Immediate Early Genes after Pulsed Radiofrequency Treatment: Neurobiology in Need of Clinical Trials (2004)

THE search for treatments that relieve chronic pain is expanding and includes biobehavioral techniques, the discovery of new drugs, novel routes of drug administration, neuroablative treatments, and innovative surgical procedures. The use of less invasive, interventional strategies for chronic pain relief has gained popularity since the publication of evidence from randomized controlled trials. Electrical stimulation techniques, such as transcutaneous nerve stimulation and spinal dorsal column stimulation, are attractive treatment options for chronic pain because the intervention can be somatotopically localized and can be removed if effectiveness declines, there are few side effects, and tolerance does not appear to be a problem. Recently, the technique of pulsed radiofrequency treatment, the application of brief, high frequency electrical stimulation adjacent to sensory ganglia, has been described for the relief of chronic, intractable pain. In this issue of Anesthesiology, Van Zundert et al. 1describe changes in the expression of c-fos , an immediate early gene, after pulsed radiofrequency treatment in laboratory rats.Conventional radiofrequency treatment, using a constant output of high-frequency electric current, produces controllable tissue destruction surrounding the tip of the treatment cannula and, when placed at precise anatomic locations, has demonstrated success in reducing a number of different chronic pain states, including chronic neck pain after whiplash injury2and trigeminal neuralgia.3Pulsed radiofrequency utilizes brief “pulses” of high-voltage, radiofrequency range (∼300 kHz) electrical current that produce the same voltage fluctuations in the region of treatment that occur during conventional radiofrequency treatment but without heating to a degree at which tissue coagulates. The idea arose from a chance meeting during a 1995 scientific conference in Austria between Dr. Menno Sluijter, M.D., Ph.D. (Professor Emeritis, Department of Anesthesia, Maastricht University, Maastricht, Netherlands), a physician who has pioneered the clinical application of radiofrequency treatment, and William Rittman, M.S. (Principal, RF Medical Devices, Middleton, MA), then an engineer with Radionics, the firm that developed the original radiofrequency treatment equipment (personal written communication, William Rittman, October, 2004). The two were discussing the mechanism behind radiofrequency treatment with a basic scientist from the former Soviet bloc who had been examining cellular changes induced by magnetic fields; this scientist challenged the conventional belief that pain relief after radiofrequency treatment was a result of tissue destruction, suggesting that the pain relief could result from the strong magnetic fields induced by voltage fluctuations in the area of treatment. Mr. Rittman returned to the bench and quickly devised a means of creating the same high-voltage fluctuations without any heating at the tip of the needle by using pulses of electrical current rather than continuous current. Dr. Sluijter immediately introduced the technique into clinical practice and within months had treated numerous patients with the new modality; based on this initial, uncontrolled clinical experience, the new technique has been aggressively promoted and its use has rapidly spread worldwide.The conceptual appeal of a minimally invasive, nondestructive technique that is useful in treating chronic pain of any sort is compelling. In clinical practice, there has been a mass migration to the use of pulsed radiofrequency with few data to support efficacy of this new technique. The modality has great appeal, specifically because it is not neurodestructive. With conventional radiofrequency, the thermal lesion occasionally leads to worsening pain and even new onset of neuropathic pain.4A small retrospective case series5and the overwhelming “word on the street” among practitioners suggest that pulsed radiofrequency results in neither increased pain nor any risk of neuropathic pain, and it is very well tolerated by patients from treatment through recovery.In the study by Van Zundert et al. ,1experimental neurobiologic techniques are used to probe the effects of pulsed radiofrequency on spinal cord sensory neurons. The gene c-fos codes for the production of fos protein and is rapidly and transiently expressed in neurons after an excitatory stimulus. Using immunohistochemical techniques, Hunt et al. 6first reported that Fos-like-immunoreactivity appears in neurons of the dorsal horn of the spinal cord in rats after noxious stimulation. Subsequently, Fos-like-immunoreactivity has been used as a marker for sensory neuron activation in preclinical animal studies allowing the investigator to determine the number of neurons activated and their segmental and laminar (or depth) location in the dorsal horn.7In many cases, the number and location of Fos-expressing neurons relates to the intensity, modality, and location of the noxious stimulus. Treatments such as opioids and local anesthetic nerve blocks not only reduce pain responses but prevent the development and reduce the maintenance of Fos-like-immunoreactivity caused by a noxious stimulus.Many studies have used c-fos expression as a tool in pain research, and within the last 10 yr our understanding of the role of Fos protein and persistent pain has been clarified.7Fos is an indicator of neuron activation; its value as a marker for plasticity and central sensitization is less well accepted. C-fos is expressed in some but not all dorsal horn neurons after noxious stimulation8,9and at least a few neurons express c-fos protein in the absence of noxious stimulation. Some treatments that reduce pain responses do not affect c-fos expression, so the link between c-fos expression and nociception is evident, but other studies demonstrate that the association between pain-related behaviors, analgesia, and c-fos is not absolute. For instance, it is hypothesized that fos-expressing neurons may be inhibitory interneurons activated by noxious stimuli because many spinal neurons with Fos-like-immunoreactivity contain inhibitory neurotransmitters that reduce nociception: gamma aminobutyric acid, glycine, and dynorphin.7In the study by Van Zundert et al. ,1c-fos expression induced by two pulsed radiofrequency paradigms was compared to c-fos expression induced by continuous (heated) radiofrequency and a sham (surgical exposure only) control. Both pulsed and continuous radiofrequency induced similar increases in the number of cells expressing c-fos , and the expression was present for 7 days after radiofrequency treatment. The observation that c-fos was present 7 days after stimulation suggests sustained activation of a pain-inhibiting process. The duration of Fos-like-immunoreactivity exceeded the expected length of time for c-fos expression caused by the acute effects of surgery and electrical stimulation of sensory nerves. The authors suggest that their clinical and experimental observations may be similar to those described by Sandkuhler et al. ,10who demonstrated in spinal cord recordings that repetitive burst-like stimulation of A-delta fibers caused depression of synaptic activation by C-fibers for several hours. The concept that pulsed radiofrequency may produce inhibition of excitatory C-fiber responses using a phenomenon such as long-term depression is indeed an attractive hypothesis.As appealing as the concept behind pulsed radiofrequency may be, we must be honest with ourselves and our patients regarding how much clinical evidence supports the efficacy of this new technique. Even the current report1references only a scant collection of uncontrolled, retrospective studies, many appearing only as preliminary reports during scientific symposia. Without controlled studies, we must remain keenly aware of the magnitude and duration of the placebo effect in patients undergoing diagnostic blocks as well as those going on to receive radiofrequency treatment for chronic pain. Lord et al. 11have emphasized how important it is to include placebo controls among the panel of diagnostic blocks used to identify those who should go on to active radiofrequency treatment, as many will report prolonged pain relief after saline injection. In a series of patients receiving conventional radiofrequency treatment for chronic whiplash injury, those receiving sham radiofrequency treatment (needle placement without an active, thermal lesion) had 50% pain reduction for an average duration of 8 days versus an average of 263 days in the active treatment group.2More than 20% of patients receiving sham treatment had 50% pain reduction that lasted more than 3 months, the average duration of pain relief reported after pulsed radiofrequency treatment.5Scientifically, it might be suggested that we move forward to examine pulsed radiofrequency in validated models of persistent pain and examine new neurobiologic markers in pain-transmitting neurons after pulsed radiofrequency treatment. However, basic scientific studies in the neurobiology of pain models and analgesic techniques are not a substitute for randomized controlled clinical trials, and studies such as that of Van Zundert et al. do not justify using the technique clinically. We have not a single randomized trial that compares the efficacy of pulsed radiofrequency to any type of control treatment or to conventional radiofrequency treatment. We urge practitioners using these techniques to conduct the randomized trials we need to demonstrate the effectiveness (or lack thereof) of pulsed radiofrequency treatment and hold hope that the evidence will soon appear to support the enthusiasm of practitioners for this new treatment. If and when it is established that particular groups of patients (e.g. , chronic cervicobrachialgia) exhibit long-term pain relief from a treatment such as pulsed radiofrequency, then demonstrating its mechanisms using basic science neurobiology and persistent pain models will provide important fundamental information to understand and advance the technique.* Department of Anesthesia, University of Iowa, Iowa City, Iowa; † Department of Anesthesiology, University of Vermont College of Medicine, Burlington, Vermont; ‡ Departments of Anesthesia and Pharmacology, University of Iowa, Iowa City, Iowa. tim-brennan@uiowa.edu