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13 Articles in Volume 11, Issue #3
Advances in Cranial Electrotherapy Stimulation
Chronic Migraine: An Interactive Case History, Part 3
Cost-effectiveness Of Treatments for Low Back Pain
Electrical Me
Lessons From The Father of Electromedicine — Dr. Luigi Galvani
Medications for Chronic Pain—Nonopioid Analgesics
Pulsed Radio Frequency Energy As an Effective Pain Treatment
The Role of Body Posture In Musculoskeletal Pain Syndromes
The Role of Body Posture In Musculoskeletal Pain Syndromes
Therapeutic Laser for the Treatment of Chronic Low Back Pain
Tolerance to Opioids
Understanding Electromagnetic Treatments
Update: Clinical Challenges in the Diagnosis And Management of Fibromyalgia

Pulsed Radio Frequency Energy As an Effective Pain Treatment

The opioid and NSAID pathways serve as models for understanding the analgesic effect of new and alternative therapeutics such as pulsed radio frequency energy (PRFE).

Pain is an essential component of the sensory nervous system and plays a vital role in the survival of the organism.1,2 Electric and magnetic fields have been used in medicine for the treatment of pain, ablation of tissue, and wound healing for more than 75 years.3 More recently, pulsed radio frequency energy (PRFE)3-6 fields have been used for the treatment of bone healing, pain, and wound healing of soft tissue. In this review, pulsed radio frequency energy fields will be discussed in relation to use in pain management, with an emphasis on the cellular and molecular mechanisms of action related to the pharmaceutical analgesics.

What Is PRFE?

PRFE refers to non-thermal, non-ionizing, non-contact electromagnetic energy with a carrier frequency of 27.12 MHz, delivered with pulse bursts of 10 µsec to 1 msec at a frequency of 1 to 1000 Hz. These devices are considered by the FDA to be non-thermal shortwave diathermy devices (category ILX) and have been cleared to market for adjunctive use in the palliative treatment of postoperative pain and edema in superficial soft tissue (Figure 1).

PRFE is to be distinguished from pulsed radio frequency electrical current,7 a modality with similar nomenclature that has been used broadly in medicine, specifically in nerve ablation and electrosurgery. Pulsed radiofrequency electrosurgical devices use an electrode to directly apply alternating current in the radiofrequency range to tissue in order to cut, vaporize, or ablate. These devices are different in design and operating principle from PRFE, which involves delivery of RF electromagnetic fields by means of a non-contact radiating antenna.

Figure 1. The commercially available Provant Pulsed Radio Frequency Energy device for the treatment of postoperative pain.Figure 1. The commercially available Provant Pulsed Radio Frequency Energy device for the treatment of postoperative pain.

In a recent review of the literature, PRFE was found to be useful in relieving chronic pain associated with oral, plastic, podiatric, gynecologic, and abdominal surgical procedures, as well as pain associated with back and neck trauma and post-traumatic algoneurodystrophy.8 Recently, a meta-analysis, which evaluated 25 controlled trials including 16 studies that examined the use of PRFE for reduction of pain, assessed the therapeutic effectiveness of PRFE for both postoperative and non-postoperative pain management.8 Using a vote counting procedure and P-value combination for pain outcomes reported, PRFE therapy was found to provide effective pain reduction, relative to controls, that was clinically and statistically significant (postoperative pain, P<0.0001; non-postoperative pain, P<0.0001).8 Studies evaluated in the analysis compared PRFE therapy to sham controls, standard therapy, as well as other treatment options (varied by study).

Figure 2. A simplified diagram showing several of the peripheral and central nervous system circuits for pain sensation

Neurological Pathways of Pain Reception and Processing

The induction of pain by noxious stimuli is received by the Aβ nerve fibers, a series of nerve fibers distinct from tactile and proprioceptive receptors. These specialized fibers (unmyelinated C fibers and thinly myelinated Aδ fibers) sense the physiochemical properties of pain stimuli. Examples of these noxious stimuli are heat, cold, pressure, and deleterious chemicals.1,9 Noxious stimuli are then converted to transient receptor potentials, which are further amplified by sodium channels to an action potential.10 These peripheral inputs are delivered by nociceptive afferents to glutamatergic synapses in the dorsal horn of the spinal cord (Figure 2). These sensory inputs to the dorsal horn are then carried by different pathways to the specific processing centers of the brain, such as the lateral thalamus, medial thymus, and limbic structures, each being implicated in different aspects of pain perception.

In contrast to nociceptive sensation of pain, neuropathic pain is the result of damage or insult to the nerve structure itself.11 This type of pain can cause neural supersensitivity and may be associated with inflammation and diabetes. In many instances, this type of pain is accompanied by hyperalgesia.12 Neuropathic pain is usually more difficult to treat and in many cases becomes chronic.13

Treatment of Nociceptive and Neuropathic Pain

The standard for the treatment of pain is the use of opioids and non-steroidal anti-inflammatory drugs (NSAIDs). The opioid compounds have a historical basis and have been used for pain treatment for hundreds of years.14 NSAIDs, as typified by aspirin and acetaminophen, are popular mild analgesics used primarily for treating inflammation and the pain associated with it.15 The cellular and molecular mechanisms responsible for the opioid and NSAID analgesic effects will be discussed and compared with what is known about PRFE as a means to determine the possible mechanism of analgesia mediated by electromagnetic fields.

Endogenous Peptide Opioid System

Three classical endogenous opioid peptide families have been identified—the endorphins, enkephalins, and dynorphins—all of which share the common amino terminal amino acid motif (opioid motif) Tyr-Gly-Gly-Phe-(Met or Leu).16 The opioid motif is followed by various carboxy-terminal amino acids ranging in length from 0 to 26 residues. Peptides in the 3 opioid families are encoded from 3 corresponding genes that are transcribed and translated into prepropeptides and later cleaved into the final opioid peptide ligands. The result of the cleavages and post-translational modifications is a large number of opioid peptides with multiple activities. The history related to the discovery of endogenous opioid peptides, including their discovery and identification by Hughes and colleagues in 1975, has been reviewed by Akil et al.17

Considering the large number of opioid peptide ligands, it is not surprising that numerous corresponding opioid receptors have been isolated. There are 3 major opioid receptor families: μ, δ, and κ (a fourth opioid-type receptor that has been isolated, the nociception/orphan FQ, will not be discussed). Opioid (endogenous or natural occurring) binding to cognate receptors produces a number of intracellular effects linked to analgesia. These effects include inhibition of adenyl cyclase activity, activation of K+-linked currents, and suppression of Ca2+ currents. The effect of the K+/Ca2+ ion currents are thought to be responsible for the inhibition of pain transmission in the central nervous system.18 Other in vitro experiments with isolated opioid receptors have shown that opioid ligand binding may also activate mitogen-activated protein (MAP) kinases and phospholipase C.18 All of these intracellular effects may contribute to opioid inhibition of pain. With the large number of opioid ligand and receptor combinations possible, determining which result in analgesia has been problematic.

Opioids produce their primary analgesic effect by inhibiting the transmission of nociceptive signals from the dorsal horn of the spinal cord to activate the pain control pathways descending from the midbrain to the dorsal horn in the spinal cord (Figure 2). Opioid peptides and their receptors are found throughout this pain control circuit, suggesting these circuits as the primary sites of action for opioid action for analgesia. Other sites of action of opioid-induced analgesia may be found in the forebrain and peripherally, especially during inflammatory pain states.19

Figure 3. The diagram illustrates the nociceptive pathways disrupted by opioids, preventing the sensation of pain

NSAID Analgesics and Inflammation

NSAIDs are considered mild analgesics and are particularly effective for pain due to inflammation.15 Pain due to the hyperalgesia most likely results from stimulation of pain fibers and enhanced excitation of neurons in the spinal cord. During inflammation, bradykinin, tumor necrosis factor (TNF)–α, interleukin (IL)-1, and other cytokines are released and induce pain by binding to their receptors and eliciting their biological effects, such as the release of prostaglandins (PGs) and substance P, which are also thought to be involved in stimulating pain at the level of the spinal cord (Figure 3).20,21

PGs and leukotrienes (LTs) are related classes of compounds synthesized from the 20-carbon essential fatty acid arachidonic acid. PGs are produced by the rate-limiting enzyme cyclo-oxygenase (COX), which catalyzes the formation of the precursor (PGG2) to PGH2. PGH2 is then used as substrate to produce the numerous PGs found in tissue. The PGs play a major role in the inflammatory and immune response. Generally, PGs are pro-inflammatory, with PGE2 being a primary PG in the response. NSAIDs decrease pain by inhibiting the formation of PGs at the rate-limiting step of synthesis, which then decreases pain due to inflammation. NSAIDs do not inhibit the effects of preformed PGs. The primary effect of PGs is to lower the threshold of nociceptors on the C fibers. By preventing the synthesis of PGs, NSAIDs decrease pain.22

Figure 4. The diagram shows how inflammatory stimuli induce pain

PRFE Effective Analgesic

Pulsed radio frequency energy and pulsed electromagnetic field (PEMF) fields are becoming increasingly popular as a treatment for pain caused by inflammation or tissue damage.3,23 Several recent studies, both in vitro and in vivo, have begun to define the cellular and molecular mechanisms of action of PRFE as an analgesic.24-26 From these new studies, it is suggested that PRFE may elicit reduction in pain by mechanisms similar to those of the NSAIDs, as well as possibly through endogenous opioid peptide pathways.

In a double-blind, randomized clinical study of 42 patients, PRFE treatment was shown to provide pain relief postoperatively.24 The treatment parameters used for PRFE delivery were determined in vitro by identifying the optimal pulse width and energy field for Ca+2 binding to calmodulin, an early step in anti-inflammation and pain reduction. In further studies performed by the same group, IL-1β levels were shown to be 275% lower at the surgical site of patients treated with PRFE field than in patients receiving sham (non-active) treatment.25 The authors propose that the analgesic mechanism of action of PRFE is anti-inflammatory via a Ca+2-mediated pathway involving calmodulin binding. This then induces endothelial nitric oxide synthase (eNOS) activity, which in turn increases nitric oxide (NO). Increases in NO reduce IL-1β and COX activity, which reduces PGs.25 This reduction in COX activity is analogous to the effect of NSAIDs in that pain relief is achieved through reduction of PG concentration.

In vitro studies using human dermal fibroblasts (HDF) and human epidermal keratinocytes (HEK) have determined the effects of PRFE on transcript levels of several key enzymes involved in the inflammatory response.26 In these studies, microarray and reverse transcription polymerase chain reaction (RT-PCR) were used to study the cascades of gene expression changes associated with PRFE treatment and revealed PRFE-mediated effects on COX and NOS transcript levels. The response differed depending on the cell type tested. For human dermal fibroblast (HDF) cells, COX messenger ribonucleic acid (mRNA) levels increased, whereas NOS mRNA levels decreased following PRFE treatment. In HEK cells, COX mRNA levels were not affected by PRFE treatment, whereas NOS mRNA levels were increased (Figure 4).

These differences may reflect different roles played by these 2 cell types in PRFE-mediated anti-inflammatory response and pain reduction. In both cell types, transcript levels of another important anti-inflammatory factor, heme oxygenase, also increased following PRFE treatment. Heme oxygenase is thought to be a molecular switch for ending inflammation after injury to tissue.27 Both the in vivo and in vitro studies point to anti-inflammatory mechanisms for pain reduction, similar to those found for NSAIDs.

Future Directions

New therapies for the treatment of pain that are effective and well tolerated are an important part of future analgesic research. Comparison of the biochemical and molecular mechanisms of opioids and NSAIDs with that of PRFE gives some indication of mechanism. A comparison between the different standard therapeutic treatments for analgesia shows that, at least in part, the mechanism of PRFE is similar to that of the NSAIDs (inhibition of COX and related pathways to inflammation). PRFE has been shown clinically to have an analgesic effect on pain, especially postoperatively. By understanding the biological and cellular mechanisms underlying PRFE-mediated effects on inflammation and the pain it causes, it is possible that additional therapeutic applications of PRFE may be uncovered.

Unlike opioid and NSAID therapeutics, the cellular and molecular mechanisms for PRFE-mediated analgesia are still poorly understood. Further clinical and basic science research are required for the understanding and further application of pulsed electromagnetic fields in medicine.

 

Last updated on: November 16, 2011
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