Back and Neck Pain
Interstitial Cystitis
Nerve Pain Syndromes e.g. Carpal Tunnel
Reflex Sympathetic Dystrophy-Chronic Regional Pain Syndrome
Sports Injuries / Bursitis / Tendonitis/ Rotator cuff tear
Vulvar Vestibulitis Syndrome (VVS) / Vulvodynia

Arthritis means inflammation of the joints. People of all ages including children and young adults can develop arthritis. The symptoms are intermittent pain, swelling, redness and stiffness in the joints. There are many different types of arthritis, some of which are rheumatoid arthritis, osteoarthritis, infectious arthritis and spondylitis. In rheumatoid arthritis, and other autoimmune diseases like systemic lupus erythematosus (SLE), the joints are destroyed by the immune system. In Osteoarthritis, the biggest risk factor is a previous injury to the joint, ligament or cartilage. Injuries that seem to heal perfectly well appear to set up a process of deterioration that can produce severe pain and disability decades later. The injury need not be sustained in one episode. Long term or repeated trauma can have the same effect. TNF-alpha and Interleukin 1-beta play an important role in rheumatoid arthritis by mediating cytokines that cause inflammation and joint destruction. TNF-alpha, Interleukin 1-beta and Substance P are elevated in the joint fluids in patients with rheumatoid arthritis [32] [20]. These inflammatory mediators are also elevated in the joint fluid in patients with osteoarthritis albeit to a far less extent. Along with mechanical factors, growth factors and cytokines such as TGF beta 1, IL-1 alpha, IL-1 beta and TNF-alpha may be involved in the formation and growth of osteophytes, since these molecules can induce growth and differentiation of mesenchymal cells. The incidence and size of osteophytes may be decreased by inhibition of direct or indirect effects of these cytokines and growth factors on osteoid deposition in treated animals[33] [34] . Inhibition of IL-1 receptor also decreases the production of metalloproteinase enzymes collagenase-1 and stomelysin-1 in the synovial membrane and cartilage. These enzymes are involved in connective tissue breakdown [35] .


Back and neck pain most commonly results from injury to the muscle, disk, nerve, ligament or facet joints with subsequent inflammation and spasm. Degeneration of the disks or joints produces the same symptoms and occurs subsequent to aging, previous injury or excessive mechanical stresses that this region is subjected to because of its proximity to the sacrum in the lower back.

Herniated disk tissue (nucleus pulposus) produces a profound inflammatory reaction with release of inflammatory chemical mediators most especially Tumor Necrosis Factor Alpha. Subsequent to release of TNF-alpha, there is an increase in the formation of inflammatory mediator prostaglandin and Nitric Oxide. It is now known that Tumor Necrosis Factor Alpha is released by herniated disk tissue (nucleus pulposus), and is primarily responsible for the nerve injury and behavioral manifestations of experimental sciatica associated with herniated lumbar discs [36] [15]. This has been confirmed by numerous animal studies and research wherein application of disk tissue (nucleus pulposus) to a nerve results in nerve fiber injury, with reduction of nerve conduction velocity, intracapillary thrombus formation, and the intraneural edema formation [37] [16] [38] [17]. One study demonstrated that disk tissue (nucleus pulposus) increases inducible nitric oxide synthetase activity in spinal nerve roots and that nitric oxide synthetase inhibition reduces nucleus pulposus-induced swelling and prevents reduction of nerve-conduction velocity. According to the authors, the results suggest that nitric oxide is involved in the pathophysiological effects of disk tissue (nucleus pulposus) in disc herniation [39] [18]. Tumor Necrosis Factor Alpha and other inflammatory mediators induce phospholipase A2 activation. High levels of phospholipase A2 previously have been demonstrated in a small number of patients undergoing lumbar disc surgery. Phospholipase A2 is the enzyme responsible for the liberation of arachidonic acid from cell membranes at the site of inflammation and is considered to be the limiting agent in the production of inflammatory mediator prostaglandins and leukotrienes [40] [19]. Subsequent to the release of inflammatory mediators, activation of motor nerves that travel from the spinal cord to the muscles results in excessive muscle tension, spasm and pain. The vast majority of herniated disk pain is inflammatory in origin, can be treated medically and does not require surgery. Surgery is only indicated when there is compression of the nerve roots producing significant muscle weakness and or urinary or bowel incontinence.

FIBROMYALGIA. Fibromyalgia is a chronic, painful musculoskeletal disorder characterized by widespread pain, pressure hyperalgesia, morning stiffness, sleep disturbances including restless leg syndrome, mood disturbances, and fatigue. Other syndromes commonly associated with fibromyalgia include irritable bowel syndrome, interstitial cystitis, migraine headaches, temporomandibular joint dysfunction, dysequilibrium including nerve mediated hypotension, sicca syndrome, and growth hormone deficiency. Fibromyalgia is accompanied by activation of the inflammatory response system, without immune activation [41] [31]. In fact, there is some evidence that fibromyalgia is accompanied by some signs of immunosuppression [42][32]. Several studies have shown that there are increased levels of the inflammatory transmitter Substance P (SP) and calcitonin gene related peptide (CGRP) in the spinal fluid of patients with fibromyalgia syndrome (FMS) [43] [33] [44] [34] [45] [35]. The levels of platelet serotonin are also abnormal [46] [36]. Furthermore, in patients with fibromyalgia, the level of pain intensity is related to the spinal fluid level of arginine, which is a precursor to the inflammatory mediator nitric oxide (NO) [47] [37]. Another study found increases over time in blood levels of cytokines Interleukin -6, Interleukin -8 and Interleukin -1R antibody (IL-1Ra) whose release is stimulated by substance P. The study authors concluded that because Interleukin-8 promotes sympathetic pain and Interleukin -6 induces hypersensitivity to pain, fatigue and depression, both cytokines play a role in producing FM symptoms [48] [38].


Interstitial cystitis is a severe debilitating bladder disease characterized by unrelenting pelvic pain and urinary frequency. This sterile painful bladder disorder is associated with a defective glycosaminoglycan bladder mucosal layer and an increased number of activated mast cells. Mast cells are ubiquitous cells derived from the bone marrow and are responsible for allergic reactions as they release numerous vasodilatory, nociceptive and pro-inflammatory mediators in response to immunoglobulin E (IgE) and specific antigen. Mast cell secretion is also triggered by a number of peptides, such as bradykinin and substance P, and may also be involved in the development of inflammatory responses [49] . SP-containing nerve fibres are increased in the submucosa of the urinary bladder of interstitial cystitis (IC) patients and are frequently seen in juxtaposition to Mast cells [50] [51] . There is enhanced sympathetic innervation of the bladder in the submucosa and detrusor muscle. In interstitial cystitis the number of neurons positive for inflammatory mediator vasoactive intestinal polypeptide and neuropeptide Y is higher [52] . Substance P (SP) and bradykinin (BK) influence the excitatory motor innervation of the urinary bladder. These peptides potentiate the responses to the purinergic component of the neurogenic stimulation (that part of the contractile response that remains after treatment with atropine) and potentiate the responses to exogenously applied adenosine triphosphate (ATP) [53] . Significant elevations in Interleuken-2, Interleukin-6, and Interleukin-8 have also been found in the urine of subjects with active interstitial cystitis compared with subjects with interstitial cystitis in remission and control subjects [54] [39]

MIGRAINE. Migraine headache is caused by activation of trigeminal sensory fibers by known and unknown migraine triggers. There is subsequent release of inflammatory mediators from the trigeminal nerve. This leads to distention of the large meningeal blood vessels in the skull and brain and the development of a central sensitization within the trigeminal nucleus caudalis (TNC). Genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual [55] .

The painful neurogenic vasodilation of meningeal blood vessels is a key component of the inflammatory process during migraine headache. The cerebral circulation is supplied with two vasodilator systems: the parasympathetic system storing vasoactive intestinal peptide, peptide histidine isoleucine, acetylcholine and in a subpopulation of nerves neuropeptide Y, and the sensory system, mainly originating in the trigeminal ganglion, storing inflammatory mediator substance P, neurokinin A and calcitonin gene-related peptide (CGRP) [56] . A clear association between migraine and the release of inflammatory mediator calcitonin gene-related peptide (CGRP) and substance P (SP) has been demonstrated. Jugular plasma levels of the potent vasodilator, calcitonin gene-related peptide (CGRP) have been shown to be elevated in migraine headache. CGRP-mediated neurogenic dural vasodilation is blocked by anti-migraine drug dihydroergotamine, triptans, and opioids [57] . In cluster headache and in chronic paroxysmal hemicrania, there is additional release of inflammatory mediator vasoactive intestinal peptide (VIP) in association with facial symptoms (nasal congestion, runny nose) [58] . Immunocytochemical studies have revealed that cerebral blood vessels are invested with nerve fibers containing inflammatory mediator neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP). In addition, there are studies reporting the occurrence of putative neurotransmitters such as cholecystokinin, dynorphin B, galanin, gastrin releasing peptide, vasopressin, neurotensin, and somatostatin. The autonomic and sensory nerves occur as a longitudinally oriented network around large cerebral arteries. There is often a richer supply of nerve fibers around arteries than veins. The origin of these nerve fibers has been studied by retrograde tracing and denervation experiments. These techniques, in combination with immunocytochemistry, have revealed a rather extensive innervation pattern. Several ganglia, such as the superior cervical ganglion, the sphenopalatine ganglion, the otic ganglion, and small local ganglia at the base of the skull, contribute to the innervation. Sensory fibers seem to derive from the trigeminal ganglion, the jugular-nodose ganglionic complex, and from dorsal root ganglia at the cervical spine level C2. The noradrenergic and most of the NPY fibers derive from the superior cervical ganglion. A minor population of the NPY-containing fibers contains vasoactive intestinal peptide (VIP), instead of noradrenaline ( NA) and emanates from the sphenopalatine ganglion. The cholinergic and the vasoactive intestinal peptide (VIP)-containing fibers derive from the sphenopalatine ganglion, the otic ganglion, and from small local ganglia at the base of the skull. Most of the substance P (SP-), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP)-containing fibers derive from the trigeminal ganglion. Minor contributions may emanate from the jugular-nodose ganglionic complex and from the spinal dorsal root ganglia. Neuropeptide Y (NPY), is a potent vasoconstrictor in vitro and in situ. Vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) act via different mechanisms to induce cerebrovascular dilatation [59] . Meningeal blood vessels are involved in the generation of migraine pain and other headaches. Classical experiments have shown that blood vessels of the cranial dura mater are the most pain-sensitive intracranial structures. Dural blood vessels are supplied by trigeminal nerve fibers, and dilate in response to activation of the trigeminal nerves and release of neuropeptide cytokines such as substance P (SP) and calcitonin gene-related peptide (CGRP) [60] [14]. CGRP can be released experimentally from dural nerve fibers, and there is evidence that this occurs also during migraine attacks. Stimulation of dural nerve fibers causes vasodilatation and an increase in dural arterial flow, which depends on the release of CGRP but not SP. SP, on the other hand, is known to mediate plasma leakage (extravasation) from small veins in the dura mater. The dural arterial flow depends also on the formation of cell wall nitric oxide. The introduction of serotonin (5-HT1) receptor agonists such as sumatriptan changed the treatment strategies for migraine. Sumatriptan and other triptans may inhibit the release of inflammatory mediators from the trigeminal nerve. Sumatriptan has been shown to block the release of vasoactive cytokines from trigeminal nerves that surround the blood vessels in the dura mater during migraine. Sumatriptan blocks nerve fiber induced plasma extravasation but has only minor effects on nerve fiber mediated vasodilatation and dural arterial flow. Foods like cheese, beer, and wine can also induce migraine in some people because they contain the mediator histamine and/or mediator-like compounds that cause blood vessels to expand. Women tend to react to histamine-containing foods more frequently than men do, on account of a deficiency in an enzyme (diamine oxidase) that breaks histamine down. Taking supplemental B6 has been shown to be helpful in migraine, as it can increase diamine oxidase activity.

NERVE (NEUROPATHIC) PAIN SYNDROMES (e.g. carpal tunnel syndrome, trigeminal neuralgia, post herpetic neuralgia, phantom limb pain)

Nociceptive pain is mediated by receptors on A-delta and C nerve fibers, which are located in skin, bone, connective tissue, muscle and viscera. These receptors serve a biologically useful role at localizing noxious chemical, thermal and mechanical stimuli. Nociceptive pain can be somatic or visceral in nature. Somatic pain tends to be well-localized, constant pain that is described as sharp, aching, throbbing, or gnawing. Visceral pain, on the other hand, tends to be vague in distribution, spasmodic in nature and is usually described as deep, aching, squeezing and colicky in nature. Examples of nociceptive pain include: post-operative pain, pain associated with trauma, and the chronic pain of arthritis.

Neuropathic pain, in contrast to nociceptive pain, is described as “burning”, “electric”, “tingling”, and “shooting” in nature. It can be continuous or paroxysmal in presentation. Whereas nociceptive pain is caused by the stimulation of peripheral A-delta and C-polymodal pain receptors, by inflammatory mediators, (e.g. histamine bradykinin, substance P, etc.) neuropathic pain is produced by injury or damage to peripheral nerves or the central nervous system
The hallmarks of neuropathic pain are chronic allodynia and hyperalgesia. Allodynia is defined as pain resulting from a stimulus that ordinarily does not elicit a painful response (e.g. light touch). Hyperalgesia is defined as an increased sensitivity to normally painful stimuli.

Examples of neuropathic pain include carpal tunnel syndrome, trigeminal neuralgia, post herpetic neuralgia, phantom limb pain, complex regional pain syndromes and the various peripheral neuropathies.

Subsequent to nerve injury, there is increase in nerve traffic. Expression of sodium channels is altered significantly in response to injury thus leading to abnormal excitability in the sensory neurons. Nerve impulses arriving in the spinal cord stimulate the release of inflammatory protein Substance P. The presence of Substance P and other inflammatory proteins such as calcitonin gene-related peptide (CGRP) neurokinin A, vasoactive intestinal peptide removes magnesium induced inhibition and enables excitatory Inflammatory proteins such as glutamate and aspartate to activate specialized spinal cord NMDA receptors. This results in magnification of all nerve traffic and pain stimuli that arrive in the spinal cord from the periphery. In one study, monocytes/macrophages (ED-1), natural killer cells, T lymphocytes, and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), were significantly produced in nerve-injured rats. Interestingly, ED-1-, TNF-alpha- and InterLeukin-6-positive cells increased more markedly in allodynic rats than in non-allodynic ones. The magnitude of the inflammatory response was not related to the extent of damage to the nerve fibers because rats with complete transection of the nerves displayed much lower production of inflammatory cytokines than rats with partial transection of the nerve [61] . This is a finding commonly observed in patients where a minor injury results in severe pain that is out of proportion to the injury. Getting back to the study, the authors determined that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of Interleukin -6 and TNF-alpha. This may relate to the generation of touch allodynia/hyperalgesia, since there was a clear correlation between the number of ED-1 and Interleukin -6-positive cells and the degree of allodynia. Abnormal development of sensory-sympathetic connections follow nerve injury, and contribute to the hyperalgesia (abnormally severe pain) and allodynia (pain due to normally innocuous stimuli). These abnormal connections between sympathetic and sensory neurons arise in part due to sprouting of sympathetic axons. Studies have shown that sympathetic axons invade spinal cord dorsal root ganglia (DRG) following nerve injury, and activity in the resulting pericellular axonal ‘baskets’ may underlie painful sympathetic-sensory coupling [62] . Sympathetic sprouting into the DRG may be stimulated by neurotrophins such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin‑3 (NT‑3) and neurotrophin 4/5 (NT‑4/5). In another study, animals exhibiting heat hyperalgesia as a sign of neuropathic pain seven days after loose ligation of the sciatic nerve exhibited a significant increase in the concentration of brain derived neurotrophic factor (BDNF) in their lumbar spinal dorsal horn. [63] Administration of nerve growth factor to rodents has resulted in the rapid onset of hyperalgesia. In clinical trials with nerve growth factor for the treatment of Alzheimer disease and peripheral neuropathy, induction of pain has been the major adverse event [64] . In one study, the use of trkA-IgG, an inhibitor of Nerve Growth Factor (NGF) reduced neuroma formation and neuropathic pain in rats with peripheral nerve injury [65] In another study, the systemic administration of anti-nerve growth factor (NGF) antibodies significantly reduced the severity of autotomy (self mutilating behavior induced by nerve damage) and prevented the spread of collateral sprouting from the saphenous nerve into the sciatic innervation territory [66] . Activity in sympathetic fibers is associated with excessive sweating, temperature instability of the extremities and can induce further activity in sensitized pain receptors and, therefore, enhance pain and allodynia (sympathetically maintained pain). This pathologic interaction acts via noradrenaline released from sympathetic terminals and newly expressed receptors on the afferent neuron membrane [67] .

Activation of motor nerves that travel from the spinal cord to the muscles results in excessive muscle tension. More inflammatory mediators are released which then excite additional pain receptors in muscles, tendons and joints generating more nerve traffic and increased muscle spasm. Persistent abnormal spinal reflex transmission due to local injury or even inappropriate postural habits may then result in a vicious circle between muscle hypertension and pain [68] [5]. Separately, constant C-fiber nerve stimulation to transmission pathways in the spinal cord results in even more release of inflammatory mediators but this time within the spinal cord. The transcription factor, nuclear factor-kappa B (NF-kappaB), plays a pivotal role in regulating the production of inflammatory cytokines [69] . Inflammation causes increased production of the enzyme cyclooxygenase-2 (Cox-2), leading to the release of chemical mediators both in the area of injury and in the spinal cord. Widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the central nervous system elevates inflammatory mediator prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is inflammatory mediator interleukin-1 in the CNS [70] [6]. Basal levels of the enzyme phospholipase A2 activity in the CNS do not change with peripheral inflammation.. The central nervous system response to pain can keep increasing even though the painful stimulus from the injured tissue remains steady. This “wind-up” phenomenon in deep dorsal neurons can dramatically increase the injured person’s sensitivity to the pain.

Neurotrophic factors are a family of growth promoting proteins that are essential for the generation and survival of nerve cells during development. Neurotrophic factors promote growth of small sensory neurons and stimulate the regeneration of damaged nerve fibers. The neurotrophins are a polypeptide family within this broad class of factors that bind and activate tropomyosin receptor kinase (Trk), a transmembrane receptor tyrosine kinase. They consist of four members, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin‑3 (NT‑3) and neurotrophin 4/5 (NT‑4/5). Other neurotrophic factor families include the fibroblast growth factor (FGF) family, the insulin-like growth factors I and II, the ciliary neurotrophic factor (CNTF) family and the glial cell line derived neurotrophic factor (GDNF) family. All of these factors have survival and nerve outgrowth-promoting effects and some have been shown to have neuroprotective actions. Nerve growth factor and glial-derived neurotrophic factor modulate the activity of a sodium channel (NaN) that is preferentially expressed in pain signaling neurons that innervate the body (spinal cord dorsal root ganglion neurons) and face (trigeminal neurons). Transection of a nerve fiber (axotomy) results in an increased production of inflammatory cytokines and induces marked changes in the expression of sodium channels within the sensory neurons [71] . Following axotomy the density of slow (tetrodotoxin-resistant) sodium currents decrease and a rapidly repriming sodium current appears. The altered expression of sodium channels leads to abnormal excitability in the sensory neurons [72] . Studies have shown that these changes in sodium channel expression following axotomy may be attributed at least in part to the loss of retrogradely transported nerve growth factor [73] .

In addition to effects on sodium channels, there is a large reduction in potassium current subtypes following nerve transection and neuroma formation. Studies have shown that direct application of nerve growth factor to the injured nerve can prevent these changes [74] .


Reflex sympathetic dystrophy (RSD) syndrome also called Chronic Regional Pain Syndrome (CRPS) has been recognized clinically for many years. It is most often initiated by trauma to a nerve, neural plexus, or soft tissue. Diagnostic criteria are the presence of regional pain and other sensory changes following a painful injury. The pain is associated with changes in skin color, skin temperature, abnormal sweating, tissue swelling. With time, tissue atrophy may occur as well as involuntary movements, muscle spasms, or pseudoparalysis [75] [21]. Like other organs with a blood supply, the bones also react to the disturbances in permeability caused by various inflammatory mediators. There is fluid accumulation in the bones and loss of bone density (osteoporosis) [76] [22]. In addition, the inflammatory mediators accelerate the rate at which bone is broken down. The bone loss is further aggravated by decreased use of the affected body part due to pain. Complex regional pain syndrome, type I (reflex sympathetic dystrophy; CRPS-I/RSD) can spread from the initial site of presentation. In one study of 27 CRPS-I/RSD patients who experienced a significant spread of pain, three patterns of spread were identified. ‘Contiguous spread (CS)’ was noted in all 27 cases and was characterized by a gradual and significant enlargement of the area affected initially. ‘Independent spread (IS)’ was noted in 19 patients (70%) and was characterized by the appearance of CRPS-I in a location that was distant and non-contiguous with the initial site (e.g. CRPS-I/RSD appearing first in a foot, then in a hand). ‘Mirror-image spread (MS)’ was noted in four patients (15%) and was characterized by the appearance of symptoms on the opposite side in an area that closely matched in size and location the site of initial presentation. Only five patients (19%) suffered from CS alone; 70% also had IS, 11% also had MS, and one patient had all three kinds of spread [77] [23].. In 1942 Paul Sudeck suggested that the signs and symptoms of RSD/CRPS including sympathetic hyperactivity might be provoked by an exaggerated inflammatory response to injury or operation of an extremity. His theory found no followers, as most doctors incorrectly believe that RSD/CRPS is solely initiated by a hyperactive sympathetic system. Recent research and studies including various clinical and experimental investigations now provide support to the theory of Paul Sudeck[78] [24].

As we now understand, soft tissue or nerve injury causes excitation of sensory nerve fibers. Reverse (antidromic) firing of these sensory nerves causes release of the inflammatory neuropeptides at the peripheral endings of these fibers. These neuropeptides may induce vasodilation, increase vascular permeability, attract other immune cells such as T helper cells and excite surrounding sensory nerve fibers — a phenomenon referred to as neurogenic inflammation. At the level of the central nervous system, the increased input from peripheral pain receptors alters the central processing mechanisms. Sympathetic dysfunction, which often has been purported to play a pivotal role in RSD/CRPS, has been suggested to consist of an increased rate of outgoing (efferent) sympathetic nerve impulses towards the involved extremity induced by increased firing of the sensory nerves. However, the results of several experimental studies suggest that sympathetic dysfunction also consists of super sensitivity to catecholamines induced by nerve injury (autonomic denervation) [79] [25]. Part of this occurs due to injured sensory nerves and immune cells developing receptors for the chemical transmitter norepinephrine and epinephrine (catecholamines), which are normally released by sympathetic nerves and also circulate in the blood. Stimulation of these receptors by locally released or circulating catecholamines produces sympathetic effects such as sweating, excessive hair growth and narrowing of blood vessels [80] [26]. In addition and under certain conditions, catecholamines may boost regional immune responses, through increased release of Interleukin-1, tumor necrosis factor-alpha, and Interleukin-8 production. In several studies, patients with RSD/CRPS showed a markedly increased level of the inflammatory peptide bradykinin as well as calcitonin gene-related peptide [81] [27]. The levels of bradykinin were four times as high as the controls. A few showed increased levels of the other inflammatory chemical mediators [82] [28]. Two pain producing pathways have been identified: inflammatory stimuli induce the production of bradykinin, which stimulates the release of TNF-alpha . The TNF-alpha induces production of (i) Interleukin -6 and Interleukin -1b, which stimulate the production of cyclooxygenase products, and (ii) InterLeuken-8, which stimulates production of sympathomimetics (sympathetic hyperalgesia) [83][29]. Abnormal development of sensory-sympathetic connections follow nerve injury, and contribute to the hyperalgesia (abnormally severe pain) and allodynia (pain due to normally innocuous stimuli). These abnormal connections between sympathetic and sensory neurons arise in part due to sprouting of sympathetic axons. This can be induced by neurotrophins such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin‑3 (NT‑3) and neurotrophin 4/5 (NT‑4/5).


Inflammation of the bursa is known as bursitis. A bursa is a small sac containing fluid that lies between bone and other moving structures such as muscles, skin or tendons. The bursa allows smooth gliding between these structures. A bursa allows a tendon or muscle to move smoothly over a bone by acting as an anti-friction device and shielding the structures from rubbing against bones.. Bursae are found in the knee, elbow, shoulder and wrist. If the tendons become thickened and bumpy from excessive use, the bursa is subjected to increased friction and may become inflamed. Tendonitis is inflammation or irritation of a tendon. Tendons are the thick fibrous cords that attach muscles to bone. They function to transmit the power generated by a muscle contraction to move a bone. Since both tendons and bursae are located near joints, inflammation in these soft tissues will often be perceived by patients as joint pain and mistaken for arthritis. Symptoms of bursitis and tendonitis are similar: pain and stiffness aggravated by movement. Pain may be prominent at night. Almost any tendon or bursa in the body can be affected, but those located around a joint are affected most often. The most common cause of tendonitis and bursitis is injury or overuse during work or play, particularly if the patient is poorly conditioned, has bad posture, or uses the affected limb in an awkward position. Occasionally an infection within the bursa or tendon sheath will be responsible for the inflammation. Tendonitis or bursitis may be associated with diseases such as rheumatoid arthritis, gout, psoriatic arthritis, thyroid disease and diabetes. In one study of patients with rotator cuff diseases, the levels of the cytokine IL-1 beta was significantly correlated with the degree of pain. The combined results of immunohistochemistry indicated that both synovial lining and sublining cells produce IL-1beta, while synovial lining cells predominantly produce the anti-inflammatory intracellular InterLeukin-1 receptor antagonist (icIL-1ra) and sublining cells secrete secreted InterLeukin-1 receptor antagonist (sIL-1ra)[84] . In another study, the levels of IL-1 beta were significantly higher in the shoulder joints in patients with anterior instability and chronic inflammation of the joint [85] . In another study, immunohistological staining demonstrated the expression of Interleukin-1 beta (IL-1 beta), Tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), and basic fibroblast growth factor (bFGF) in subacromial bursa derived from the patients suffering from rotator cuff tear [86] .


Vulvar vestibulitis syndrome is a major subtype of vulvodynia. It is a constellation of symptoms and findings involving and limited to the vulvar vestibule that consists of: (1) severe pain on vestibular touch to attempted vaginal entry, (2) tenderness to pressure localized within the vulvar vestibule, and (3) physical findings confined to vulvar erythema of various degrees. The syndrome has been seen in association with subclinical human papillomavirus, chronic recurrent candidiasis, chronic recurrent bacterial vaginosis, chronic alteration of vaginal pH, and the use of chemical and destructive therapeutic agents [87] . In a study of VVS cases and asymptomatic controls, median tissue levels of inflammatory cytokines: IL-1 b and TNF-a, from selected regions of the vulva,, vestibule, and vagina were 2.3-fold and 1.8-fold elevated, respectively, in women with VVS compared to pain-free women. Analysis revealed a significant 2.2-fold higher median level of TNF alpha at the vulvar site compared to the vestibule. Cytokine elevations correlated poorly with inflammatory cell infiltrate and suggested cytokine production from another cell source. The study authors concluded that inflammatory cytokine elevation may contribute to the pathophysiology of mucocutaneous hyperalgesia [88]