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Referred pain

Referred pain is a clinical phenomenon characterized by the perception of pain at a site distant from the actual source of noxious stimulation, often without involvement of nerve root compression or direct injury to the referred area.^[1] This type of pain typically arises from somatic structures such as muscles, joints, or viscera and is mediated by shared neural pathways in the central nervous system, leading to mislocalization by the brain.^[2] The primary mechanism underlying referred pain is the convergence-projection theory, first proposed by Ruch in 1961, which posits that visceral or deep somatic nociceptive afferents converge with somatic afferents from superficial structures onto the same second-order neurons in the spinal cord or brainstem.^[1] This convergence causes the central nervous system to attribute the pain signal to the more familiar somatic dermatome or myotome rather than the true origin, such as interpreting cardiac ischemia as arm or jaw discomfort.^[3] Additional mechanisms include dichotomizing afferent fibers, where single nociceptors branch to both the primary painful site and a distant referral zone, potentially activating reflex arcs that amplify the sensation.^[2] These processes often result in central sensitization, enhancing pain transmission and contributing to secondary hyperalgesia in the referred area.^[2] Clinically, referred pain presents as a dull, aching, or pressing sensation that spreads across broad regions, frequently overlapping with dermatomal patterns but not strictly confined to them, and it is reported in 17% to 84% of cases involving low back pain or other musculoskeletal disorders.^[2] Common examples include myocardial infarction pain radiating to the left shoulder and neck, or gallbladder disease perceived in the right scapular region.^[1] Diagnosis can be challenging due to these overlapping patterns, often leading to misattribution and unnecessary interventions, such as dental extractions for jaw pain actually stemming from cardiac or temporomandibular sources.^[3] Management typically targets the primary lesion through local anesthetic blocks, radiofrequency ablation, or surgical intervention, though outcomes remain variable and require further research for optimization.^[2]

Fundamentals

Definition

Referred pain is the perception of pain in a somatic region distant from the site of noxious stimulation or tissue damage, arising from the shared innervation of visceral or deep somatic structures with superficial somatic areas via common spinal cord segments.^[4] This occurs because afferent nerves from internal organs or deep tissues, such as those from the viscera or musculoskeletal structures, converge on the same dorsal horn neurons in the spinal cord as nerves from the skin or superficial muscles.^[2] Nociception forms the foundational process in referred pain, involving the detection of potentially harmful stimuli—such as mechanical injury, extreme temperatures, or chemical irritants—by specialized peripheral sensory receptors known as nociceptors, which transmit signals through primary afferent fibers to the central nervous system.^[4] In this context, the primary zone refers to the localized area of actual noxious stimulation or injury, where pain is initially generated, whereas the secondary zone denotes the remote somatic area where the pain is subsequently perceived due to neural overlap.^[4] The scope of referred pain excludes conditions like radicular pain, which stems from direct irritation or compression of spinal nerve roots and manifests along a dermatomal distribution often with neurological deficits, and phantom pain, which involves sensations in an absent body part following amputation.^[2]

Historical Development

The concept of referred pain emerged in the 19th century through early clinical and experimental observations of visceral-somatic pain patterns. French physiologist Claude Bernard, in his experiments during the 1850s, demonstrated that stimulation of anterior spinal roots could produce pain resembling visceral sensations, and that sectioning posterior roots failed to alleviate certain internal pains, suggesting alternative pathways for visceral afferent signals beyond traditional sensory routes.^[5] This laid foundational insights into the non-localized nature of some pain experiences, shifting attention from purely somatic explanations. Building on such physiological groundwork, Louis Antoine Ranvier proposed an early theory of referred pain in 1875, attributing it to the branching of axons discovered via Camillo Golgi's silver staining method (the "black reaction" of 1873), which allowed irritated visceral fibers to converge on somatic nerve branches, displacing pain perception to the skin surface.^[6] The late 19th century saw more systematic clinical mapping, with British neurologist Sir Henry Head's 1893 thesis on "Disturbances of Sensation with Especial Reference to the Pain of Visceral Disease" identifying zonal patterns of hyperalgesia (now known as Head's zones) through studies of herpes zoster and visceral disorders, establishing dermatomal overlaps as key to referral mechanisms.^[7] Concurrently, physician James MacKenzie documented similar sensory referrals from viscera to somatic areas in 1893, linking them to deep nerve irritations.^[8] In the 1920s, French surgeon René Leriche advanced surgical perspectives on pain management, observing through sympathectomies and nerve blocks that interrupting autonomic pathways could alter referred visceral pain, as detailed in his clinical reports on ischemia and neuralgia.^[9] The 1930s marked a milestone with experimental validations, as John H. Kellgren's hypertonic saline injections in humans (1938–1939) confirmed segmental referral patterns from deep somatic and visceral sites, providing empirical maps that refined Head's zones. This era's pattern theory of pain, emphasizing temporal and spatial summation, influenced the 1930s–1950s research landscape, culminating in Ronald Melzack and Patrick Wall's gate control theory (1965), which integrated referral via spinal gating of convergent inputs from visceral and somatic afferents.^[10] Post-1960s, understanding evolved toward neurophysiological models, with functional neuroimaging like fMRI revealing central convergence in areas such as the insula and thalamus during referred pain tasks, bridging anatomical observations with brain-level processing.^[2] This progression highlighted a shift from static anatomical views to dynamic, integrative explanations, though gaps persisted in pre-20th-century mechanistic details.

Characteristics

Key Features

Referred pain exhibits distinct temporal characteristics compared to primary pain at the injury site. It often demonstrates a delayed onset, typically emerging seconds to minutes after the initial stimulus, once local pain has persisted for a period.^[11] Furthermore, referred pain may continue for minutes to hours even after removal of the stimulus, sometimes becoming fixed in a specific region.^[12]^[2] Spatially, referred pain manifests in areas remote from the primary zone, frequently aligning with dermatomal or myotomal distributions but not strictly following dermatomal boundaries like radicular pain.^[13]^[2] These patterns can occur ipsilaterally or, less commonly, contralaterally to the origin.^[14] In terms of intensity and quality, referred pain is generally milder and less localized than primary pain, presenting as dull, aching, gnawing, or burning sensations rather than sharp or shooting.^[2] Its perception can be modulated by emotional factors, with higher negative emotionality—encompassing distress, fear, and catastrophic thinking—linked to increased odds of experiencing referred pain and greater local intensity.^[15] Physiologically, episodes of referred pain are often accompanied by autonomic manifestations in the referral zones, including sudomotor changes like altered sweating and vasomotor responses such as skin temperature or color variations.^[16] Recent studies highlight gender differences in referral patterns, with women tending to exhibit larger areas of referred pain and prolonged persistence compared to men in experimental models of visceral hypersensitivity.^[17]^[18]

Distinctions from Other Pain Types

Referred pain differs from radicular pain primarily in its etiology and distribution pattern. Radicular pain arises from compression or irritation of a spinal nerve root, often due to conditions like herniated discs or spinal stenosis, resulting in sharp, shooting pain that radiates along a specific dermatome with associated neurological deficits such as numbness or weakness.^[19] In contrast, referred pain lacks direct nerve root involvement and does not follow dermatomal boundaries; it typically manifests as a dull, aching sensation in a broader, non-segmental area away from the injury site, without motor or sensory loss.^[2] Unlike phantom limb pain, which occurs in the absence of a limb following amputation and stems from maladaptive cortical reorganization in the somatosensory cortex, referred pain involves intact body parts and arises from actual nociceptive stimuli in visceral or somatic structures.^[20] Phantom limb pain is characterized by perceptions of movement or sensation in the missing limb, driven by remapping of adjacent cortical areas, whereas referred pain reflects a misattribution of signals from an existing source to a distant site due to neural convergence.^[21] Referred pain is also distinct from allodynia and hyperalgesia, which are hallmarks of central sensitization in neuropathic conditions. Allodynia involves pain elicited by non-noxious stimuli, such as light touch, due to lowered pain thresholds, while hyperalgesia denotes an exaggerated response to normally painful stimuli.^[22] Referred pain, however, represents a location-specific mislocalization of nociceptive input without inherent amplification of stimulus intensity; it can coexist with these phenomena but is defined by the perceptual shift rather than altered sensory processing at the site of referral.^[23] In comparison to sympathetically maintained pain (SMP), which is a form of neuropathic pain sustained by aberrant sympathetic efferent activity and relieved by sympathetic nerve blockade, referred pain does not depend on sympathetic outflow for its persistence.^[24] SMP, often seen in complex regional pain syndrome, features autonomic changes like vasomotor instability and responds to interventions targeting the sympathetic chain, whereas referred pain typically resolves with treatment of the primary nociceptive source and shows no such blockade dependency.^[22] Modern neuroimaging, particularly functional magnetic resonance imaging (fMRI) studies since 2000, has provided evidence for these phenomenological distinctions through differential neural activation patterns. For instance, visceral stimuli inducing referred pain activate distinct brainstem and cortical regions, such as the periaqueductal gray and anterior cingulate cortex, compared to the more localized somatosensory activations in radicular or somatic neuropathic pain.^[25] Similarly, fMRI reveals that referred pain from visceral sources shares overlaps with somatic pain in the "pain matrix" but exhibits unique connectivity in the insula and thalamus, differentiating it from the cortical remapping seen in phantom limb pain or the sensitized pathways in allodynia/hyperalgesia.^[26] These findings underscore how referred pain involves convergent projections without the structural or sensitization elements characteristic of other pain types.^[27]

Mechanisms

Convergent Projection Theory

The convergent projection theory, first formalized by Ruch in 1961, explains referred pain as resulting from the anatomical convergence of nociceptive afferent fibers from visceral and somatic structures onto common second-order neurons in the dorsal horn of the spinal cord, particularly within the spinothalamic tract.^[1] This shared projection modifies the classical labeled line theory, in which specific sensory pathways transmit distinct signals to the brain; instead, the brain attributes the pain to the somatic territory due to its greater density of sensory innervation and prior associative learning, leading to mislocalization of visceral pain signals.^[28] Anatomically, this convergence occurs at specific spinal segments where visceral and somatic inputs overlap; for instance, cardiac visceral afferents entering at segments T1-T5 project to the same dorsal horn neurons as somatic afferents from the left arm and chest wall, resulting in referred pain during myocardial ischemia.^[29] Early evidence supporting this theory came from animal experiments in the 1940s, such as those by Sinclair et al., who injected hypertonic saline into deep somatic tissues in humans and observed pain referral patterns consistent with multi-receptive fields in spinal neurons receiving inputs from both primary and secondary sites. Despite its foundational role, the theory has limitations in accounting for certain clinical observations, such as the delayed onset of referred pain after intense or prolonged visceral stimulation, which suggests additional central processing beyond simple projection overlap.^[30] It also fails to fully explain modulatory influences from emotional states or higher cortical areas on referral patterns, indicating the involvement of supraspinal mechanisms not captured by spinal convergence alone.^[30]

Convergence Facilitation Theory

The convergence facilitation theory posits that referred pain arises from the enhanced excitability of convergent neurons in the spinal cord, where subthreshold somatic inputs are amplified by visceral nociceptive signals, leading to the perception of pain in somatic regions. This mechanism builds upon the anatomical overlap of visceral and somatic afferents in the dorsal horn but emphasizes dynamic facilitation rather than mere convergence. Originally proposed by James Mackenzie in 1893, the theory suggests that irritation from internal organs lowers the threshold for somatic sensory activation in shared projection pathways, resulting in cutaneous or muscular pain referral without direct somatic injury.^[31] At the core of this process is central sensitization in the dorsal horn, where somatic inputs facilitate visceral nociceptor signals through heterosynaptic potentiation. Repeated or sustained low-level visceral stimulation induces the wind-up phenomenon, a form of temporal summation that progressively lowers neuronal activation thresholds and amplifies responses to subsequent inputs. This involves N-methyl-D-aspartate (NMDA) receptor activation, triggered by glutamate release from primary afferents, which leads to intracellular calcium influx and phosphorylation of synaptic proteins, enhancing excitatory transmission in wide-dynamic-range neurons. Human studies from the 1990s using microneurography and psychophysical assessments demonstrated this temporal summation in referred pain zones, showing increased pain ratings and lowered thresholds in somatic areas during repeated muscle stimulation, indicative of facilitated central processing.^[32]^[33]^[34] Recent research highlights the role of glial cells in this facilitation, particularly astrocytes and microglia in the dorsal horn, which contribute to sustained sensitization beyond acute neuronal changes. Activated glia release proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), which further potentiate NMDA receptor function and promote synaptic plasticity in response to visceral inputs. For instance, studies since 2015 have shown that TNF-α from spinal glia enhances visceral nociception and associated somatic referral in models of chronic inflammation, amplifying the disproportionate pain response to minor visceral irritation observed clinically, such as in irritable bowel syndrome where gut signals elicit widespread abdominal wall pain. This glial-neuronal interaction explains the persistence of referred pain and its resistance to peripheral interventions.^[35]

Axon Reflex Theory

The axon reflex theory posits that referred pain arises from the peripheral branching of nociceptor axons, known as dichotomizing fibers, which innervate both the primary site of injury and remote tissues. When nociceptors are stimulated at the injury site, the impulse travels orthodromically along the main axon but also propagates antidromically through collateral branches to distant areas, activating sensory endings there without central nervous system involvement. This peripheral mechanism explains how local stimulation can elicit pain or sensations in anatomically separate but axonally connected regions, such as from a lumbar disc to the groin.^[36] Physiologically, antidromic activation triggers the release of neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), from the peripheral terminals of these branched axons. These neuropeptides induce neurogenic inflammation in the referral zone, manifesting as vasodilation, plasma extravasation, and a characteristic flare response that contributes to perceived pain. For instance, substance P sensitizes local nociceptors and promotes the release of inflammatory mediators, amplifying pain signals in the distant area. This process is mediated by unmyelinated C-fibers, which are prevalent in cutaneous and some deep tissues. Early evidence for this theory stems from observations of the triple response in human skin, where mechanical or chemical stimulation produces a localized red line, a surrounding flare, and a wheal, attributed to axon reflex-mediated neuropeptide release. This was first detailed in studies of cutaneous vascular responses, demonstrating antidromic vasodilation independent of central pathways. More recent double-labeling immunohistochemistry in animal models has confirmed dichotomizing axons innervating visceral structures like the lumbar disc and somatic sites such as the groin, supporting the theory's applicability to certain somatic referrals. Despite these findings, the axon reflex theory primarily accounts for superficial, cutaneous referred pain and has limited explanatory power for deep or visceral referrals, where dichotomizing fibers constitute less than 0.5% of afferents and central mechanisms predominate.^[37]

Hyperexcitability Theory

The hyperexcitability theory posits that peripheral or central injury induces a state of heightened neuronal excitability in the dorsal horn of the spinal cord, resulting in the expansion of receptive fields for wide dynamic range (WDR) neurons. This expansion allows these neurons to respond to inputs from remote or non-injured areas, thereby generating referred pain. Unlike normal sensory processing, where receptive fields are localized, injury-triggered hyperexcitability causes dorsal horn neurons to integrate signals from broader somatic territories, mimicking pain referral patterns observed clinically.^[38] The underlying process involves molecular changes such as the upregulation of voltage-gated sodium channels, particularly Nav1.3, in second-order dorsal horn neurons following nerve injury. This upregulation facilitates ectopic firing and sustained depolarization, amplifying synaptic inputs and leading to central sensitization. Consequently, this manifests as secondary hyperalgesia, where innocuous stimuli from surrounding areas evoke exaggerated pain responses, contributing to the spatial spread characteristic of referred pain.^[39] Evidence for this theory derives primarily from animal models in the 1980s, where C.J. Woolf and colleagues demonstrated that conditioning stimulation of C-fibers in rats caused prolonged expansion of mechanical receptive fields in dorsal horn neurons, persisting beyond the stimulus duration. Post-nerve damage experiments further showed that dorsal horn WDR neurons developed novel receptive fields in remote dermatomes, correlating with behavioral signs of referred hyperalgesia. These findings established hyperexcitability as a key driver of receptive field plasticity in pain referral.^[38]^[40] In clinical contexts, this theory explains chronic referred pain in conditions like fibromyalgia, where widespread musculoskeletal pain arises from augmented central excitability without identifiable peripheral injury. Patients exhibit expanded pain referral zones and secondary hyperalgesia, linked to sustained dorsal horn hyperexcitability that amplifies visceral and somatic inputs across multiple body regions.^[41] Recent research from the 2010s has incorporated epigenetic mechanisms to account for the persistence of this hyperexcitability. For instance, injury-induced DNA methylation changes in dorsal horn neurons regulate genes like BDNF and Cdk5, promoting long-term upregulation of excitability-related proteins and maintaining expanded receptive fields in chronic pain states. These epigenetic modifications, such as histone acetylation and TET enzyme-mediated demethylation, provide a molecular basis for why hyperexcitability transitions from acute to enduring, influencing referred pain in neuropathic disorders.^[42]^[43]

Thalamic Convergence Theory

The Thalamic Convergence Theory proposes that referred pain results from the integration of divergent somatosensory inputs within specific thalamic nuclei, particularly the ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei, which relay and process nociceptive signals to cortical areas, often leading to erroneous localization onto somatic body maps. This mechanism involves the convergence of visceral and somatic afferents at the thalamic level, where neurons fail to distinguish the origin of the input due to shared receptive fields, causing pain to be projected to anatomically unrelated but representationally adjacent regions in the somatosensory cortex. Originally articulated by Theobald in 1941, the theory emphasizes a central summation process in the thalamus as a key contributor to pain referral, distinct from peripheral or spinal-level convergence.^[44]^[28]^[45] A critical aspect of this theory lies in the overlap of thalamo-cortical projections, where fibers from multiple peripheral sources terminate in overlapping thalamic territories, facilitating the blending of signals before cortical interpretation. Additionally, attentional modulation influences thalamic processing, as cognitive factors can amplify or alter the perceived location of pain by enhancing specific neural pathways within these nuclei. This higher-level integration builds upon prerequisite spinal convergence but shifts focus to supraspinal mislocalization. Evidence from functional magnetic resonance imaging (fMRI) studies in the 2000s, such as those examining visceral pain referral, has demonstrated increased thalamic activation in non-stimulated referral zones during experimentally induced angina-like stimuli, supporting the role of thalamic summation in generating referred sensations.^[46]^[47]^[48] Recent advances, including diffusion tensor imaging (DTI) studies from 2022 onward, have revealed thalamic tract anomalies—such as reduced fractional anisotropy in thalamocortical pathways—in patients with chronic pain conditions, indicating microstructural disruptions that may perpetuate referral patterns by impairing precise signal localization. These findings underscore the theory's relevance to long-term pain disorders, where thalamic alterations contribute to sustained misreferral. However, the theory is primarily pertinent to the cognitive and perceptual dimensions of pain localization rather than initial nociceptive transmission, and it is considered secondary to foundational spinal mechanisms in most models of referred pain.^[49]^[50] These theories are not mutually exclusive and often interact in the generation of referred pain.

Examples

Visceral Referred Pain

Visceral referred pain arises when nociceptive signals from internal organs are misinterpreted by the central nervous system as originating from somatic structures on the body surface, often due to shared neural pathways such as convergent projection.^[51] In the cardiac system, myocardial ischemia, as seen in angina pectoris, commonly produces referred pain to the left arm, jaw, or chest wall. This pattern occurs because cardiac visceral afferents converge with somatic afferents from dermatomes T1-T5 in the spinal cord. Women are more likely to experience atypical cardiac referred pain, such as to the back, jaw, or epigastrium, compared to men who more often report classic left-arm radiation.^[51]^[52]^[53] Gastrointestinal disorders provide classic examples of visceral referral. Acute appendicitis initially causes diffuse periumbilical pain due to midgut innervation at the T10 spinal segment, which later localizes to the right lower quadrant as parietal peritoneum involvement occurs.^[54] Similarly, biliary colic from gallstones can refer pain to the right shoulder via irritation of the phrenic nerve (originating from C3-C5), as the inflamed gallbladder shares diaphragmatic innervation with somatic shoulder regions.^[55] These patterns often follow embryological origins, where foregut structures like the biliary system refer to the epigastrium, midgut to the umbilicus, and hindgut to the suprapubic area.^[56] In the urogenital system, renal colic from kidney stones typically manifests as severe flank pain that radiates to the groin or lower abdomen, reflecting the stone's migration along the ureter and convergence of visceral afferents with somatic nerves from T12-L1 segments.^[57] This referral can intensify as the stone approaches the ureterovesical junction, mimicking testicular or labial pain in some cases.^[58]

Somatic Referred Pain

Somatic referred pain arises from musculoskeletal structures, such as muscles, joints, ligaments, and deep tissues, and is perceived in distant somatic regions due to shared neural pathways.^[2] Unlike localized pain, it typically manifests as a dull ache that does not follow the exact anatomical path of the affected structure, often complicating diagnosis. In hip osteoarthritis, pain originating from the joint frequently refers to the knee, mimicking primary knee pathology and delaying identification of the hip source.^[59] This referral occurs via shared innervation from the L3-L4 spinal segments, where hip joint afferents converge with those from the knee.^[2] Similarly, shoulder impingement syndrome, involving compression of the rotator cuff tendons under the acromion, can produce pain radiating down the arm to the elbow region.^[60] Myofascial trigger points in the upper trapezius muscle commonly refer pain to the temple and jaw, contributing to tension-type headaches or temporomandibular symptoms.^[61] Palpation of these points elicits pain in the temple area in approximately 80% of cases, following predictable referral zones along the muscle's fascial attachments.^[62] Deep somatic irritation, such as in pleurisy affecting the diaphragm, often refers pain to the neck or scapular area via the phrenic nerve (C3-C5 origins).^[63] This can present as sharp, pleuritic pain exacerbated by breathing, spreading ipsilaterally to the shoulder blade.^[64] Temporomandibular joint (TMJ) disorders frequently cause referred pain to the ear, known as otalgia, due to proximity and shared trigeminal nerve branches.^[65] Post-2010 studies confirm this in up to 70% of TMD patients, with ear pain persisting even after TMJ treatment resolves jaw symptoms. Evidence from 2021 highlights auriculotemporal nerve sensitization as a key mechanism.^[66] These patterns of somatic referred pain often align with fascial planes, where myofascial tension transmits signals, or shared myotomes, reflecting segmental spinal convergence.^[2] For instance, trapezius referrals follow upper cervical myotomes, while hip-to-knee pain traces lumbosacral distributions.^[67]

Experimental Methods

Algogenic Substance Techniques

Algogenic substance techniques involve the administration of chemical agents that excite nociceptors to induce localized and referred pain in controlled human experiments, providing insights into pain referral pathways. Common substances include hypertonic saline, capsaicin, and bradykinin, which are injected subcutaneously or intramuscularly to simulate inflammatory nociceptor activation without causing tissue damage. These methods, pioneered in the late 1930s, allow researchers to quantify pain characteristics and referral patterns under standardized conditions.^[68] Protocols typically entail injecting small volumes of the agent—such as 0.1–0.5 mL of 5–6% hypertonic saline, 0.01–1% capsaicin solution, or 10 μmol bradykinin—into targeted muscles like the tibialis anterior or masseter using a syringe or infusion pump for precise dosing. Pain onset occurs rapidly (within 10–60 seconds), with intensity rated on a 0–10 visual analog scale (VAS) and referred areas delineated through participant pain drawings at intervals up to 30 minutes post-injection. Measurements include latency to referral (often 20–30 seconds for saline), referral area size, and duration (typically 3–10 minutes), enabling dose-response analyses by varying concentrations or volumes. Bradykinin may be combined with serotonin to enhance effects, while capsaicin injections are guided by ultrasound in some protocols to ensure intramuscular placement.^[68]^[69] Key findings demonstrate that these techniques replicate clinical referred pain patterns; for instance, hypertonic saline injected into the calf induces thigh referral, mirroring somatic-visceral convergence, with VAS intensities reaching 4–6/10 and referral areas expanding with repeated stimuli. Capsaicin evokes burning, cramplike pain with frequent referral to adjacent dermatomes, activating TRPV1 receptors on C-fibers, while bradykinin produces a deeper ache that sensitizes surrounding tissues, supporting central facilitation mechanisms. Quantitative studies show reproducible referral latencies and areas, with hypertonic saline yielding the most consistent results across sessions. These patterns align with convergent projection theory observed in prior mechanistic research.^[70]^[68]^[69] The advantages of algogenic substance techniques lie in their controlled, reproducible nature, allowing ethical exploration of pain modulation, hyperalgesia, and analgesic efficacy without invasive procedures. They facilitate dose-response curves and mechanistic validation, with hypertonic saline being the most utilized due to its safety profile—over 6,000 injections reported without serious adverse events in aggregated studies. Ethical guidelines mandate that stimuli remain below individual tolerance limits, with immediate termination options and debriefing to minimize distress. Recent advancements include alternatives like ATP analogs targeting P2X receptors for purinergic pain signaling, though their human application remains limited compared to traditional agents.^[71]^[72]^[73]

Electrical Stimulation Methods

Electrical stimulation methods involve the application of controlled electrical currents to peripheral nerves or muscles to experimentally induce and characterize referred pain, allowing researchers to map pain referral patterns and receptive fields in healthy human subjects. These techniques primarily utilize transcutaneous electrical nerve stimulation (TENS), which applies surface electrodes non-invasively, or percutaneous intramuscular electrical stimulation (IMES), which employs needle electrodes for deeper tissue targeting. Frequencies typically range from 2 to 100 Hz, with lower frequencies (e.g., 2-10 Hz) often used to activate nociceptive afferents and elicit sustained pain responses, while higher frequencies (e.g., 90-130 Hz) can modulate pain perception but are less common for induction in experimental settings.^[74] The protocol generally begins with threshold determination to distinguish local pain at the stimulation site from referred pain in distant areas. Electrodes are placed to target specific dermatomes or myotomes, such as the tibialis anterior muscle or groin region, with stimulus intensity gradually increased from subthreshold levels (e.g., 0.02 mA) until pain ratings reach a predefined level, like 6/10 on a numerical rating scale (NRS). For IMES, rectangular pulses of 0.2-0.4 ms duration are delivered at intensities 50-150% above the local pain threshold, often for 10 minutes to assess temporal summation and referral onset, which is typically delayed by 20-40 seconds compared to local pain. Referred pain thresholds are consistently higher than local ones (e.g., 72% greater on average), and stimulation is repeated across sessions to evaluate reproducibility, with pain areas mapped via subject drawings or verbal reports.^[74]^[74] Key findings demonstrate that high-frequency stimulation (e.g., 10-50 Hz) can mimic aspects of chronic referred pain by facilitating spatial and temporal summation, expanding pain referral areas (correlations of r=0.74-0.98 between intensity and area size), and altering cutaneous hyperalgesia thresholds by 2-4°C in both local and referred zones. In healthy subjects, these methods reliably map receptive fields, revealing reproducible referral patterns such as from the abdominal rectus to the thigh or testicle (90-100% consistency across sessions). Recent advancements post-2015 integrate microneurography with intraneural electrical microstimulation (INMS), enabling selective activation of specific afferent fibers (e.g., C-mechanosensitive nociceptors) to study fiber-type contributions to referred sensations, which often manifest as dull or sharp pain depending on skin type.^[74]^[75] Advantages of electrical stimulation include non-invasive options like TENS for initial screening, precise segmental targeting without tissue damage or pharmacological side effects, and high reproducibility for longitudinal studies. These methods provide a controlled, quantifiable model for investigating pain convergence, superior to chemical induction in terms of rapid onset and adjustable parameters.^[74]^[75]

Clinical Applications

Diagnostic Strategies

Referred pain patterns play a pivotal role in diagnosing underlying conditions across medical disciplines by enabling clinicians to trace symptoms to their visceral or somatic origins, often preventing misattribution to superficial issues. In orthopedics, knee pain may signal hip joint pathology, such as osteoarthritis, where pain from the hip is referred to the knee via shared neural pathways, necessitating evaluation of the hip to confirm the source.^[76] Palpation serves as a key differentiator, with superficial tenderness suggesting joint or muscular sources while deeper, diffuse discomfort points to visceral referrals, allowing practitioners to distinguish between somatic and internal etiologies through careful assessment of pain quality and location.^[77] In general diagnostic contexts, particularly emergency triage, referred pain from cardiac ischemia manifests as discomfort in the jaw, arm, or back, often identified by Levine's sign—a patient's instinctive clenched fist over the sternum—which has low sensitivity but high specificity for ischemic events when present.^[78] For gastrointestinal disorders, Kehr's sign indicates diaphragmatic irritation from intra-abdominal pathology, such as splenic rupture, producing left shoulder pain that worsens with inspiration and guides urgent evaluation.^[79] Core techniques for diagnosis include pain mapping, where patients delineate symptom distribution on body diagrams to reveal non-dermatomal patterns typical of visceral referrals, aiding localization beyond obvious sites.^[80] Dermatome charts further assist by correlating reported pain areas with spinal nerve segments, helping differentiate radicular from convergent visceral pain in cases like cervical referrals.^[81] Provocation tests, such as controlled hyperventilation, can elicit transient referred pain in cardiac conditions by inducing coronary spasm, providing dynamic confirmation when baseline symptoms are ambiguous.^[82] Diagnostic challenges stem from the overlap between referred and localized pain, which can mimic unrelated conditions and contribute to misdiagnosis; for example, upper abdominal discomfort may represent cardiac ischemia rather than primary gastrointestinal issues, underscoring the importance of holistic history-taking and risk stratification to avert life-threatening delays.^[83] Recent advancements integrate imaging modalities like positron emission tomography (PET) for confirmation, with 2010s studies using FDG-PET/MRI to visualize heightened metabolic activity in peripheral nerves and central pain pathways, thereby validating referred mechanisms in chronic cases and refining differential diagnoses.^[84]

Therapeutic Interventions

Therapeutic interventions for referred pain primarily aim to address the underlying source of the nociceptive input or modulate the peripheral and central mechanisms that propagate the pain signal, thereby providing relief in both the primary and referred areas. Treating the primary site is a cornerstone approach, as resolution of the originating pathology often eliminates the referred component. For instance, in cases of cardiac ischemia causing referred pain to the left arm or jaw, percutaneous coronary intervention (PCI), such as angioplasty, has been shown to provide significant symptom relief by restoring blood flow and reducing ischemic pain, which in turn alleviates the associated referred sensations.^[85] Similarly, surgical interventions targeting visceral sources, like laparoscopic cholecystectomy for acute cholecystitis, can normalize somatosensory function in the referred pain area, such as the right shoulder, by eliminating the primary inflammatory stimulus.^[86] Pharmacological management of the primary site, including nitrates or anti-inflammatory agents for conditions like angina or pancreatitis, further supports this strategy by directly mitigating the nociceptive drive without solely relying on invasive procedures.^[2] Symptom management strategies focus on alleviating pain in the referral zones to improve patient comfort and function while the primary issue is addressed. Local anesthetics applied directly to the referred pain areas can interrupt peripheral sensitization and provide temporary relief; for example, ketocaine compresses in labor-related referred pain has demonstrated efficacy in reducing discomfort in a randomized, double-blind study.^[87] Transcutaneous electrical nerve stimulation (TENS) modulates pain transmission by activating non-nociceptive afferents, with evidence from experimental models showing that both high- and low-frequency TENS significantly reduce the intensity of referred hyperalgesia induced by intramuscular hypertonic saline, without affecting primary guarding behaviors.^[88] Additionally, cognitive-behavioral therapy (CBT) targets pain perception and coping mechanisms, reducing overall distress and improving daily functioning in chronic pain conditions that include referred components, as supported by meta-analyses of behavioral interventions.^[89] Mechanism-based interventions leverage neurophysiological insights, such as convergence and sensitization, to disrupt pain referral pathways. NMDA receptor antagonists, like ketamine, counteract central sensitization that amplifies referred pain signals in neuropathic and inflammatory contexts, offering analgesic effects in chronic pain states where wind-up phenomena contribute to referral.^[90] Nerve blocks targeting convergence sites in the spinal cord or peripheral nerves can selectively inhibit shared pathways; for example, local anesthetic blocks have successfully abolished referred pain elicited by hypertonic saline injections, confirming their role in interrupting convergent projections from visceral to somatic territories.^[2] Neuromodulation devices represent an advanced option for refractory referred pain, particularly in chronic myofascial or neuropathic cases. Spinal cord stimulators (SCS) deliver electrical impulses to the dorsal columns, modulating ascending pain signals and providing substantial relief (70-90%) in axial and extremity pain, including patterns consistent with referral from cervical or lumbar sources.^[91] Post-2020 advancements, such as closed-loop SCS systems, enhance efficacy by adapting stimulation in real-time to neural activity, yielding superior pain reduction and functional improvements compared to traditional open-loop devices in chronic pain cohorts.^[92] Clinical outcomes from randomized controlled trials (RCTs) underscore these benefits; for instance, a 2016 RCT on trigger point injections with lidocaine for myofascial pain syndrome demonstrated significant reductions in referred pain intensity and improved range of motion when combined with physical therapy, compared to either alone.^[93] Overall, multimodal approaches integrating these interventions yield the most durable results, with RCTs from the 2000s highlighting up to 50% pain reduction in myofascial referral patterns following targeted injections.^[94]

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Therapy of Pain
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The other mechanism of muscular referred pain: the "connective ...
... referred pain showing delayed onset. But it is hard to explain the non segmental pattern of referred pain areas of superficial-seated or limb girdle and ...
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Referred pain is the perception of pain at a site that is different from the origin of the painful stimulus. Its origin is in visceral organs and it is ...
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Apr 9, 2025 · Referred pain in dermatomes ; T1–T4, Heart, Upper thorax and left arm ; T5–T9, Foregut (organs supplied by the celiac trunk), Lower thorax and ...
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[PDF] Neurobiology of Visceral Pain - IASP
Referred pain has two components: (1) a ... contact with both superficial and deep dorsal horn neurons ipsilateral and contralateral to the side of entry.
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Psychological Factors Predict Local and Referred Experimental ...
... referred pain compared to the lowest negative emotionality cluster. ... delayed onset muscle soreness). However, ours is the first study to suggest a ...<|separator|>
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16.2 Autonomic Reflexes and Homeostasis - Oregon State University
This irregular pattern of projection of conscious perception of visceral sensations is called referred pain. Depending on the organ system affected, the ...Afferent Branch · Autonomic Tone · Chapter Review<|separator|>
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Jul 29, 2021 · Sex differences in experimental measures of pain sensitivity and endogenous pain inhibition. ... Hypoalgesia in the referred pain areas after bilateral ...<|control11|><|separator|>
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Mar 15, 2024 · Sex differences in visceromotor response to colorectal distention and referred pain in comorbid pain hypersensitivity model. The VMR was recorded at baseline ...
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It should also be recognized that with allodynia the stimulus and the response are in different modes, whereas with hyperalgesia they are in the same mode.
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Autonomically Mediated Pain-Autonomic Pain Syndromes
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Aug 10, 2005 · We used functional magnetic resonance imaging to image the neural correlates of visceral and somatic pain within the brainstem.
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Nov 23, 2020 · Different pain types may be encoded in different brain circuits. Here, we examine similarities and differences in brain processing of visceral and somatic pain.
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Differentiation of Visceral and Cutaneous Pain in the Human Brain
Our study addresses this dilemma by directly comparing human neural processing of intensity-equated visceral and cutaneous pain. Seven subjects underwent fMRI ...
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Referred Pain - an overview | ScienceDirect Topics
Referred pain is defined as pain of somatic visceral origin that is projected to a distant location, often seen in conditions such as cardiac pain ...Missing: spatial autonomic
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Cardiac Pain | Circulation - American Heart Association Journals
Pain from the heart is in large part referred to the cutaneous distribution of the upper 4 thoracic spinal segments.
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[PDF] 1893: James Mackenzie MD; Sensory Disorders and Visceral Disease
PART III., 1893. Original Articles. SOME POINTS BEARING ON THE. ASSOCIATION OF SENSORY DISORDERS AND. VISCERAL DISEASE. BY JAMES MACKENZIE, M.D.,. Honorary ...
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Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings.
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The aim of the present study was to assess temporal summation within saline-induced, localized and referred muscle pain areas. The sensibility to single and ...
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In the central nervous system, bidirectional signaling between glial cells and neurons ('neuroimmune communication') facilitates the development of persistent ...
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Neuropathic pain caused by miswiring and abnormal end organ ...
May 25, 2022 · A form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation.
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These results demonstrate for the first time that Na v 1.3 is upregulated in second-order dorsal horn sensory neurons after nervous system injury.
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Nociceptive primary afferents have the capacity to induce a state of increased excitability or central sensitization in dorsal horn neurones.
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Basically, the referral of pain is a mislocalization of pain. Some aspects of muscle pain referral in patients cannot be explained by the convergence-projection ...
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Jun 14, 2016 · The convergence–projection theory suggests that afferents from deep tissues share second-order neurons with more superficial tissues. The ...Neurophysiology Of Pain · Nociception Of Somatic And... · Cutaneous Nociception<|control11|><|separator|>
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Examine brain correlates of mental stress in patients with CAD with and without a history of angina.
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a systematic review of diffusion tensor imaging studies
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Visceral Pain – the Ins and Outs, the Ups and Downs - PMC
Axons can send peripheral terminals to anatomically distinct segments to produce pain sensations distant to the primary site (36).
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Oct 16, 2021 · Women commonly had squeezing and tightness type of pain and men reported tightness, burning, pricking type of pain.
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Sex differences exist in the presentation of IHD. Women less often report chest pain and diaphoresis and more often complain of back pain, jaw pain, epigastric ...
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Feb 5, 2024 · Flank pain is the classic presenting symptom of urinary calculi and is the predominant cause of flank pain in the absence of fever.
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Feb 19, 2015 · Referred pain is a well-recognised feature of osteoarthritic hip pain. This is likely to be due to the nerve anatomy of the pelvis and leg. The ...
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Shoulder impingement syndrome is a painful condition of the upper extremity resulting from a structural narrowing of the subacromial space.
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Referred pain from myofascial trigger points in head and neck ...
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Referred pain from myofascial trigger points in head and neck ...
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Nov 14, 2024 · The phrenic nerve innervates the central diaphragm, and inflammation in this area can cause referred pain to the ipsilateral neck or shoulder.
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Mar 15, 2024 · Patients with pain-related TMD frequently report otalgia and may be referred to an Ear, Nose and Throat (ENT) surgeon for additional workup. The ...
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The Ear-Temporomandibular Joint Complex: A Narrative Review of ...
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Myofascial Pain - Physiopedia
It originates from muscle and surrounding fascia. It causes a localized pain in a restricted area or referred pain of various patterns.<|control11|><|separator|>
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[PDF] Human Studies of Experimental Pain From Muscle
Injection of hypertonic saline (4 to 6%) has been by far the most frequently used chemical stimulus in human exper- imental muscle pain research and therefore ...
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Quantification of local and referred muscle pain in humans after ...
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Experimental human muscle pain induced by intramuscular ...
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Quantification of local and referred muscle pain in humans after ...
The first aim of this human study was to test if experimental muscle pain produced by infusion of hypertonic saline is influenced by temporal and spatial ...
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[PDF] Pain sensitivity and referred pain in human tendon, fascia and ...
This study aims to investigate the sensory manifestations to experimental pain induction in muscle, tendon, tendon-bone junction and fascial tissue in humans.
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Ethical Guidelines for Pain Research in Humans
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[PDF] Human experimental pain models: A review of standardized ...
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Somatic vs. Visceral Pain and Their Causes - Verywell Health
Mar 21, 2025 · An example of referred visceral pain is when an ectopic pregnancy presents as shoulder pain. ... Angina (cardiac chest pain); Pancreatitis ...Missing: urogenital | Show results with:urogenital
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The utility of gestures in patients with chest discomfort - PubMed
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Feb 15, 2025 · Pain referred to the left shoulder that worsens with inspiration is called Kehr's sign and is due to blood adjacent to the left hemidiaphragm ...
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18 F-FDG PET/MRI Can Be Used to Identify Injured Peripheral ...
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Somatosensory changes in the referred pain area in patients with ...
Somatosensory changes in the referred pain area in patients with acute cholecystitis before and after treatment with laparoscopic or open cholecystectomy.<|control11|><|separator|>
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Local Application of Ketocaine for Treatment of Referred Pain in ...
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Treatment with either high or low frequency TENS reduces the ...
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Behavioral and cognitive-behavioral treatment for chronic pain
Overall, BT-CBT for chronic pain reduces patients' pain, distress, and pain behavior, and improves their daily functioning.
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The Emerging Role of NMDA Antagonists in Pain Management
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Neuromodulation of the cervical spinal cord in the ... - PubMed
In all cases, patients reported significant (70-90%) reductions in pain, including axial neck pain and upper extremity pain. Interestingly, 2 patients with ...
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Closed-Loop Spinal Cord Stimulation in Chronic Pain Management
Apr 30, 2025 · Closed-loop spinal cord stimulation provides superior pain relief, functional improvement, and reduced opioid dependence compared to traditional open-loop ...
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Treatment of myofascial pain syndrome with lidocaine injection and ...
Feb 24, 2016 · The objective of this study was to determine whether LI into trigger points combined with a PT program would be more effective than each separate treatment ...
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Normal Saline Trigger Point Injections vs Conventional Active Drug ...
MPS presents with referred pain specific for each muscle and a trigger point that reproduces the symptoms. Trigger-point-injection (TPI) is an effective ...Missing: RCT | Show results with:RCT