Pathophysiology of Leg Pain – Inflammation, Ischemia, Neuropathy

Sensory perception depends on both reception and interpretation of information and is in part a subjective process which varies with an individual’s experience. Specialized somatic sensory receptors detect the quality of normal sensory information, differentiating between light touch, stretch or pressure, vibration, change in position and pain. For each type of stimulus, the quantity of sensory input is proportional to the frequency of the afferent signals transmitted from the receptor along afferent pathways, and depends on modulation by central nervous system (CNS, spinal cord and brain) mechanisms.

In the lower extremity, sensory receptors occur in higher concentrations at anatomic boundaries such as the skin, deep fascia, periosteum and joint linings (but not cartilage). Receptors are also present in tendons, muscle, and connective tissue between muscle fibers and within blood vessel walls.


Pain processing depends on transmission of noxious stimulii (mechanical, thermal, and chemical irritants) via peripheral sensory nerves. This afferent input creates an electrical impulse which reaches a threshold for encoding the stimulus and insuring propagation into the CNS. Chemical mediators may sensitize nociceptor endings and lower the threshold for response. In general, nociceptor stimulation implies the presence of noxious input sufficiently strong to represent potential danger or harm to the individual. The phenomenon of ‘itch’ is also signaled via these receptors, perhaps channeled centrally to differentiate from pain. Both myelinated rapid conduction (Aδ) and unmyelinated slow conduction fibers (C) are involved. The former typically serve the skin and transmit focused, sharp pain and the latter serve the deeper tissues carrying sensations of dull, poorly localized pain and temperature. In addition, there is evidence that stimulation of abnormally sensitized large fiber mechanoreceptors (Aβ) may also result in nociception.

Repeated or constant stimulation of nociceptors by tissue injury produces a sensitization phenomenon. Under such circumstances the threshold for receptor stimulation is lowered so that minimal stimulation such as light stroking of the skin produces pain at both the injured site and the surrounding uninjured tissue. Hyperalgesia is defined as an accentuated painful response

from a normally noxious stimulus whereas allodynia is defined as a perception of pain from a normally non-painful stimulus.

Sensory stimulation results in a spectrum of response which eventually leads to nociception. Mild mechanical aberrations may be interpreted as transient, variable or constant pressure, tightness, or pain. With increasing afferent barrage, sensory input increases until the sensory receptors reach a nociceptive threshold which is transmitted to first-order central neurons of the spinal cord gray matter and to the dorsal columns. Chemical modulators present in inflammation or after tissue injury enhance pain perception by reducing the stimulation threshold of nociceptors. Ascending pathways of nociception are then modulated by descending inhibitory controls and ultimately integrated into the somatosensory cerebral cortex, resulting in conscious pain perception. In the lower extremities, reduced nutritive blood sup-ply to tissues can cause immediate pain at an early stage which progresses to sensory impairment and finally anesthesia as ischemia persists. Motor nerves and muscles exposed to profound ischemia also become dysfunctional but are relatively tolerant compared with sensory nerves.

In addition to afferent input involving sensory receptors, pain may be produced by direct mechanical compression of a peripheral nerve or nerve root. In the case of the lower extremity, the site of compression is frequently above the inguinal ligament, although the pain radiates along the course of the nerve in the leg itself. Other neuropathic symptoms may be caused by diseases particular to the nerves themselves or by systemic illnesses with associated neuropathological changes.

Ultimately, chronic painful stimuli may initiate a series of complicated inter-connections and responses within the spinal cord and brain, producing histopathological and physiological changes in the CNS. These CNS abberations can then themselves cause a persistence of pain, even when the original afferent stimulus is no longer causing nociception. This is thought to be the basis of centrally mediated chronic pain syndromes such as deafferentiation pain, spinal cord injury pain, and phantom pain. Finally, pain has effects on cognition and affect (anxiety and fear), autonomic function (reflex vasoconstriction, pupillary dilatation, tachycardia) and involuntary motor function (reflex withdrawal, muscle cramping adjacent to injury).

Mechanical stimulation

Mechanical distortion of normal tissue anatomy produces stimulation of a variety of sensory receptors located throughout the lower extremity. External stimuli are sensed at the skin level. Pacinian corpuscles in the subcutaneous tissue detect pressure. Merkel’s cells and tactile disks in the subepidermal region gauge pressure intensity. Meissner’s corpuscles and hair follicle receptors in the dermis detect motion of hair or skin. Ruffini endings in the dermis detect skin stretch. All of these receptors transmit afferent signals via myelinated fast fibers. More sparsely distributed mechanoreceptors conduct sensa-tions of tickling or crawling via unmyelinated slow fibers. Internal stimuli are sensed by receptors in joints, muscles and tendons. Pacinian corpuscles or free nerve endings in the joints, muscle spindles, and tendons are responsible for proprioception, which allows determination of position, movement and force.

Thermal and mechanical nociceptors are distributed at the skin level. Noxious mechanical insults such as pinching, compression, and sprains stimulate mechanical nociceptors in the subcutaneous and deeper tissues. When tissues are traumatized by mechanical forces, inflammatory mediators are released which greatly magnify receptor sensitivity and result in heightened pain perception.

Support's development and hosting


Inflammation accompanies a variety of insults including mechanical trauma, infection, intravascular thrombosis, tissue infarction, and autoimmune or aller-gic phenomena. Numerous substances are released after these insults which mediate or facilitate the inflammatory process. These substances include histamine, serotonin, bradykinin, substance P, platelet activating factor, free radicals, tumor necrosis factor, prostaglandins, thromboxanes and leukotrienes. Histamine is released from mast cells immediately following injury and results in local vasodilatation with increased local blood flow (rubor, calor). Increased flow and capillary permeability as well as release of intracellular contents by tissue injury contribute to swelling (tumor). Pain (dolor) is produced by a combination of nociceptor stimulation related to the inciting injury, stretching of tissues due to swelling, and a lowering of nociceptive thresholds induced by inflammatory mediators and resulting in hyperalgesia and allodynia.

Sensitivity of nociceptors in peripheral tissues is increased especially by bradykinin, histamine, prostaglandins, cytokines, and by tumor necrosis factor. Prostaglandins and leukotrienes are arachidonic acid metabolites which work synergistically via vasoactive amines/kinins and leukocytes, respectively, to amplify pain. Cyclo-oxygenase inhibitors such as ibuprofen decrease pain by decreasing production of these metabolites, as well as via central mechanisms. Though the release of inflammatory mediators is essential to eventual healing, the inflammatory process itself may compound injury and result in persistent pain states in some instances.


Decreased oxygen delivery to tissues results in localized acidosis. Persistence of hypoxia results in cellular injury with release of intracellular products such as potassium and production of oxygen free radicals. An inflammatory response occurs with involvement of the mediators mentioned above. All of these byproducts of ischemia stimulate nociceptors. In syndromes involving reversible ischemia such as intermittent claudication, clearance of noxious byproducts by resumption of normal circulation results in diminution of pain. With prolonged ischemia, afferent nerves themselves suffer permanent ischemic damage and this may result in a chronic neuropathic pain state. Motor nerves and muscles tend to be more resistant than sensory nerves to the effects of prolonged ischemia.


Neuropathic pain results from increased peripheral and central sensitization, which may abnormally persist even after afferent impulses originating in the nerves themselves eventually diminish. This occurs because of (i) abnormally lowered pain thresholds due to increased sensitivity of the nervous system, (ii) increased ectopic discharge related to peripheral nerve injury, compression or disease, and (iii) increased afferent convergence which is accompanied by dysfunctional central modulation. The net result may be a ‘centralization’ of pain, with CNS changes which result in chronic pain which is independent of peripheral input.

In the case of blunt nerve trauma, injury over the trunk of the nerve usually creates a brief discharge with subsequent near-total loss of afferent and efferent traffic, including pain. Often, the loss of peripheral afferent input from either trauma to the nerve receptor or sharp partial or complete nerve transaction results in hyperexcitability of the severed nerve endings. In these cases, ectopic afferent signals are generated by a variety of stimuli such as mechanical, thermal, ischemic and chemical (such as tissue acidosis, histamine, bradykinins, 5-hydroxytryptamine, prostaglandins, cytokines, neutrophils, etc.). Spontaneous firing with little or no ongoing stimulus is also typical of chronic neuropathic pain. As regeneration occurs after injury, free nerve endings create ectopic hyperexcitability (i.e. neuromas), which is thought to result from the proliferation of excess voltage-sensitive sodium channels in the damaged nerve remnant. The absence of myelin in an injured nerve and the upregulation of sodium channel synthesis which results from an injury lead to enhanced neuropathic sensitivity which may become chronic if the nerve endings fail to reconnect distally.

Many diseases are associated with nerve degeneration with accompanying cycles of demyelination and regeneration. This activity leads to abnormal spontaneous discharging of the nerve, which is interpreted as a mixed array of unpleasant afferent sensations. In addition, coupling between the sensory afferent system and the sympathetic nervous system may occur, a phenomenon which is thought to contribute to allodynia and ongoing pain after nerve injury. In sympathetically maintained pain states, such as some cases of reflex sympathetic dystrophy (RSD, now called CRPS, type 1 ‘complex regional pain syndrome’), pain may be relieved by sympathetic blockade. Injured afferent neurons may exhibit upregulation of adrenoreceptors, with increased á2 adrenoreceptor release of norepinephrine, all of which may exacerbate pain.

Central modulation and plasticity

Permanent integration of pain into the CNS involves the complex interface between perception and transduction of peripheral stimuli into the CNS along with processing and modulation of stimuli and perception. Chronic noxious mechanical, inflammatory, ischemic or neuropathic sensory input initiates a series of events within the CNS with the result that perception of pain persists either out of proportion to the stimulus or in the absence of the original stimulus.

Noxious stimulation results in a hyperexcitable state in dorsal horn neurons which manifests itself by the development of ‘windup’, by enhancement of cutaneous receptive fields, and by the nociceptive neuron’s acquisition of wide-dynamic-range (WDR) neuron properties. Windup describes a progressively increased response which occurs when nociceptive fibers are stimulated. As the nociceptive neuron acquires WDR neuron characteristics, it begins to respond even to innocuous stimuli. Activation of WDR neurons involves release of glutamate, an excitatory neurotransmitter, which stimulates the N-methyl-D-aspartate receptor, sustaining a hypersensitized state.

Chronically painful conditions such as phantom limb pain, complex regional pain syndrome, and persistent lumbar radiculopathy involve a complex interplay between the mechanisms of peripheral and central sensitization.

Amputation involves the severing of sensory and motor axons, which leads to abnormal, ectopic impulse discharge, stimulating spinal sensory pathways and triggering central sensitization. Increased sympathetic efferent activity will often exacerbate phantom pain. The fact that phantom pain can persist in spite of dorsal rhizotomy or spinal cord transection illustrates a probable central component of pain. In addition, the ‘memory’ that patients have of painful ulcers and other lesions on amputated extremities suggests centralization of pain. Habitual perception of pain and other sensory stimuli continues for a variable time despite the absence of the limb.

Complex regional pain syndrome is an example in which a relatively small initial stimulus in the form of trauma may result in a chronic pain syndrome which may progress to disuse atrophy and disability despite apparent healing at the site of the trauma. Sympathetic stimulation and relief of pain by sympathetic blockade in some cases suggests that sympathetic efferents may be coupled to nociceptive afferents. It has been shown that nerve injury causes sprouting of sympathetic endings in the dorsal root ganglion (DRG), thereby stimulating discharge from the DRG. Finally, in chronic lumbar radiculopathy, an initial disc herniation may lead to a release of inflammatory mediators or to actual compression, both of which may cause neuronal dam-age and ectopic discharge. The DRG may be compressed directly or be pulled by a herniated disc, and this may cause further ectopic neuronal discharge, possibly leading to central sensitization of pain.


In summary, sensory pain perception involves a complex interplay of afferent nociceptive pathway stimulation, impulse modulation, and peripheral and central sensitization. Mechanical stimulation and ischemia may cause release of inflammatory mediators, which results in neuronal damage and sensitization. Neuropathic pain mechanisms depend on peripheral afferent input, spontaneous ectopic discharge, and integration of pain into the CNS. Sensory coupling may occur with the sympathetic nervous system. The phenomenon of windup may occur, along with an expansion of receptive fields and the perception of non-noxious stimuli as painful.

Suggested reading

  • Bridges D, Thompson SWN, Rice ASL. Mechanisms of neuropathic pain. Br J Anaes 2001; 87:12–26.
  • Codere TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to patho-logical pain: review of clinical and experimental evidence. Pain 1993; 52:259–285.
  • Devor M. Pain mechanisms. Neuroscientist 1996; 2:233–244.
  • Devor M. Neurobiology of normal and pathophysiological pain. In: Aronoff GM, ed. Evaluation and Treatment of Chronic Pain, 3rd edn. Baltimore: Williams & Wilkins, 1999; 11–25.
  • Jensen TS. Mechanisms of neuropathic pain. In: Campbell JN, ed. PainAn Updated Review. Seattle: IASP Press, 1996; 77–86.
  • Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413:203–210. Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th edn. New York: McGraw-Hill, Inc., 2000.
  • Katz J, Melzack R. Pain “memories” in phantom limbs: review and clinical observations. Pain 1990; 43:319–336.
  • Levine J, Taiwo Y. Inflammatory pain. In: Wall PD, Melzack R, eds. Textbook of Pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994; 45–56.
  • McLachlan EM, Janig W, Devor M, Michaelis M. Peripheral nerve injury triggers noradrener-gic sprouting within dorsal root ganglia. Nature 1993; 363:543–546.
  • Meyer RA, Campbell JN, Raja SN. Peripheral neural mechanisms of nociception. In: Wall PD,
  • Melzack R, eds. Textbook of Pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994; 13–44. Newshaw DJ, Edwards RHT, Mills KR. Skeletal muscle pain, In: Wall PD, Melzack R, eds.
  • Textbook of Pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994; 423–440.
  • Rang HP, Bevan S, Dray A. Peripheral neuropathies. In: Wall PD, Melzack R, eds. Textbook of Pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994; 57–78.
  • Scadding JW. Peripheral neuropathies. In: Wall PD, Melzack R, eds. Textbook of Pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994; 667–683.

About the author

Many tips are based on recent research, while others were known in ancient times. But they have all been proven to be effective. So keep this website close at hand and make the advice it offers a part of your daily life.