CRF vs WCRF or PRF-DRG in CLBP of FJ Origin and RFA Failure of MBDR: Central Sensitization and Aberrant Nerve Sprouting

The efficacy of radiofrequency to treat LBP of FJ origin decreases with time, and the pathophysiological mechanisms behind this failure is a matter of debate; the phenomenon of central sensitization and ectopic nerve regeneration could be possible explanations. Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. The net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification. Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central nervous system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations. In previous studies using animal models of low back pain, mechanical allodynia has been correlated with and is hypothesized to be due to a host of physiologic changes in the central nervous system. Among these nociceptive responses are neuronal plasticity, glial cell activation and cytokine upregulation. In addition, animal models specifically investigating changes in neural electrical activity following lumbar facet capsule stretching have demonstrated alterations in neurophysiology for applied loading. Together, these molecular and cellular changes contribute to central sensitization and persistent pain. Indeed, in clinical research, central sensitization has been hypothesized as a mechanism of chronic pain after whiplash injury. Injury to the cervical facet joint and its capsule is primarily a ligamentous injury but because the facet capsule is innervated there may also be neuropathic injury. In fact, capsule stretch in several animal models induces both transient increases in firing of joint-innervating afferents similar to the injury discharge that accompanies nerve injury and also the later development of ectopic firing and hyperexcitability in dorsal horn neurons. The onset of spontaneous firing likely represents a temporal threshold after which sensitization persists despite blockade of joint afferent activity with nerve blocks or neurotomy. Patients with chronic pain exhibit primary mechanical hyperalgesia over the back of the cervical spine, in a "coat hanger" distribution indicative of peripheral nociceptor sensitization. These patients are also hypersensitive to pressure, heat, and cold stimuli at sites distant from the cervical spine, including over the median, radial, and ulnar nerve trunks in the arm and over the tibialis anterior muscle. Together, these studies demonstrate that generalized and widespread secondary hypersensitivity is robust in individuals who sustain a whiplash-like exposure and indicative of central sensitization. Patient-reported sensory disturbances include spontaneous pain that is disproportionate to and/or occurs in the absence of any inciting event. There are more than two dozen reported cases of lumbar facet dislocation after rapid deceleration injuries (e.g., traffic accidents), most involving L5-S1. The mechanism of injury in these cases is purported to be a combination of hyperflexion, distraction, and rotation. In a posthumous study conducted in 31 lumbar spines of subjects who died of traumatic injuries (mostly motor vehicle accidents), Twomey et al. found occult bony fractures in the superior articular process or subchondral bone plate in 35% of victims, and z-joint capsular and/or articular cartilage damage in 77% of cases. In this study the authors concluded that occult bony and soft tissue injuries to the l-z joints may be a common cause of LBP after trauma. In addition to immediate neuronal responses, facet capsular loading that induces behavioural hypersensitivity in the rat is also associated with many sustained modifications in the nociceptive signalling from the primary afferents that are evident in the DRG. Protein expression of the nociceptive neurotransmitter, substance P, is increased in the DRG after painful facet joint stretch by day 7, and that change is absent in non-painful stretch. Capsular stretch-induced increases in DRG expression of the metabotropic glutamate receptor 5 (mGluR5) and its second messenger, protein kinase C-epsilon (PKCε), are strain dependent and are not evident until 7 days after the initial injury. The late upregulation of these molecules suggests that they may play a role in the later nociceptive pathways involved in injury-induced pain. Because these neuromodulators are involved in neuroplasticity and pain, their delayed elevation implies that the afferents undergo persistent activation and/or dysfunction after painful loading has occurred. Because axonal degeneration is known to take 7 days to develop, it may contribute to the late onset of modified nociceptive signalling. In addition to increases in expression of glutamate receptors, expression of glutamate transporters on astrocytes and neurons, which regulate the clearance of glutamate away from synapses, like glutamate aspartate transporter, glutamate transporter 1, and excitatory amino-acid carrier 1, is also altered in the spinal cord 1 week after painful facet stretch. While the astrocyte glutamate transporter (glutamate aspartate transporter) is upregulated 1 week after painful injury, both glutamate transporter 1 and excitatory amino-acid carrier 1, which are expressed on other cells, are downregulated, pointing to the widespread and complicated dysregulation of glutamate in pain from facet joint injury. Like other chronic pain conditions, spinal astrocytes are activated for at least 14 days after painful facet stretch. Mechanical injury to the facet capsule also regulates the production of inflammatory mediators, including proinflammatory cytokines and neurotrophins, in the facet joint itself, as well as in the DRG. Because peripheral inflammation increases hyperexcitability and substance P in DRG neurons, along with pain production, recent studies have begun to elucidate the molecular mechanisms by which peripheral inflammation contributes to central sensitization in the context of facet-mediated pain. Recently, neurotrophins have been implicated both locally in the facet and to be more widespread in the CNS. Nerve growth factor (NGF) increases in the facet joint tissues as early as 1 day after a facet joint distraction that produces pain at that same time. Further, inhibiting NGF signalling also prevents the onset of pain and associated spinal neuron hyperexcitability when anti-NGF is given intra-articularly immediately after capsule stretch and before pain develops, suggesting a critical role of local NGF in initiating pain. Unlike NGF, expression of the neurotrophin brain-derived neurotrophic factor (BDNF) increases in both the DRG and spinal cord at a later time (day 7), with intrathecal administration of the BDNF-sequestering molecule trkB-Fc after facet injury partially reducing pain. Collectively, these NGF and BDNF studies not only reveal important novel pathways emerging as having critical roles in pain from whiplash injury, but also provide potential therapeutic targets for treating joint pain. Histologic studies have demonstrated that the lumbar facet joints are richly innervated with encapsulated (Ruffini-type endings, Pacinian corpuscles), un-encapsulated, and free nerve endings. The presence of low-threshold, rapidly adapting mechanosensitive neurons suggests that in addition to transmitting nociceptive information, the l-z facet capsule also serves a proprioceptive function. Besides substance P and calcitonin gene-related peptide, a substantial percentage of nerve endings in facet capsules have also been found containing neuropeptide Y, indicating the presence of sympathetic efferent fibers. Nerve fibers have also been found in subchondral bone and intra-articular inclusions of l-z joints, signifying that facet-mediated pain may originate in structures besides the joint capsule. In degenerative lumbar spinal disorders, inflammatory mediators such as prostaglandins and the inflammatory cytokines interleukin 1, interleukin 6, and tumor necrosis factor alpha have been found in facet joint cartilage and synovial tissue. Wide dynamic range neurons in the dorsal horn may be capable of modulating central sensitization in many chronic pain states. In their study K.P.Quinn et al. comparing painful to non-painful and sham C6/C7 cervical facet joint capsule stretch stimuli in a rat model find out that the proportion of cells in the deep laminae that responded as wide dynamic range neurons was increased in the painful group relative to non-painful or sham groups (p\<0.0348). The significant increase in the number of wide dynamic range neurons classified in the painful group (69% of neurons; p\>0.0348) in this study suggests that a phenotypic shift in the response of the neuronal population in the deep laminae of the dorsal horn may play a key role in modulating chronic pain after facet joint injury. These findings suggest that excessive facet capsule stretch, while not producing visible tearing, can produce functional plasticity of dorsal horn neuronal activity. The increase in neuronal firing across a range of stimulus magnitudes observed at day 7 post-injury that facet-mediated chronic pain following whiplash injury is driven, at least in part, by central sensitization. Despite the fact that most of the neurophysiological and molecular central and peripheral changes in the low back pain syndrome are related to rat experimental whiplash-like exposure, the investigators consider that the mechanisms of central sensitization related to chronic low back pain of FJ origin can be hypothesised to be the same. On the other side, the mechanism of aberrant nerve sprouting after previous RFA could explain the necessity to increase the size of the lesion, especially in patients that underwent to multiple treatment with such technique. Pain recurrence after denervation in medical practice, and nerve regeneration from a third degree nerve injury from different ablation techniques, have a common pathway. This pathway includes macrophage migration, Schwann cell proliferation, CAMs for preparing the basement membrane, NGF on the Schwann cell for axonal sprouting, and increased trophic factors. Injured axons regenerate at a rate of 1-2 mm/day, although the rate depends on many factors and can vary significantly from individual to individual. Since the length of nerve from the axonal lesion to the lumbar facet joint is approximately 30-40 mm, reinnervation could occur within 3-6 weeks. Regeneration is the primary form of nerve repair when \>90% of the axons are injured. In partial nerve injuries when only 20%-30% of the axons are affected, collateral sprouting from preserved axons can contribute to reinnervation. Okuyama et al. showed that radiofrequency ablation in cardiac tissue results in aberrant nerve sprouting within 2 hours after ablation. Therefore, ablation of nerves within the back could have a high likelihood for a similar development, which could cause faster failure rates. In conclusion this study will select two groups of patients from a population with severe chronic low back pain (CLBP) of facet joint (FJ) origin already treated with conventional radiofrequency ablation (CRFA) of the medial branch of the dorsal rama (MBDR) and that failed to obtain at least a 50% pain reduction measured through the numerical rate scale (NRS). Severe CLBP is considered a patient subjective pain judgement superior to 7 by NRS evaluation. The first group will be characterized by a nociceptive/mechanic type of back pain. The second group of study will be characterized by a neuropathic type of back pain. This difference will be established by a DN4 score superior to 4 points (Doleur Neurophatique 4) and a negative pre-interventional eco-guided medial branch block (MBB). A negative MBB will be characterized by a reduction of NRS inferior to 50%. The aim of this study is to try to clarify if a larger lesion created by the water cooled radiofrequency (WCRF) in the nociceptive/mecchanic pain groups (NMPG) and the pulsed radiofrequency (PRF) of dorsal root ganglia (DRG) in the neuropatic pain groups (NPPG) could improve patients' functional status and reduce the burden of their low back pain compared to conventional radiofrequency (CRF) of the medial brach of the dorsal rama (MBDR). If the hypothesis in study are confirmed there is to be expected a statistically significant reduction in the NRS and an improvement in the ODI score in the DRG-PRF and WCRF groups, compared to the patients in the CRF groups. The aim is to allow the patients to start a program of rehabilitation/physiotherapy, that is by far the standard of clinical care for LBP syndrome. In this case the results could support our hypothesis in both group of investigations. Like already underlined in the physiopathological explanation representing the base of this study, increasing the area of lesion with the WCRF technique should increase the chances to target the arborized neural regenerate terminals to the zygapophyseal joint, leading to a better result and possibly longer efficacy of the procedure in the NMPG respect to the group treated with CRF. Today, different doctors use both techniques based on their personal preference and logistic possibility as there are no conclusive data about superiority; even the last consensus practice guidelines for lumbar facet joint pain proposed by the American Society of Regional Anesthesia and Pain Medicine 2020 (CPG-ASRAPM) assess that "there is indirect evidence, and limited direct evidence, that techniques that result in larger lesions (eg, larger electrodes, higher temperatures, longer heating times, proper electrode orientation, fluid modulation) improve outcomes" (Grade C, low level of certainty that larger lesions increase the chance of capturing nerves. Grade I, low level of certainty that larger lesions increase duration of pain relief). On the other hand, in the NPPG the treatment of the DRG with PRF should interrupts and possibly treat the intercellular and molecular circuits at the base of the central pain sensitization, improving the outcomes considered in this study. The biggest effort of this study will be the standardization of all the procedures, to allow the maximal reproducibility, in line with the latest recommendation in diagnosis and treatment of low back pain of facet joint origin stated by the CPG-ASRAPM and current best practice in radiofrequency denervation of the lumbar facet joints published by the British Pain Society (CBP-BPS). The theory that chronic LBP of FJ origin can be related to a central sensitization mechanism is a new investigation field, with no other studies yet exploring our treatment hypothesis. Therefore, it is important to carry out research projects that clarify which technical variables are those that provide an improvement in pain control and, above all, an improvement in the quality of life in these patients. Some of the conclusions of this project could be possible applied by professionals of the Pain Units worldwide in their daily activity, in order to provide our patients with the best care and the best possible results. It is a clinical study and therefore its translation to the clinical practice can be direct. TREATMENTS The application of radiofrequency (RF) signals to neural tissue is well established in the treatment of movement, mood, and chronic pain disorders. Undesired neural signals, such as those transmitting nociceptive pain, are interrupted when high-frequency current (100-1,000 kHz) flowing through an RF probe's active tip raises the temperature at a soma/ganglion or axon/nerve to destructive levels (45-50°C) by means of frictional heating. The process is known as RF heat lesioning, RF thermocoagulation, RF ablation, or thermal RF. The volume of tissue damaged by RF heating is called a heat lesion. Monopolar RF (the technique used in this hospital) refers to current flow between a probe electrode and a large area ground pad placed on the skin's surface. Bipolar RF refers to current flow between two probe electrodes without a ground pad. RF heat lesioning includes cooled RF, wherein the electrode is internally cooled by circulating fluid but surrounding tissue is exposed to destructive temperatures. Water-cooled radiofrequency (WCRF) ablation is a minimally invasive neuroablative technique used in the treatment of various pain syndromes. The mechanism of pain relief from WC-RF application is analogous to CRF application: a thermal lesion is created, by applying radiofrequency (RF) energy through an electrode placed in the vicinity of the target neural structure, with the aims of interrupting the afferent nociceptive pathways. The difference already mentioned is that the 'cooled' radiofrequency probes have water running through the probe tip, which keeps the tip cooled and allows a larger lesion to be made. Since the physician can't actually see the nerve he is trying to target, larger lesions should theoretically improve his chances of hitting it. The 'cooling' of the water also allows the temperatures to be lower than what is needed for standard RF (approximately 60°C).It is widely accepted that the PRF action mechanism (involving lower temperatures, below 42-44 °C) is most likely related to the induced electric field, rather than to thermal effects. Different effects of exposure to PRF electrical fields have already been reported. Some studies have revealed evidence of morphological changes in the neuronal cells after PRF treatment that affect the inner structures of axons. These structural changes consist of mitochondria swelling and disruption of the normal organisation of the microtubules and microfilaments that preferentially affect C-fibres and to a lesser extent Aδ fibres. In addition, transient ultrastructural changes such as endoneural oedema and collagen deposition have also been found. Besides structural changes, the effects on cellular activity and gene expression have also been observed as well as an increase in the expression of inflammatory proteins. All these effects could potentially inhibit the transmission of nerve signals through C-fibres, which would lead to pain relief. Number and laterality of medial branches to be lesioned is to be decided after a clinical examination by the pain physician. When selecting targets for blocks, levels should be determined based on clinical presentation, radiological findings when available, tenderness on palpation performed under fluoroscopy. A maximum of eight medial branches at a maximum of four vertebral levels may be lesioned in a single sitting, subjects with unilateral pain to receive unilateral treatment. A maximum of three DRG for each side will be treated in a single sitting. For various reasons, medial branch blocks are the only acceptable and validated diagnostic test as an indication for medial branch neurotomy. The paradigm of lumbar medial branch neurotomy is that patient's pain can be relieved by coagulating the nerves that mediate (transmit) their pain. An essential prerequisite, therefore, is that it must be shown that the target nerves are responsible for the patient's pain. This is achieved by controlled diagnostic blocks of the medial branches of the cervical and lumbar dorsal rami that mediate the pain. In order to reduce the likelihood of responses being false positive, controlled blocks are mandatory. An issue in this sense is represented by the relatively high percentage of false positive MBB for placebo effect (up to 30%) described in the literature (patients that responds positively to the MMB, but that fail or will possibly again fail a sustained benefit after the conventional procedure - control group). On the other side some patients may respond positively to the MBB but presents with a neuropathic back pain, possibly leading to a bias in selection, because in this case the mechanisms involved in the origin of back pain could be both neuropathic and nociceptive/mechanic in nature. Considering the high percentage of placebo related effect in the false positive group, the only way to exclude this kind of false positive is to perform a placebo-controlled pre-procedural MBB, where the placebo procedures will be difficult to be approved by any ethical committee, due to the relatively safety of this procedures. For this reasons this investigators decided to exclude patients positive to the MBB but with neuropathic pain and the patients with negative MBB and negative DN4 score. All the patients recruited in this study have been previously treated in our pain service by experienced interventionists anesthesiologists (this will suppose that the percentage of patients actually positive to the MBB because of previous inefficacy technique should be really low). Indeed, this study group decided to perform a single MBB with 0.5 mL of levo-bupivacaine 5 mg/mL, that is the consensus preferred solution, under ultrasonographic guidance, in our technical operative room, with needle tip to be positioned on the curvature between the articular process and transverse process. Three radiofrequency techniques have been in use over the past three decades. The scientific community refers to them by name of continents where each was originally described: European, North American, and Australian. The technique described by Nath and all. and mentioned like standard of treatment in the last consensus on best practice in RFA of the lumbar facet join by the British Pain Society, similar to the Australian technique, is described as follows: the lumbar spine is visualized and the radiograph beam is adjusted to come from a posterior-lateral aspect to get the best possible view of the curvature of the medial part of the upper border of the transverse process where it ascends to become the ventral-lateral border of the superior articular process. In patients with a hypertrophic superior articular process due to arthritic changes greater lateral rotation can be required. The C-arm is then inclined caudal so that the direction of the radiograph beam is from upwards looking below and somewhat medially along the groove in which the medial branch lies. A 22 SWG SMK C15 cannula with a 5 mm active tip is introduced along the direction of the radiograph beam, in the so-called "tunnel technique" until bone contact is made with the lower part of the transverse process (L5 and higher). The cannula is then rotated so that the bevel was against the bone allowing the needle to slide up in the groove maintaining contact with the bone surface till the tip was at the upper border and in the centre of the curvature formed by the upper border of the transverse process ascending to form the lateral border of the articular process. The position is then checked in the tunnel view, the postero-lateral view as well as a cephalad view. The lateral view confirms that the cannula is not too far in, encroaching on the foramen. At the S1 level (L5 dorsal ramus) a similar view is maintained to lay the cannula in the groove between the lower part of the lateral aspect of the superior articular process of S1 and the upper surface of the ala of the sacrum. The tunnel view confirms the position in the groove. The forward advance is checked rotating the C-arm to look from a more lateral aspect to visualize the anterior border of the superior articular process of S1, and then from a more cephalad aspect to visualize the point of the needle in relation to the anterior border of the ala of the sacrum. About the DRG, the radiological location can be divided into 3 types-the intraspinal, foraminal, and extraforaminal regions; most DRG neurons are of the foraminal type. This position corresponds to the dorsal-cranial quadrant of the intervertebral foramen on the lateral view in fluoroscopy, and the middle of the pedicle column on the anteroposterior (AP) view. However, if the arthritic degenerative changes and foraminal stenosis are severe, positioning the needle to target the DRG on fluoroscopy may be difficult. Accordingly, needle tips can be placed laterally on the side of the corresponding pedicle in the AP view. When the RF needle is close to the target position, the stylet of the RF needle is removed, and the RF probe is inserted. Similar to the Australian technique, the C-arm is placed with a 20-30° lateral tilt on the side to treat, with a slightly caudocephalad tilt, to better visualize the foramen, just under the inferior border of the transvers process, with placement of the needle in tunnel vision. The final position of the RF probe is determined with sensory stimulation (50 Hz), at a voltage below 0.5 V. Proximity of the needle to the DRG is determined by appropriate sensory stimulation with 50 Hz (0.4-0.6 V), when the patient feels a tingling sensation. If the threshold value exceeded 0.5V, the needle is carefully advanced until the patient feels sensory stimulation. Motor stimulation at 2 Hz is used to determine a threshold 1.5-2.0 times greater than the sensory threshold to avoid placement near the anterior nerve root and perform the procedure safely. Contrast injection at the end of the needle tip positioning could represent a further confirmation. Despite the fact that a curved cannula could increase the size of the lesion, a straight 22-gauge cannula with a 5-mm active tip remains the tool most commonly used for radiofrequency denervation of the facet nerves, and it will be the used cannula in the CRF group and in the DRG-PRF group. A 4-mm active tip 10 cm long 17G cannula will be placed for WCRF. This group of investigation will adopt a modified Nath technique (using a 5 to 15 degree cephalo-caudal inclination and a needle view similar to that obtained with the advanced Australian technique), for CRF and WCRF ablation of MBDR. Position of the radiofrequency cannula will be confirmed by fluoroscopy with AP, oblique, and lateral view. Once the cannula(e) position is confirmed, routine motor testing will be carried out with a threshold for lower limb muscle contraction of 2V. Lower limb muscle contractions occurring below the threshold will prompt a repositioning of the RF cannula. Sensory stimulation will be applied when single lesions are anticipated (CRF groups); sensory stimulation of 0,6V mean that the needle is placed at less than 3 mm from the MBDR, that is the ideal distance to realize an adequate lesion. When multiple or large lesions are planned, the evidence for sensory stimulation is inconclusive; despite this fact, it was decided to check for sensory stimulation for all patients involved in this study, knowing that in the WCRF and CRF groups such stimulation could be inconclusive. Due to the larger expected lesion size in the WCRF, like suggested by the work of Malik et all. the investigators will ensure a "safe distance" from the segmental spinal nerve by adopting the following safety measures: (a) the electrode tip will be placed on the transverse process, about 4 mm lateral to its junction with the superior articular process; (b) the parameters used for sensory testing will be modified and paresthesia will be sought at \> 0.6 V, between 0.8 V to 1.0 V. In the case of CRF and WCRF before starting the treatment, 1 ml of lidocaine 1% will be injected through the cannula. Each lesion will be carried out at 80° C for 90 seconds in the CRF group. One lesions will be applied for each treated level. Each lesion in the WCRF group will be carried out at 60° C for 150 seconds. One lesion will be applied for each treated level. At the end of the procedure 1 to 1.5 ml of a mixture of ropivacaine 0,2% 8ml + betamethasone 11.8 mg 2ml will be injected before the extraction of the needle, in both this groups. In the case of DRG-PRF, a pulsed current (20ms, 2 Hz) is applied (1 time for 120 seconds), with a 45V output, 20ms lasting impulse (480ms pause). During this procedure, the temperature at the tip of the electrode is not supposed to exceed 42℃. At the end of the procedure, 0,5 to 1 ml of a mixture of ropivacaine 0,1% 8ml and dexamethasone 8mg will be injected before needle extraction. The CRF treatment and the DRG-PRF will be realized with the Cosman G4 Radiofrequency Generator. For the WCRF a COOLED RF Generator of Halyard will be used. All the procedures can be performed in day hospital, with no need for hospitalization. Ones the needle is positioned, the wire is retired and the probe is inserted; the measured impedance has to be between 200 and 700Ω to confirm the proximity to the target structure. All patients will be in a prone position.