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.

Network model of nociceptive processing in the superficial spinal dorsal horn reveals mechanisms of hyperalgesia, allodynia, and spinal cord stimulation.

The spinal dorsal horn (DH) processes sensory information and plays a key role in transmitting nociception to supraspinal centers. Loss of DH inhibition during neuropathic pain unmasks a pathway from nonnociceptive Aß-afferent inputs to superficial dorsal horn (SDH) nociceptive-specific (NS) projection neurons, and this change may contribute to hyperalgesia and allodynia. We developed and validated a computational model of SDH neuronal circuitry that links nonnociceptive Aß-afferent inputs in lamina II/III to a NS projection neuron in lamina I via a network of excitatory interneurons. The excitatory pathway and the NS projection neuron were in turn gated by inhibitory interneurons with connections based on prior patch-clamp recordings. Changing synaptic weights in the computational model to replicate neuropathic pain states unmasked a low-threshold excitatory pathway to NS neurons similar to experimental recordings. Spinal cord stimulation (SCS) is an effective therapy for neuropathic pain, and accumulating experimental evidence indicates that NS neurons in the SDH also respond to SCS. Accounting for these responses may inform therapeutic improvements, and we quantified responses to SCS in the SDH network model and examined the role of different modes of inhibitory control in modulating NS neuron responses to SCS. We combined the SDH network model with a previously published model of the deep dorsal horn (DDH) and identified optimal stimulation frequencies across different neuropathic pain conditions. Finally, we found that SCS-generated inhibition did not completely suppress model NS activity during simulated pinch inputs, providing an explanation of why SCS does not eliminate acute pain.NEW & NOTEWORTHY Chronic pain is a severe public health problem that reduces the quality of life for those affected and exacts an enormous socio-economic burden worldwide. Spinal cord stimulation (SCS) is an effective treatment for chronic pain, but SCS efficacy has not significantly improved over time, in part because the mechanisms of action remain unclear. Most preclinical studies investigating pain and SCS mechanisms have focused on the responses of deep dorsal horn (DDH) neurons, but neural networks in the superficial dorsal horn (SDH) are also important for processing nociceptive information. This work synthesizes heterogeneous experimental recordings from the SDH into a computational model that replicates experimental responses and that can be used to quantify neuronal responses to SCS under neuropathic pain conditions.

Evaluating optimized temporal patterns of spinal cord stimulation (SCS).

BACKGROUND: Temporal patterns of stimulation represent a novel dimension for improving the efficacy of spinal cord stimulation to treat chronic neuropathic pain. OBJECTIVE: We hypothesized that nonregular temporal patterns of stimulation designed using a computational model would be superior to conventional stimulation at constant frequencies or completely random patterns of stimulation. METHODS: Using a computational model of the dorsal horn network and an optimization algorithm based on biological evolution, we designed an optimized pattern of spinal cord stimulation with comparable efficacy and increased efficiency relative to constant frequency (CF) stimulation. We evaluated the effect of different temporal patterns on individual neurons recorded in the dorsal horn of urethane-anesthetized rats. RESULTS: The optimized pattern and 50 Hz CF stimulation produced greater inhibition of spontaneously firing neurons recorded in vivo than random 50 Hz stimulation or a pattern designed intentionally with poor fitness. Spinal Cord Stimulation (SCS) led to significant changes in the firing patterns of recorded units, and stimulation patterns that generated significant inhibition also tended to reduce entropy and regularize the firing patterns of units, suggesting that patterns of dorsal horn neuron activity may be important for pain perception in addition to the firing rate. CONCLUSIONS: These results demonstrate that the computational model can be used as a tool for optimizing stimulation parameters and suggest that optimized temporal patterns may increase the efficacy of spinal cord stimulation.

Surround Inhibition Mediates Pain Relief by Low Amplitude Spinal Cord Stimulation: Modeling and Measurement.

Low-frequency (<200 Hz), subperception spinal cord stimulation (SCS) is a novel modality demonstrating therapeutic efficacy for treating chronic neuropathic pain. When stimulation parameters were carefully titrated, patients experienced rapid onset (seconds-minutes) pain relief without paresthesia, but the mechanisms of action are unknown. Using an integrated computational model and in vivo measurements in urethane-anesthetized rats, we quantified how stimulation parameters (placement, pulse width, frequency, and amplitude) influenced dorsal column (DC) axon activation and neural responses in the dorsal horn (DH). Both modeled and recorded DC axons responded with irregular spiking patterns in response to low-amplitude SCS. Maximum inhibition of DH neurons occurred at ∼80% of the predicted sensory threshold in both modeled and recorded neurons, and responses were strongly dependent on spatially targeting of stimulation, i.e., the complement of DC axons activated, and on stimulation parameters. Intrathecal administration of bicuculline shifted neural responses to low-amplitude stimulation in both the model and experiment, suggesting that analgesia is dependent on segmental GABAergic mechanisms. Our results support the hypothesis that low-frequency subperception SCS generates rapid analgesia by activating a small number of DC axons which inhibit DH neuron activity via surround inhibition.