MD* O Didem Akc¸alı, MD* Pelin C ¸ izmeci, MD* Avni Babacan, MD* Alex Cahana, MD, DAAPM, FIPP† Hayrunnisa Bolay, MD, PhD‡
BACKGROUND: Neuropathic pain is a result of a primary lesion or dysfunction of the peripheral or central nervous system, and its treatment is challenging. Animal models have been helpful in understanding mechanisms of neuropathic pain and in developing new treatment strategies. In this study, we examined the effect of percutaneous pulsed radiofrequency (PRF), which is a minimally invasive pain treatment method, on mechanical allodynia in a neuropathic pain rat model. METHODS: Neuropathic pain was achieved in a peripheral nerve pain model by performing L5– 6 spinal nerve ligation. On the 14th postoperative day, percutaneous PRF was applied to the plantar side of the left rear paw. Animals were evaluated for mechanical allodynia with both dynamic plantar aesthesiometer (DPA) (weight and paw withdrawal time) and von Frey filaments (VF) on the 14th postoperative day and 1, 3, 5, 7, 10, and 14 days after PRF treatment. Experiments were conducted in six groups: Sham-operated ⫹ placebo PRF 6 min, shamoperated ⫹ PRF 6 min, neuropathic (NP) ⫹ 2 min placebo PRF, NP ⫹ 2 min PRF, NP ⫹ 6 min placebo PRF, and NP ⫹ 6 min PRF. RESULTS: Allodynia developed in all animals in the NP groups compared to sham-operated animals (P ⫽ 0.0001). DPA and VF showed that PRF application for 2 min significantly improved allodynia on 1–14th post-PRF day, compared to placebo PRF (P ⫽ 0.0001). Although DPA (both weight and paw withdrawal time) did not show any therapeutic effect from 6 min PRF application on 1–14th post-PRF days (P ⫽ 1.00), VF demonstrated transient improvement for the first week, which disappeared on later evaluations of the 6 min PRF group. CONCLUSIONS: Percutaneous PRF is an effective treatment option in the NP pain model, and further studies are needed to clarify its underlying mechanisms of action. (Anesth Analg 2008;107:1406 –11)
P
ulse radiofrequency (PRF) is a pain treatment modality, and is used for various painful states in clinical practice with the advantage of safe, easy application, and less side effects, compared to conventional radiofrequency thermocoagulation. Since PRF does not produce heat around the probe or the tissue high enough to damage nerves, there is no risk of deafferentation pain.1 PRF waves of 500 kHz and low voltage are given as pulses lasting 20 ms and its From the *Department of Algology, Gazi University, Ankara, Turkey; †Department of Anesthesiology, Postoperative and Interventional Pain Program, Geneva University Hospital, Geneva, Switzerland; and ‡Department of Neurology, Neuropsychiatry Center, Gazi University, Ankara, Turkey. Accepted for publication May 5, 2008. The first two authors have equally contributed to this work. This work was supported by Gazi University grants 01/2003-19 and GU-ET 05 048. Presented in the 5th Congress of the European Federation of IASP Chapters (EFIC) Pain in Europe, I˙stanbul, Turkey on September 13–16th, 2006. Address correspondence and reprint requests to Hayrunnisa Bolay, Department of Neurology, Neuropsychiatry Centre, Gazi University, Besevler, 06510 Ankara Turkey. Address e-mail to
[email protected]. Copyright © 2008 International Anesthesia Research Society DOI: 10.1213/ane.0b013e31818060e1
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application is painless. PRF, during which short bursts of radiofrequency energy is applied to the nerve, is thought to be a safer alternative since there is no clinical evidence of neural damage, and with less post-procedure soreness as experienced after thermal radiofrequency lesioning.2 Neuropathic pain (NP) can be induced by producing peripheral nerve injury in experimental animals.3– 6 The spinal nerve ligation defined by Kim and Chung,6 produces unilateral deafferentation on the ipsilateral rear paw which causes hyperalgesia and allodynia. The mechanism by which PRF works remains unclear, and the efficacy of cutaneous PRF has not been investigated in animals although transcutaneous and percutaneous PRF were applied successfully for NP in humans.7,8 The objective of our study was to constitute a NP model by spinal nerve ligation to investigate the effects of PRF administered percutaneously to the area where mechanical allodynia was detected.
METHODS All animal procedures were performed after obtaining approval from the Animal Care Committee of the Gazi University Medical Center in accordance with the Turkish Animal Welfare Act. The study was Vol. 107, No. 4, October 2008
conducted in Gazi University Neuropsychiatry Center, Neuroscience Laboratory. Rats were cared for, in transparent cages containing 4 –5 rats with a hard base covered with 3– 6 cm thick wood shavings. Cages were placed in a special environment without exposure to sunlight: 12 h daylight, 12 h dark with 22 ⫾ 2°C fixed temperature. Adult male Wistar rats 200 –250 g were divided into the following groups by a blinded observer to form placebo and PRF groups: Group I, sham-operated ⫹ placebo PRF (n ⫽ 9), received a sham operation, and on the 14th postoperative day PRF needles were placed in the paws of animals for 6 min but radiofrequency current was not administered. Group II, sham-operated ⫹ PRF (n ⫽ 4), received a sham operation and on the 14th postoperative day, PRF was administered for 6 min. Group III, NP ⫹ 2 min placebo PRF (n ⫽ 8), underwent a L5– 6 spinal nerve ligation as explained below, neuropathy was documented on the 14th postoperative day. PRF needles were placed in the paws of animals for 2 min, but current was not administered. Group IV, NP ⫹ 2 min PRF (n ⫽ 8), underwent a L5– 6 spinal nerve ligation and PRF was administered for 2 min. Group V, NP ⫹ 6 min placebo PRF (n ⫽ 5), underwent a L5– 6 spinal nerve ligation as explained below, neuropathy was documented on the 14th postoperative day. PRF needles were placed in the paws of animals for 6 min, but current was not administered. Group VI, NP ⫹ 6 min PRF (n ⫽ 5), underwent a L5– 6 spinal nerve ligation and PRF was administered for 6 min. Animals were evaluated for mechanical allodynia with von Frey (VF) filaments and Dynamic Plantar Aesthesiometery (DPA) (weight and paw withdrawal time) on the 14th postoperative day (baseline) and 1, 3, 5, 7, 10, and 14 days after PRF treatment.
NP Model A surgical NP model was created by the spinal nerve ligation method described by Kim and Chung.6 Rats fasted one night before they were anesthetized with 50 mg/kg ketamine-xylasine injection (rat cocktail) intraperitoneally. The back fur was shaved; the animal was placed prone for surgery and the skin was scrubbed with betadine solution. The animals’ rectal body temperature was maintained at 37°C using a heating pad. Under a surgical microscope, skin and percutaneous tissues were incised. L4–S2 level left paraspinal muscles were bluntly dissected from spinal processes. Left L4 – 6 spinal nerves were visualized after careful dissection of L6 spinous process. In NP groups (Groups III, IV, V, and VI), L5 and L6 spinal nerves were ligated tightly by 3-0 silk surgical suture. In the sham-operated groups (Groups I and II), these Vol. 107, No. 4, October 2008
nerves were left unligated. Surgery ended after proper closure with subcutaneous and skin sutures. After the recovery period animals were transferred to their cages.
Behavioral Tests All rats were evaluated with VF filaments and DPA (Dynamic Plantar Aesthesiometer: Ugo Basile, Italy) for mechanical allodynia on the 14th postoperative day and 1, 3, 5, 7, and 14 days after the PRF procedure. Mechanical allodynia was evaluated with VF filaments using the up-down method as described by Chaplan et al.9 The paw withdrawal threshold was calculated according to a response pattern based on Dixon’s nonparametric statistical method.10 For evaluation of mechanical allodynia with DPA, mechanic stimulus was performed on the left rear paw plantar side by an automated test machine through a meshed base. Incremental force was applied by a 2 mm diameter metal rod to the left paw plantar side. Force was increased from 0 to 50 g in 10 s. When the rat withdrew its paw, mechanical stimulus stopped automatically, time (seconds) and force (weight in grams) of paw withdrawal was recorded with approximately 0.1 g sensitivity. Paw withdrawal responses were repeated four times with 10-s intervals. Paw withdrawal threshold and time was accepted as the average of four measurements.
PRF On the 14th postoperative day, after control behavioral tests, PRF was performed. PRF was performed via a perpendicularly placed 22G SMK 54 mm, 5 mm active tip needle (NeuroTherm 22 GA), by a lesion generator (NeuroTherm, Morgan Automation, UK) producing radiofrequency waves of 500 kHz carrier frequency, with an adjusted voltage of 50V, 1 ms pulse width for periods of 50 ms every 500 ms using an electrocautery disk for ground. Maximum needle tip temperature was ⬍42°C at all times. A rat was placed in a transparent box limiting its movement and an electrocautery disk was attached to its abdomen. The radiofrequency needle was placed at 90 degrees to the skin as the active tip was completely inside the skin percutaneously (2–3 mm deep) into the left rear paw plantar side. Impedance was tested and PRF was applied for 120 s to Group IV (NP⫹ PRF). PRF was applied for 6 min to Group II (SHM⫹PRF) and VI (NP⫹ PRF). In Groups I (sham ⫹ placebo PRF 6 min), III (NP⫹ placebo PRF 2 min) and V (NP⫹ placebo PRF 6 min), the RF needle was inserted, but no current was applied. In this study, the probe was inserted perpendicularly to the paw and impedance and temperature of the tip of the electrode for each rat were recorded. The last behavioral tests were performed on the 14th day after PRF and rats were killed with intraperitoneal injection of a lethal dose (150 mg/kg) thiopental sodium. © 2008 International Anesthesia Research Society
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Figure 1. Comparison of paw withdrawal threshold recorded by von Frey filaments. Von Frey results of Group IV (NP⫹ PRF 2 min) were significantly different than Group III (NP⫹ placebo PRF 2 min) on post PRF day 5, 7, 10, and 14. There was no significant difference between Group IV (NP⫹ PRF 2 min) and Group VI (NP⫹ PRF 6 min) on post PRF days 1, 3, 5, and 7, but this difference disappeared on days 10 and 14 (P ⬍ 0.05). *P ⬍ 0.05 between NP/PRF 2 min and NP/PLS 2 min. NP ⫽ Neuropathic pain; PRF ⫽ Pulsed radiofrequency; SHM/PRF 2 min ⫽ sham operated ⫹ placebo PRF 2 min; NP/PLS 2 min ⫽ neuropathic⫹ placebo PRF 2 min; NP/PRF 2 min ⫽ neuropathic⫹ PRF 2 min; SHM/PLS 6 min ⫽ sham operated ⫹ placebo PRF 6 min; NP/PLS 6 min ⫽ neuropathic⫹ placebo PRF 6 min; NP/PRF 6 min ⫽ neuropathic⫹ PRF 6 min.
Statistics Data were given as mean ⫾ sd. Statistical tests were performed by SPSS 12.0 computer program. Normalization of data was investigated by the KolmogorovSmirnof test. Group comparisons were done by two-way analysis of variance (Friedman). Differences among groups were determined by the nonparametric Kruskal-Wallis test and post hoc comparisons were done with the Wilcoxon test.11 P ⬍ 0.05 was accepted as statistically significant.
RESULTS In the NP groups (Group III, IV, V, and VI), allodynia in response to mechanical stimulus was evaluated by behavioral tests. Fifty percent withdrawal threshold was determined from the series of responses.10 The threshold evaluated with VF filaments ⬍4.00 g was assumed to indicate allodynia.9 There was no rat in the NP groups with a threshold over 4.00 g. Paw withdrawal thresholds for the NP groups (Group III, IV, V, VI) recorded by DPA and VF filaments were found to be significantly lower compared to the sham-operated groups (Groups I and II) on the 14th postoperative day (P ⫽ 0.0001) (Fig. 1). No neuropathy was found in the sham-operated groups. There was no difference in allodynia among NP groups on the 14th postoperative day (P ⬎ 0.05). The main finding of the present study is that exposure of animals to PRF energy for 2 min (120 s) in Group IV (NP⫹ PRF 2 min) resulted in a significant increase of paw withdrawal thresholds, compared to placebo Group III (NP⫹ placebo PRF 2 min) on days 5, 7, 10, and 14 (P ⬍ 0.05), both with VF filaments (Fig. 1) 1408
and DPA (Figs. 2 and 3). The results between VF filaments and DPA were correlated (Figs. 1–3). The VF results for Group IV (NP⫹ PRF 2 min) were significantly higher than Group III (NP⫹ placebo PRF 2 min) on post-PRF day 5, 7, 10, and 14 (P ⬍ 0.05) (Fig. 1). There was no significant difference between Group IV (NP⫹ PRF 2 min) and Group VI (NP⫹ PRF 6 min) on post-PRF days 1, 3, 5, and 7, but on days 10 and 14 Group IV values were higher than Group VI. There was no significant difference between Group III (NP⫹ placebo PRF 2 min) and Group V (NP⫹ placebo PRF 6 min) at any time (Fig. 1). No statistically significant difference was detected (P ⬎ 0.05) when values of Group IV (NP⫹ PRF 2 min) was compared with Group I (Sham ⫹ placebo PRF 6 min) on post RF days 1 and 14, indicating the therapeutic efficacy of 2 min PRF application for reversing neuropathic features. DPA results for paw withdrawal time were compared and Group IV values (NP⫹ PRF 2 min) were found to be significantly higher than Group III (NP⫹ placebo PRF 2 min) on post-PRF day 10 (Fig. 3). Group IV (NP⫹ PRF 2 min) values were also significantly higher than Group VI (NP⫹ PRF 6 min) beginning from post-PRF day 3 until day 14 (P ⬍ 0.05) (Fig. 2). When Group IV values (NP⫹ PRF 2 min) were compared with Group I (sham ⫹ placebo PRF 6 min) values, no significant difference was found on postPRF days 1 and 14 which shows the treatment (P ⬎ 0.05) (Fig. 2).
Impedance and Temperature Impedance values were similar among groups (1670 ⫾ 102.3 in Group II (sham ⫹ PRF 2 min),
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Figure 2. Comparison of paw withdrawal thresholds according to weight recorded by dynamic plantar aesthesiometer. Group IV (NP⫹ PRF 2 min) was found statistically higher compared to Group III (NP⫹ placebo PRF 2 min) on post PRF day 10 and 14. Group IV (NP⫹ PRF 2 min) values were also significantly higher than Group VI (NP⫹ PRF 6 min) beginning from post RF day 3 till day 14 (P ⬍ 0.05). *P ⬍ 0.05 between NP/PRF 2 min and NP/PLS 2 min. NP ⫽ Neuropathic pain; PRF ⫽ Pulsed radiofrequency; SHM/PRF 2 min ⫽ sham operated ⫹ placebo PRF 2 min; NP/PLS 2 min ⫽ neuropathic⫹ placebo PRF 2 min; NP/PRF 2 min ⫽ neuropathic⫹ PRF 2 min; SHM/PLS 6 min ⫽ sham operated ⫹ placebo PRF 6 min; NP/PLS 6 min ⫽ neuropathic⫹ placebo PRF 6 min; NP/PRF 6 min ⫽ neuropathic⫹ PRF 6 min.
Figure 3. Comparison of paw withdrawal thresholds according to time recorded by dynamic plantar aesthesiometer. Group IV (NP⫹ PRF 2 min) was found significantly higher than Group III (NP⫹ placebo PRF 2 min) on post PRF day 10. Group IV (NP⫹ PRF 2 min) values were also significantly higher than Group VI (NP⫹ PRF 6 min) beginning from post RF day 3 till day 14 (P ⬍ 0.05). *P ⬍ 0.05 between NP/PRF 2 min and NP/PLS 2 min. NP ⫽ Neuropathic pain; PRF ⫽ Pulsed radiofrequency; SHM/PRF 2 min ⫽ sham operated ⫹ placebo PRF 2 min; NP/PLS 2 min ⫽ neuropathic⫹ placebo PRF 2 min; NP/PRF 2 min ⫽ neuropathic⫹ PRF 2 min; SHM/PLS 6 min ⫽ sham operated ⫹ placebo PRF 6 min; NP/PLS 6 min ⫽ neuropathic⫹ placebo PRF 6 min; NP/PRF 6 min ⫽ neuropathic⫹ PRF 6 min. 1607.6 ⫾ 109.5 in Group IV (NP⫹ PRF 2 min) and 1607.6 ⫾ 109.5 in Group VI [NP⫹PRF 6min]). All of the electrode tip temperature values were lower than 42°C, however, the mean maximum electrode tip temperature was significantly higher in Group VI (NP⫹ PRF 6 min) (38.6 ⫾ 3.2) compared to Group IV (NP⫹ PRF 2 min) (34.4 ⫾ 1.3) and Group II (sham ⫹ PRF 2 min) (35.3 ⫾ 2.2) (P ⬍ 0.05).
DISCUSSION We investigated the effects of percutaneous PRF on NP. To our knowledge, this is the first animal study to show an antiallodynic effect of percutaneous PRF Vol. 107, No. 4, October 2008
treatment. PRF applied for 2 min (120 s) percutaneously was found effective for reversing mechanical allodynia symptoms induced by spinal nerve ligation. Increasing the duration of percutaneous PRF did not significantly reduce NP symptoms (Figs. 1–3). The spinal nerve ligation model was successful for making allodynia in the ipsilateral rear paw. In the NP groups, allodynia was confirmed by both behavioral tests whereas no allodynia was detected in shamoperated groups. NP was evaluated by two behavioral tests, VF and DPA in animals. VF is a commonly used method and the most validated for mechanical allodynia despite being subjective to the observer. DPA is © 2008 International Anesthesia Research Society
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able to test the threshold for weight in agreement with the VF method automatically and also provides a paw withdrawal time for allodynia. Both behavioral tests confirm the efficacy of percutaneous PRF particularly 1 wk after the procedure. Radiofrequency thermocoagulation, which is a recent treatment modality, was used for NP. We preferred to use PRF peripherally since the application of PRF to dorsal root ganglion (DRG) is an invasive procedure requiring fluoroscopy and is associated with a higher risk of infection, bleeding, nerve injury, and other complications. Peripheral PRF is an easy and safe method for the specialist, the patient and the environment. During PRF, the tip of the electrode does not exceed 42°C, which is lower than neurondestructive levels so any heat lesion is avoided.12–17 PRF practices for pain are usually applied to DRG18,19 and cervical medial branches of dorsal rami.20 In the present study, we applied PRF percutaneously to the symptomatic hindpaw where allodynia was detected in experimental animals. There are few clinical studies in which transcutaneous and percutaneous PRF applications were found effective in humans. Balogh8 reported successful results in four patients after 10 min of transcutaneous PRF; the procedure was repeated monthly for long-term results. In another case, percutaneous PRF to the greater occipital nerve for occipital neuralgia was performed for 4 min, and pain relief was obtained for 4 –5 mo.7 As the effect of PRF usually lasts an average of 3– 6 mo in patients, animals were tested beyond 14 days in our study; however, further experimental studies will explore the time window of the pain-free period after PRF treatment. The duration of peripheral PRF application to the DRG is usually 2 min,12 however, a longer duration has also been reported.7,8 Therefore, we compared the 2 and 6-min periods for peripheral PRF and found that the former effectively reduced NP symptoms. Increased duration of PRF did not exert a significant antiallodynic effect in this study. The mechanism of PRF is thought to be a neuromodulatory effect caused by a pulsed electric field which might interfere with sensory neuron-specific gene expression and molecules involved in sensitization and development of NP.21 When PRF is applied to the DRG, the direct effect of the electrical field is plausible for inducing changes in the neurons of dorsal horn. Since percutaneous application to the paw is obviously far from the dorsal horn neurons, it is unlikely that electric pulses applied to paw directly affected the dorsal horn neurons. Therefore, neural tissue and nociceptors in the periphery could be targeted by a percutaneous approach. PRF may inhibit excitatory C-fiber responses by repetitive, burst-like stimulation of A-␦ fibers22,23 and reduce evoked synaptic activity.24 Currently which mechanism plays a prominent role in analgesia has not been identified.3 1410
The failure of longer duration PRF in this experimental setting could be partially attributed to the electrode tip temperature. Although the tip temperature was higher in the 6 min group, values never exceeded 42°C, which is the highest point for PRF and was not associated with any pain behavior. In NP states, TRPV-1 channels are sensitized and the activation threshold is reduced as low as 35°C. Therefore it is tempting to speculate that the temperature increase proportional to duration of PRF could mask the therapeutic effect of PRF when applied longer, possibly due to the increased activation of TRPV-1 channels.25,26 It is obvious that further studies are needed to determine the optimum duration of effect and the mechanisms underlying the therapeutic action of percutaneous PRF.
CONCLUSION The results of this study revealed an antiallodynic effect of percutaneous PRF which probably induces a neuromodulatory rather than a neurodestructive effect. If, indeed, this is the case, its use as a new treatment alternative for NP may be of interest. The mechanisms mediating the effect of peripheral PRF in regard to comparison with DRG application are not clear. Longer duration may not be needed for percutaneous PRF, though the ideal duration of treatment has to be established for percutaneous PRF in humans. REFERENCES 1. Hamann W, Abou-Sherif S, Thompson S, Hall S. Pulsed radiofrequency applied to dorsal root ganglia causes a selective increase in ATF3 in small neurons. Eur J Pain 2006;10:171– 6 2. Cahana A, Van Zundert J, Macrea L, van Kleef M, Sluijter M. Pulsed radiofrequency: current clinical and biological literature available. Pain Med 2006;7:411–23 3. Obata K, Yamanaka H, Dai Y, Mizushima T, Fukuoka T, Tokunaga A, Yoshikawa H, Noguchia K. Contribution of degeneration of motor and sensory fibers to pain behavior and the changes in neurotrophic factors in rat dorsal root ganglion. Exp Neurol 2004;188:149 – 60 4. Bennet GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87–107 5. Seltzer S, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990;205–18 6. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50:355– 63 7. Navani A, Mahajan G, Kreis P, Fishman SM. A case of pulsed radiofrequency lesioning for occipital neuralgia. Pain Med 2006;7:453– 6 8. Balogh SE. Transcutaneous application of pulsed radiofrequency: four case reports. Pain Pract 2004;4:310 –13 9. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994;53:55– 63 10. Dawson B, Trapp RG. Research Questions About Means in Three or More Groups. In: Dawson B, Trapp RG, eds. Basic and clinical biostatistics. 3rd ed. McGraw Hill, USD, 2001;161– 82 11. Cahana A, Vutskits L, Muller D. Acute differential modulation of synaptic transmission and cell survival during exposure to pulsed and continuous radiofrequency energy. J Pain 2003;4: 197–202 12. Erdine S, Yucel A, Cimen A, Aydin S, Sav A, Bilir A. Effects of pulsed versus conventional radiofrequency current on rabbit dorsal root ganglion morphology. Eur J Pain 2005;9:251– 6
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19. Munglani R. The longer term effect of pulsed radiofrequency for neuropathic pain. Pain 1999;80:437–9 20. Sluiter ME. Radiofrequency. In: Sluiter ME, ed. Radiofrequency Flivopress SA, Switzerland, 2004:49 –73 21. Randic´ M, Jiang MC, Cerne R. Long term potentiation and long term depression of primary afferent neurotransmission in the rat spinal cord. J Neurosci 1993;13:5228 – 41 22. Sandku¨hler J, Chen JG, Cheng G, Randic´ M. Low frequency stimulation of afferent A␦-fibers induces long term depression at primary afferent synapses with substantia gelatinosa neurons in the rat. J Neurosci 1997;17:6483–91 23. Manzerra P, Brown IR. Expression of heat shock genes in the rabbit spinal cord: localization of constitutive and hyperthermia inducible mRNA species. J Neurosci Res 1992;31:606 –15 24. Butera JA. Miniperspectives: recent approaches in the treatment of neuropathic pain. J Med Chem 2007;50:2543– 6 25. Zeilhofer HU, Brune K. Analgesic strategies beyond the inhibition of cyclooxygenases. Trends Pharmacol Sci 2006;27:467–74 26. Martin DC, Willis ML, Mullinax A, Clarke NL, Homburger JA, Berger IH. Pulsed radiofrequency application in the treatment of chronic pain. Pain Practice 2007:31–5
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