Nerve injury primarily leads to neuropathic pain but may also have overlapping elements of nociplastic pain or ongoing nociceptive pain. Electrical stimulation is particularly effective in the treatment of neuropathic pain and may be effective for nociplastic and nociceptive pain. While multiple mechanisms contribute to the analgesic effect of electrical stimulation, the most widely accepted theory for the predominant effect is that of Melzack and Wall's gate control theory. According to this theory, non-painful sensory input carried by low-threshold large-diameter Aβ fibres disrupt the transmission of pain signals in small pain fibers (Aδ and C fibres). This occurs through the activation of inhibitory interneurons in the dorsal horn, which ultimately blocks pain signal transmission.This theory has been employed for different forms of stimulation, including transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS), and peripheral nerve stimulation (PNS). Each of these methods offers a different approach to localized stimulation and neuromodulation for the treatment of pain. TENS is a non-invasive technique, that delivers electrical currents via surface electrodes placed on the skin. PENS, in contrast, is a minimally invasive method that applies electrical currents through small needles inserted near a target muscle or neural structure. PNS involves the implantation of temporary or permanent electrodes to deliver electrical stimulation directly to peripheral nerves. These modalities are widely used to manage various pain conditions including non-malignant, chronic musculoskeletal and neuropathic pain, such as chronic low back pain, neck pain, neuropathic pain, myofascial pain, and post-operative pain. TENS is particularly notable as a non-invasive device that is affordable, over-the-counter, self-administered, and nonpharmacological option that does not pose the risk of toxicity or overdose. PENS stands out for its ability to integrate electrical stimulation therapy with electroacupuncture through a minimally invasive technique. PNS, on the other hand, is unique in its capacity to precisely target specific nerves and provide a range of stimulation options for extended treatment durations.This article provides a narrative overview of TENS, PENS and PNS with a particular focus on their application for neuropathic pain management and for athletes. We will review mechanisms of action, indications, diagnostic and treatment algorithms, as well as complications and limitations. The overview concludes with a complex case study demonstrating the use of various electrical stimulation therapies, ultimately to successful pain resolution for the patient.

In spinal cord stimulation (SCS) therapy, electricity is the medication delivered to the spinal cord for pain relief. In contrast to conventional medication where dose is determined by desired therapeutic plasma concentration, there is lack of equivalent means of determining dose delivery in SCS. In open-loop (OL) SCS, due to the dynamic nature of the epidural space, the activating electric field delivered is inconsistent at the level of the dorsal columns. Recent Food and Drug Administration guidance suggests accurate and consistent therapy delivered using physiologic closed-loop control (PCLC) devices can minimize underdosage or overdosage and enhance medical care. PCLC-based evoked compound action potential (ECAP)-controlled technology provides the ability to prescribe a precise stimulation dose unique to each patient, continuously measure neural activation, and objectively inform SCS therapy optimization.

Neurophysiological indicator metrics of therapy dose, usage above neural activation threshold, and accuracy of SCS therapy were assessed for relationship with pain reduction in over 600 SCS patients.

Significant relationships between objective metrics and pain relief across the patient population are shown, including first evidence for a dose-response relationship in SCS.

Higher dose, more time over ECAP threshold, and higher accuracy are associated with better outcomes across patients. There is potential to optimize individual patient outcomes based on unique objective measurable electrophysiological inputs.

This review aimed to compile the literature on synaptic plasticity induced by electrical nerve stimulation (ENS) in nociceptive and somatosensory circuits within the central nervous system, with a particular focus on its effects on both the brain and spinal cord. Understanding the mechanisms underlying synaptic changes, enhances our comprehension of how ENS contributes to both pain relief and the development of experimental pain models.

We conducted a systematic search of PubMed, Scopus, PEDro, SciELO, and Cochrane databases, adhering to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, and evaluated the quality of evidence using SYRCLE's risk of bias tool. The inclusion criteria were application of ENS to peripheral nerves, reporting of a detailed methodology, providing direct physiological measurements of synaptic activity (eg, field potentials or intracellular recordings), and publication in English or Spanish. From 8094 results, 85 studies met the inclusion criteria.

ENS was found to induce synaptic potentiation in 70 studies, depression in 7, and both effects in 8. These outcomes were determined by specific stimulation parameters and individual characteristics, with distinct molecular mechanisms involved in each case. Notably, most research focused on long-term potentiation in nociceptive pathways to create experimental pain models, with most studies conducted in the spinal cord. Few studies explored the link between ENS-induced synaptic plasticity and its analgesic effects or the role of plasticity in supraspinal brain regions, suggesting promising areas for future research.

ENS-induced synaptic plasticity presents a valuable opportunity for both pain management and the development of experimental pain models. Further research is needed to explore the connections between plasticity, analgesia, and higher brain regions.

Objective. Evoked compound action potentials (ECAPs) measured during epidural spinal cord stimulation (SCS) can help elucidate fundamental mechanisms for the treatment of pain and inform closed-loop control of SCS. Previous studies have used ECAPs to characterize neural responses to various neuromodulation therapies and have demonstrated that ECAPs are highly prone to multiple sources of artifact, including post-stimulus pulse capacitive artifact, electromyography (EMG) bleed-through, and motion artifact. However, a thorough characterization has yet to be performed for how these sources of artifact may contaminate recordings within the temporal window commonly used to determine activation of A-beta fibers in a large animal model.Approach. We characterized sources of artifacts that can contaminate the recording of ECAPs in an epidural SCS swine model using the Abbott Octrode™ lead.Main results. Spinal ECAP recordings can be contaminated by capacitive artifact, short latency EMG from nearby muscles of the back, and motion artifact. The capacitive artifact can appear nearly identical in duration and waveshape to evoked A-beta responses. EMG bleed-through can have phase shifts across the electrode array, similar to the phase shift anticipated by propagation of an evoked A-beta fiber response. The short latency EMG is often evident at currents similar to those needed to activate A-beta fibers associated with the treatment of pain. Changes in CSF between the cord and dura, and motion induced during breathing created a cyclic oscillation in all evoked components of recorded ECAPs.Significance. Controls must be implemented to separate neural signal from sources of artifact in SCS ECAPs. We suggest experimental procedures and reporting requirements necessary to disambiguate underlying neural response from these confounds. These data are important to better understand the framework for epidural spinal recordings (ESRs), with components such as ECAPs, EMG, and artifacts, and have important implications for closed-loop control algorithms to account for transient motion such as postural changes and cough.

Poorly controlled pain during the acute postoperative period is associated with the development of persistent or 'chronic' pain lasting months or years after surgery. Relatively small trials suggest that local anesthetic-based peripheral nerve blocks lasting hours or a few days may decrease persistent postsurgical pain for some surgical procedures, but definitive data is lacking. Two possible alternatives-percutaneous cryoneurolysis and peripheral nerve stimulation-are analgesic modalities with the potential to provide weeks or months of pain relief following surgery. This increase in analgesic duration raises the possibility of decreased transition from acute to chronic postsurgical pain.

This review aims to summarize the available evidence involving the use of percutaneous cryoneurolysis and peripheral nerve stimulation within the immediate perioperative period and its effects on decreasing chronic postoperative pain.

Two randomized trials (n=66 and 16) comparing active percutaneous peripheral nerve stimulation to sham stimulation and two randomized trials (n=60 and 7) comparing percutaneous cryoneurolysis to a sham procedure for postoperative pain are described in this review. In each trial, participants were followed for at least three months.

This review describes percutaneous cryoneurolysis and peripheral nerve stimulation for perioperative analgesia as well as the available evidence supporting their use to prevent persistent postsurgical pain.

Peripheral nerve field stimulation (PNFS) can effectively manage pain localized to one or two dermatomes that are refractory to conventional approaches, such as chronic low back pain. However, its utility in pain management in the upper limbs is limited due to the risk of lead displacement related to articular and mobile segment constraints.In this technical note, we describe a 58-year-old man with neuropathic pain refractory to extensive medical treatment, and dorsal root entry zone lesion. Considering the patient's favorable response to transcutaneous electrical nerve stimulation, we used a two-step lead placement approach to improve the permanent placement of the electrode leads in the upper limb. After 1 year follow-up, the patient achieved at least 50% pain relief, with no signs of lead displacement or resistance during flexion and extension movements of the involved upper limb, illustrating the success of PNFS.

Mental nerve stimulation is recognised as a treatment option for neuropathic facial pain. Historically however, lead migration across the mobile temporomandibular joint has prevented this procedures utility.

We describe a new method of insertion and anchoring of a mental nerve stimulator for the management of refractory neuropathic pain in the distribution of the mental nerve. We anchored the stimulator lead to the mandibular body.

Significant analgesic effect was achieved and no lead migration had occurred at 1 year post-operatively.

This report describes in detail the procedure of mental nerve stimulator insertion, with a novel technique of mandibular anchoring of the lead.

Peripheral nerve stimulation (PNS) refers to the technique of utilizing electrical stimulation of peripheral nerves to inhibit the transmission of pain signals. PNS is used to treat chronic intractable pain and post-surgical or post-traumatic pain alongside a variety of other pain conditions, including headaches, facial pain, pelvic and urogenital pain, chest wall pain, residual limb or phantom limb pain, and back pain.

More recently, PNS has been used temporarily for periods of time less than 60 days to treat acute post-surgical pain. Peripheral nerve stimulation is believed to be effective due to its effects on both central and peripheral pathways. Centrally, it is proposed that the electrical pulses of PNS inhibit alpha-delta and C fibers, which decreases pain signaling in the higher centers of the central nervous system. Peripherally, gate theory is applied as it is theorized that PNS downregulates inflammatory mediators, endorphins, and neurotransmitters associated with pain signaling to decrease the transmission of efferent nociception and reduce pain sensations.

This narrative review examines the therapeutic efficacy of peripheral nerve stimulation (PNS) in the treatment of neuropathic pain (NP), a type of pain arising from lesions or diseases of the somatosensory system with a global prevalence ranging from 6.90% to 10.00%. Traditional pharmacological interventions often fall short for many persons, highlighting the need for alternative treatments such as PNS, which has demonstrated significant promise with minimal side effects. The review summarizes the effectiveness of PNS in various NP conditions, including trigeminal neuralgia and postherpetic neuralgia, and underscores the need for further research to refine treatment approaches. The mechanism of PNS is discussed, involving the activation of non-nociceptive Aβ fibers and modulation of neurotransmitters, and offering pain relief through both peripheral and central pathways. Despite the proven efficacy of PNS, challenges remain, including the need for randomized controlled trials and the optimization of stimulation parameters. The review concludes that PNS is a promising treatment modality for NP, warranting additional high-quality trials to solidify its role in clinical practice.

In this study, we aimed to characterize the recruitment and maintenance of action potential firing in Aα/β-fibers generated during tonic dorsal root ganglion stimulation (DRGS) applied over a range of clinically relevant stimulation parameters.

We delivered electrical stimulation to the L5 dorsal root ganglion and recorded antidromic evoked compound action potentials (ECAPs) in the sciatic nerve during DRGS in Sprague Dawley rats. We measured charge thresholds to elicit ECAPs in Aα/β-fibers during DRGS applied at multiple pulse widths (50, 150, 300, 500 μs) and frequencies (5, 20, 50, 100 Hz). We measured the peak-to-peak amplitudes, latencies, and widths of ECAPs generated during 180 seconds of DRGS, and excitation threshold changes to investigate potential mechanisms of ECAP suppression.

Tonic DRGS produced ECAPs in Aα/β-fibers at charge thresholds below the motor threshold. Increasing the pulse width of DRGS led to a significant increase in the charge required to elicit ECAPs in Aα/β-fibers, while varying DRGS frequency did not influence ECAP thresholds. Over the course of 180 seconds, ECAP peak-to-peak amplitude decreased progressively in a frequency-dependent manner, where 5- and 100-Hz DRGS resulted in 22% and 87% amplitude reductions, respectively, and ECAP latencies increased from baseline measurements during DRGS at 10, 20, 50, and 100 Hz. Regardless of DRGS frequency, ECAP amplitudes recovered within 120 seconds after turning DRGS off. We determined that ECAP suppression may be attributed to increasing excitation thresholds for individual fibers during DRGS. Following 180 seconds of DRGS, an average of 7.33% increase in stimulation amplitude was required to restore the ECAP to baseline amplitude.

DRGS produces a progressive and frequency-dependent reduction in ECAP amplitude that occurs within and above the frequency range used clinically to relieve pain. If DRGS-mediated analgesia relies on Aβ-fiber activation, then the frequency or duty cycle of stimulation should be set to the lowest effective level to maintain sufficient activation of Aβ-fibers.

"Somehow scientists still pursue the same questions, if now on higher levels of theoretical abstraction rooted in deeper layers of empirical evidence… To paraphrase an old philosophy joke, science is more like it is today than it has ever been. In other words, science remains as challenging as ever to human inquiry. And the need to communicate its progress… remains as essential now as then." - Tom Siegfried, Science News 2021In fact, essential questions about pain have not changed since IASP's creation in Issaquah: what causes it and how can we treat it? Are we any closer to answering these questions, or have we just widened the gap between bench and bedside? The technology used to answer questions about pain mechanisms has certainly changed, whether the focus is on sensory neurons, spinal cord circuitry, descending controls or cortical pain processing. In this paper, we will describe how transgenics, transcriptomics, optogenetics, calcium imaging, fMRI, neuroimmunology and in silico drug development have transformed the way we examine the complexity of pain processing. But does it all, as our founders hoped, help people with pain? Are voltage-gated Na channels the new holy grail for analgesic development, is there a pain biomarker, can we completely replace opioids, will proteomic analyses identify novel targets, is there a "pain matrix," and can it be targeted? Do the answers lie in our tangible discoveries, or in the seemingly intangible? Our founders could barely imagine what we know now, yet their questions remain.

This retrospective review evaluates pain and patient-defined functional goal improvement utilizing bipolar peripheral nerve stimulation (PNS) in chronic neuropathic and nociceptive pain states.

Our dataset includes 24 patients who underwent implantation of a permanent peripheral nerve stimulator from January 2018 through December 2022. A total of 29 leads were implanted amongst 24 patients, with 5 patients having leads at 2 different dermatomes. Fifteen leads were placed for primarily neuropathic pain, and 14 leads were placed for nociceptive pain. Inclusion criteria were the following: pain duration greater than 6 months, documented peri-procedural Numerical Pain Rating Scale (NPRS) and greater than 60 days follow-up post implant.

Data was collected and analyzed showing that 89.6% of implants at 6 months follow-up and 70% at 12 months follow-up achieved 50% or greater pain relief. A significant reduction in NPRS scores when comparing pre-procedure pain scores (Median = 7, n = 29) to 6-month follow-up data (Median = 2, n = 29), p<0.001 with a large effect size, r = 0.61. Ninety-three percent of patients reported achieving their personal functional goal. Twelve of the fourteen (86%) leads implanted for primary nociceptive pain and fourteen of the fifteen (93%) leads implanted for neuropathic pain achieved ≥50% relief at 6 months. At twelve months, seven leads in each group provided ≥50% sustained pain relief. Of the 14 patients that were on opioids, 6 discontinued, while another 2 had a reduction in oral morphine milligram equivalents (MME) at the 12-month follow-up.

This retrospective review demonstrates the potential clinical application of PNS in both nociceptive and neuropathic pain states. Further prospective studies are warranted to validate the effectiveness of PNS in the treatment of refractory nociceptive and neuropathic pain states.

Peripheral Nerve Stimulation (PNS) is an established therapy for chronic neuropathic pain of peripheral origin, typically following nerve injury. However, there is a paucity of Randomized Controlled Trials (RCTs) demonstrating the therapeutic benefits of PNS. The goals of the current study (COMFORT Study) are to document the safety and efficacy of the Nalu Neurostimulation in a PNS RCT, compared to conventional medical management (CMM).

This is a prospective, multicenter, RCT evaluating the treatment of neuropathic pain with PNS therapy. One of the following four regions will be targeted for treatment: low back, shoulder, knee or foot/ankle. Consented subjects will undergo a baseline evaluation, after which they are randomized 2:1 (PNS+CMM arm to CMM arm). Subjects randomized to PNS+CMM arm will undergo a trial implant period using best clinical practices. Subjects who pass the trial phase, by showing a ≥ 50% reduction in pain relative to baseline, will receive the permanent implant. All subjects receiving a permanent implant will be followed for a total of 36 months. At the 3-month primary end point, subjects in CMM arm will be given the option to crossover into PNS+CMM arm, beginning with a trial implant. The study duration is expected to be 5.5 years from first enrollment to last follow-up of last subject and subsequent study closure. Adverse events will be captured throughout the study.

The COMFORT study, described here, has the potential to demonstrate the efficacy and safety of the Nalu Neurostimulation System in the treatment of peripheral neuropathy. Results of this study will be the first Level-I evidence, out to 36 months, validating the use of this PNS system in the treatment of chronic pain. This study is designed to enroll the largest cohort, to date, of subjects comparing PNS+CMM vs CMM alone.

For over 60 years, spinal cord stimulation has endured as a therapy through innovation and novel developments. Current practice of neuromodulation requires proper patient selection, risk mitigation and use of innovation. However, there are tangible and intangible challenges in physiology, clinical science and within society.

We provide a narrative discussion regarding novel topics in the field especially over the last decade. We highlight the challenges in the patient care setting including selection, as well as economic and socioeconomic challenges. Physician training challenges in neuromodulation is explored as well as other factors related to the use of neuromodulation such as novel indications and economics. We also discuss the concepts of technology and healthcare data.

Patient safety and durable outcomes are the mainstay goal for neuromodulation. Substantial work is needed to assimilate data for larger and more relevant studies reflecting a population. Big data and global interconnectivity efforts provide substantial opportunity to reinvent our scientific approach, data analysis and its management to maximize outcomes and minimize risk. As improvements in data analysis become the standard of innovation and physician training meets demand, we expect to see an expansion of novel indications and its use in broader cohorts.

The aim of this study was to present key technologic and regulatory milestones in spinal cord stimulation (SCS) for managing chronic pain on a narrative timeline with visual representation, relying on original sources to the extent possible.

We identified technical advances in SCS that facilitated and enhanced treatment on the basis of scientific publications and approvals from the United States (US) Food and Drug Administration (FDA). We presented milestones limited to first use in key indications and in the context of new technology validation. We focused primarily on pain management, but other indications (eg, motor disorder in multiple sclerosis) were included when they affected technology development.

We developed a comprehensive visual and narrative timeline of SCS technology and US FDA milestones. Since its conception in the 1960s, the science and technology of SCS neuromodulation have continuously evolved. Advances span lead design (from paddle-type to percutaneous, and increased electrode contacts) and stimulator technology (from wireless power to internally powered and rechargeable, with miniaturized components, and programmable multichannel devices), with expanding stimulation program flexibility (such as burst and kilohertz stimulation frequencies), as well as usage features (such as remote programming and magnetic resonance imaging conditional compatibility).

This timeline represents the evolution of SCS technology alongside expanding FDA-approved indications for use.

Spinal cord stimulation (SCS) is a surgical treatment for severe, chronic, neuropathic pain. It is based on one to two lead(s) implanted in the epidural space, stimulating the dorsal column. It has long been assumed that when deactivating SCS, there is a variable interval before the patient perceives the return of the pain, a phenomenon often termed echo or carryover effect. Although the carryover effect has been problematized as a source of error in crossover studies, no experimental investigation of the effect has been published. This open, prospective, international multicenter study aimed to systematically document, quantify, and investigate the carryover effect in SCS.

Eligible patients with a beneficial effect from their SCS treatment were instructed to deactivate their SCS device in a home setting and to reactivate it when their pain returned. The primary outcome was duration of carryover time defined as the time interval from deactivation to reactivation. Central clinical parameters (age, sex, indication for SCS, SCS treatment details, pain score) were registered and correlated with carryover time using nonparametric tests (Mann-Whitney/Kruskal-Wallis) for categorical data and linear regression for continuous data.

In total, 158 patients were included in the analyses. A median carryover time of five hours was found (interquartile range 2.5;21 hours). Back pain as primary indication for SCS, high-frequency stimulation, and higher pain score at the time of deactivation were correlated with longer carryover time.

This study confirms the existence of the carryover effect and indicates a remarkably high degree of interindividual variation. The results suggest that the magnitude of carryover may be correlated to the nature of the pain condition and possibly stimulation paradigms.

The Clinicaltrials.gov registration number for the study is NCT03386058.

Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain involves peripheral and central pathological modifications. Peripheral mechanisms entail nerve damage, leading to neuronal hypersensitivity and ectopic action potentials. Central sensitization involves a neuropathological process with increased responsiveness of the nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold input due to persistent stimuli, leading to sustained electrical discharge, synaptic plasticity, and aberrant processing in the CNS. Current treatments, both pharmacological and non-pharmacological, aim to alleviate symptoms but often face challenges due to the complexity of neuropathic pain. Neuromodulation is emerging as an important therapeutic approach for the treatment of neuropathic pain in patients unresponsive to common therapies, by promoting the normalization of neuronal and/or glial activity and by targeting cerebral cortical regions, spinal cord, dorsal root ganglia, and nerve endings. Having a better understanding of the efficacy, adverse events and applicability of neuromodulation through pre-clinical studies is of great importance. Unveiling the mechanisms and characteristics of neuromodulation to manage neuropathic pain is essential to understand how to use it. In the present article, we review the current understanding supporting dorsal root ganglia and spinal cord neuromodulation as a therapeutic approach for neuropathic pain.

Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.

Neuropathic pain occurs in people experiencing lesion or disease affecting the somatosensorial system. It is present in 7 % of the general population and may not fully respond to first- and second-line treatments in up to 40 % of cases. Neuromodulation approaches are often proposed for those not tolerating or not responding to usual pharmacological management. These approaches can be delivered surgically (invasively) or non-invasively. Invasive neuromodulation techniques were the first to be employed in neuropathic pain. Among them is spinal cord stimulation (SCS), which consists of the implantation of epidural electrodes over the spinal cord. It is recommended in some guidelines for peripheral neuropathic pain. While recent studies have called into question its efficacy, others have provided promising data, driven by advances in techniques, battery capabilities, programming algorithms and software developments. Deep brain stimulation (DBS) is another well-stablished neuromodulation therapy routinely used for movement disorders; however, its role in pain management remains limited to specific research centers. This is not only due to variable results in the literature contesting its efficacy, but also because several different brain targets have been explored in small trials, compromising comparisons between these studies. Structures such as the periaqueductal grey, posterior thalamus, anterior cingulate cortex, ventral striatum/anterior limb of the internal capsule and the insula are the main targets described to date in literature. SCS and DBS present diverse rationales for use, mechanistic backgrounds, and varying levels of support from experimental studies. The present review aims to present their methodological details, main mechanisms of action for analgesia and their place in the current body of evidence in the management of patients with neuropathic pain, as well their particularities, effectiveness, safety and limitations.

Lower extremity pain is deemed by Center for Disease Control and Prevention (CDC) to be a significant source of chronic pain in adults. If not appropriately managed, patients are subjected to risks of prolonged musculoskeletal dysfunction, disruption to quality of life, and elevated healthcare expenditures. Peripheral nerve stimulation (PNS) has shown great potential in recent years demonstrating efficacy in multiple diagnoses ranging from acute post-surgical pain to complex regional pain syndrome (CRPS). This study seeks to delineate efficacy of peripheral neuromodulation in the context of chronic lower extremity pain.

Prevailing clinical studies demonstrate evidence levels ranging from II to V (Oxford Centre of Level of Evidence) in lower limb PNS, attaining positive outcomes in pain scores, opioid use, and quality of life measures. Nerves most frequently targeted are the sciatic and femoral nerves with post-amputation pain and CRPS most commonly investigated for efficacy. PNS is a promising therapeutic modality demonstrated to be effective for a variety of nociceptive and neuropathic pain conditions in the lower extremity. PNS offers chronic pain physicians a powerful tool in the multi-modal management of lower limb chronic pain.

There has been ongoing debate about the efficacy and mechanism of action of neuromodulation devices in pain relief applications. It has recently been suggested that both issues may be resolved if electromagnetic theory is incorporated into the understanding and application of this technology, and we therefore undertook an in silico analysis to further explore this idea. We created a CAD replication of a standard neuromodulation electrode array with a generic linear 3/6 mm 8-contact lead, developed a parameterized algorithmic model for the pulse delivered by the device and assigned material properties to biologic media to accurately reflect their electromagnetic properties. We then created a physical simulation of the device's output both in air and in the biophysical environment. The simulations confirmed the presence of an electromagnetic field (EM field). Variations in programming of the device affected the strength of the EM field by orders of magnitude. The biologic media all absorbed the EM field, an effect which was particularly pronounced in cerebrospinal fluid and muscle. We discuss the implications of all these findings in relation to the literature. We suggest that knowledge of electromagnetic theory and its application within the biophysical space is required for the optimal use of neuromodulation devices in pain relief applications.

Peripheral nerve injuries often result in severe personal and social burden, and even with surgical treatment, patients continue to have poor clinical outcomes. Over the past two decades, electrical stimulation has been shown to promote axonal regeneration and alleviate refractory neuropathic pain. The aim of this study was to analyse this field using a bibliometric approach. Literature was searched through Web of Science Core Collection (WOSCC) for the years 2002-2023. Literature analysis included: (1) Describing publication trends in the field. (2) Exploring collaborative network relationships. (3) Finding research advances and research hotspots in the field. (4) Summarizing research trends in the field. With the number of studies in this field still increasing, a total of 693 publications were included in the analysis. This field of research is interdisciplinary in nature. Research hotspots include peripheral nerve regeneration, the treatment of neuropathic pain, materials for nerve injury repair, and the restoration of sensory function in patients with peripheral nerve injury. Correspondingly, the development of nerve conduits and systems for peripheral nerve electrical stimulation, clinical trials of peripheral nerve electrical stimulation, and tactile recovery and movement for amputees have shown significant promise as future research trends in this field.

Neuromodulation is the alteration of neural activity in the central, peripheral, or autonomic nervous systems. Consequently, this term lends itself to a variety of organ systems including but not limited to the cardiac, nervous, and even gastrointestinal systems. In this review, we provide a primer on neuromodulation, examining the various technological systems employed and neurological disorders targeted with this technology. Ultimately, we undergo a historical analysis of the field's development, pivotal discoveries and inventions gearing this review to neuro-adjacent subspecialties with a specific focus on neurointerventionalists.

Spasticity is a form of muscle hypertonia secondary to various diseases, including traumatic brain injury, spinal cord injury, cerebral palsy, and multiple sclerosis. Medical treatments are available; however, these often result in insufficient clinical response. This review evaluates the role of epidural spinal cord stimulation (SCS) in the treatment of spasticity and associated functional outcomes.

A systematic review of the literature was performed using the Embase, CENTRAL, and MEDLINE databases. We included studies that used epidural SCS to treat spasticity. Studies investigating functional electric stimulation, transcutaneous SCS, and animal models of spasticity were excluded. We also excluded studies that used SCS to treat other symptoms such as pain.

Thirty-four studies were included in the final analysis. The pooled rate of subjective improvement in spasticity was 78% (95% confidence interval, 64%-91%; I2 = 77%), 40% (95% confidence interval, 7%-73%; I2 = 88%) for increased H-reflex threshold or decreased Hoffman reflex/muscle response wave ratio, and 73% (65%-80%; I2 = 50%) for improved ambulation. Patients with spinal causes had better outcomes compared with patients with cerebral causes. Up to 10% of patients experienced complications including infections and hardware malfunction.

Our review of the literature suggests that SCS may be a safe and useful tool for the management of spasticity; however, there is significant heterogeneity among studies. The quality of studies is also low. Further studies are needed to fully evaluate the usefulness of this technology, including various stimulation paradigms across different causes of spasticity.

(1) Background: Spinal cord injury (SCI) represents a major health challenge, often leading to significant and permanent sensorimotor and autonomic dysfunctions. This study reviews the evolving role of epidural spinal cord stimulation (eSCS) in treating chronic SCI, focusing on its efficacy and safety. The objective was to analyze how eSCS contributes to the recovery of neurological functions in SCI patients. (2) Methods: We utilized the PRISMA guidelines and performed a comprehensive search across MEDLINE/PubMed, Embase, Web of Science, and IEEE Xplore databases up until September 2023. We identified studies relevant to eSCS in SCI and extracted assessments of locomotor, cardiovascular, pulmonary, and genitourinary functions. (3) Results: A total of 64 studies encompassing 306 patients were identified. Studies investigated various stimulation devices, parameters, and rehabilitation methods. Results indicated significant improvements in motor function: 44% of patients achieved assisted or independent stepping or standing; 87% showed enhanced muscle activity; 65% experienced faster walking speeds; and 80% improved in overground walking. Additionally, eSCS led to better autonomic function, evidenced by improvements in bladder and sexual functions, airway pressures, and bowel movements. Notable adverse effects included device migration, infections, and post-implant autonomic dysreflexia, although these were infrequent. (4) Conclusion: Epidural spinal cord stimulation is emerging as an effective and generally safe treatment for chronic SCI, particularly when combined with intensive physical rehabilitation. Future research on standardized stimulation parameters and well-defined therapy regimens will optimize benefits for specific patient populations.

Despite remarkable improvements in the management of heart failure (HF), HF remains one of the most rapidly growing cardiovascular condition resulting in a substantial burden on healthcare systems worldwide. In clinical practice, however, a relevant proportion of patients are treated with suboptimal combinations and doses lower than those recommended in the current guidelines. Against this background, it remains important to identify new targets and investigate additional therapeutic options to alleviate symptoms and potentially improve prognosis in HF. Therefore, non-pharmacological interventions targeting autonomic imbalance in HF have been evaluated. This paper aims to review the physiology, available clinical data, and potential therapeutic role of device-based neuromodulation in HF.

Neuromodulation therapies use a variety of treatment modalities (eg, electrical stimulation) to treat chronic pain. These therapies have experienced rapid growth that has coincided with escalating confusion regarding the nomenclature surrounding these neuromodulation technologies. Furthermore, studies are often published without a complete description of the effective stimulation dose, making it impossible to replicate the findings. To improve clinical care and facilitate dissemination among the public, payors, research groups, and regulatory bodies, there is a clear need for a standardization of terms.

We formed an international group of authors comprising basic scientists, anesthesiologists, neurosurgeons, and engineers with expertise in neuromodulation. Because the field of neuromodulation is extensive, we chose to focus on creating a taxonomy and standardized definitions for implantable electrical modulation of chronic pain.

We first present a consensus definition of neuromodulation. We then describe a classification scheme based on the 1) intended use (the site of modulation and its indications) and 2) physical properties (waveforms and dose) of a neuromodulation therapy.

This framework will help guide future high-quality studies of implantable neuromodulatory treatments and improve reporting of their findings. Standardization with this classification scheme and clear definitions will help physicians, researchers, payors, and patients better understand the applications of implantable electrical modulation for pain and guide informed treatment decisions.

Spinal cord stimulation (SCS) is a surgical treatment for chronic neuropathic pain refractory to medical management. An SCS system comprised one or more leads implanted in the epidural space, typically connected to an implantable pulse generator. This review discusses the history, indications, surgical technique, technological advances, and future directions of SCS.

Since its foundation in the 1960s, neuromodulation has become an increasingly used treatment option for chronic pain. This bibliometric analysis examines the most cited research in this field with the aim of uncovering existing trends and future directions.

Clarivate's Web of Science data base was searched for the top 25 most cited studies focusing on neuromodulation for chronic pain. Various bibliometric parameters were then extracted and analyzed. Randomized controlled trials (RCTs) were compared with non-RCTs.

The top 25 articles had a mean of 347 citations and 22.2 citations per year, with more recent articles having a higher citation rate. Most were published in the last two decades and predominantly originated from the United States. There were 13 RCTs, which were significantly more recent (p = 0.004) and more cited per year (p = 0.001) than the 12 non-RCTs. Sources included 15 journals with a mean impact factor of 13.896. The most studied modality was spinal cord stimulation with 20 articles (76.9%), followed by intrathecal drug delivery (15.4%), dorsal root ganglion stimulation (3.8%), and peripheral nerve stimulation (3.8%).

Analysis of the most cited articles on neuromodulation reveals a focal shift from historical reports to innovative RCTs that have increasingly guided pain practice in the recent years. As novel techniques and technologies continue to develop, high-quality evidence coupled with broadening indications will likely direct further expansion of this field.

Chronic knee pain following total knee arthroplasty (TKA) affects a subset of patients that is refractory to pharmacological and non-pharmacological modalities. Peripheral nerve stimulation (PNS) has been used in patients with chronic knee pain following TKA and has shown some efficacy. Methods: Comprehensive search of Ovid Medline, Elsevier Embase, Cochrane Central Register of Controlled Trials, CINAHL Plus with Full Text, Scopus, SPORTDiscus with Full Text and the Web of Science platform. From inception to August 2022, for studies using PNS to treat chronic knee pain following TKA. Primary outcomes included pain scores, functional status and medication usage. Results: Nine studies were extrapolated with all demonstrating effectiveness of PNS for patients with chronic knee pain following TKA. Discussion: PNS for chronic knee pain following TKA has been shown to be an efficacious treatment modality. The level of evidence is low and more research is needed to assess its safety and effectiveness.

Though peripheral nerve stimulation has long been utilized in the field of chronic pain management, its use in acute pain management in the postoperative period is relatively novel and warrants further consideration.

In the postsurgical period, peripheral nerve stimulation may offer an additional low-risk, opioid-sparing analgesic option, which is particularly pertinent in the setting of the ongoing opioid epidemic, as inadequate postsurgical analgesia has been shown to increase the risk of developing persistent or chronic postsurgical pain. In this review, we discuss the current literature that illustrate the emerging role of peripheral nerve stimulation as an effective treatment modality in the postoperative period for the management of acute pain, as various studies have recently been conducted evaluating the feasibility of utilizing percutaneous peripheral nerve stimulation as an adjunct in postsurgical analgesia. Nonetheless, future studies are necessary to continue to elucidate the short- and long-term impacts of peripheral nerve stimulation use in acute postsurgical analgesia.

This study aimed to review the best evidence on the long-term efficacy of neurostimulation for chronic pain.

We systematically reviewed PubMed, CENTRAL, and WikiStim for studies published between the inception of the data bases and July 21, 2022. Randomized controlled trials (RCTs) with a minimum of one-year follow-up that were of high methodologic quality as ascertained using the Delphi list criteria were included in the evidence synthesis. The primary outcome was long-term reduction in pain intensity, and the secondary outcomes were all other reported outcomes. Level of recommendation was graded from I to III, with level I being the highest level of recommendation.

Of the 7119 records screened, 24 RCTs were included in the evidence synthesis. Therapies with recommendations for their usage include pulsed radiofrequency (PRF) for postherpetic neuralgia, transcutaneous electrical nerve stimulation for trigeminal neuralgia, motor cortex stimulation for neuropathic pain and poststroke pain, deep brain stimulation for cluster headache, sphenopalatine ganglion stimulation for cluster headache, occipital nerve stimulation for migraine, peripheral nerve field stimulation for back pain, and spinal cord stimulation (SCS) for back and leg pain, nonsurgical back pain, persistent spinal pain syndrome, and painful diabetic neuropathy. Closed-loop SCS is recommended over open-loop SCS for back and leg pain. SCS is recommended over PRF for postherpetic neuralgia. Dorsal root ganglion stimulation is recommended over SCS for complex regional pain syndrome.

Neurostimulation is generally effective in the long term as an adjunctive treatment for chronic pain. Future studies should evaluate whether the multidisciplinary management of the physical perception of pain, affect, and social stressors is superior to their management alone.

Continuous peripheral nerve blocks (cPNB) decrease pain scores and opioid consumption while improving patient satisfaction following ambulatory surgery. This review focuses on the history and evolution of ambulatory cPNBs, recent developments in infusion technology that may prolong the duration of analgesia, optimal choice of cPNB for various surgical procedures, and novel analgesic modalities that may prove to be alternatives or supplements to cPNBs.

The primary factor limiting the duration of an ambulatory cPNB is the size of the local anesthetic reservoir. Recent evidence suggests the use of automated boluses, as opposed to continuous infusions, may decrease the rate of consumption of local anesthetic and, thereby, prolong the duration of analgesia. Utilizing a long-acting local anesthetic (e.g. ropivacaine) for initial block placement and an infusion start-delay timer may further increase this duration.

Patients undergoing painful ambulatory surgery are likely to have less pain and require fewer opioid analgesics when receiving a cPNB for postoperative analgesia. Advances in electronic pumps used for cPNBs may increase the duration of these benefits.

Peripheral nerve stimulation has seen a recent upsurge in utilization for various chronic pain conditions, specifically from a neuropathic etiology, where a single peripheral nerve can be pinpointed as a culprit for pain.

There is conflicting evidence about the efficacy and long-term outcomes of peripheral nerve stimulation for chronic pain, with most studies being small sized. The focus of this article is to review available evidence for the utilization of peripheral nerve stimulation for chronic pain syndromes as well as upcoming evidence in the immediate postoperative realm. The indications for the use of PNS have expanded from neuropathic pain such as occipital neuralgia and post-amputation pain, to more widespread disease processes such as chronic low back pain. 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.

Seventy years ago, Hodgkin and Huxley published the first mathematical model to describe action potential generation, laying the foundation for modern computational neuroscience. Since then, the field has evolved enormously, with studies spanning from basic neuroscience to clinical applications for neuromodulation. Computer models of neuromodulation have evolved in complexity and personalization, advancing clinical practice and novel neurostimulation therapies, such as spinal cord stimulation. Spinal cord stimulation is a therapy widely used to treat chronic pain, with rapidly expanding indications, such as restoring motor function. In general, simulations contributed dramatically to improve lead designs, stimulation configurations, waveform parameters and programming procedures and provided insight into potential mechanisms of action of electrical stimulation. Although the implementation of neural models are relentlessly increasing in number and complexity, it is reasonable to ask whether this observed increase in complexity is necessary for improved accuracy and, ultimately, for clinical efficacy. With this aim, we performed a systematic literature review and a qualitative meta-synthesis of the evolution of computational models, with a focus on complexity, personalization and the use of medical imaging to capture realistic anatomy. Our review showed that increased model complexity and personalization improved both mechanistic and translational studies. More specifically, the use of medical imaging enabled the development of patient-specific models that can help to transform clinical practice in spinal cord stimulation. Finally, we combined our results to provide clear guidelines for standardization and expansion of computational models for spinal cord stimulation.

Neurotechnologies for treating pain rely on electrical stimulation of the central or peripheral nervous system to disrupt or block pain signaling and have been commercialized to treat a variety of pain conditions. While their adoption is accelerating, neurotechnologies are still frequently viewed as a last resort, after many other treatment options have been explored. We review the pain conditions commonly treated with electrical stimulation, as well as the specific neurotechnologies used for treating those conditions. We identify barriers to adoption, including a limited understanding of mechanisms of action, inconsistent efficacy across patients, and challenges related to selectivity of stimulation and off-target side effects. We describe design improvements that have recently been implemented, as well as some cutting-edge technologies that may address the limitations of existing neurotechnologies. Addressing these challenges will accelerate adoption and change neurotechnologies from last-line to first-line treatments for people living with chronic pain.

Chronic facial pain is considered one of the conditions that affect quality of daily life of patients significantly and makes them seek medical help. Intractable facial pain with failed trials of medical treatment and other pain management therapies presents a challenge for neurologists, pain specialists, and neurosurgeons. We describe the possibility of proposing peripheral nerve stimulation of the supraorbital nerves to treat patients with medically intractable facial pain. Stimulation of the supraorbital nerves is performed using percutaneously inserted electrodes that are positioned in the epi-fascial plane, traversing the course of the supraorbital nerves. The procedure has two phases starting with a trial by temporary electrodes that are inserted under fluoroscopic guidance and are anchored to the skin. This trial usually lasts for a few days to 2 weeks. If successful, we proceed to the insertion of a permanent electrode that is tunneled under the skin behind the ear toward the infraclavicular region in which we make a pocket for the implantable pulse generator.

This procedure has been used in multiple patients with promising results which was published in literature. Literature shows that it provides relief of medically intractable pain, without the need for destructive procedures or more central modulation approaches with a preferable safety profile compared to other invasive procedures. Supraorbital nerve stimulation is now considered a valid modality of treatment for patients with medically intractable facial pain and can be offered as a reliable alternative for the patients while discussing the proper plan of management.

The role of neuromodulation in fascial plane blocks is unknown. This case report presents a complex patient who underwent shoulder arthroplasty with a high thoracic-erector spinae plane (HT-ESP) catheter that provided electrical and chemical neuromodulation, highlighting the potential of electrical stimulation in the identification of and therapy at the fascial plane level.

The use of opioids in pain management is hampered by the emergence of analgesic tolerance, which leads to increased dosing and side effects, both of which have contributed to the opioid epidemic. One promising potential approach to limit opioid analgesic tolerance is activating the endocannabinoid system in the CNS, via activation of CB1 receptors in the descending pain inhibitory pathway. In this review, we first discuss preclinical and clinical evidence revealing the potential of pharmacological activation of CB1 receptors in modulating opioid tolerance, including activation by phytocannabinoids, synthetic CB1 receptor agonists, endocannabinoid degradation enzyme inhibitors, and recently discovered positive allosteric modulators of CB1 receptors. On the other hand, as non-pharmacological pain relief is advocated by the US-NIH to combat the opioid epidemic, we also discuss contributions of peripheral neuromodulation, involving the electrostimulation of peripheral nerves, in addressing chronic pain and opioid tolerance. The involvement of supraspinal endocannabinoid systems in peripheral neuromodulation-induced analgesia is also discussed. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Spinal cord injury (SCI) is a devastating condition that causes severe loss of motor, sensory and autonomic functions. Additionally, many individuals experience chronic neuropathic pain that is often refractory to interventions. While treatment options to improve outcomes for individuals with SCI remain limited, significant research efforts in the field of electrical stimulation have made promising advancements. Epidural electrical stimulation, peripheral nerve stimulation, and functional electrical stimulation have shown promising improvements for individuals with SCI, ranging from complete weight-bearing locomotion to the recovery of sexual function. Despite this, there is a paucity of mechanistic understanding, limiting our ability to optimize stimulation devices and parameters, or utilize combinatorial treatments to maximize efficacy. This review provides a background into SCI pathophysiology and electrical stimulation methods, before exploring cellular and molecular mechanisms suggested in the literature. We highlight several key mechanisms that contribute to functional improvements from electrical stimulation, identify gaps in current knowledge and highlight potential research avenues for future studies.

The combination of Transcranial Direct Current Stimulation (tDCS) with peripheral stimulation may optimize their effects and bring positive results in treatment of people with chronic pain.

A systematic review with meta-analysis of randomized and non-randomized trials was performed to investigate the combination of tDCS with peripheral stimulation in adults with chronic pain. The primary outcome was pain intensity. Six studies were included in this review (sample of 228 participants), which investigated the combination of tDCS and transcutaneous electrical nerve stimulation, peripheral electrical stimulation, breathing-controlled electrical stimulation and intramuscular electrical stimulation. The conditions studied were knee osteoarthritis, spinal cord injury, chronic low back pain, and neurogenic pain of the arms. Pain intensity, measured by visual analog scale or numerical rating scale, was reduced in all included studies when at least one of the interventions was active, regardless they were combined or alone, with or without tDCS. However, meta-analysis showed superiority of tDCS used in combination with peripheral stimulation.

This systematic review and meta-analysis suggests positive effects of tDCS combined with peripheral stimulation in chronic pain conditions. However, the evidence of the primary outcome was classified as low quality due to the limited number of studies.

During the last two decades, with the advent of recent technology, peripheral nerve stimulation has become an appealing modality at the forefront of pain management. In this case series, we document the clinical rationale and technical considerations on three of the most challenging cases, refractory to previous interventions, that were treated by our team with an ultrasound-guided percutaneous peripheral nerve stimulator targeting the musculocutaneous, bilateral greater occipital and subcostal nerves. At the 6-month follow-up, all patients experienced greater than 50% relief of baseline pain, with a near-complete resolution of pain exacerbations. Furthermore, to our knowledge, this is the first report of an ultrasound-guided percutaneous technique of a peripheral nerve stimulator targeting the musculocutaneous and subcostal nerves.

Peripheral nerve stimulation (PNS) has become an essential component in the pain management plan for individuals suffering from peripheral nerve-mediated pain. The recent surge in interest in PNS can be attributed to the advancements in imaging techniques and the availability of minimally invasive stimulation systems along with a deeper grasp of PNS physiology. These advancements have made PNS more accessible to clinicians and patients alike. However, it is important to note that PNS requires a different set of technical requirements and skills compared to other pain management procedures. The work, knowledge, and surgical and interventional skillset required for PNS are in a class of their own. This article aims to educate and clarify the differences between procedures that may have similar names but are vastly different in terms of technology, expertise, and skill sets necessary for their safe implementation. Some of the procedures that this article will cover include indirect peripheral nerve field stimulation (PNfS), indirect percutaneous electrical nerve stimulation (PENS), PENS-Field Stimulation (PENFS), and transcutaneous electrical nerve stimulation (TENS). By understanding the differences between these procedures, patients and health-care providers can make informed decisions about the best approach for managing pain.

The aim of this review is to draw attention to neurosurgical approaches for treating chronic and opioid-resistant pain. In a first chapter, an up-to-date overview of the main pathophysiological mechanisms of pain has been carried out, with special emphasis on the details in which the surgical treatment is based. In a second part, the principal indications and results of different surgical approaches are reviewed. Cordotomy, Myelotomy, DREZ lesions, Trigeminal Nucleotomy, Mesencephalotomy, and Cingulotomy are revisited. Ablative procedures have a limited role in the management of chronic non-cancer pain, but they continues to help patients with refractory cancer-related pain. Another ablation lesion has been named and excluded, due to lack of current relevance. Peripheral Nerve, Spine Cord, and the principal possibilities of Deep Brain and Motor Cortex Stimulation are also revisited. Regarding electrical neuromodulation, patient selection remains a challenge.