Sustained Relief of Complex Regional Pain Syndrome (CRPS) Pain Following a 60-Day Peripheral Nerve Stimulation: A Report of Three Cases.

Patients who present to pain clinics with complex regional pain syndrome (CRPS) typically have debilitating pain, including hyperalgesia and allodynia, and additional substantial quality-of-life concerns related to the motor and autonomic-related symptoms of CRPS. Present treatments for CRPS such as neuropathic pain medications and sympathetic blocks are often unsatisfactory for managing symptoms. The present cases highlight the use of a 60-day percutaneous peripheral nerve stimulation (PNS) treatment for three patients with CRPS Type I affecting the foot. In all three patients, the tibial and common peroneal nerves were targeted separately at the popliteal fossa with two percutaneous leads each placed a remote distance (~1 cm) from the target nerve under ultrasound guidance. All three patients reported substantial pain relief and resolution of autonomic symptoms (e.g., swelling, edema, erythema), with sustained relief lasting 8-10 months in two patients, and 34 months (as of this writing) in the third patient. There were no medical complications. These three cases suggest that 60-day PNS is a safe and efficacious treatment for CRPS.

A Retrospective Review of Real-world Outcomes Following 60-day Peripheral Nerve Stimulation for the Treatment of Chronic Pain.

BACKGROUND: Real-world data can provide important insights into treatment effectiveness in routine clinical practice. Studies have demonstrated that in multiple different pain indications temporary (60-day) percutaneous peripheral nerve stimulation (PNS) treatment can produce significant relief, but few real-world studies have been published. The present study is the first real-world, retrospective review of a large database depicting outcomes at the end of a 60-day PNS treatment period. OBJECTIVES: Evaluate outcomes during a 60-day PNS treatment in routine clinical practice. STUDY DESIGN: Secondary retrospective review. METHODS: Anonymized records of 6,160 patients who were implanted with a SPRINT PNS System from August 2019 through August 2022 were retrospectively reviewed from a national real-world database. The percentage of patients with ? 50% pain relief and/or improvement in quality of life was evaluated and stratified by nerve target. Additional outcomes included average and worst pain score, patient-reported percentage of pain relief, and patient global impression of change. RESULTS: Overall, 71% of patients (4,348/6,160) were responders with >= 50% pain relief and/or improvement in quality of life; pain relief among responders averaged 63%. The responder rate was largely consistent across nerve targets throughout the back and trunk, upper and lower extremities, and posterior head and neck. LIMITATIONS: This study was limited by its retrospective nature and reliance on a device manufacturer's database. Additionally, detailed demographic information and measures for pain medication usage and physical function were not assessed. CONCLUSIONS: This retrospective analysis supports recent prospective studies demonstrating that 60-day percutaneous PNS can provide significant relief across a wide range of nerve targets. These data serve an important role in complementing the findings of published prospective clinical trials.

Real-world evidence of sustained improvement following 60-day peripheral nerve stimulation treatment for pain: a cross-sectional follow-up survey.

Objective: This study presents real-world data from a cross-sectional follow-up survey of patients who previously received 60-day peripheral nerve stimulation (PNS) treatment for pain. Materials & methods: A survey including validated pain and other related outcome measures was distributed to patients who previously underwent implantation of temporary PNS leads for 60-day PNS treatment. Results: Among survey respondents who were at least 3 months from the start of treatment, most reported sustained clinically significant improvements in pain and/or quality of life, with the length of follow-up at the time of survey completion ranging from 3 to 30 months. Conclusion: These real-world data support recent prospective studies indicating that 60-day percutaneous PNS provides significant and sustained relief across a wide range of pain conditions.

This study presents the findings from a survey that was sent to patients who previously received a 60-day peripheral nerve stimulation (PNS) treatment for their chronic pain. Patients were asked about their current pain levels, how their quality of life and physical function have changed since their PNS treatment, and whether they had changed their usage of pain medications. The survey showed that most patients who were at least 3 months from the start of the PNS treatment continued to have meaningful pain relief and/or improvement in their quality of life. This information is consistent with clinical studies that were previously published and supports that the 60-day PNS treatment can provide patients with long-term relief of chronic pain.

60-Day PNS Treatment May Improve Identification of Delayed Responders and Delayed Non-Responders to Neurostimulation for Pain Relief.

Objective: Conventional neurostimulation typically involves a brief (eg, ≤10-day) trial to assess presumed effectiveness prior to permanent implantation. Low trial conversion rates and high explant rates due to inadequate pain relief highlight the need for improved patient identification strategies. The development of a 60-day percutaneous peripheral nerve stimulation (PNS) system enables evaluation of outcomes following an extended temporary treatment period of up to 60 days, that may obviate or validate the need for permanent implant. The present study provides the first real-world evidence regarding patient response throughout a 60-day PNS treatment period. Methods: Anonymized data listings were compiled from patients who underwent implantation of temporary percutaneous leads and opted-in to provide real-world data to the device manufacturer during routine interactions with device representatives throughout the 60-day treatment. Results: Overall, 30% (222/747) of patients were early responders (≥50% pain relief throughout treatment). Another 31% (231/747) of patients initially presented as non-responders but surpassed 50% pain relief by the end of treatment. Conversely, 32% (239/747) of patients were non-responders throughout treatment. An additional 7% (55/747) of patients initially presented as responders but fell below 50% relief by the end of the treatment period. Conclusion: An extended, 60-day PNS treatment may help identify delayed responders, providing the opportunity for sustained relief and improving access to effective PNS treatment. Compared to a conventionally short trial of ≤10 days, a longer 60-day PNS treatment may also help reduce explant rates by identifying delayed non-responders unlikely to benefit long-term. These scenarios support the importance of an extended 60-day temporary PNS stimulation period to help inform stepwise treatment strategies that may optimize outcomes and cost-effectiveness.

Peripheral nerve stimulation for the management of acute and subacute post-amputation pain: a randomized, controlled feasibility trial.

Introduction & aim: Temporary (60-day) percutaneous peripheral nerve stimulation (PNS) has demonstrated effectiveness for the treatment of chronic post-amputation pain, and this pilot study aims to evaluate the feasibility of temporary percutaneous PNS for the treatment of acute post-amputation pain. Patients & methods: Sixteen veterans undergoing lower extremity amputation received PNS and standard medical therapy or standard medical therapy alone. Results: The PNS group reported greater reductions in average phantom limb pain, residual limb pain and daily opioid consumption, and there were fewer participants taking opioids through 3 months post-amputation. Conclusion: This pilot study suggests that PNS is feasible in the acute postoperative period following lower limb amputation and may provide a non-pharmacologic analgesic therapy that lowers pain scores and reduces opioid consumption, and thus warrants further investigation.

A small study was done to evaluate placing a wire lead near a nerve to electrically stimulate it for 60 days after a leg amputation surgery to see if it helps reduce pain. The study looked at 16 veterans who had an amputation to their leg. These patients were divided into either a group that received nerve stimulation plus normal pain control medications or a group that just received pain medications. The group that received nerve stimulation had less pain in the remaining leg and less phantom pain (pain in the missing leg). They also required fewer narcotic medications. The study suggested that nerve stimulation may provide an effective way to manage pain after amputation and reduce the use of pain medications. Clinical Trial Registration Number: NCT03484429.

Peripherally Induced Reconditioning of the Central Nervous System: A Proposed Mechanistic Theory for Sustained Relief of Chronic Pain with Percutaneous Peripheral Nerve Stimulation.

Peripheral nerve stimulation (PNS) is an effective tool for the treatment of chronic pain, although its efficacy and utilization have previously been significantly limited by technology. In recent years, purpose-built percutaneous PNS devices have been developed to overcome the limitations of conventional permanently implanted neurostimulation devices. Recent clinical evidence suggests clinically significant and sustained reductions in pain can persist well beyond the PNS treatment period, outcomes that have not previously been observed with conventional permanently implanted neurostimulation devices. This narrative review summarizes mechanistic processes that contribute to chronic pain, and the potential mechanisms by which selective large diameter afferent fiber activation may reverse these changes to induce a prolonged reduction in pain. The interplay of these mechanisms, supported by data in chronic pain states that have been effectively treated with percutaneous PNS, will also be discussed in support of a new theory of pain management in neuromodulation: Peripherally Induced Reconditioning of the Central Nervous System (CNS).

Percutaneous 60-day peripheral nerve stimulation implant provides sustained relief of chronic pain following amputation: 12-month follow-up of a randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Peripheral nerve stimulation (PNS) has historically been used to treat chronic pain, but generally requires implantation of a permanent system for sustained relief. A recent study found that a 60-day PNS treatment decreases post-amputation pain, and the current work investigates longer-term outcomes out to 12 months in the same cohort. METHODS: As previously reported, 28 traumatic lower extremity amputees with residual and/or phantom limb pain were randomized to receive 8 weeks of PNS (group 1) or 4 weeks of placebo followed by a crossover 4 weeks of PNS (group 2). Percutaneous leads were implanted under ultrasound guidance targeting the femoral and sciatic nerves. During follow-up, changes in average pain and pain interference were assessed using the Brief Pain Inventory-Short Form and comparing with baseline. RESULTS: Significantly more participants in group 1 reported ≥50% reductions in average weekly pain at 12 months (67%, 6/9) compared with group 2 at the end of the placebo period (0%, 0/14, p=0.001). Similarly, 56% (5/9) of participants in group 1 reported ≥50% reductions in pain interference at 12 months, compared with 2/13 (15%, p=0.074) in group 2 at crossover. Reductions in depression were also statistically significantly greater at 12 months in group 1 compared with group 2 at crossover. CONCLUSIONS: This work suggests that percutaneous PNS delivered over a 60-day period may provide significant carry-over effects including pain relief, potentially avoiding the need for a permanently implanted system while enabling improved function in patients with chronic pain. TRIAL REGISTRATION NUMBER: NCT01996254.

Percutaneous Peripheral Nerve Stimulation for the Treatment of Chronic Pain Following Amputation.

INTRODUCTION: Chronic pain and reduced function are significant problems for Military Service members and Veterans following amputation. Peripheral nerve stimulation (PNS) is a promising therapy, but PNS systems have traditionally been limited by invasiveness and complications. Recently, a novel percutaneous PNS system was developed to reduce the risk of complications and enable delivery of stimulation without surgery. MATERIALS AND METHODS: Percutaneous PNS was evaluated to determine if stimulation provides relief from residual and phantom limb pain following lower-extremity amputation. PNS leads were implanted percutaneously to deliver stimulation to the femoral and/or sciatic nerves. Patients received stimulation for up to 60 days followed by withdrawal of the leads. RESULTS: A review of recent studies and clinical reports found that a majority of patients (18/24, 75%) reported substantial (≥50%) clinically relevant relief of chronic post-amputation pain following up to 60 days of percutaneous PNS. Reductions in pain were frequently associated with reductions in disability and pain interference. CONCLUSIONS: Percutaneous PNS can durably reduce pain, thereby enabling improvements in quality of life, function, and rehabilitation in individuals with residual or phantom limb pain following amputation. Percutaneous PNS may have additional benefit for Military Service members and Veterans with post-surgical or post-traumatic pain.

Painful Cervical Facet Joint Injury Is Accompanied by Changes in the Number of Excitatory and Inhibitory Synapses in the Superficial Dorsal Horn That Differentially Relate to Local Tissue Injury Severity.

STUDY DESIGN: Immunohistochemistry labeled pre- and postsynaptic structural markers to quantify excitatory and inhibitory synapses in the spinal superficial dorsal horn at 14 days after painful facet joint injury in the rat. OBJECTIVE: The objective of this study was to investigate the relationship between pain and synapse density in the spinal cord after facet injury. SUMMARY OF BACKGROUND DATA: Neck pain is a major contributor to disability and often becomes chronic. The cervical facet joints are susceptible to loading-induced painful injury, initiating spinal central sensitization responses. Although excitatory synapse plasticity has been reported in the superficial dorsal horn early after painful facet injury, whether excitatory and/or inhibitory synapse density is altered at a time when pain is maintained is unknown. METHODS: Rats underwent either a painful C6/C7 facet joint distraction or sham surgery. Mechanical hyperalgesia was measured and immunohistochemistry techniques for synapse quantification were used to quantify excitatory and inhibitory synapse densities in the superficial dorsal horn at day 14. Logarithmic correlation analyses evaluated whether the severity of facet injury correlated with either behavioral or synaptic outcomes. RESULTS: Facet joint injury induces pain that is sustained until day 14 (P <0.001) and both significantly greater excitatory synapse density (P = 0.042) and lower inhibitory synapse density (P = 0.0029) in the superficial dorsal horn at day 14. Injury severity is significantly correlated with pain at days 1 (P = 0.0011) and 14 (P = 0.0002), but only with inhibitory, not excitatory, synapse density (P = 0.0025) at day 14. CONCLUSION: This study demonstrates a role for structural plasticity in both excitatory and inhibitory synapses in the maintenance of facet-mediated joint pain, and that altered inhibitory, but not excitatory, synapse density correlates to the severity of painful joint injury. Understanding the functional consequences of this spinal structural plasticity is critical to elucidate mechanisms of chronic joint pain. LEVEL OF EVIDENCE: N /A.

Modulation of activity and conduction in single dorsal column axons by kilohertz-frequency spinal cord stimulation.

Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a potential paresthesia-free treatment for chronic pain. However, the effects of KHF-SCS on spinal dorsal column (DC) axons and its mechanisms of action remain unknown. The objectives of this study were to quantify activation and conduction block of DC axons by KHF-SCS across a range of frequencies (1, 5, 10, or 20 kHz) and waveforms (biphasic pulses or sinusoids). Custom platinum electrodes delivered SCS to the T10/T11 dorsal columns of anesthetized male Sprague-Dawley rats. Single DC axons and compound action potentials were recorded during KHF-SCS to evaluate SCS-evoked activity. Responses to KHF-SCS in DC axons included brief onset firing, slowly accommodating asynchronous firing, and conduction block. The effects of KHF-SCS mostly occurred well above motor thresholds, but isolated units were activated at amplitudes shown to reduce behavioral sensitivity in rats. Activity evoked by SCS was similar across a range of frequencies (5-20 kHz) and waveforms (biphasic and sinusoidal). Stimulation at 1-kHz SCS evoked more axonal firing that was also more phase-synchronized to the SCS waveform, but only at amplitudes above motor threshold. These data quantitatively characterize the central nervous system activity that may modulate pain perception and paresthesia, and thereby provide a foundation for continued investigation of the mechanisms of KHF-SCS and its optimization as a therapy for chronic pain. Given the asynchronous and transient nature of DC activity, it is unlikely that the same mechanisms underlying conventional SCS (i.e., persistent, periodic DC activation) apply to KHF-SCS. NEW & NOTEWORTHY: Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a new mode of SCS that may offer better pain relief than conventional SCS. However, the mechanism of action is poorly characterized, especially the effects of stimulation on dorsal column (DC) axons, which are the primary target of stimulation. This study provides the first recordings of single DC axons during KHF-SCS to quantify DC activity that has the potential to mediate the analgesic effects of KHF-SCS.

Spinal Astrocytic Thrombospondin-4 Induced by Excitatory Neuronal Signaling Mediates Pain After Facet Capsule Injury.

Thrombospondin-4 (TSP4) is a synaptogenic molecule that is upregulated in the spinal cord after painful facet joint injury and may contribute to spinal hyperexcitability. However, the mechanisms leading to increased spinal TSP4 are unclear. Because primary afferent activity is critical in the development of spinal hyperexcitability after facet joint injury, this study evaluated the role of afferent firing in the increase of spinal TSP4 and excitatory synapses. Intra-articular bupivacaine was administered immediately or 4 days after painful facet joint injury in male Holtzman rats, and TSP4 and excitatory synapses were quantified in the spinal cord at day 7. Immediate, but not delayed bupivacaine treatment, prevents the injury-induced increase in TSP4 and excitatory synapses in the dorsal horn (p < 0.0001). Preliminary in vitro experiments suggest that the excitatory signaling molecules ATP and glutamate may stimulate astrocytic TSP4 expression (p ≤ 0.04). Collectively, these results suggest that afferent activity early after facet joint injury is critical for the induction of spinal TSP4. This study advances the understanding of the timing and role of afferent activity in TSP4 expression after injury, which is critical for the therapeutic targeting of TSP4 to treat persistent pain conditions.

Burst and Tonic Spinal Cord Stimulation Differentially Activate GABAergic Mechanisms to Attenuate Pain in a Rat Model of Cervical Radiculopathy.

OBJECTIVE: Spinal cord stimulation (SCS) is widely used to treat neuropathic pain. Burst SCS, an alternative mode of stimulation, reduces neuropathic pain without paresthesia. However, the effects and mechanisms of burst SCS have not been compared to conventional tonic SCS in controlled investigations. This study compares the attenuation of spinal neuronal activity and tactile allodynia, and the role of γ-aminobutyric acid (GABA) signaling during burst or tonic SCS in a rat model of cervical radiculopathy. METHODS: The effects of burst and tonic SCS were compared by recording neuronal firing before and after each mode of stimulation at day 7 following a painful cervical nerve root compression. Neuronal firing was also recorded before and after burst and tonic SCS in the presence of the GABAB receptor antagonist, CGP35348. RESULTS: Burst and tonic SCS both reduce neuronal firing. The effect of tonic SCS, but not burst SCS, is blocked by CGP35348. In a separate study, spinal cord stimulators were implanted to deliver burst or tonic SCS beginning on day 4 after painful nerve root compression; allodynia and serum GABA concentration were measured through day 14. Burst and tonic SCS both reduce allodynia. Tonic SCS attenuates injury-induced decreases in serum GABA, but GABA remains decreased from baseline during burst SCS. CONCLUSION AND SIGNIFICANCE: Together, these studies suggest that burst SCS does not act via spinal GABAergic mechanisms, despite its attenuation of spinal hyperexcitability and allodynia similar to that of tonic SCS; understanding other potential spinal inhibitory mechanisms may lead to enhanced analgesia during burst stimulation.

Stimulation parameters define the effectiveness of burst spinal cord stimulation in a rat model of neuropathic pain.

INTRODUCTION: Although burst spinal cord stimulation (SCS) has been reported to reduce neuropathic pain, no study has explicitly investigated how the different parameters that define burst SCS may modulate its efficacy. The effectiveness of burst SCS to reduce neuronal responses to noxious stimuli by altering stimulation parameters was evaluated in a rat model of cervical radiculopathy. METHODS: Neuronal firing was recorded in the spinal dorsal horn before and after burst SCS on day 7 following painful cervical nerve root compression (N = 8 rats). The parameters defining the stimulation (number of pulses per burst, pulse frequency, pulse width, burst frequency, amplitude) were individually varied in separate stimulation trials while holding the remaining parameters constant. The percent reduction of firing of wide-dynamic-range (WDR) and high-threshold neurons after SCS and the percentage of neurons responding to SCS were quantified for each parameter and correlated to the charge per burst delivered during stimulation. RESULTS: Pulse number, pulse width, and amplitude each were significantly correlated (p <0.009) to suppression of neuronal firing after SCS. Pulse frequency and amplitude significantly affected (p <0.05) the percentage of responsive neurons. Charge per burst was correlated to a reduction of WDR neuronal firing (p <0.03) and had a nonlinear effect on the percentage of neurons responding to burst SCS. CONCLUSIONS: Burst SCS can be optimized by adjusting relevant stimulation parameters to modulate the charge delivered to the spinal cord during stimulation. The efficacy of burst SCS is dependent on the charge per burst.

Thrombospondin-4 and excitatory synaptogenesis promote spinal sensitization after painful mechanical joint injury.

Facet joint injury induces persistent pain that may be maintained by structural plasticity in the spinal cord. Astrocyte-derived thrombospondins, especially thrombospondin-4 (TSP4), have been implicated in synaptogenesis and spinal sensitization in neuropathic pain, but the TSP4 response and its relationship to synaptic changes in the spinal cord have not been investigated for painful joint injury. This study investigates the role of TSP4 in the development and maintenance of persistent pain following injurious facet joint distraction in rats and tests the hypothesis that excitatory synaptogenesis contributes to such pain. Painful facet joint loading induces dorsal horn excitatory synaptogenesis along with decreased TSP4 in the DRG and increased astrocytic release of TSP4 in the spinal cord, all of which parallel the time course of sustained tactile allodynia. Blocking injury-induced spinal TSP4 expression with antisense oligonucleotides or reducing TSP4 activity at its neuronal receptor in the spinal cord with gabapentin treatment both attenuate the allodynia and dorsal horn synaptogenesis that develop after painful facet joint loading. Increased spinal TSP4 also facilitates the development of allodynia and spinal hyperexcitability, even after non-painful physiological loading of the facet joint. These results suggest that spinal TSP4 plays an important role in the development and maintenance of persistent joint-mediated pain by inducing excitatory synaptogenesis and facilitating the transduction of mechanical loading of the facet joint that leads to spinal hyperexcitability.

Early afferent activity from the facet joint after painful trauma to its capsule potentiates neuronal excitability and glutamate signaling in the spinal cord.

Cervical facet joint injury induces persistent pain and central sensitization. Preventing the peripheral neuronal signals that initiate sensitization attenuates neuropathic pain. Yet, there is no clear relationship among facet joint afferent activity, development of central sensitization, and pain, which may be hindering effective treatments for this pain syndrome. This study investigates how afferent activity from the injured cervical facet joint affects induction of behavioral sensitivity and central sensitization. Intra-articular bupivacaine was administered to transiently suppress afferent activity immediately or 4 days after facet injury. Mechanical hyperalgesia was monitored after injury, and spinal neuronal hyperexcitability and spinal expression of proteins that promote neuronal excitability were measured on day 7. Facet injury with saline vehicle treatment induced significant mechanical hyperalgesia (P<.027), dorsal horn neuronal hyperexcitability (P<.026), upregulation of pERK1/2, pNR1, mGluR5, GLAST, and GFAP, and downregulation of GLT1 (P<.032). However, intra-articular bupivacaine immediately after injury significantly attenuated hyperalgesia (P<.0001), neuronal hyperexcitability (P<.004), and dysregulation of excitatory signaling proteins (P<.049). In contrast, intra-articular bupivacaine at day 4 had no effect on these outcomes. Silencing afferent activity during the development of neuronal hyperexcitability (4 hours, 8 hours, 1 day) attenuated hyperalgesia and neuronal hyperexcitability (P<.045) only for the treatment given 4 hours after injury. This study suggests that early afferent activity from the injured facet induces development of spinal sensitization via spinal excitatory glutamatergic signaling. Peripheral intervention blocking afferent activity is effective only over a short period of time early after injury and before spinal modifications develop, and is independent of modulating spinal glial activation.

Gabapentin alleviates facet-mediated pain in the rat through reduced neuronal hyperexcitability and astrocytic activation in the spinal cord.

UNLABELLED: Although joint pain is common, its mechanisms remain undefined, with little known about the spinal neuronal responses that contribute to this type of pain. Afferent activity and sustained spinal neuronal hyperexcitability correlate to facet joint loading and the extent of behavioral sensitivity induced after painful facet injury, suggesting that spinal neuronal plasticity is induced in association with facet-mediated pain. This study used a rat model of painful C6-C7 facet joint stretch, together with intrathecal administration of gabapentin, to investigate the effects of one aspect of spinal neuronal function on joint pain. Gabapentin or saline vehicle was given via lumbar puncture prior to and at 1 day after painful joint distraction. Mechanical hyperalgesia was measured in the forepaw for 7 days. Extracellular recordings of neuronal activity and astrocytic and microglial activation in the cervical spinal cord were evaluated at day 7. Gabapentin significantly (P = .0001) attenuated mechanical hyperalgesia, and the frequency of evoked neuronal firing also significantly decreased (P < .047) with gabapentin treatment. Gabapentin also decreased (P < .04) spinal glial fibrillary acidic protein expression. Although spinal Iba1 expression was doubled over sham, gabapentin did not reduce it. Facet joint-mediated pain appears to be sustained through spinal neuronal modifications that are also associated with astrocytic activation. PERSPECTIVE: Intrathecal gabapentin treatment was used to investigate behavioral, neuronal, and glial response in a rat model of painful C6-C7 facet joint stretch. Gabapentin attenuated mechanical hyperalgesia, reduced evoked neuronal firing, and decreased spinal astrocytic activation. This study supports that facet joint pain is sustained through spinal neuronal and astrocytic activation.

Spinal neuronal plasticity is evident within 1 day after a painful cervical facet joint injury.

Excessive stretch of the cervical facet capsular ligament induces persistent pain and spinal plasticity at later time points. Yet, it is not known when such spinal modifications are initiated following this painful injury. This study investigates the development of hyperalgesia and neuronal hyperexcitability in the spinal cord after a facet joint injury. Behavioral sensitivity was measured in a model of painful C6/C7 facet joint injury in the rat, and neuronal hyperexcitability in the spinal cord was evaluated at 6h and 1 day after injury or a sham procedure, in separate groups. Extracellular recordings of C6/C7 dorsal horn neuronal activity (229 neurons) were used to quantify spontaneous and evoked firing. Rats exhibited no change in sensitivity to mechanical stimulation of the forepaw at 6h, but did exhibit increased sensitivity at 1 day after injury (p=0.012). At 6h, both spontaneous neuronal activity and firing evoked by light brushing, pinch, and von Frey filaments (1.4-26g) applied at the forepaw were not different between sham and injury. At 1 day, spontaneous firing was noted in a greater number of neurons after injury than sham (p<0.04). Evoked firing was also increased 1 day after injury compared to normal and sham (p<0.03). Dorsal horn hyperexcitability and increased spontaneous firing developed between 6 and 24h after painful facet injury, suggesting that the development of hyperalgesia parallels dorsal horn hyperexcitability following mechanical facet joint injury, and these spinal mechanisms are initiated as early as 1 day after injury.

Anomalous fiber realignment during tensile loading of the rat facet capsular ligament identifies mechanically induced damage and physiological dysfunction.

Many pathophysiological phenomena are associated with soft tissue loading that does not produce visible damage or tissue failure. As such, there is an unexplained disconnect between tissue injury and detectable structural damage during loading. This study investigated the collagen fiber kinematics of the rat facet capsular ligament to identify the onset of subfailure damage during tensile loading conditions that are known to induce pain. Quantitative polarized light imaging was used to determine the collagen fiber orientation in the capsular ligament (n=7) under tension, and an alignment vector correlation measurement was employed to identify local anomalous fiber realignment during loading. During the initial portion of loading when tissue stiffness was increasing, anomalous realignment was more likely to be detected than mechanical evidence of structural damage, and as a result, anomalous fiber realignment was identified significantly (p=0.004) before gross failure. The occurrence of anomalous fiber realignment was significantly associated (p=0.013) with a decrease in tangent stiffness during loading (ligament yield), suggesting this optical metric may be associated with a loss of structural integrity. The presence of localized anomalous realignment during subfailure loading in this tissue may explain the development of laxity, collagen fiber disorganization, and persistent pain previously reported for facet joint distractions comparable to that required for anomalous realignment. These optical data, together with the literature, suggest that mechanically induced tissue damage may occur in the absence of any macroscopic or mechanical evidence of failure and may produce local pathology and pain.