Electromagnetic neuromodulation for chronic pain: historical context, contemporary modalities, and evidence gaps

1 Introduction: from early electroanalgesia to modern neuromodulation

Pharmacologic therapy is widely used to treat chronic pain, but its clinical utility is often limited by incomplete efficacy, adverse effects, and, for some agents, risks of misuse and dependence. In response to these limitations, electrical and magnetic neuromodulation approaches have emerged as adjunctive or alternative strategies for pain management, with several technologies cleared or approved by the Food and Drug Administration (FDA) for select pain indications. This review focuses on invasive and noninvasive neuromodulation methods, in which the therapeutic stimulus is principally electrical or magnetic, broadly considered here under the umbrella of electromagnetic neuromodulation, with emphasis on their application to chronic pain.

The first recorded use of electricity in medicine is commonly attributed to Scribonius Largus, who in Compositiones (around AD 47) described the use of a live torpedo fish to treat gout pain and headache (1, 2). The therapeutic use of electric fish persisted into late antiquity, and Galen also discussed the torpedo fish in relation to pain relief (3). Later developments replaced animal-derived electricity with man-made electrical sources. In the 1700s, Leyden jars (4), an early precursor to batteries, were explored as an electrical source for therapeutic pain relief (5). Work by Galvani and Aldini also helped establish electrical stimulation as an experimental tool for probing neuromuscular and brain function (6–8). In the late 1800s and early 1900s, electrical instruments were deployed for a variety of pain therapies, culminating in a chapter on “Electrical Analgesia, Sleep, and Resuscitation” in Gwathmey and Baskerville's 1914 “Anesthesia” textbook (9).

Electrical stimulation for pain entered the modern era in the late 1960s, amid broader interest in transcranial “electrical anesthesia,” when Reynolds demonstrated that microstimulation of the rat midbrain central gray could produce analgesia (10). Human case reports soon followed, describing analgesic effects of stimulation targeting the internal capsule (IC) (11) and periventricular/periaqueductal gray (PVG/PAG) (12, 13). The advent of modern noninvasive brain stimulation further expanded the field. Following the demonstration of noninvasive magnetic stimulation of human motor cortex in 1985 (14), repetitive transcranial magnetic stimulation (rTMS) protocols were subsequently explored as analgesic interventions, initially emphasizing the primary motor cortex (M1) and later extending to prefrontal and parietal targets to engage both sensory–discriminative and cognitive–affective dimensions of pain.

Conceptual advances in pain neuroscience also shaped device development: the gate control theory of pain proposed by Melzack and Wall (15) provided a mechanistic framework for why activation of large-diameter afferents might inhibit nociceptive transmission, helping motivate the clinical uptake of peripheral and spinal stimulation approaches. Moreover, these ideas, together with evolving concepts of descending pain modulation and, later, central sensitization, supported interest in cortical and supraspinal targets for analgesia (16–18). These developments helped establish electromagnetic neuromodulation as a broader strategy for pain management, with several technologies cleared for specific chronic pain conditions and acute-use applications, most prominently primary headache disorders.

Pain processing is distributed across multiple interacting levels of the nervous system rather than being confined to a single anatomical site. Peripheral noxious stimuli are transduced by nociceptors and conveyed primarily by thinly myelinated Aδ and unmyelinated C fibers (19) to the dorsal horn, where segmental gating, convergence of nociceptive and non-nociceptive inputs, and activity-dependent sensitization shape onward transmission (15, 16, 18, 20–22). Ascending pathways relay signals to thalamic, somatosensory, insular, cingulate, and related limbic-cortical regions involved in the sensory, affective, attentional, and evaluative dimensions of pain (23–26). In parallel, descending modulatory systems involving structures such as the PAG, rostral ventromedial medulla (RVM), and brainstem monoaminergic pathways can suppress or facilitate nociceptive processing (27, 28). In chronic pain states, maladaptive plasticity may emerge across this system, including central sensitization, impaired inhibitory control, abnormal facilitation, and altered network-level processing (29). This framework provides a rationale for organizing electromagnetic neuromodulation strategies according to their primary anatomical targets, while recognizing that many ultimately exert distributed downstream effects across the broader pain network.

Pain can further be classified in several ways, including by duration (acute or chronic) and by dominant mechanism (nociceptive, neuropathic, or central), although these categories often overlap in clinical practice. We use the term chronic to refer to pain that persists long enough to permit maladaptive changes within the nervous system, including central sensitization (29). Mechanistically, however, ample evidence shows that pain definitions are not mutually exclusive and instead share overlapping features; moreover, shared pathophysiology may add to the overlap of pain syndromes (18, 29–32). As a result, clinicians frequently encounter patients with mixed mechanisms for pain. Specifically, conditions originating in the periphery can induce central sensitization (16, 18, 32), i.e., neuroplastic changes associated with remodeling, reorganization, and altered neural excitability of the central nervous system (26, 33–38). Within this overlapping mechanistic framework, neuromodulation strategies can be considered according to where they act along the pain pathway: in the periphery [e.g., peripheral nerve stimulation (PNS)], along ascending pathways [e.g., TENS or spinal cord stimulation (SCS)], indirectly through cortical network effects [e.g., motor cortex stimulation (MCS) over M1, thought to ultimately influence the PAG and RVM], and/or directly within the brain [e.g., deep brain stimulation (DBS) implanted in the PAG]. Thus, as part of this review, we also consider the hypothesized mechanisms of action of each stimulation modality, although these mechanisms remain incompletely understood and, in many cases, debated. Figure 1 summarizes major conceptual milestones alongside key device innovations in electromagnetic neuromodulation.

The sections below are organized by modality and principal anatomical target, while also situating each approach within its historical development and current evidence base. Figure 2 provides a schematic overview of the principal electromagnetic neuromodulation modalities discussed below, organized by anatomical target and mode of delivery.

Given the breadth of the field, this review integrates modalities with differing levels of clinical maturity, evidence strength, and regulatory status to provide a cross-modality perspective on how electromagnetic neuromodulation is currently applied and evolving in pain medicine. We emphasize a recurring pattern in which early mechanistic models drive technological innovation and subsequent clinical adoption, followed by heterogeneous outcomes that stimulate an iterative process of updated knowledge of pain physiology and subsequent device optimization towards better clinical outcomes. In addition to summarizing the historical development, mechanisms, regulatory status, and clinical applications of these modalities, this review highlights evidence gaps that limit interpretation and translation of the current literature. By synthesizing these limitations across electromagnetic neuromodulation approaches, we aim to clarify where these technologies have shown clinical promise and where stronger evidence is needed.

1.1 Scope and literature search strategy

This narrative review examines the historical development, current clinical use, and remaining evidence gaps in electromagnetic neuromodulation for pain management, with primary emphasis on chronic pain. The review includes implanted and noninvasive approaches acting across the peripheral, spinal, autonomic, cranial/transcranial, cortical, and intracranial levels of the nervous system, as well as selected combined approaches. Selected short-term or acute-use paradigms, such as transcutaneous electrical nerve stimulation (TENS) and noninvasive vagal nerve stimulation (nVNS) for acute migraine and cluster headache episodes, are briefly noted when they help contextualize the development or regulatory status of technologies also relevant to chronic pain. Because several electromagnetic neuromodulation devices carry regulatory indications spanning both chronic pain and episodic headache disorders, FDA-cleared or approved uses are summarized separately for chronic and acute/episodic indications in Tables 1, 2. The sections that follow, together with Table 3, address the broader literature, including applications beyond current regulatory labeling.

Table 1. FDA-cleared/approved electromagnetic neuromodulation devices for chronic pain.

Representative devices organized by modality and labeled indication, spanning invasive spinal neuromodulation (SCS, DRG stimulation), peripheral neuromodulation (implanted PNS; restorative multifidus neurostimulation), and transcutaneous approaches (TENS) with chronic pain labeling. “Authorization type” reflects the primary U.S. regulatory pathway [PMA vs 510(k)]; device generations are often updated via supplements/iterations under the same regulatory file. Applicant names reflect the original PMA holder where historically relevant, with current successor companies noted when applicable. This table is not intended to be exhaustive, particularly for categories with numerous substantially equivalent 510(k) devices (e.g., TENS).

Use statements were summarized and harmonized from FDA marketing authorization documents for comparability and may not reproduce the exact original wording.

Table 2. FDA-cleared/approved electromagnetic neuromodulation devices for acute pain indications.

Representative devices organized by modality and labeled acute-use indication, including acute post-operative/post-traumatic pain (TENS; temporary percutaneous PNS; auricular PENS) and acute primary headache disorders (sTMS; external trigeminal stimulation; noninvasive vagus nerve stimulation; remote electrical neuromodulation; cranial trigeminal + occipital stimulation). “Authorization type” reflects the primary U.S. regulatory pathway [510(k) vs De Novo]. Where applicable, the labeled duration of use (e.g., up to 3 days or up to 60 days) is noted. This table is not intended to be exhaustive for device families with multiple substantially equivalent clearances.

Use statements were summarized and harmonized from FDA marketing authorization documents for comparability and may not reproduce the exact original wording.

Table 3. Representative clinical evidence for electromagnetic neuromodulation modalities in pain.

For each modality–indication pair, we prioritized higher-level evidence syntheses (Cochrane reviews, systematic reviews, and meta-analyses). When such evidence was limited, inconsistent, or unavailable, we selected representative sham-controlled randomized trials or other illustrative prospective studies, emphasizing studies with clearly described stimulation parameters and quantitative pain outcomes. This table is intended to summarize representative evidence rather than provide an exhaustive systematic inventory.

The cited study includes chronic, acute, and/or experimental pain populations; this table emphasizes the findings most relevant to chronic pain.

Includes episodic and chronic cluster headache populations.

To support this broad, cross-modality review, targeted searches were conducted using bibliographic and regulatory sources, including PubMed/MEDLINE, Cochrane reviews, and publicly available FDA documents. Searches combined terms related to pain management, with emphasis on chronic pain and selected acute or episodic pain/headache indications, with modality-specific terms spanning peripheral nerve, spinal cord, dorsal root ganglion, vagal/autonomic, cranial/transcranial, cortical, and deep brain neuromodulation approaches, including implanted and noninvasive modalities where applicable.

Historical, mechanistic, technical, clinical, and regulatory sources were used to contextualize the development, rationale, stimulation paradigms, and current clinical positioning of each modality. Primary sources were prioritized for foundational concepts, historical milestones, and specific clinical or experimental findings. Reviews, guidelines, evidence syntheses, and regulatory sources were used to support broader summaries of clinical evidence, regulatory status, mechanistic frameworks, evidence strength, and limitations across modalities. Clinical evidence discussion prioritized systematic reviews, meta-analyses, Cochrane reviews, randomized controlled trials, and selected clinical studies relevant to pain, emphasizing pain-related outcomes, safety, durability, and limitations. Because the goal was to provide a narrative review rather than a systematic review, searches were not intended to be exhaustive, and no formal risk-of-bias or evidence-grading framework was applied.

2 Implanted neuromodulation approaches

2.1 MCS: historical development of motor cortex stimulation

MCS, typically delivered as epidural brain stimulation (EBS) over M1, involves epidural placement of electrodes over the dura covering M1 to modulate downstream pain networks. Although MCS was formally introduced clinically in 1991 (39), the concept emerged earlier from experimental observations and from efforts to identify cortical targets that might provide analgesia when other central stimulation approaches showed limited success (40). Tsubokawa et al. first reported motor cortex stimulation for pain control in patients with central pain in 1991 (39). In 1993, Meyerson et al. (41) described the use of MCS in different forms of neuropathic pain. In 1995, Migita et al. (42) and Peyron et al. (43) independently reported further evidence of MCS efficacy in central pain studies, with Migita also suggesting that response to TMS over M1 might help predict response to implanted MCS. Over time, implantation and targeting strategies evolved from early epidural approaches toward more refined localization using neuronavigation, intraoperative electrophysiology, and, in some centers, functional imaging (44, 45). Programming, however, remained largely empirical, with stimulation parameters and electrode-contact configurations adjusted according to individual pain response (40, 46). By 2020, a systematic review and meta-analysis for orofacial pain noted that MCS had been performed in approximately 700 cases worldwide for a variety of refractory neuropathic pain syndromes (47).

Mechanisms of analgesia from MCS remain incompletely established, but converging electrophysiological and functional imaging findings support a distributed network-level effect rather than a purely local cortical action. MCS appears to engage thalamic circuitry, together with slower, longer-lasting modulation of medial pain-network regions, including the anterior cingulate and orbitofrontal cortices, as well as midbrain structures such as the PAG (38, 48, 49). Proposed mechanisms include altered affective appraisal of pain through cingulate-orbitofrontal modulation, recruitment of descending inhibitory pathways, and possible involvement of endogenous opioid systems (38, 48).

Clinical evidence for MCS remains largely based on case series and observational cohorts, with relatively few controlled trials and substantial heterogeneity in patient selection and outcome reporting. Analgesic benefit has been reported in selected patients with refractory neuropathic pain, but response rates and durability vary across studies, and overall confidence is limited by small samples, inconsistent follow-up, and limited sham-controlled evidence (47, 50–52).

Stimulation has been delivered using several epidural electrode designs, most commonly 4-contact paddle electrodes, as described in technical and review literature on MCS, and, in some reports, newer 8-contact leads developed specifically for this application (40, 53). Reported programming approaches include monopolar or bipolar/anode-cathode configurations, with contact assignment and amplitude adjusted according to clinical response and tolerability. Published stimulation parameters vary widely, with reported ranges of approximately 0.5–10 V, 5–130 Hz, and 60–450 µs, underscoring the lack of a standardized programming paradigm across studies (40, 46). Daily duration and overall stimulation exposure are not reported consistently; when described, stimulation is often delivered in cycling mode rather than continuously, with on-times ranging from 10 min to 3 h and off-times from 15 min to 6 h (46). Overall, the evolution of MCS reflects a broader challenge in neuromodulation, in which the ability to influence cortical and subcortical networks has not consistently translated into predictable or durable clinical benefit partly because dosing parameters and programming remain heterogeneous (40). MCS is therefore generally reserved as a specialized neurosurgical option for carefully selected patients with refractory neuropathic pain, with broader adoption limited by the scarcity of high-quality controlled evidence (54, 55).

2.2 DBS: early intracranial analgesia and evolving targets

DBS involves the direct implantation of stimulating electrodes in selected brain targets to modulate pain processing and has been explored for refractory chronic pain for several decades. Early DBS technology emerged through adaptation of implantable cardiac pacing systems, with Medtronic playing a central role in translating pacemaker-derived neurostimulation hardware into chronic brain stimulation platforms (56). Temporary intracranial stimulation relevant to pain had already been explored in the 1950s (57–60), and chronic implanted DBS approaches for pain were reported in the 1970s (11–13, 61), spurred in part by rodent microstimulation experiments in the late 1960s (10). Initial studies focused on treating intractable pain secondary to cortical injury, anesthesia dolorosa, post-cancer pain, and diabetic neuropathic pain via direct stimulation of the internal capsule (IC), sensory thalamus, or periventricular and periaqueductal gray matter (PVG/PAG) (11, 12, 62–65). Early electrodes were mainly custom-made, featuring a diverse range of materials and dimensions, including's Heath's stainless steel or silver depth probes measuring up to ∼2.0–3.0 mm in diameter; Mazars's fine gold/copper Teflon-insulated wires at ∼0.5 mm in diameter; and Hosobuchi's custom platinum-iridium cylindrical contacts measuring 0.5 mm in diameter and 0.5 mm in length [see (66) for a review of electrode characteristics]. Across early pain-DBS series, stimulation parameters varied by target and center, with frequencies ranging roughly from 2 to 100 Hz, pulse widths from about 0.1 to 0.8 ms, and amplitudes commonly reported in the 0.5–8 V range; historical summaries suggest that PVG/PAG stimulation tended to use lower frequencies (for example, around 25–50 Hz), whereas sensory thalamic stimulation was often reported at 50–100 Hz (66).

Early custom pain-DBS systems were later replaced by commercial Medtronic platforms, initially including radio-frequency systems with transcutaneous power transfer and, in later chronic pain trials, first-generation and subsequent Medtronic leads (56, 67). Later Medtronic DBS leads adopted a standardized quadripolar geometry with a diameter of approximately 1.27 mm, four 1.5-mm-long contacts, and model-dependent edge-to-edge electrode spacing: 1.5 mm for the 3387 and 0.5 mm for the 3389 (68, 69). During this commercial expansion of DBS in the 1990s and 2000s, implanted pulse generators were largely constant-voltage systems. Typical therapeutic programming used amplitudes of about 1–3.5 V, pulse widths of 60–210 μs, and high-frequency stimulation commonly around 130 Hz and extending to 185 Hz; battery longevity depended strongly on the selected stimulation parameters and device circuitry. Because these systems were voltage-controlled, changes in electrode-tissue impedance could alter the actual current delivered and the resulting extent of neural activation (70–73).

Beginning in the mid-2010s, DBS hardware evolved from conventional ring-contact electrodes toward directional segmented leads that enabled current steering. Early commercial directional systems included 8-contact leads with segmented middle levels that could be independently activated to shape the stimulation field more selectively than traditional omnidirectional leads (70, 74). Although this development was first established in the broader DBS field, directional leads have also been used in selected chronic neuropathic pain applications, particularly sensory thalamic DBS (75–77). Boston Scientific's Vercise platform was among the earliest commercial DBS systems to implement multiple independent current control (MICC) (78), a constant-current architecture that allows independent current distribution across contacts, supports more flexible stimulation-field shaping, and can reduce impedance-related fluctuations in delivered stimulation compared with voltage-controlled systems (73). More recent systems have extended this trend to higher-contact-count designs, including 16-contact directional leads, further increasing programming flexibility and spatial selectivity (78, 79). Modern platforms also offer broad programming ranges, with pulse widths reaching up to 450 μs in some systems (70). In parallel, sensing-enabled and biomarker-driven neuromodulation studies have strengthened the rationale for adaptive DBS in chronic pain, but this remains investigational rather than an established clinical standard in pain DBS (80, 81).

Early patient investigations suggested that intermittent rather than sustained stimulation could be more effective, as continuous stimulation was associated with waning efficacy and possible tolerance to narcotic medications (12). Subsequent clinical work shifted toward evaluating long-term efficacy across different pain etiologies and anatomical targets. A meta-analysis of studies published between 1977 and 1997 found that long-term outcomes depended strongly on both pain type and stimulation target: nociceptive pain showed better long-term success than deafferentation pain (63% vs. 47%), and the highest success rates were reported with PVG/PAG stimulation alone (79%) or combined PVG/PAG plus sensory thalamus/internal capsule stimulation (87%) (82). Sensory thalamic targets were used particularly for neuropathic pain, whereas PVG/PAG stimulation was favored in nociceptive pain and linked to endogenous opioid-mediated mechanisms (12, 64, 65, 82). Despite these refinements, durability remained a major limitation, as some patients lost benefit over time and the pivotal Medtronic multicenter pain trials failed to meet prespecified efficacy thresholds. Specifically, the Model 3380 study enrolled 196 patients and the Model 3387 study enrolled 50 patients, but neither achieved the criterion of at least 50% pain relief in half of implanted patients at 1 year (67). Thus, early enthusiasm for DBS in chronic pain was limited by inconsistent long-term outcomes and failure to meet efficacy thresholds in multicenter trials. The lack of FDA-approved DBS indications for chronic pain, together with limited and region-specific European use, underscores a recurring pattern in neuromodulation in which a strong mechanistic rationale does not consistently translate into durable clinical benefit. As a result, DBS remains an off-label or investigational option for chronic pain in most settings, although interest has resurged with recent sensing-enabled and adaptive approaches (80, 81).

Overall, the DBS-for-pain evidence base remains heterogeneous and is still dominated by small case series and observational cohorts spanning diverse pain etiologies and targets, with relatively few modern controlled trials (83). Structured reviews of the multicenter trial experience and subsequent evidence syntheses highlight target- and indication-dependent variability in response and durability, and note limitations related to small samples and inconsistent outcome definitions and follow-up (67, 84). DBS is nevertheless used in highly selected cases, including in post-stroke pain, neuropathy, and pain refractory to prior SCS.

Common stimulation targets include the PVG/PAG, IC, anterior cingulate cortex (ACC), and the ventral posterolateral nucleus and ventral posteromedial nucleus (VPL/VPM), with stimulation delivered using commercial DBS hardware such as Medtronic 3387/3389 leads paired with compatible Medtronic neurostimulators, Abbott Infinity systems, and Boston Scientific Vercise systems with Cartesia directional leads, although stimulation settings in pain DBS remain highly variable across targets and studies.

DBS analgesia is generally considered target-dependent, engaging different components of the pain system (84, 85). Even when initial benefit is achieved, long-term durability remains a major limitation despite advances in hardware and programming. PVG/PAG stimulation is thought to recruit descending pain modulatory circuits, with human data supporting endogenous opioid involvement in at least a subset of patients (e.g., naloxone-reversible effects) (12, 86), although non-opioid and mixed mechanisms have also been reported (87). Sensory thalamic targets (VPL/VPM) are proposed to modulate ascending nociceptive transmission and sensory encoding (84, 85), whereas ACC, particularly dorsal ACC (dACC), stimulation is framed as reducing the affective–motivational burden of pain by modulating limbic–cognitive control networks (88, 89). Across targets, mechanisms remain debated and likely reflect network-level effects rather than a single pathway. Furthermore, although outside the scope of this article, DBS is moving towards closed-loop and personalized dosing and targeting for pain treatment, see (90) for details.

2.3 SCS: evolution of dorsal column stimulation and modern waveforms

The evolution of SCS mirrors a broader pattern in neuromodulation, where early physiological models supported rapid clinical adoption, followed by increasing recognition of heterogeneous responses and more complex, network-level mechanisms.

SCS, first introduced in 1967 under the term dorsal column stimulation (91), has evolved considerably as a treatment for intractable chronic pain (92). Its early clinical rationale was closely tied to the gate control theory proposed by Melzack and Wall, which held that activation of large-diameter, non-nociceptive afferents could suppress nociceptive transmission at the dorsal horn (15). After its initial clinical introduction, SCS was progressively formalized through commercial and regulatory development from the 1970s through the early 1990s (93), while parallel technological advances included percutaneous trial stimulation before permanent implantation, adoption of fully implantable pulse generators (IPGs), and development of multichannel systems that expanded programming flexibility and paresthesia targeting (93–96). Later advances in SCS have led to the development of high-frequency (HF) SCS and burst SCS. High-frequency SCS (10-kHz SCS, often referred to as HF10) was developed to reduce or avoid paresthesia associated with traditional SCS by applying a waveform at 10,000 Hz at a subthreshold level (97, 98). Burst SCS delivers stimulation in packets of pulses, classically five pulses per burst, at reduced amplitudes to achieve subthreshold stimulation with little to no paresthesia while maintaining analgesic benefit (99–101).

SCS is delivered by placing electrodes in the epidural space to modulate pain signaling, historically often through paresthesia-based stimulation (102). Temporary percutaneous stimulation before permanent implantation was introduced early in the development of SCS (94), and in current practice patients typically undergo a trial with temporary epidural leads connected to an external pulse generator to assess pain relief and tolerability before placement of a permanent subcutaneous pulse generator (103, 104). If the trial is successful, a permanent subcutaneous pulse generator is implanted to deliver long-term therapy (104). Pulse frequencies may range from approximately 2 to 1,200 Hz, with conventional tonic stimulation frequencies typically in the 40–60 Hz range (104). Pulse magnitudes are patient-specific and are typically programmed in the mA range [commonly across a 0–20 mA device range (105); reported clinical amplitudes for paresthesia-based tonic SCS are often in the low single-digit mA range, e.g., ∼4–9 mA (106)].

Although SCS was initially framed through the gate control theory, contemporary evidence suggests that analgesia likely reflects a combination of segmental spinal effects and supraspinal network modulation, including altered dorsal horn excitability, recruitment of large-diameter afferent fibers, and engagement of descending inhibitory pathways; the relative contribution of these mechanisms may differ across tonic, burst, and high-frequency paradigms (107–111).

Clinically, SCS has been used across selected neuropathic and radicular pain indications, including failed back surgery syndrome, complex regional pain syndrome (CRPS), and painful diabetic neuropathy (112–114). FDA-authorized SCS indications are device-specific, with selected labeling including chronic intractable pain of the trunk and/or limbs and conditions such as failed back surgery syndrome, CRPS, radicular pain, and painful diabetic neuropathy (115, 116). Interpretation of the SCS evidence is also influenced by the common use of trial stimulation before permanent implantation, which may affect patient selection and the composition of implanted cohorts (103). Systematic reviews and network meta-analyses generally support SCS as being associated with improved pain outcomes vs. conventional medical management in selected chronic neuropathic pain populations, although certainty varies by indication, trial design, and outcome assessed (117). In contrast, for chronic low back pain populations studied with placebo/sham comparators, some evidence syntheses have reached more skeptical conclusions, underscoring that comparator choice, patient selection, and follow-up duration can materially influence inferred efficacy (118). SCS has also been reported in post-amputation pain, including phantom limb pain, but the evidence remains limited to small heterogeneous series and a recent scoping review suggesting possible benefit in a subset of patients (119, 120). Cross-study interpretation is complicated by two layers of heterogeneity: tonic, burst, and high-frequency SCS paradigms differ in waveform design, paresthesia profile, and inferred mechanism, and the studies evaluating them also vary in comparator design.

2.4 Dorsal root ganglion (DRG) stimulation: targeted stimulation for focal pain syndromes

DRG stimulation emerged as a more anatomically targeted neuromodulation approach within the broader SCS family, designed to improve coverage of focal pain distributions that may be difficult to treat with conventional dorsal column stimulation (121, 122). By placing leads near the dorsal root ganglion, DRG stimulation enables more selective modulation of sensory signaling at the level of the affected dermatome and has been particularly applied in conditions such as CRPS and focal causalgia (106, 121). Because the dorsal root ganglion contains the cell bodies of primary sensory neurons and has been implicated in pathological sensory signaling in chronic pain states, it represents a biologically relevant target for neuromodulation (121). This anatomical specificity may be particularly advantageous in focal neuropathic pain confined to discrete dermatomal or localized regions (106, 123). Compared with conventional SCS, DRG stimulation may offer more stable paresthesia coverage in anatomically discrete pain regions, although programming remains individualized and evidence varies by indication (106, 122, 123). In the United States, DRG stimulation received FDA approval in 2016 for neuropathic pain associated with CRPS and causalgia of the lower extremity (124, 125), and the strongest comparative clinical evidence remains concentrated in these focal neuropathic pain populations (106). Overall, DRG stimulation represents the move in the neuromodulation field toward anatomically precise targeting. Nevertheless, the variability in clinical response highlights that increased spatial specificity does not fully resolve the physiological puzzle of pain network modulation.

3 Vagal neuromodulation

3.1 VNS: evolution of implanted and noninvasive approaches

VNS targets vagal afferent pathways to modulate central pain networks and autonomic-neuroimmune signaling (126, 127). Although VNS was first clinically evaluated as an implanted cervical therapy for refractory epilepsy (128) and later for treatment-resistant depression (129), implanted cervical VNS has also been explored in treatment-resistant fibromyalgia (130). More recently, noninvasive VNS approaches have emerged, including cervical nVNS for headache disorders (131) and auricular VNS for acute and chronic pain conditions (132, 133). Accordingly, this subsection considers both implanted and noninvasive VNS approaches.

Clinically, VNS can be delivered invasively via an implanted cervical vagus nerve stimulator or noninvasively via transcutaneous auricular VNS (taVNS) or cervical nVNS (126, 134). Although these approaches are often grouped under the VNS umbrella, implanted cervical VNS, cervical nVNS, and taVNS differ substantially in hardware, dosing, anatomical access, and current clinical positioning (126, 134, 135). In pain medicine, the strongest regulatory and clinical support relates to cervical nVNS for headache disorders, whereas implanted VNS and transcutaneous/auricular VNS applications in non-headache chronic pain remain more exploratory and are supported by a heterogeneous evidence base (132, 134, 136).

Dosing and programming vary by device and indication. In taVNS clinical studies, commonly reported settings include ∼25 Hz stimulation with a pulse width of ∼0.5 ms, with intensity titrated to the maximum tolerated sensory level (often within the low-mA range), sometimes delivered in duty cycles for session-based use (137). For cervical nVNS used for headache indications, dosing is typically delivered as short, repeated ∼2-minute applications per treatment episode (acute use), with preventive regimens depending on the labeled indication (138, 139).

Mechanistically, VNS is thought to engage vagal afferent pathways projecting to brainstem relay nuclei, particularly the nucleus tractus solitarius, with downstream effects on networks involved in ascending pain processing and descending inhibitory control. VNS has also been linked to autonomic and neuroimmune pathways, although the relative contribution of these mechanisms may differ across implanted cervical, noninvasive cervical, and auricular approaches (127, 133). A recent randomized, sham-controlled trial in rheumatoid arthritis further supports the clinical relevance of vagus-mediated neuroimmune modulation, showing that implanted cervical VNS can modulate inflammatory disease activity in humans. These findings support target engagement of the inflammatory reflex, although they do not directly establish analgesic efficacy in chronic pain (140).

Evidence for VNS in pain is indication-dependent. nVNS has regulatory clearance for certain headache indications, including migraine and cluster headache (138), and has also been studied in other chronic pain conditions with heterogeneous results. A recent systematic review and meta-analysis of transcutaneous VNS reported measurable pain reduction across some chronic pain conditions, but emphasizes variability in populations, stimulation parameters, comparators, and outcomes (136). Overall, the development of VNS embodies the expansion of neuromodulation beyond traditional somatosensory networks. Its heterogeneous outcomes underscore the challenges of translating autonomic/neuroimmunological modulation into consistent analgesic effects in the context of different stimulation sites (auricular vs. cervical), dosing schedules, and comparator conditions. Evidence is strongest for labeled headache indications, whereas magnitude and durability of benefit in non-headache chronic pain conditions remain uncertain and appear sensitive to protocol and population differences (134, 136, 138, 139).

4 Noninvasive central/cranial neuromodulation

4.1 TMS: from noninvasive cortical stimulation to analgesic protocols

TMS was developed in the mid-1980s as a noninvasive method for stimulating the human cortex (14) through the intact scalp and was later extended from single-pulse neurophysiologic applications to repetitive and patterned therapeutic protocols (141, 142). TMS uses electromagnetic coils to generate brief, rapidly changing magnetic fields that induce electric currents in neural tissue, thereby activating cortical neurons and modulating neural excitability (2, 14, 143). TMS can produce pulsed fields of up to 4 Tesla, but commonly near 2 T, with pulse durations on the order of approximately a millisecond for single-pulse stimulators (with shorter rise times) and approximately a quarter of a millisecond duration for rapid stimulators (14, 144, 145). Stimulation effects can be inhibitory or excitatory depending on the frequency and pattern of stimulation and can persist beyond the duration of stimulation (143). The most widely used therapeutic form, rTMS, is typically delivered with a figure-of-eight coil and primarily reaches superficial cortical targets (typically 2–3 cm in depth). Deep TMS, which is postulated to reach deeper structures than conventional rTMS, albeit with reduced focality, can be delivered with different coils, such as double-cone, Halo, and H-coils (146). Finally, theta-burst stimulation (TBS) is a patterned form of rTMS in which short high-frequency bursts (classically 3 pulses at 50 Hz) are repeated at a theta rate (classically 5 Hz) and delivered in continuous (cTBS) or intermittent (iTBS) patterns (147). In M1 physiology studies, cTBS is often associated with reduced and iTBS with increased corticospinal excitability, although direction and duration can vary with protocol and context (147). TBS over M1 has also been explored in pain indications within the broader evidence base for therapeutic rTMS (141).

Both rTMS and deep TMS have been investigated for pain modulation, with the bulk of research focused on rTMS. The most studied target of stimulation is the motor cortex, but other targets, such as the dorsolateral prefrontal cortex (DLPFC) or the parietal cortex, have also been explored (141, 148–150). Neuropathic pain syndromes have been shown to be among the conditions most responsive to TMS (142, 151). In this patient population, stimulation applied to the contralateral side of pain has been shown to induce analgesic effects; different therapeutic protocols have been explored with various stimulation parameters, such as frequency (e.g., 10 Hz or 20 Hz); intensity [expressed as a percentage of the resting motor threshold (RMT)]; number of pulses (1,500–3,000); and number of sessions [see (141, 142) for a more complete list of stimulation parameters]. A typical protocol used by many laboratories consists of 10 consecutive weekday sessions followed by maintenance sessions at 1 week, 2 weeks apart, and a month apart (142). All of the above parameters might influence the magnitude and duration of pain relief (152).

The mechanisms underlying the analgesic effect of TMS remain incompletely established, but TMS is thought to modulate the activity of cortical and subcortical brain structures that are involved in pain processing (148). While TMS is considered a safe and well-tolerated form of brain stimulation, efficacy results have been mixed (153). A recent Cochrane review on rTMS applied to M1 showed that the analgesic effects of neither single-session nor multi-session protocols are likely to be clinically significant or improve disability (153). The mixed efficacy observed with TMS reflects a recurring challenge in neuromodulation, where heterogeneity among studies remains high and subsequently the ability to modulate neural circuits does not consistently translate into conclusive results pertaining clinical efficacy, optimal target site, and optimal dosing (152).

4.2 Transcranial direct current stimulation (tDCS): from cortical polarization to analgesic montages

Although weak transcranial direct current stimulation had been explored in human studies in the 1960s and 1970s, contemporary tDCS was revitalized in the early 2000s after reproducible demonstrations of polarity-dependent modulation of cortical excitability and has since been increasingly investigated as a noninvasive approach for pain modulation (154, 155).

tDCS uses electrodes placed on the scalp to deliver low-intensity direct current to underlying cortical targets, thereby modulating cortical excitability and influencing pain-related networks. tDCS typically delivers 1–2 mA of constant direct current through electrodes of ∼25–35 cm² for 20 min/session (156), increasing or decreasing excitability of neural targets depending on the relative electrode orientation (i.e., field polarity relative to neural targets) (154). When stimulation is provided over multiple sessions, more persistent network effects can be induced; for chronic pain therapy, stimulation is typically delivered in repeated 20-min sessions, often over 5–10 sessions.

tDCS has been used to target different conditions by using different montages. There are two main approaches for tDCS modulation of chronic pain, either placing the electrodes over M1, thereby modulating plasticity of motor circuits related to pain (see MCS above), or over the DLPFC to impact cognitive–affective control of pain (e.g., attentional control, reappraisal, catastrophizing) (157, 158). These montages reflect two complementary therapeutic frameworks: M1 stimulation is generally interpreted as engaging sensorimotor and descending modulatory pathways, whereas DLPFC stimulation is used to influence cognitive–affective dimensions of pain. In both cases, analgesic effects are thought to arise from modulation of distributed pain-related networks rather than direct focal suppression of nociceptive input (157, 158). These network-level effects are thought to involve distributed cortico-subcortical networks, including frontostriatal and descending modulatory pathways, with putative interactions with reward- and brainstem-modulatory nodes (e.g., the nucleus accumbens and PAG). Sham-controlled trials have reported short-term analgesic effects of anodal M1 tDCS (2 mA, 20 min, 5 consecutive days) in fibromyalgia (159, 160), central neuropathic pain after traumatic spinal cord injury (160), and painful diabetic polyneuropathy, with benefits persisting for weeks in follow-up (161). However, across indications the literature remains heterogeneous in populations, dosing, sham methods, and outcomes, and a 2018 Cochrane review concluded that “very low-quality evidence suggests that tDCS may have short-term effects on chronic pain” (153). These findings further illustrate the gap between physiologically plausible modulation of neural networks and reproducible clinical benefit, with evidence suggesting modest, short-term analgesic benefit in selected conditions, but durability and optimal montage/dose remain uncertain due to variability in protocols and outcomes (153).

4.3 Transcranial alternating current stimulation (tACS): oscillatory modulation in pain

Human experimental studies of tACS began in the late 2000s, and subsequent work established the technique as an oscillation-oriented form of transcranial electrical stimulation designed to interact with endogenous brain rhythms (162, 163). Similar to tDCS, tACS uses scalp-placed electrodes to apply weak alternating currents noninvasively to cortical targets. tACS delivers a weak (<2 mA) alternating electrical current between conventional scalp electrodes (typically ∼25–35 cm² saline-soaked sponge pads; e.g., 5 × 5 or 5 × 7 cm) (164, 165) and aims to interact with the naturally rhythmic electrophysiologic activity of the brain, which can be detected by electroencephalography (EEG) and magnetoencephalography (MEG). tACS is thought to promote entrainment (i.e., synchronization or desynchronization) of brain oscillations to the stimulation frequency (163), and may also modulate long-range oscillatory coupling between distributed brain regions (e.g., phase-specific changes in interhemispheric functional connectivity) (166). The stimulation frequency can be fixed or matched to specific features of oscillatory activity recorded from the patient (167). As with other transcranial electrical stimulation techniques, the physiological and behavioral effects of tACS likely depend on montage, current intensity, stimulation frequency, session duration, and baseline brain state of the participant, which complicates comparison across studies (164–167). In pain-related studies, montages have typically been designed to target somatosensory or prefrontal regions, although the optimal electrode configuration for engaging pain-relevant oscillatory networks remains uncertain (167–170). Typical experimental montages include bilateral or unilateral primary somatosensory cortex or frontally oriented configurations targeting the dorsolateral prefrontal cortex, sometimes combined with extracephalic reference electrodes (165, 167). In the brain, pain has been associated with oscillations at alpha (8–13 Hz) and gamma (30–100 Hz) frequencies over somatosensory and prefrontal areas (171); these oscillations can be targeted using tACS at the same frequency to promote entrainment (163), which may in turn influence pain perception. This oscillation-based framework provides a compelling mechanistic rationale for the use of tACS in pain modulation, particularly considering evidence that pain-related alterations in alpha and gamma activity occur across somatosensory and frontal networks (171). However, whether these oscillatory signatures are causally related to clinically meaningful analgesia remains uncertain, and the therapeutic value of frequency-matched or individualized tACS protocols has yet to be established (168–170, 172).

To date, relatively few studies have investigated the use of tACS for pain modulation, with mixed results. Clinical evidence remains preliminary and consists largely of small pilot trials with heterogeneous protocols and outcomes, so effectiveness and durability are uncertain and not yet guideline-established (168–170, 172). While some studies have provided preliminary evidence that tACS at alpha frequencies delivered over somatosensory areas during one or more sessions [e.g., 10 sessions over 2 weeks in (172)] may produce analgesic effects (168, 170, 172), other studies using tACS at alpha and gamma frequencies over prefrontal and somatosensory areas have been inconclusive or shown no effect (169).

Overall, tACS provides a mechanistically appealing approach grounded in oscillatory brain dynamics, yet its clinical trajectory reflects the broader challenge of translating modulation of neural rhythms into consistent and clinically meaningful analgesia.

4.4 Cranial electrical stimulation (CES): from electrosleep to cranial electrotherapy

CES is a noninvasive neuromodulation technique that applies very low-intensity pulsed electrical currents to the head, commonly via ear-clip (earlobe) electrodes and, less commonly, scalp montages, with the aim of modulating brain networks relevant to pain and related symptoms such as sleep and mood (173). Historically, CES emerged from early 20th-century “electrosleep” approaches, which were intended to induce a sleep- or sedative state, although later investigators argued that any apparent sleep-promoting effects were more likely indirect and related to relaxation rather than true sleep induction (174). Over time, the clinical framing shifted from attempts to induce electrosleep toward broader symptomatic modulation of pain, anxiety, insomnia, and related conditions, such that modern CES is better understood as an evolution rather than a direct continuation of early electrosleep paradigms. CES gained broader clinical use in the United States in the 1960s and 1970s, making it one of the earliest low-intensity cranial electrical neuromodulation modalities to enter broader clinical use (175). CES is often described as a form of transcranial pulsed current stimulation (tPCS) and is technically distinct from tDCS/tACS in that it typically uses pulsed waveforms and can be delivered at low current intensities through infra- or supra-auricular electrode placements (176). Early electrosleep protocols generally used pulsed currents in the 30–100 Hz range (174), whereas contemporary CES devices use device-specific parameters, with commonly reported modern settings including microcurrent intensities and frequencies such as 0.5 or 100 Hz (177). Current systems provide a versatile range of output parameters, with pulse durations ranging from microseconds to milliseconds and current intensities from microamps to upwards of 1 mA. These devices typically utilize biphasic square-wave pulse forms. Proposed mechanisms remain incompletely established and are generally framed in terms of broad modulation of cortical and subcortical network activity, rather than a single established analgesic pathway (177).

CES exemplifies a longstanding gap in neuromodulation in chronic pain between early clinical technological adoption and mechanistic clarity. Systematic evidence assessments have concluded that clinical benefits are uncertain and the evidence base is heterogeneous across populations, comparators, and outcomes (173), although some individual studies in specific conditions such as fibromyalgia have reported improvements in pain and related symptoms (178, 179). Interpretation of the CES literature is further complicated by substantial variability in study design, stimulation parameters, and outcome measures, as well as by the inclusion of earlier studies conducted prior to contemporary trial standards, making it difficult to define a clear therapeutic role for CES in chronic pain management.

5 Peripheral neuromodulation

Peripheral neuromodulation includes both noninvasive surface stimulation techniques and implanted or percutaneously placed systems targeting either named peripheral nerves or broader painful fields.

5.1 Noninvasive peripheral stimulation

5.1.1 TENS: gate-control foundations and clinical Use

TENS emerged in the early 1970s, shortly after the publication of gate control theory, and became one of the earliest noninvasive electrical therapies used for pain management (15, 180, 181). TENS is delivered across the skin surface to stimulate peripheral nerves through electrode pads. Standard TENS is generally considered safe and inexpensive, typically consisting of a battery-powered hand-held device that generates pulsed electrical currents (182).

Stimulation is characterized by current amplitude, pulse width, and frequency. In clinical use, intensity is typically titrated above sensory threshold to produce a perceptible, non-painful paresthesia. Typical clinical TENS uses frequencies of ∼2–150 Hz and pulse widths of ∼50–400 μs, with sessions commonly lasting ∼20–60 min (183–185). FDA 510(k) summaries for commercial TENS devices report maximum output currents commonly in the tens to low hundreds of milliamperes, with values depending on device and load condition (186–188). The original principle of TENS derives from the gate control theory of pain, which proposes that activation of non-nociceptive afferent input can inhibit transmission of painful signals at the spinal level (15). This is commonly framed as preferential activation of large-diameter, non-nociceptive afferent fibers (182), which may inhibit nociceptive transmission at the spinal level and engage descending inhibitory systems (182). Mechanistic studies have further extended the original gate-control framework to include frequency-dependent neurochemical modulation (e.g., endogenous opioid and serotonergic signaling) and recruitment of descending inhibitory pathways that regulate spinal nociceptive transmission (182, 189–191). These mechanisms reflect convergence of small- and large-diameter sensory inputs onto spinal neurons involved in transmitting sensory information to the brain, together with modulation by descending control pathways (15, 182). Overall, TENS became an established, portable, noninvasive option whose development paralleled the evolving understanding of frequency-dependent neurochemical modulation. Its clinical efficacy, however, has remained inconsistent across pain conditions and study designs. Earlier reviews reached negative or limited conclusions, in part because of methodological limitations and insufficient data suitable for quantitative pooling (192, 193). More recently, Paley et al. conducted a descriptive analysis of 169 reviews (eight overviews, seven hybrid reviews and 154 systematic reviews with 49 meta-analyses), and they recommended TENS as a treatment option for symptomatic relief of pain (194). Their appraisal found that pain intensity was lower during or immediately after TENS compared with control interventions for acute and chronic pain (194). In perioperative settings, TENS has also been evaluated as an adjunct to conventional analgesic management, with evidence suggesting reductions in postoperative pain and analgesic consumption (195). These apparently divergent findings may reflect differences in treatment delivery, because analgesic response depends in part on achieving adequate stimulation intensity and underdosing may contribute to negative or inconsistent trial results (184, 196, 197). Overall, the strongest signals of benefit are observed during active TENS and, in some contexts, in reduced analgesic use, but confidence in broader and longer-term efficacy remains limited by frequent shortcomings in randomized clinical trials (RCTs), insufficient pooled data, and substantial variability across pain conditions and outcomes (194).

5.2 Implanted and percutaneously placed peripheral stimulation

5.2.1 Peripheral nerve stimulation (PNS): from surgical implants to percutaneous systems

PNS has been used for pain control for more than five decades, evolving from surgically implanted systems to modern percutaneous approaches. Early clinical work by Shelden and colleagues (198) reported temporary suppression of trigeminal neuralgia pain using implanted PNS electrodes (including high-frequency stimulation delivered via an implanted receiver). In 1967, Wall and Sweet described pain suppression during stimulation in a series of eight patients with chronic cutaneous pain (199). Historically, PNS required open surgical dissection to visualize the nerve and position the lead (200), and subsequent surgical modifications (e.g., interposing a fascial graft between lead and nerve) were later deemphasized due to complexity and complications (201). The modern shift toward percutaneous PNS was catalyzed in 1999 by Weiner and colleagues, who reported that percutaneous lead placement provided analgesia in occipital neuralgia (202). PNS involves placement of a stimulating lead adjacent to a specific peripheral nerve, typically percutaneously under image guidance, to deliver electrical pulses intended to reduce pain. Although mechanisms are not fully established, PNS is generally thought to reduce pain through activation of non-nociceptive afferent fibers and modulation of peripheral and spinal excitability, with possible downstream effects on central sensitization and broader pain network processing (203, 204).

The evolution of PNS reflects a broader trend toward less invasive and more anatomically targeted approaches. The persistent variability in outcomes highlights the ongoing challenge of translating peripheral modulation into consistent therapeutic effects within larger nociceptive networks. Evidence-based clinical guidelines and systematic reviews support PNS as an option for selected acute and chronic pain conditions, although the strength of evidence varies by indication and target nerve (205). However, across indications the literature remains heterogeneous in trial design, comparators, and follow-up duration, and higher-quality controlled evidence is stronger for some targets and conditions than others (205). Dosing/programming is individualized by target and system; example settings reported in clinical studies include pulse widths around ∼200 μs and frequencies around ∼100 Hz, with amplitude titrated to a comfortable sensory percept (paresthesia) (206).

5.2.2 Peripheral nerve field stimulation (PNFS): development of field-based stimulation

Whereas PNS targets a specific named peripheral nerve, PNFS evolved as a field-based strategy for regional pain distributions that are less amenable to focal nerve targeting. Field-based subcutaneous peripheral stimulation approaches were described in the early 2000s under related terms, including targeted subcutaneous stimulation and peripheral nerve field stimulation. Early reports described targeted subcutaneous stimulation and PNFS for neuropathic, abdominal, axial, and chronic low back pain; these case reports and small case series were later followed by larger observational reports that helped define PNFS as a distinct neuromodulation approach (207–211).

PNFS involves placement of leads within the subcutaneous tissues of the painful region to create a “field” of stimulation, rather than targeting a named peripheral nerve as in conventional PNS (209). It has been used both as stand-alone therapy and as an adjunct to SCS in patients with regional pain distributions (212). This field-based approach may be advantageous when a discrete peripheral nerve target cannot be identified. Although mechanisms are not fully established, PNFS is generally thought to modulate afferent input from the painful region by stimulating local nerve branches and cutaneous afferents, with downstream convergence at the spinal cord (209). It has most commonly been applied to localized or regional pain syndromes, particularly chronic axial low back pain. Stimulation is programmed in a patient-specific manner, typically titrated to comfortable paresthesia when paresthesia-based paradigms are used (209). In chronic low back pain, prospective multicenter observational data suggest improvements in pain and function, though study designs and comparators vary (213). A recent narrative review of PNFS for chronic low back pain and persistent spinal pain syndrome similarly concluded that PNFS, used alone or as an adjunct to SCS, appears to reduce pain and analgesic use and improve physical function, although high-quality long-term evidence remains limited (214). Overall, PNFS reflects a shift towards less invasive yet targeted peripheral approaches. However, its heterogeneous outcomes underscore the difficulty of achieving consistent analgesia across variable presentations.

6 Hybrid, multimodal, and dual energy approaches

Hybrid neuromodulation refers to pairing two stimulation modalities to engage complementary nodes or mechanisms within the pain system (including combinations of central and peripheral approaches), two peripheral strategies, or multimodal central stimulation. At present, hybrid approaches are better understood as an emerging design direction in pain neuromodulation than as a mature evidence class. In practice, such combinations are most often explored when a single modality provides incomplete relief or insufficient coverage of a complex pain distribution. The mechanistic rationale is that hybrid modalities may allow modulation of complementary peripheral, spinal, and supraspinal components of pain processing, although cumulative effects remain incompletely established. Clinically, most hybrid strategies remain exploratory and are typically used to address incomplete coverage or partial response, such as combining SCS with PNFS for axial low back and leg pain (212), or combining tDCS with peripheral stimulation in chronic pain (215, 216). While not classically an electrical approach, emerging central approaches may also be considered within this framework, including electrosonic stimulation, which combines tDCS with transcranial ultrasound (217, 218). Many hybrid and multimodal neuromodulation approaches recognize that single-target strategies may be insufficient to address the distributed and plastic nature of pain networks. Overall, the published literature on hybrid and multimodal approaches remains limited and heterogeneous, with variability in study design, stimulation protocols, and patient selection (215).

To complement the regulatory summaries in Tables 1–2, Table 3 synthesizes representative clinical evidence across the major electromagnetic neuromodulation modalities discussed in this review. Table 4 summarizes typical stimulation characteristics across these modalities.

Table 4. Typical stimulation characteristics of major electromagnetic neuromodulation modalities used in pain research and clinical practice.

7 Discussion

The evolution of neuromodulation in pain reflects the constant tension between mechanistic understanding and technological prowess. Initial basic physiology and pathophysiology knowledge historically triggered advances in device precision, which often outpaced the identification of more complex anatomical and network-level mechanisms needed to achieve consistent clinical efficacy. A central theme of this review is the divergence between the relatively narrow set of FDA-cleared or approved indications and the much broader published literature spanning additional pain conditions, targets, stimulation paradigms, and outcomes. This distinction matters when interpreting clinical claims, because a larger literature does not necessarily imply regulatory alignment, evidentiary maturity, or translational readiness. Despite advances in device development, anatomical targeting, and regulatory translation, important evidence gaps persist.

7.1 Evidence gaps across electromagnetic neuromodulation modalities

The strength and maturity of evidence remain uneven across electromagnetic neuromodulation approaches. The contrast between FDA-cleared or approved indications summarized in Tables 1, 2 and the broader representative evidence base summarized in Table 3 highlights an important translational gap: many modality-indication pairs remain supported by limited, heterogeneous, or non-definitive evidence despite substantial published literature. Although this narrative review does not apply a formal evidence-rating framework, this organization provides a narrative assessment of the relative maturity, limitations, and translational readiness of the available literature.

Several recurring evidence gaps can be grouped into methodological, dosing/programming, comparator selection, sham credibility, blinding, outcome, and technical domains. Methodologically, many studies are limited by small sample sizes, short follow-up durations, and heterogeneous patient populations without adequate stratification. These limitations make it difficult to determine whether inconsistent results reflect true differences in efficacy, differences in patient selection, or variability in trial design. With respect to dosing and programming, stimulation parameters are highly variable and often incompletely reported. The modality-specific differences summarized in Table 4 further illustrate the importance of clearly reporting targets, stimulation parameters, treatment schedules, and implementation details. Many studies do not clearly distinguish the nominal, protocol-specified regimen from the treatment actually administered, which may vary because of titration, placement variability, adherence, session completion, and protocol deviations.

Comparator selection, sham credibility, and blinding limitations may also complicate interpretation across both noninvasive and implanted interventions. In neuromodulation trials, active stimulation can produce sensory, auditory, procedural, autonomic, or device-related cues that are difficult to reproduce in sham conditions. In rTMS, many sham methods have historically failed to reproduce the look, sound, and somatosensory experience of active stimulation while avoiding delivery of a significant magnetic field (219). For tDCS, brief ramp-up stimulation followed by discontinuation at the beginning and end of treatment sessions can produce comparable early cutaneous sensations and support blinding under specific stimulation parameters (220). In implanted neuromodulation, particularly SCS, comparator selection, sham design, and blinding are also challenging because paresthesia, device programming, patient interaction with implanted hardware, and incomplete reporting of sham procedures can affect interpretation (221). Because pain outcomes are subjective and sensitive to expectations, placebo analgesia and nonspecific procedural effects can be difficult to separate from stimulation-specific effects in neuromodulation trials (222). Inadequate sham control or incomplete blinding may therefore inflate apparent treatment effects when participants can infer treatment assignment. These issues limit interpretability when comparator methods, sham credibility, and blinding integrity are incompletely reported or not formally assessed.

Outcome heterogeneity is another recurring limitation, as trials differ substantially in their assessment of pain intensity, function, quality of life, sleep, mood, medication use, and durability of benefit. This variability makes it difficult to compare modalities or determine whether short-term pain reduction translates into sustained clinical benefit. Additional technical limitations include limited precision in target engagement, insufficient mechanistic biomarkers, incomplete personalization of stimulation parameters, and limited development of adaptive or closed-loop control strategies. Together, these methodological, dosing/programming, comparator, sham, blinding, outcome, and technical gaps make it difficult to draw firm conclusions about efficacy, durability, comparative effectiveness across modalities, or which patient populations are most likely to benefit.

7.2 Future directions

Future work should focus on adequately powered multi-center trials with standardized reporting of stimulation parameters, longer follow-up to evaluate durability and tolerance, and harmonized core outcomes that include function and quality of life. To improve interpretability and enable cross-study comparison, future trials of electromagnetic neuromodulation for pain should report, at minimum, the following, organized by domain:

Population and condition: The pain condition and diagnostic criteria, and patient characteristics relevant to treatment response (e.g., pain phenotype, duration, prior therapies).

Stimulation and delivery: The stimulation target and localization method, device type, planned (nominal) stimulation parameters, session number and duration, and overall treatment schedule. Critically, trials should also report the treatment actually delivered, distinguishing it from the nominal protocol, since titration, parameter adjustment, adherence, session completion, and protocol deviations can cause planned and delivered treatments to differ.

Comparator and blinding: The comparator or sham procedure in sufficient detail to judge its credibility, and whether and how blinding was assessed.

Clinical and safety outcomes: Prespecified pain intensity, function, quality of life, medication use, and adverse events, each with follow-up duration adequate to assess durability. Where feasible, trials should report not only pain and function but whether functional gains track analgesic gains, as these two outcomes may diverge.

Modality-specific reporting: For invasive approaches, implantation and procedural variables (lead type and position, target verification). For noninvasive approaches used repeatedly outside the clinic, particularly transcutaneous or home-capable modalities, studies should report placement verification, intensity-adjustment procedures, adherence to the prescribed schedule, and device-recorded usage logs where available.

Improved phenotyping and prespecified subgroup analyses are needed to refine patient selection for specific interventions. Mechanistic and target-engagement measures, such as sensory profiling, autonomic metrics, and neurophysiology, may also help optimize stimulation parameters and complement patient-reported and functional outcomes by assessing whether the intended biological target is being engaged. Future studies should define more clearly where each modality fits within the clinical care pathway, including integration with multimodal pain management, long-term safety and maintenance considerations, and practical issues of implementation, access, and reimbursement. Lastly, emerging adaptive and closed-loop neuromodulation systems represent an effort to address a central limitation of earlier approaches (i.e., the lack of real-time feedback linking stimulation delivery to physiological effect and clinical response). The addition of sensing capabilities and biomarker-driven adjustment of stimulation parameters may help bridge the gap between mechanistic modulation and consistent therapeutic efficacy.

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Footnotes

Edited by: Xueshu Tao, The First Affiliated Hospital of China Medical University, China

Reviewed by: Chang-Chia Liu, University of Virginia, United States

Gabrielly Santos Pereira, University of São Paulo, Brazil