Randomized Placebo-Controlled Trial of 60-Day Percutaneous Peripheral Nerve Stimulation Treatment Indicates Relief of Persistent Postoperative Pain, and Improved Function After Knee Replacement.

OBJECTIVES: Total knee arthroplasty (TKA) is an effective surgery for end-stage knee osteoarthritis, but chronic postoperative pain and reduced function affect up to 20% of patients who undergo such surgery. There are limited treatment options, but percutaneous peripheral nerve stimulation (PNS) is a promising nonopioid treatment option for chronic, persistent postoperative pain. The objective of the present study was to evaluate the effect of a 60-day percutaneous PNS treatment in a multicenter, randomized, double-blind, placebo-controlled trial for treating persistent postoperative pain after TKA. MATERIALS AND METHODS: Patients with postoperative pain after knee replacement were screened for this postmarket, institutional review board-approved, prospectively registered (NCT04341948) trial. Subjects were randomized to receive either active PNS or placebo (sham) stimulation. Subjects and a designated evaluator were blinded to group assignments. Subjects in both groups underwent ultrasound-guided placement of percutaneous fine-wire coiled leads targeting the femoral and sciatic nerves on the leg with postoperative pain. Leads were indwelling for eight weeks, and the primary efficacy outcome compared the proportion of subjects in each group reporting ≥50% reduction in average pain relative to baseline during weeks five to eight. Functional outcomes (6-minute walk test; 6MWT and Western Ontario and McMaster Universities Osteoarthritis Index) and quality of life (Patient Global Impression of Change) also were evaluated at end of treatment (EOT). RESULTS: A greater proportion of subjects in the PNS groups (60%; 12/20) than in the placebo (sham) group (24%; 5/21) responded with ≥50% pain relief relative to baseline (p = 0.028) during the primary endpoint (weeks 5-8). Subjects in the PNS group also walked a significantly greater distance at EOT than did those in the placebo (sham) group (6MWT; +47% vs -9% change from baseline; p = 0.048, n = 18 vs n = 20 completed the test, respectively). Prospective follow-up to 12 months is ongoing. CONCLUSIONS: This study provides evidence that percutaneous PNS decreases persistent pain, which leads to improved functional outcomes after TKA at EOT.

Percutaneous Neuromodulation of the Brachial Plexus and Sciatic Nerve for the Treatment of Acute Pain Following Surgery: Secondary Outcomes From a Multicenter, Randomized, Controlled Pilot Study.

OBJECTIVES: We recently reported that percutaneous peripheral nerve stimulation (PNS or "neuromodulation") decreased pain and opioid consumption within the first two weeks following ambulatory surgery. However, the anatomic lead locations were combined for the analysis, and benefits for each location remain unknown. We therefore now report the effects of percutaneous PNS for brachial plexus and sciatic nerve leads separately. MATERIALS AND METHODS: Before surgery, leads were implanted percutaneously to target the brachial plexus (N = 21) for rotator cuff repair or sciatic nerve (N = 40) for foot/ankle surgery, followed by a single injection of local anesthetic. Postoperatively, subjects were randomized in a double masked fashion to 14 days of electrical stimulation (N = 30) or sham/placebo (N = 31) using an external pulse generator. The primary outcome of interest was opioid consumption and pain scores evaluated jointly. Thus, stimulation was deemed effective if superior on either outcome and at least noninferior on the other. RESULTS: For brachial plexus leads, during the first seven postoperative days pain measured with the numeric rating scale in participants given active stimulation was a median [interquartile range] of 0.8 [0.5, 1.6] versus 3.2 [2.7, 3.5] in patients given sham (p < 0.001). For this same group, opioid consumption in participants given active stimulation was 10 mg [5, 20] versus 71 mg [35, 125] in patients given sham (p = 0.043). For sciatic nerve leads, pain scores for the active treatment group were 0.7 [0, 1.4] versus 2.8 [1.6, 4.6] in patients given sham (p < 0.001). During this same period, participants given active stimulation consumed 5 mg [0, 30] of opioids versus 40 mg [20, 105] in patients given sham (p = 0.004). Treatment effects did not differ statistically between the two locations. CONCLUSIONS: Ambulatory percutaneous PNS of both the brachial plexus and sciatic nerve is an effective treatment for acute pain free of systemic side effects following painful orthopedic surgery.

Percutaneous Peripheral Nerve Stimulation (Neuromodulation) for Postoperative Pain: A Randomized, Sham-controlled Pilot Study.

BACKGROUND: Percutaneous peripheral nerve stimulation is an analgesic technique involving the percutaneous implantation of a lead followed by the delivery of electric current using an external pulse generator. Percutaneous peripheral nerve stimulation has been used extensively for chronic pain, but only uncontrolled series have been published for acute postoperative pain. The current multicenter study was undertaken to (1) determine the feasibility and optimize the protocol for a subsequent clinical trial and (2) estimate the treatment effect of percutaneous peripheral nerve stimulation on postoperative pain and opioid consumption. METHODS: Preoperatively, an electrical lead was percutaneously implanted to target the sciatic nerve for major foot/ankle surgery (e.g., hallux valgus correction), the femoral nerve for anterior cruciate ligament reconstruction, or the brachial plexus for rotator cuff repair, followed by a single injection of long-acting local anesthetic along the same nerve/plexus. Postoperatively, participants were randomized to 14 days of either electrical stimulation (n = 32) or sham stimulation (n = 34) using an external pulse generator in a double-masked fashion. The dual primary treatment effect outcome measures were (1) cumulative opioid consumption (in oral morphine equivalents) and (2) mean values of the "average" daily pain scores measured on the 0 to 10 Numeric Rating Scale within the first 7 postoperative days. RESULTS: During the first 7 postoperative days, opioid consumption in participants given active stimulation was a median (interquartile range) of 5 mg (0 to 30) versus 48 mg (25 to 90) in patients given sham treatment (ratio of geometric means, 0.20 [97.5% CI, 0.07 to 0.57]; P < 0.001). During this same period, the average pain intensity in patients given active stimulation was a mean ± SD of 1.1 ± 1.1 versus 3.1 ± 1.7 in those given sham (difference, -1.8 [97.5% CI, -2.6 to -0.9]; P < 0.001). CONCLUSIONS: Percutaneous peripheral nerve stimulation reduced pain scores and opioid requirements free of systemic side effects during at least the initial week after ambulatory orthopedic surgery.

Percutaneous Peripheral Nerve Stimulation to Control Postoperative Pain, Decrease Opioid Use, and Accelerate Functional Recovery Following Orthopedic Trauma.

Orthopedic trauma is a significant military problem, causing several of the most disabling conditions with high rates of separation from duty and erosion of military readiness. The objective of this report is to summarize the findings of case series of a non-opioid therapy-percutaneous peripheral nerve stimulation (PNS) - and describe its potential for postoperative analgesia, early opioid cessation, and improved function following orthopedic trauma. Percutaneous PNS has been evaluated for the treatment of multiple types of pain, including two case series on postoperative pain following total knee replacement (n = 10 and 8, respectively) and a case series on postamputation pain (n = 9). The orthopedic trauma induced during TKR is highly representative of multiple types of orthopedic trauma sustained by Service members and frequently produces intense, prolonged postoperative pain and extended opioid use following surgery. Collectively, the results of these three clinical studies demonstrated that percutaneous PNS can provide substantial pain relief, reduce opioid use, and improve function. These outcomes suggest that there is substantial potential for the use of percutaneous PNS following orthopedic trauma.

A Feasibility Study of Percutaneous Peripheral Nerve Stimulation for the Treatment of Postoperative Pain Following Total Knee Arthroplasty.

INTRODUCTION: The objective of the present feasibility study was to investigate the use of a new treatment modality-percutaneous peripheral nerve stimulation (PNS)-in controlling the often severe and long-lasting pain following total knee arthroplasty (TKA). METHODS: For patients undergoing a primary, unilateral TKA, both femoral and sciatic open-coil percutaneous leads (SPR Therapeutics, Cleveland, OH) were placed up to seven days prior to surgery using ultrasound guidance. The leads were connected to external stimulators and used both at home and in the hospital for up to six weeks total. RESULTS: In six of seven subjects (86%), the average of daily pain scores across the first two weeks was <4 on the 0-10 Numeric Rating Scale for pain. A majority of subjects (four out of seven; 57%) had ceased opioid use within the first week (median time to opioid cessation for all subjects was six days). Gross sensory/motor function was maintained during stimulation, enabling stimulation during physical therapy and activities of daily living. At 12 weeks following surgery, six of seven subjects had improved by >10% on the Six-Minute Walk Test compared to preoperative levels, and WOMAC scores improved by an average of 85% compared to before surgery. No falls, motor block, or lead infections were reported. CONCLUSIONS: This feasibility study suggests that for TKA, ultrasound-guided percutaneous PNS is feasible in the immediate perioperative period and may provide analgesia without the undesirable systemic effects of opioids or quadriceps weakness induced by local anesthetics-based peripheral nerve blocks.

Percutaneous Peripheral Nerve Stimulation for the Treatment of Chronic Low Back Pain: Two Clinical Case Reports of Sustained Pain Relief.

As the leading cause of disability among U.S. adults, chronic low back pain (LBP) is one of the most prevalent and challenging musculoskeletal conditions. Neuromodulation provides an opportunity to reduce or eliminate the use of opioids to treat chronic LBP, but the cost and invasiveness of existing methods have limited its broad adoption, especially earlier in the treatment continuum. The present case report details the results of a novel method of short-term percutaneous peripheral nerve stimulation (PNS) in 2 subjects with chronic LBP. At the end of the 1-month therapy, stimulation was discontinued and the leads were withdrawn. PNS produced clinically significant improvements in pain (62% average reduction in Brief Pain Inventory Question #5, average pain), and functional outcomes (73% reduction in disability, Oswestry Disability Index; 83% reduction in pain interference, Brief Pain Inventory). Both subjects reduced nonopioid analgesic use by 83%, on average, and the one subject taking opioids ceased using all opioids. The only adverse event was minor skin irritation caused by a topical dressing. The clinically significant improvements were sustained at least 4 months after start of therapy (79% average reduction in pain; both reported minimal disability; 100% reduction in opioids; 74% reduction nonopioids). The results reveal the utility of this novel, short-term approach and its potential as a minimally invasive neuromodulation therapy for use earlier in the treatment continuum to produce sustained pain relief and reduce or eliminate the need for analgesic medications, including opioids, as well as more expensive and invasive surgical or therapeutic alternatives.

Ultrasound-guided percutaneous peripheral nerve stimulation for analgesia following total knee arthroplasty: a prospective feasibility study.

BACKGROUND: Peripheral nerve stimulation has been used for decades to treat chronic pain but has not been used for postoperative analgesia due to multiple limitations, beginning with invasive electrode placement. With the development of small-diameter/gauge leads enabling percutaneous insertion, ultrasound guidance for accurate introduction, and stimulators small enough to be adhered to the skin, neurostimulation may now be provided in a similar manner to continuous peripheral nerve blocks. Here, we report on the use of ultrasound-guided percutaneous peripheral nerve stimulation to treat postoperative pain. MATERIALS AND METHODS: Subjects within 60 days of a total knee arthroplasty with pain insufficiently treated with oral analgesics had a 0.2-mm-diameter electrical lead (pre-loaded into a 20 gauge needle) introduced percutaneously using ultrasound guidance with the tip located approximately 0.5-1.0 cm from the femoral nerve (a second lead was inserted approximately 1.0-3.0 cm from the sciatic nerve for posterior knee pain). An external stimulator delivered current. Endpoints were assessed before and after lead insertion and the leads subsequently removed. Due to the small sample size for this pilot/feasibility study, no statistics were applied to the data. RESULTS: Leads were inserted in subjects (n = 5) 8-58 days postoperatively. Percutaneous peripheral nerve stimulation decreased pain an average of 93% at rest (from a mean of 5.0 to 0.2 on a 0-10 numeric rating scale), with 4 of 5 subjects experiencing complete resolution of pain. During passive and active knee motion pain decreased an average of 27 and 30%, respectively. Neither maximum passive nor active knee range-of-motion was consistently affected. CONCLUSIONS: Ultrasound-guided percutaneous peripheral nerve stimulation may be a practical modality for the treatment of postoperative pain following orthopedic surgical procedures, and further investigation appears warranted.

Neurostimulation for Postsurgical Analgesia: A Novel System Enabling Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation.

While neurostimulation-stimulation of the nervous system using electrical current-has been used to treat chronic pain, its use treating postsurgical pain has been limited. Here, we report on the clinical application of a novel investigational lead to provide analgesia following total knee arthroplasty. In 5 subjects, leads were inserted percutaneously using ultrasound guidance within 0.5 to 3.0 cm of the femoral and/or sciatic nerve(s). With the delivery of current, pain decreased an average of 63% at rest, with 4 of 5 subjects having relief of > 50%. During passive and active knee flexion, pain decreased an average of 14% and 50%, with 0/3 and 1/2 subjects attaining > 50% relief, respectively. Ultrasound-guided percutaneous peripheral nerve stimulation may be a practical modality for the treatment of postsurgical pain.

Infection Rates of Electrical Leads Used for Percutaneous Neurostimulation of the Peripheral Nervous System.

BACKGROUND: Percutaneous neurostimulation of the peripheral nervous system involves the insertion of a wire "lead" through an introducing needle to target a nerve/plexus or a motor point within a muscle. Electrical current may then be passed from an external generator through the skin via the lead for various therapeutic goals, including providing analgesia. With extended use of percutaneous leads sometimes greater than a month, infection is a concern. It was hypothesized that the infection rate of leads with a coiled design is lower than for leads with a noncoiled cylindrical design. METHODS: The literature was retrospectively reviewed for clinical studies of percutaneous neurostimulation of the peripheral nervous system of greater than 2 days that included explicit information on adverse events. The primary endpoint was the number of infections per 1,000 indwelling days. RESULTS: Forty-three studies were identified that met inclusion criteria involving coiled (n = 21) and noncoiled (n = 25) leads (3 studies involved both). The risk of infection with noncoiled leads was estimated to be 25 times greater than with coiled leads (95% confidence interval [CI] 2 to 407, P = 0.006). The infection rates were estimated to be 0.03 (95% CI 0.01 to 0.13) infections per 1,000 indwelling days for coiled leads and 0.83 (95% CI 0.16 to 4.33) infections per 1,000 indwelling days for noncoiled leads (P = 0.006). CONCLUSIONS: Percutaneous leads used for neurostimulation of the peripheral nervous system have a much lower risk of infection with a coiled design compared with noncoiled leads: approximately 1 infection for every 30,000 vs. 1,200 indwelling days, respectively.

Computer-based model of epidural motor cortex stimulation: effects of electrode position and geometry on activation of cortical neurons.

OBJECTIVE: The aim of this study was to determine the effects of electrode placement, geometry, and polarity during epidural cortical stimulation (ECS) on thresholds for direct activation of cortical neurons. METHODS: We used a computational model of epidural electrical stimulation of the motor cortex coupled to compartmental models of cortical neurons. RESULTS: Thresholds varied with stimulation polarity and neuron position, and neurons deep within the sulci had much larger thresholds than those on the crowns or lips of the gyri. Axons were more excitable than cell bodies or dendrites. Delivering stimulation with the lead placed above or perpendicular to the sulci resulted in substantial stimulation of the gyri adjacent to the target gyrus. Electrode diameter and inter-electrode spacing influenced thresholds and affected the spread of activation in the cortex. CONCLUSIONS: Electrode placement, geometry, and polarity during ECS influence excitation properties of cortical neurons substantially. SIGNIFICANCE: Epidural leads have varying geometries, and in clinical studies of ECS the placement of the lead has been inconsistent. These results provide an improved understanding of the effects of electrode placement, geometry, and polarity on the outcome of ECS and can facilitate the rational implantation and programming of ECS systems.

Effects of stimulation parameters and electrode location on thresholds for epidural stimulation of cat motor cortex.

Epidural electrical stimulation (ECS) of the motor cortex is a developing therapy for neurological disorders. Both placement and programming of ECS systems may affect the therapeutic outcome, but the treatment parameters that will maximize therapeutic outcomes and minimize side effects are not known. We delivered ECS to the motor cortex of anesthetized cats and investigated the effects of electrode placement and stimulation parameters on thresholds for evoking motor responses in the contralateral forelimb. Thresholds were inversely related to stimulation frequency and the number of pulses per stimulus train. Thresholds were lower over the forelimb representation in motor cortex (primary site) than surrounding sites (secondary sites), and thresholds at sites <4 mm away from the primary site were significantly lower than at sites >4 mm away. Electrode location and montage influenced the effects of polarity on thresholds: monopolar anodic and cathodic thresholds were not significantly different over the primary site, cathodic thresholds were significantly lower than anodic thresholds over secondary sites and bipolar thresholds were significantly lower with the anode over the primary site than with the cathode over the primary site. A majority of bipolar thresholds were either between or equal to the respective monopolar thresholds, but several bipolar thresholds were greater than or less than the monopolar thresholds of both the anode and cathode. During bipolar stimulation, thresholds were influenced by both electric field superposition and indirect, synaptically mediated interactions. These results demonstrate the influence of stimulation parameters and electrode location during cortical stimulation, and these effects should be considered during the programming of systems for therapeutic cortical stimulation.

Energy-efficient waveform shapes for neural stimulation revealed with a genetic algorithm.

The energy efficiency of stimulation is an important consideration for battery-powered implantable stimulators. We used a genetic algorithm (GA) to determine the energy-optimal waveform shape for neural stimulation. The GA was coupled to a computational model of extracellular stimulation of a mammalian myelinated axon. As the GA progressed, waveforms became increasingly energy efficient and converged upon an energy-optimal shape. The results of the GA were consistent across several trials, and resulting waveforms resembled truncated Gaussian curves. When constrained to monophasic cathodic waveforms, the GA produced waveforms that were symmetric about the peak, which occurred approximately during the middle of the pulse. However, when the cathodic waveforms were coupled to rectangular charge-balancing anodic pulses, the location and sharpness of the peak varied with the duration and timing (i.e., before or after the cathodic phase) of the anodic phase. In a model of a population of mammalian axons and in vivo experiments on a cat sciatic nerve, the GA-optimized waveforms were more energy efficient and charge efficient than several conventional waveform shapes used in neural stimulation. If used in implantable neural stimulators, GA-optimized waveforms could prolong battery life, thereby reducing the frequency of recharge intervals, the volume of implanted pulse generators, and the costs and risks of battery-replacement surgeries.

Efficiency analysis of waveform shape for electrical excitation of nerve fibers.

Stimulation efficiency is an important consideration in the stimulation parameters of implantable neural stimulators. The objective of this study was to analyze the effects of waveform shape and duration on the charge, power, and energy efficiency of neural stimulation. Using a population model of mammalian axons and in vivo experiments on cat sciatic nerve, we analyzed the stimulation efficiency of four waveform shapes: square, rising exponential, decaying exponential, and rising ramp. No waveform was simultaneously energy-, charge-, and power-optimal, and differences in efficiency among waveform shapes varied with pulse width (PW). For short PWs (< or = 0.1 ms), square waveforms were no less energy-efficient than exponential waveforms, and the most charge-efficient shape was the ramp. For long PW s (> or = 0.5 ms), the square was the least energy-efficient and charge-efficient shape, but across most PW s, the square was the most power-efficient shape. Rising exponentials provided no practical gains in efficiency over the other shapes, and our results refute previous claims that the rising exponential is the energy-optimal shape. An improved understanding of how stimulation parameters affect stimulation efficiency will help improve the design and programming of implantable stimulators to minimize tissue damage and extend battery life.

Genetic algorithm reveals energy-efficient waveforms for neural stimulation.

Energy consumption is an important consideration for battery-powered implantable stimulators. We used a genetic algorithm (GA) that mimics biological evolution to determine the energy-optimal waveform shape for neural stimulation. The GA was coupled to NEURON using a model of extracellular stimulation of a mammalian myelinated axon. Stimulation waveforms represented the organisms of a population, and each waveform's shape was encoded into genes. The fitness of each waveform was based on its energy efficiency and ability to elicit an action potential. After each generation of the GA, waveforms mated to produce offspring waveforms, and a new population was formed consisting of the offspring and the fittest waveforms of the previous generation. Over the course of the GA, waveforms became increasingly energy-efficient and converged upon a highly energy-efficient shape. The resulting waveforms resembled truncated normal curves or sinusoids and were 3-74% more energy-efficient than several waveform shapes commonly used in neural stimulation. If implemented in implantable neural stimulators, the GA optimized waveforms could prolong battery life, thereby reducing the costs and risks of battery-replacement surgery.

Computational modeling of epidural cortical stimulation.

Epidural cortical stimulation (ECS) is a developing therapy to treat neurological disorders. However, it is not clear how the cortical anatomy or the polarity and position of the electrode affects current flow and neural activation in the cortex. We developed a 3D computational model simulating ECS over the precentral gyrus. With the electrode placed directly above the gyrus, about half of the stimulus current flowed through the crown of the gyrus while current density was low along the banks deep in the sulci. Beneath the electrode, neurons oriented perpendicular to the cortical surface were depolarized by anodic stimulation, and neurons oriented parallel to the boundary were depolarized by cathodic stimulation. Activation was localized to the crown of the gyrus, and neurons on the banks deep in the sulci were not polarized. During regulated voltage stimulation, the magnitude of the activating function was inversely proportional to the thickness of the CSF and dura. During regulated current stimulation, the activating function was not sensitive to the thickness of the dura but was slightly more sensitive than during regulated voltage stimulation to the thickness of the CSF. Varying the width of the gyrus and the position of the electrode altered the distribution of the activating function due to changes in the orientation of the neurons beneath the electrode. Bipolar stimulation, although often used in clinical practice, reduced spatial selectivity as well as selectivity for neuron orientation.

Fabrication and evaluation of conductive elastomer electrodes for neural stimulation.

This study explored the feasibility of applying nanocomposites derived from conducting organic polymers and silicone elastomers to fabricate electrodes for neural stimulation. A novel combination of nanoparticulate polypyrrole polymerized within a processable elastomeric silicone host polymer was evaluated in vitro and in vivo. The electrical properties of the elastomeric conductors were strongly dependent on their composition, and mixtures were identified that provided high and stable conductivity. Methods were developed for incorporating conductive polymer-siloxane co-polymer nanocomposite and silicone insulating polymers into thin-layered structures for simple single-poled electrode fabrication. In vitro testing revealed that the materials were stable under continuous pulsing for at least 10 days. Single contact prototype nerve cuff electrodes were fabricated and device functionality was demonstrated in vivo following acute implantation. The results of this study demonstrate the feasibility of conductive elastomers for peripheral nerve stimulating electrodes. Matching the mechanical properties of cuff electrode to those of the underlying neural tissue is expected to improve the long-term tissue response to the presence of the electrode.