Reducing and eliminating Neuropathic pain.
Abstract: Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the central and/or peripheral nervous systems, including infection, trauma, metabolic abnormalities, and nerve compression, and is typically accompanied by hyperalgesia and allodynia. Neuropathic pain can be mild to excruciating, debilitating, difficult to manage, cause depression, decrease the quality of life, require extremity amputations, and has a variety of clinical symptoms. It effects up to 5% of the population, 70% of patients with advanced cancer and inflammatory pathologies, and 95% of patients with spinal cord injuries. The primary treatments of neuropathic pain are antidepressants, anticonvulsants, local anesthetic/topical agents, and opioids. The rapidly evolving symptom- and mechanism-based approaches to the treatment of neuropathic pain holds promise for improving the quality of life of patients with neuropathic pain. However, pharmacological treatment of the symptoms are difficult because of the limited understanding of the underlying causes of the pain, and the systemic levels of multiple side effects induced by various agents at an effective dose. Further, neuropathic pain is often refractory to conventional analgesic treatments, with most patients obtaining only partial relief with these agents, and with tolerability or side effects often limiting their use. Alternative treatments to pharmacology include peripheral or neuraxial nerve blockade, and implanted cortical or spinal cord stimulators. However, the great need remains for development of new and more effective approaches to reducing neuropathic pain. This review examines various approaches currently used for treatment of neuropathic pain and potential new and more effective approaches.

Key words: Chronic pain, Nerve injury, Peripheral nerve trauma

El dolor neuropatico es iniciado, o causado por una lesion primaria o disfuncion en el sistema nervioso central y/o periferal. Esto incluye infeccion, trauma, abnormalidades metabolicas y compresion nerviosa; y esta acompanado tipicamente por hiperalgesia y alodinia. El dolor neuropatico puede ser de leve a alta intensidad y causarproblemas de debilidad motora, depresion, afectar la calidad de vida, amputaciones de extremidades, y una variedad de sintomas clinicos. Esta condicion, afecta hasta un 5% de la poblacion general, a un 70% de los pacientes con cancer en estadios avanzados y patologia inflamatoria, y a 95% de los pacientes con lesiones en la espina dorsal. Los tratamientos primarios para el dolor neuropatico incluyen el use de antidepresivos, anticonvulsantes, anestesicos locales/agentes topicos y opioides. Los tratamientos basados en la sintomatologia del dolor neuropatico evolucionan rapidamente y poseen la promesa de mejorar la calidad de vida de estos pacientes. Sin embargo, el tratamiento farmacologico de los sintomas es dificil por el conocimiento limitado de las causas que llevan al dolor, y los multiples efectos secundarios de varios agentes en sus dosis efectivos. Mas aun, el dolor neuropatico es frecuentemente refractario a tratamientos analgesicos convencionales, con la mayoria de los pacientes obteniendo solo un alivio parcial con estos agentes, y con tolerancia o efectos secundarios que limitan su uso. Los tratamientos alternos a los farmacologicos incluyen bloqueo periferal o neuralgial e implantes de estimuladores corticales o espinales. Sin embargo, existe una gran necesidad de nuevos y mss efectivos acercamientos para reducir el dolor neuropatico. Este articulo examina varios acercamientos utilizados actualmente para el tratamiento del dolor neuropatico, y ademas de posibles y mss efectivos tratamientos.
Article Type: Perspectiva general de la condicion medica
Authors: Santiago-Figueroa, Jose
Kuffler, Damien P.
Pub Date: 12/01/2009
Publication: Name: Puerto Rico Health Sciences Journal Publisher: Universidad de Puerto Rico, Recinto de Ciencias Medicas Language: Spanish Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 Universidad de Puerto Rico, Recinto de Ciencias Medicas ISSN: 0738-0658
Issue: Date: Dec, 2009 Source Volume: 28 Source Issue: 4
Geographic: Geographic Name: Puerto Rico
Accession Number: 212102667
Full Text: Neuropathic pain is defined as chronic pain initiated or caused by a primary lesion or dysfunction in either the central or peripheral nervous systems, including infection, trauma, metabolic abnormalities, and nerve compression. It is characterized by spontaneous burning pain and/or ongoing pain with accompanying hyperalgesia and allodynia (1-2). Traumatic peripheral nerve injury also increases the excitability of nociceptors in and around nerve trunks and involves components released from nerve terminals (neurogenic inflammation) and immunological and vascular components (pronociceptive mediators) from cells resident within or recruited into the affected area (3-4).

Neuropathic pain is difficult to manage, devastating, debilitating, causes depression, decreases quality of life, and has a variety of clinical symptoms. It has been estimated that up to 5% of the population suffers, 70% of patients with advanced cancer and inflammatory pathologies, and about 95% of patients with spinal cord injuries suffer neuropathic pain (5-7).

The primary agents used to treat neuropathic pain are antidepressants, anticonvulsants, local anesthetic/topical agents, and opioids (8-10). The efficacy of these treatments, excepting opioids, was discovered serendipitously. The rapidly evolving symptom- and mechanism-based approach to the treatment of neuropathic pain holds promise for improving the quality of life of patients with neuropathic pain.

The pharmacological treatment of the symptoms of painful neuropathy is difficult, because of the limited understanding of the underlying causes of the pain, and the systemic levels of multiple side effects induced by various agents at an effective dose. Further, neuropathic pain is often refractory to conventional analgesic treatments, with most patients obtaining only partial relief with these agents and the tolerability of side effects is often limiting (11-12). Although most pharmacological agents have been used alone, some have been found to be more effective when combined. In addition to pharmacological interventions, there are alternative treatments including peripheral or neuraxial nerve blockade, implanted spinal cord stimulators.

There is an extensive and exciting literature dealing with the biophysics of pain receptors, and the mechanisms of their activation and inactivation. Discussing this area is beyond the scope of this review. Therefore, we have restricted ourselves to an examination of some, but not all of the many and varied pharmacological and cellular approaches being pursued to reduce or eliminate neuropathic pain. What is clear is that although many techniques are effective, few are ideal. Still, novel compounds and new regimens are emerging for drug treatment to influence activity-dependent long-term changes in pain transducing and suppressive systems (pain matrix). However, work that is far more extensive is required to develop an approach with consistent, permanent and effective analgesic effects.

Neuropathic Pain

Complete or even partial peripheral nerve injury leads to the sensitization of nociceptors in the skin to mechanical and heat stimuli (13-14). This nociceptor sensitization can contribute to neuropathic pain (13, 15). Despite many decades of drug development, effective therapies for reducing neuropathic pain remain elusive thus, neuropathic pain, caused or initiated by a primary lesion in the peripheral or central nervous system, can result in a dramatic reduction in the patient's quality of life. The expression neuropathic pain covers a heterogeneous group of conditions including peripheral neuropathy, complex regional pain syndrome, trigeminal neuralgia and central pain. Neuropathic pain poorly responds to conventional analgesics. However, with appropriate therapy, a significant proportion of patients experience a substantial pain reduction.

The term "spinal neuropathic pain" describes chronic neuropathic pain resulting from the aggravation of spinal nerve roots by scar tissue, and is different from the pain of spinal cord injury (16). Spinal neuropathic pain involves longstanding back and radicular pain (nerve root pain, predominantly in the limbs) caused by scar or inflammatory tissue around the nerve roots. The cause of the pain is at least in part due to spinal cord adhesions that compromise biomechanics of the nerve. Since movement can generate additional pain, physiotherapy for such patients may induce increased pain. Therefore, physical therapy for such patients must be tailored to their situation (16).

Elimination of Neuropathic Pain by Target Reinnervation

For years it has been hypothesized that reduction in neuropathic pain following a nerve trauma is in part correlated to the extent of neurological recovery, with the greater the recovery the greater the reduction or elimination of neuropathic pain (17-22). However, neuropathic pain can persist even following good nerve re-innervation, or when there is no apparent loss of neurological function (21-23). In the case of peripheral neuropathies or amputations in which there is no peripheral target to reinnervate, how can the neuropathic pain be reduced or eliminated? Therefore, questions remain as to whether there is really a correlation between the extent of neuropathic pain and the extent of nerve reinnervation, and how can neuropathic pain be reduced or eliminated in the many types of cases in which it exists.

Peripheral plus Central Nervous System Involvement in Neuropathic Pain

Aunilateral nerve section andligationleads to abilateral decrease in nociceptive threshold (24). This bilateral development indicates the both the central and peripheral nervous systems are involved in the establishment and maintenance of chronic pain (25-26).

Mediators and Blockers of Neuropathic Pain

Nerve Hyperexcitability

Nerve injury frequently triggers hyperexcitability and the ectopic initiation of action potentials in primary afferent axons leading to neuropathic pain (22-23). Primary afferent hyperexcitability results from injury causing modifications of sodium channel turnover in neural membranes, and sodium channels to accumulate in preterminal axolemma, neuroma end bulbs and DRG somata (27-29). These changes appear to occur because of the myelin removal and the loss of the targets the axons innervate, which restrict sodium channel accumulation, which in turn prevents afferent hyperexcitability in injured nerve (27).

Sodium Channel Blockers

The voltage-gated sodium channels that underlie the action potential are main targets for clinically useful drugs in the pain therapy, especially because they have therapeutic efficacy with doses are far below those that impair nerve impulse propagation or cardiovascular function (30-32). Lidocaine and tramadol, both sodium channel Mockers, provide pain relief against neuropathic pain in patients with spinal cord injury (33-34). Intravenous lidocaine administration is also effective for opioid refractory pain and is well tolerated (35). However, direct NMDA receptor antagonists and high-affinity channel Mockers show limited therapeutic potential (36).

Tetrodotoxin-resistant and tetrodotoxin-sensitive Na+ channels contribute to the abnormal spontaneous firing in dorsal root ganglion neurons, which is associated with neuropathic pain (37). The actions of the antinociceptive agent ralfinamide results from its inhibition of tetrodotoxin-resistant and tetrodotoxin-sensitive sodium currents in rat dorsal root ganglion neurons (37).

Efforts have also focused on glycine/d-seriee co-agonist function, including partial glycine agonists, pain in the antagonist dose range, for the treatment of neuropathic (36). An alternate approachto partial glycine agonists is to inhibit the uptake carriers for glycine and thus potentiating the lifetime of synaptic glycine (36).

Glial Cells

Activated glial cells (microglia and astroglia) in the spinal cord play a major role in mediating enhanced pain states by releasing proinfiammatory cytokines and other substances thought to facilitate pain transmission (38-46). Intrathecal administration of minocycline, a selective inhibitor of microglial cell activation, inhibits low threshold mechanical allodynia (42, 47). However, its ameliorating influences are short-lived, suggesting that microglial activation is involved in initiating, rather than maintaining, enhanced neuropathic pain responses (47).

Nerve transection leads to CNS neuroimmune activation and subsequent cytokine expression (48-50), whichleads to the stimulation of membrane-bound microglial Toll-like receptor 4 (TLR4) and painful neuropathy (51). This it turn leads to hypersensitivity in a mouse and rat model of neuropathy, which is prevented by blocking TLR4 (51).

Activation of extracellular signal-regulated kinase (ERK), a mitogen activated-protein kinase (MAPK), in dorsal horn and DRG neurons contributes to inflammatory pain by transcription-dependent and -independent means and with different time courses (52).

5HT / Serotonin

The intrathecal injection of a chronically applied, low local dose of 5-hydroxytryptamine (serotonin) near the dorsal horn reverses the development of chronic neuropathic pain (53-54). This activation cooperates with nociceptive stimulation, paradoxically causing analgesia, and inverse tolerance develops so that the resulting analgesia increases (54). This action against nociceptive pain is as effective as large doses of high-efficacy muopioid receptor agonists.

Opiates

Opioids are typically reserved for moderate to severe pain that cannot be relieved by the non-steroidal anti-inflammatory drugs (NSAIDs). Opioids are often used in combination with other adjuvants or other analgesic agents. The advantage of opioids is the lack of a ceiling effect of the pure mu opioid agonists. Their disadvantages are a series of mechanism-based opioids-related side effects (e.g., nausea, drowsiness, constipation) and the potential issue of their abuse and misuse. Each patient needs to undergo a comprehensive evaluation and receive education on the treatment. The physician must be well conversant with the differential diagnosis and definitions of physical dependence, tolerance, pseudotolerance, aberrant behaviors, addiction, and pseudoaddiction. No specific opioid drug is intrinsically "better" than the others are. Opioid rotation refers to the switch from one opioid to another when the degree of analgesia obtained is limited by the persistence of adverse effects or the occurrence of clinically relevant tolerance (55).

Transdermal vs. Oral Delivery

As chronic pain increases special consideration is required with respect to drug delivery, drug interactions and adherence. In particular, patients with chronic neurological diseases often require multiple administrations of drugs during the day to maintain constant plasma medication levels, which in turn increases the likelihood of poor adherence. Transdermal delivery of opioids fentanyl, morphine and buprenorphine play an important role in the management of neuropathic pain (56-57) with their-benefits comparable to those seen with oral formulations.

NMDA + Opioids

There are mixed results from many pre-clinical and clinical studies as to whether the addition of N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan (DM), to opioid analgesics, such as morphine (MS), enhances the analgesic effects and prevent the tolerance that may result from chronic opioid administration. A recent large study determined that no statistically significant differences between treatment groups in any primary or secondary efficacy variables were demonstrated, suggesting that adding the NMDA antagonist, dextromethorphan, to opioids does not add any clinical benefit (58).

The available drugs to treat neuropathic pain have incomplete efficacy and dose-limiting adverse effects. Gabapentin and morphine are effective analgesics in patients withpainful diabetic neuropathy orposttherapeutic neuralgia (59-60). However, when combined they achieve better analgesia at lower doses of each drug than either as a single agent (60-62).

In some patients with long-lasting or recurrent pain, severe enough to markedly reduce their quality of life, and for whom no other more effective and less risky therapy is available, opioid analgesics may reduce intensity of pain, increase functioning and improve quality of life for prolonged periods. The type of pain and pain history of the patients do not predict reliably the chance of long-term success or risk of complications from opioid therapy. However, the outlook for successful long term opioid therapy is better in a patient with a stable psychosocial situation having nociceptive type pain that is markedly relieved by a moderate dose of a long lasting oral or transdermal opioid, than a patient from a complex and unstable psychosocial background having neuropathic type pain that is relieved only partly by a higher dose of a potent opioid.

Following sciatic nerveligation, somepain-relatedbrain nuclei of neuropathic pain model rats show a significant increase in the opioid receptor like 1 receptor (ORL(1) mRNA expression, which last for 2 weeks. Nociceptin/ orphanin FQ (N/OFQ), the endogenous ligand of ORL(1), plays an important role in nociceptive transmission of neuropathic pain through its receptor.

Ketamine + Morphine

Low doses of epidural ketamine combined with morphine and bupivacaine increases their mean duration of satisfactory analgesia without severe adverse effects and restores quality of life when traditional therapy fails (63-64). Ketamine plus morphine is also recommended when morphine alone is no longer effective (64).

Methadone

Methadone appears to have unique properties, including N-methyl-D-aspartate antagonist activity, which may make it especially useful in the management of intractable neuropathic pain (65-67).

Proenkephalin A

Local overproduction of proenkephalin A-derived peptides in trigeminal ganglion sensory neurons evokes a potent antiallodynic effect through the stimulation of mainly peripherally located opioid receptors (68-69). This finding suggests that targeted delivery of endogenous opioids may serve to treat some severe forms of neuropathic pain.

Anti-depressants and Anti-Epileptics

Antidepressants and antiepileptic drugs are useful in the treatment of neuropathic pain (70-71). Tricyclic antidepressants are the most cost-effective agents, but second-generation antiepileptic drugs are associated with fewer safety concerns in elderly patients (72). Recent evidence suggests that duloxetine and pregabalin have modest efficacy in patients with fibromyalgia (73).

Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain (74).

Antidepressants that variously affect both noradrenalin and serotonin levels have more potent and efficacious antinociceptive effects than serotonin reuptake inhibitors (SSRIs) (as exemplified by citalopram), against a range of pain-like behaviors in an animal model of neuropathic pain (75-76).

Anti-Convulsants

Pregabalin and Gabapentin are anticonvulsant drugs used for the treatment of adults withperipheral neuropathic pain and inflammatory pain in animal and human studies. They result in significant decreases in pain scores in about 50% of the patients (77-78). Gabapentin administration was associated with sedation and anxiolysis but not lightheadedness, dizziness, nausea, or vomiting (78).

Calcium Channels

Hyperexcitability of axotomized dorsal root ganglion neurons is thought to play a role in neuropathic pain (79-80). Numerous changes in ionic channels expression or current amplitude are reported after an axotomy. One of the most significant changes is an increased intracellular calcium concentration, whichleads to increased excitability of axotomized sensory neurons (81). Pregabalin, a new drug that interacts with the alpha(2)-delta protein subunit of the voltage-gated calcium channel, is an efficacious in reducing calcium channel-induced pain (82).

Anti-inflammatories

Spinal cord glia and glial pro-inflammatory cytokines are important contributors to neuropathic pain. Acetaminophen and anti-infiammatories are first-line drugs for mild to moderate pain (83-84). The anti-inflammatory cytokine interleukin-10 (IL-10) suppresses the production of pro-inflammatory cytokines and intrathecal administration of IL-10 transiently prevents and reversing neuropathic pain (83-84). Similarly, peripheral nerve injury results in a significant increase in IL,-6 protein and messenger RNA in the rat spinal cord associated with and neuropathic pain (85). Administration of antibodies that neutralize interleukin-6 block the pain (85).

Monoamine Uptake Inhibitors

Chronic intrathecal administration of the selective uptake inhibitors of the monoamines noradrenalin and serotonin (antidepressants) provide antiallodynic effects against neuropathic pain due to ligation of spinal nerves (75, 86-88).

Yanilloid Receptor

The vanilloid receptor 1 (VR1) is highly localized on nociceptive neurons and their peripheral and central processes (89). Potent and selective antagonists of the vanilloid receptor 1 (VR1) effectively relieve acute and chronic inflammatory pain and post-operative pain (90-91).

Resiniferatoxin (RTX), an excitotoxic VR1 agonist, kills VRl-positive neurons (92-93). Intraganglionic RTX infusion ablates VR1-positive neurons and selectively eliminates hyperalgesia and neurogenic inflammation without affecting tactile sensation and motor function (92).

Neurotrophic Factors

CGRP and NGF

The calcitonin gene-related peptide (CGRP) is involved in neuropathic pain (94-96), and is up-regulated in a small population of large- and medium-sized primary sensory neurons after peripheral nerve injury. In adult animals, the expression of CGRP is regulated by nerve growth factor (NGF). After nerve injury, NGF is up-regulated at the injury site for several weeks, and this up-regulation contributes to the onset of neuropathic pain (94).

Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization (97).

BDNF Sequestering

The binding of spinally released BDNF to the TrkB receptor following nerve ligation results in the development of a neuropathic pain (3 9, 98-99). However, the thermal hyperalgesia and tactile allodynia are completely suppressed by repeated intrathecal injection of the TrkB protein, which sequesters endogenous brain-derived neurotrophic factor (BDNF) (99).

GDNF

Glial cell line-derived neurotrophic factor (GDNF) both prevents and reverses sensory abnormalities that develop in neuropathic pain models, without affecting pain-related behavior in normal animals (100-101). GDNF acts by reducing ectopic discharges within sensory neurons after nerve injury. This may arise because of the reversal by GDNF of the injury-induced plasticity of several sodium channel subunits (100). Chronic nerve constriction injury in the rat results in significant increases in protein and mRNA levels of GDNF and GFRalpha-1 in the dorsal root ganglions (DRG), and of GDNF protein in the spinal dorsal horn (102). These increases are further enhanced by electro-acupuncture, which leads to potent analgesia of neuropathic pain (103).

Tumor necrosis factor-alpha (TNF-?) and norepinephrine (NE)

Following trauma, and with the onset of neuropathic pain, brain neurons show increased levels of tumor necrosis factor-alpha (TNF), and the TNF inhibits norepinephrine (NE) release dependent on alpha(2)-adrenergic activation(44). However, the enhanced inhibition of NE release by TNF at the peak hyperalgesia (day-8) changes to a facilitation of NE release at later times, which parallels the decreased neuron production of TNF (74). Chronic antidepressant drug administration also lead to similar results (74). Therefore, adrenergic drugs inhibit increased pain sensitivity (hyperalgesia) by decreasing TNF production, thereby inducing increased NE release (104-105). Thus, while TNF directs the development of hyperalgesia, it is also involved in the resolution of pain, which points to a possible mechanism for management of chronic pain.

Neurotransmitters

Action potentials generated in nociceptors and injured nerve fibers release excitatory neurotransmitters at their synaptic terminals such as L-glutamate and substance P and trigger cellular events in the central nervous system that extend over different time frames. Short-term alterations of neuronal excitability, reflected for example in rapid changes of neuronal discharge activity, are sensitive to conventional analgesics, and do not commonly involve alterations in activity-dependent gene expression.

GABA

The gamma-amino butyric acid (GABA) transporter inhibitor has anti-thermal hyperalgesia and anti-tactile allodynia effects in neuropathic rats (106-107).

Nociceptinlorphanin FQ NlOFQ receptor antagonist

Nociceptin, also called orphanin FQ (N/OFQ), is the natural ligand of the opioid receptor-like 1 receptor (ORL-1), and is classified as the fourth member of the opioid family of receptors and named OP(4). Systemic and spinal administration of the nociceptin receptor antagonist JTC-801 exerts anti-allodynic and anti-hyperalgesic effects in rats (108). This suggests that the nociceptin system is involved in the modulation of neuropathic pain and inflammatory hyperalgesia (108-109).

Glutamate

Changes in glutamatergic neurotransmission within the spinal cord, resulting from the expression and efficacy of glutamate transporters following nerve injury, contributes to hyperalgesic and allodynia (110-112). This results from spinal nerve ligation producing attenuated glutamate uptake activity in the deep dorsal and ventral horn, the projection regions of excitatory, pain transmitting primary afferent neurons that utilize glutamate as an excitatory neurotransmitter (111).

Peripheral and central metabotropic glutamate receptors (mG1uRs) play a role in pain nociceptive synaptic transmission during inflammatory or neuropathic pain states (106, 113-114). Therefore, mG1uR5 antagonists provide a therapeutic treatment of post-operative pain (106, 114-116).

Acetylcholine

Neuronal acetylcholine receptor (nAChR) agonists have anti-allodynic effect (117-118). However, spinal nerve ligation is associated with a marked down regulation of functional nAChRs in DRG somata in parallel to development of allodynia (119).

Adrenoreceptor

Systemic administration of the alphal-adrenoreceptor (AR) antagonist prazosin attenuates in a dose-dependent manner cold allodynia in a rat tall model of neuropathic pain (120). However, the pain is exacerbated by alpha2-AR antagonistyohimbine (106).

Peripheral axotomy induces the expression of plasminogen activators in dorsal root ganglia (DRG) neurons, which play crucial roles in generating neuropathic pain (121-122). The plasminogen activator inhibitor-1 and -2 (PAI-1 and PAI-2) mRNA, endogenous inhibitors of tPA and uPA, are induced in the DRG following sciatic nerve transection and may act in an autocrine manner to modulate extracellular proteolytic activity after nerve injury (121).

Cannabinoid: CB1 and CB2-cannabinoid-receptor agonist

Cannabinoids are potent therapeutic agents in chronic pain management. Central and systemic administration of natural, synthetic and endogenous Cannabinoids produce antinociceptive and antihyperalgesic effects in both acute and chronic animal pain models. Much of the existing data suggest that the analgesic effects of Cannabinoids are mediated via neuronal CB 1 receptors, CB 1-receptor stimulation modulates the activity of the vanilloid receptor 1 (VRl) transient receptor potential in cultured rat DRG cells. CB1 analgesia could act by inhibiting either capsaicin-induced Ca(2+) influx, or potentiating capsaicin-induced substance-P release through involvement of a cyclic-AMP-dependent PKA pathway (59).

However, there is increasing evidence for a role for peripheral CB2 receptors, which are expressed preferentially on immune cells (123). Chronic pain models associated with peripheral nerve injury, but not peripheral inflammation, induce CB2 receptor expression in a highly restricted and specific manner within the lumbar spinal cord and the appearance of CB2 expression coincides with the appearance of activated microglia (123). Selective cannabinoid CB2 receptor agonists reduce neuropathic pain and inhibit acute inflammatory responses. These influences are without eliciting central nervous system-mediated side effects, associated with non-selective cannabinoid agonists, since the CNS lacks CB(2) receptors (124-126).

Alternative Techniques

Surgical interventions used to reduce neuropathic pain include nerve resection (127), neuroma removal (128-131), and dorsal root lesions (131-137). However, further studies are required to examine the efficacy combinations of several methods using analgesics, surgery and introduction of compounds such as neurotrophic factors in reducing neuropathic pain.

Caloric Intake

Long-term caloric restriction leads to significant hypoalgesia (138).

Electrical Stimulation

An alternative treatment to pharmacological interventions to reduce neuropathic pain is electrical stimulation of peripheral nerves (136, 139-142), in the brain (136, 143-145), and the spinal cord (145-152).

Electrical stimulation of the spinal cord stimulation provides a significant (>50%)and long-lasting (>1 year) reduction in chronic neuropathic pain in the majority of patients tested (124, 136, 152-153). Spinal cord stimulation also reduces by half the number of patients who require opiate analgesics (151-152).

Frequency-modulated electromagnetic neural stimulation results in a significant reduction in painful diabetic neuropathy (150).

Electrical stimulation of the motor cortex produces significant transient inhibition of the responses of spinal cord dorsal horn neurons to higher intensity mechanical stimuli without affecting their response to an innocuous stimulus (154-155). Although the magnitude and duration of the benefit are highly variable, with a significant percentage of patients losing pain relief over time, intensive reprogramming can recapture the benefit of MCS in patients who have lost pain control (155).

New Alternatives for Alleviating Neuropathic Pain

Although many pharmacological approaches reduce or eliminate neuropathic pain, each alone has its limitations. More extensive studies are required to examine the efficacy combinations of several analgesics and other compounds acting in concert. However, pharmacological treatment of the symptoms of painful neuropathy is difficult because of the limited understanding of the underlying causes of the pain, and the multiple and sometimes incapacitating side effects of agents at their effective doses. Since neuropathic pain is often refractory to conventional analgesic treatments, most patients obtain only partial relief with these agents, and their tolerability is often limiting, alternative non-pharmacological approaches to treating neuropathic pain are still required.

We recently completed a small IRB-approved clinical study examining a novel approach for reestablishing neurological function following peripheral nerve trauma (unpublished results). The technique induced significantly more neurological recovery than the clinical "gold standard" using sensory nerve grafts. However, in addition to inducing restoration of sensory and motor function, the technique also reduced or eliminated the neuropathic pain in each patient, including two who were suffering excruciating neuropathic pain.

The technique involves the resection of the central nerve stump to the point where the nerve appears anatomically normal to visual inspection. Similarly, the distal nerve stump is trimmed until it looks to visual inspection to be free of scar tissue. Although trimming the nerve ends creates a longer nerve gap, it is essential to remove the scar tissue, which otherwise inhibits axon regeneration. A sheet of resorbable bovine pericardium collagen is then sewn into a tube slightly larger than the diameter of the nerve to be repaired. The nerve ends are then secured with sutures about 3-mm into the ends of the collagen tube. The collagen tube is then filled with a 3-dimensional fibrin matrix of autologous platelet-rich fibrin. The fibrin provides a matrix through which to regenerate, while the platelet-released factors that promote axon regeneration.

All the patients recovered from minimal to complete neurological function. In addition, 88% of the patients had a complete elimination in the neuropathic pain they suffered prior to the surgery, while one patient had his excruciating neuropathic pain reduced to tolerable.

Part of the elimination of neuropathic pain may have resulted from the damaged axons establishing appropriate neurological connections. However, we found no apparent correlation between the extents of neurological recovery and the reduction or elimination of neuropathic pain. In the case of one patient with excruciating neuropathic pain, his pain was reduced to tolerable, even though his neurological recovery was the least of all the patients. These results indicate that, although increasing neurological recovery may influence the reduction or elimination of neuropathic pain, additional other aspects of the technique probably played the major role in reducing and eliminating the neuropathic pain.

As stated earlier, neuropathic pain is in part attributed to neuroma and scar tissue formation of the proximal nerve stump. In addition to inducing neuropathic pain neuroma and scar tissue prevents axon regeneration (156). Such scars are produced by invading fibroblasts and this migration of fibroblasts is blocked by collagen tubularization (157). Therefore, we hypothesize that part of the reduction in neuropathic pain results from the collagen tube bridging the nerve gap reducing fibroblast invasion, neuroma and scar formation and thus the hyperexcitability of the lesioned axons.

The neuropathic pain may also be reduced by the platelet-released neurotrophic and wound healing factors. These factors could act directly on the severed axons and their growth cones to reduce the excitability of the damaged nociceptive axons. Such a reduction in excitability would reduce or eliminate spontaneously evoked action potentials that propagate along the axons of the nociceptive neurons and give rise to pain.

An alternative mode of action is that the platelet-released factors may be picked up by the damaged axons and be transported to the somas of the nociceptive neurons where they reduce the neuron's hyperexcitability. This could be accomplished by reestablishing the normal balance of calcium and sodium channels in the cell membrane, thereby increasing the neuron's threshold for excitation. The factors may function by acting on various targets, such as ion channels, G-protein coupled receptors, purinergic receptors, and chemokine receptors, and downstream regulators of protein phosphorylation.

[FIGURE 1 OMITTED]

Eliminating Neuropathic Pain in Amputees

The data from the patients on whom we applied our new nerve repair technique indicate that neuropathic pain was reduced or eliminated even when there was only marginal target reinnervation and neurological recovery. Therefore an exciting aspect of these findings is that even excruciating neuropathic pain can be reduced/ eliminated when the technique is applied many years post nerve trauma. Thus, as stated above, we hypothesize that the pain reduction or elimination results from the fibrin and the platelet-released factors acting singly or when combined, directly on the resectioned axons. This suggests that application of a variation of this technique might also reduce or eliminate the neuropathic pain of amputees. Approaches that might be effective are resectioning the nerve stump followed by applying autologous platelet-rich fibrin in an open or closed collagen tube, or its direct the application to the resectioned nerve stump without any collagen tube.

Testing whether application of platelet-rich fibrin is effective in reducing or eliminating neuropathic pain is a simple clinical study that is begging to be tested. It is also critical that the study be performed because of the large numbers of individuals who undergo amputations due to the current lack of a technique to repair long peripheral nerve gaps, and then suffer neuropathic pain. Such amputations are presently taking place in very large numbers, especially in individuals involved in present military conflicts.

Conclusion

We have seen the pain of patients suffering years of chronic excruciating neuropathic pain eliminated following a single application of platelet-rich fibrin to the central end of transected nerves. It is also remarkable that the neuropathic pain never reoccurred, even up to 4 years following the nerve repair surgery. Thus, application of this simple technique may make it possible to eliminate a lifetime of treatment with potent opioid and other pharmacological agents, with their attending side effects and even lack of effectiveness. Application of this technique may also be beneficial in reducing or eliminating other types of neuropathic pain. Clearly, it is vital to continue to study the application of additional techniques, such as electrical stimulation of the lesioned region of a nerve, administration of neurotrophic or other factors for their ability to reduce or eliminate neuropathic pain, when applied singly or in combination with platelet-rich fibrin.

References

(1.) Maag R, Baron R. Neuropathic pain: translational research and impact for patient care. Curr Pain Headache Rep 2006;10: 191-19s.

(2.) Niederberger E, Kuhlein H, Geisslinger G. Update on the pathobiology of neuropathic pain. Expert Rev Proteomics 2008;5: 799-818.

(3.) Jimenez-Diaz L, Geranton SM, Passmore GM, Leith JL, et al. Local translation in primary afferent fibers regulates nociception. PLoS ONE 2008;3:e1961.

(4.) Zieglgansberger W, Berthele A, Tolle TR. Understanding neuropathic pain. CNS Spectr 2005;10:298-308.

(5.) Goodchild CS, Nelson J, Cooke I, Ashby M, et al. Combination therapy with flupirtine and opioid: open-label case series in the treatment of neuropathic pain associated with cancer. Pain Med 2008;9:939-949.

(6.) de Leon-Casasola OA. Current developments in opioid therapy for management of cancer pain. Clin J Pain 2008;24(Suppl 10): S3-7.

(7.) Gosselin RD, Dansereau MA, Pohl M, Kitabgi P, et al. Chemokine network in the nervous system: a new target for pain relief. Curr Med Chem 2008;15:2866-2875.

(8.) Tzellos TG, Papazisis G, Amaniti E, Kouvelas D. Efficacy of pregabalin and gabapentin for neuropathic pain in spinal-cord injury: an evidence-based evaluation of the literature. Eur J Clin Pharmaco12008;64:851-858.

(9.) Baastrup C, Finnerup NB. Pharmacological management of neuropathic pain following spinal cord injury. CNS Drugs 2008;22:455-475.

(10.) Stepanovic-Petrovic RM, Tomic MA, Vuckovic SM, Paranos S, et al. The antinociceptive effects of anticonvulsants in a mouse visceral pain model. Anesth Analg 2008;106:1897-1903.

(11.) Freye E, Anderson-Hillemacher A, Ritzdorf I, Levy JV. Opioid rotation from high-dose morphine to transdermal buprenorphine (Transtec) in chronic pain patients. Pain Pract 2007;7: 123-129.

(12.) Jackson KC, 2nd. Pharmacotherapy for neuropathic pain. Pain Pract 2006;6:27-33.

(13.) Shim B, Kim DW, Kim BH, Nam TS, et al. Mechanical and heat sensitization of cutaneous nociceptors in rats with experimental peripheral neuropathy. Neuroscience 2005;132:193-201.

(14.) Katz EJ, Gold MS. Inflammatory hyperalgesia: a role for the C-fiber sensory neuron cell body? J Pain 2006;7:170-178.

(15.) Twining CM, Sloane EM, Schoeniger DK, Milligan ED, et al. Activation of the spinal cord complement cascade might contribute to mechanical allodynia induced by three animal models of spinal sensitization. J Pain 2005;6:174-183.

(16.) Lewis C. Physiotherapy and spinal nerve root adhesion: a caution. Physiother Res Int 2004;9:164-173.

(17.) Navarro X, Vivo M, Valero-Cabre A. Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol 2007;82:163-201.

(18.) Henry JL. Future basic science directions into mechanisms of neuropathic pain. J Orofac Pain 2004;18:306-310.

(19.) Gybels J, Kupers R, Nuttin B. What can the neurosurgeon offer in peripheral neuropathic pain? Acta Neurochir Suppl (alien) 1993;58:136-140.

(20.) Yoon YW, Na HS, Chung JM. Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain 1996;64:27-36.

(21.) Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006;52:77-92.

(22.) Berrios I, Castro C, Kuffler DP. Morphine: axon regeneration, neuroprotection, neurotoxicity, tolerance, and neuropathic pain. P R Health Sci J 2008;27:119-128.

(23.) Sung YJ, Ambron RT. Pathways that elicit long-term changes in gene expression in nociceptive neurons following nerve injury: contributions to neuropathic pain. Neural Res 2004;26:195-203.

(24.) Attal N, Filliatreau G, Perrot S, Jazat F, et al. Behavioural pain-related disorders and contribution of the saphenous nerve in crush and chronic constriction injury of the rat sciatic nerve. Pain 1994;59:301-312.

(25.) Yasuda T, Miki S, Yoshinaga N, Senba E. Effects of amitriptyline and gabapentin on bilateral hyperalgesia observed in an animal model of unilateral axotomy. Pain 2005;115:161-170.

(26.) Ma W, Eisenach JC. Morphological and pharmacological evidence for the role of peripheral prostaglandins in the pathogenesis of neuropathic pain. Eur J Neurosci 2002;15:1037-1047.

(27.) Devor M, Govrin-Lippmann R, Angelides K. Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J Neurosci 1993;13:1976-1992.

(28.) Shah BS, Rush AM, Liu S, Tyrrell L, et al. Contactin associates with sodium channel Nav 1.3 in native tissues and increases channel density at the cell surface. J Neurosci 2004;24:7387-7399.

(29.) Jiang YQ, Sun Q, Tu HY, Wan Y Characteristics of HCN channels and their participation in neuropathic pain. Neurochem Res 2008;33:1979-1989.

(30.) Amir R, Argoff CE, Bennett GJ, Cummins TR, et al. The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain 2006;7:S 1-29.

(31.) Akada Y, Ogawa S, Amano K, Fukudome Y, et al. Potent analgesic effects of a putative sodium channel blocker M58373 on formalin-induced and neuropathic pain in rats. Eur J Pharmacol 2006;536:248-255.

(32.) Kalso E. Sodium channel blockers in neuropathic pain. Curr Pharm Des 2005;11:3005-3011.

(33.) Finnerup NB, Biering-Sorensen F, Johannesen IL, Terkelsen AJ, et al. Intravenous Lidocaine Relieves Spinal Cord Injury Pain: A Randomized Controlled Trial. Anesthesiology 2005;102: 1023-1030.

(34.) Gunes Y, Mert T, Daglioglu YK, Ozbek H, et al. Effect of tramadol on regeneration after experimental sciatic nerve injury. Agri 2005;17:33-38.

(35.) Thomas J, Kronenberg R, Cox MC, Naco GC, et al. Intravenous lidocaine relieves severe pain: results of an inpatient hospice chart review. J Palliat Med 2004;7:660-667.

(36.) Wood PL. The NMDA receptor complex: a long and winding road to therapeutics. DDrugs 2005;8:229-235.

(37.) Stummann TC, Salvati P, Fariello RG, Faravelli L. The antinociceptive agent ralfinamide inhibits tetrodotoxin-resistant and tetrodotoxin-sensitive Na+ currents in dorsal root ganglion neurons. Eur J Pharmacol 2005;510:197-208.

(38.) Hansson E. Could chronic pain and spread of pain sensation be induced and maintained by glial activation? Acta Physiol (Oxf) 2006;187:321-327.

(39.) Li L, Xian CJ, Zhong JH, Zhou XF. Upregulation of brain-derived neurotrophic factor in the sensory pathway by selective motor nerve injury in adult rats. Neurotox Res 2006;9:269-283.

(40.) Narita M, Yoshida T, Nakajima M, Narita M, et al. Direct evidence for spinal cord microglia in the development of a neuropathic pain-like state in mice. J Neurochem 2006;97:1337-1348.

(41.) Milligan ED, Twining C, Chacur M, Biedenkapp J, et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 2003;23:1026-1040.

(42.) Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003;306:624-630.

(43.) Watkins LR, Milligan ED, Maier SF. Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Bio12003;521:1-21.

(44.) Xu JT, Xin WJ, Zang Y, Wu CY, et al. The role of tumor necrosis factor-alpha in the neuropathic pain induced by Lumbar 5 ventral root transection in rat. Pain 2006;123:306-321.

(45.) Tanga FY, Raghavendra V, Nutile-McMenemy N, Marks A, et al. Role of astrocytic S100beta in behavioral hypersensitivity in rodent models of neuropathic pain. Neuroscience 2006;140: 1003-1010.

(46.) Gordh T, Chu H, Sharma HS. Spinal nerve lesion alters blood-spinal cord bamer function and activates astrocytes in the rat. Pain 2006;124:211-221.

(47.) Ledeboer A, Sloane EM, Milligan ED, Frank MG, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005;115:71-83.

(48.) Tawfik VL, Nutile-McMenemy N, Lacroix-Fralish ML, Deleo JA. Efficacy of propentofylline, a glial modulating agent, on existing mechanical allodynia following peripheral nerve injury. Brain Behav Immun 2007;21:238-246.

(49.) Xie W, Liu X, Xuan H, Luo S, et al. Effect of betamethasone on neuropathic pain and cerebral expression of NF-kappaB and cytokines. Neurosci Lett 2006;393:255-259.

(50.) Ruohonen S, Khademi M, Jagodic M, Taskinen HS, et al. Cytokine responses during chronic denervation. J Neuroinflammation 2005;2:26.

(51.) Tanga FY, Nutile-McMenemy N, DeLeo JA. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci U S A 2005;102:5856-5861.

(52.) Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005;114:149-159.

(53.) Eaton MJ, Santiago DI, Dancausse HA, Whittemore SR. Lumbar transplants of immortalized serotonergic neurons alleviate chronic neuropathic pain. Pain 1997;72:59-69.

(54.) Colpaert FC. 5-HT(lA) receptor activation: new molecular and neuroadaptive mechanisms of pain relief. Curr Opin Investig Drugs 2006;7:40-47.

(55.) Coluzzi F, Pappagallo M. Opioid therapy for chronic noncancer pain: practice guidelines for initiation and maintenance of therapy. Minerva Anestesiol 2005;71:425-433.

(56.) Priano L, Gasco MR, Munro A. Transdermal treatment options for neurological disorders: impact on the elderly. Drugs Aging 2006;23:357-375.

(57.) Sittl R. Transdermal buprenorphine in the treatment of chronic pain. Expert Rev Neurother 2005;5:315-323.

(58.) Galer BS, Lee D, Ma T, Nagle B, et al. MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance. Pain 2005;115:284-295.

(59.) Sotozono C, He J, Tei M, Honma Y, et al. Effect of metalloproteinase inhibitor on corneal cytokine expression after alkali injury. Invest Ophthalmol Vis Sci 1999;40:2430-2434.

(60.) Chen LE, Liu K, Seaber AV, Katragadda S, et al. Recombinant human glial growth factor 2 (rhGGF2) improves functional recovery of crushed peripheral nerve (a double-blind study). Neurochem Int 1998;33:341-351.

(61.) Gilron I, Watson CP, Cahill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. Cmaj 2006;175:265-275.

(62.) Bennett MI. Gabapentin significantly improves analgesia in people receiving opioids for neuropathic cancer pain. Cancer Treat Rev 2005;31:58-62.

(63.) Sen S, Aydin ON, Aydin K. Beneficial effect of low-dose ketamine addition to epidural administration of morphine-bupivacame mixture for cancer pain in two cases. Pain Med 2006;7: 166-169.

(64.) Legge J, Ball N, Elliott DP. The potential role of ketamine in hospice analgesia: a literature review. Consult Pharm 2006;21: 51-57.

(65.) Moulin DE, Palma D, Wading C, Schulz V Methadone in the management of intractable neuropathic noncancer pain. Can J Neurol Sci 2005;32:340-343.

(66.) Sang CN. NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials. J Pain Symptom Manage 2000;19: S21-25.

(67.) Gagnon B, Bruera E. Differences in the ratios of morphine to methadone in patients with neuropathic pain versus non-neuropathic pain. JPain Symptom Manage 1999;18:120-125.

(68.) Meunier A, Latremoliere A, Mauborgne A, Bourgoin S, et al. Attenuation of pain-related behavior in a rat model of trigeminal neuropathic pain by viral-driven enkephalin overproduction in trigeminal ganglion neurons. Mol Ther 2005;11:608-616.

(69.) Przewlocki R, Przewlocka B. Opioids in chronic pain. Eur J Pharmacol 2001;429:79-91.

(70.) Coluzzi F, Mattia C. Mechanism-based treatment in chronic neuropathic pain: the role of antidepressants. Curr Pharm Des 2005;11:2945-2960.

(71.) Mico JA, Ardid D, Berrocoso E, and Eschalier A. Antidepressants and pain. Trends Pharmacol Sci 2006;27:348-354.

(72.) Gilron I and Flatters SJ. Gabapentin and pregabalin for the treatment of neuropathic pain: A review of laboratory and clinical evidence. Pain Res Manag 2006;11:16A-29A.

(73.) Maizels M and McCarberg B. Antidepressants and antiepileptic drugs for chronic non-cancer pain. Am Fam Physician 2005;71:483-490.

(74.) Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkelsen JD, et al. Retigabine: chemical synthesis to clinical application. CNS Drug Rev 2005;11:1-20.

(75.) Pedersen LH, Nielsen AN, and Blackburn-Munro G. Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain. Psychopharmacology (Berl) 2005;182:551-561.

(76.) Bomholt SF, Mikkelsen JD, and Blackburn-Munro G. Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain. Neuropharmacology 2005;48:252-263.

(77.) Hadj Tahar A. Pregabalin for peripheral neuropathic pain. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA) 2005: 4.

(78.) Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, et al. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med 2006;31:237-247.

(79.) Newton RA, Bingham S, Case PC, Sanger GJ, et al. Dorsal root ganglion neurons show increased expression of the calcium channel alpha2delta-1 subunit following partial sciatic nerve injury. Brain Res Mol Brain Res 2001;95:1-8.

(80.) Kim DS, Yoon CH, Lee SJ, Park SY, et al. Changes in voltage-gated calcium channel alpha(1) gene expression in rat dorsal root ganglia following peripheral nerve injury. Brain Res Mol Brain Res 2001;96:151-156.

(81.) Hilaire C, Inquimbert P, Al-Jumaily M, Greuet D, et al. Calcium dependence of axotomized sensory neurons excitability. Neurosci Lett 2005;380:330-334.

(82.) Richter RW, Portenoy R, Sharma U, Lamoreaux L, et al. Relief of painful diabetic peripheral neuropathy with pregabalin: A randomized, placebo-controlled trial. J Pain 2005;6:253-260.

(83.) Milligan ED, Sloane EM, Langer SJ, Cruz PE, et al. Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10. Mol Pain 2005;1:9.

(84.) Milligan ED, Langer SJ, Sloane EM, He L, et al. Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur J Neurosci 2005;21:2136-2148.

(85.) Arruda JL, Sweitzer S, Rutkowski MD, DeLeo JA. Intrathecal anti-IL-6 antibody and IgG attenuates peripheral nerve injury-induced mechanical allodynia in the rat: possible immune modulation in neuropathic pain. Brain Res 2000;879:216-225.

(86.) Yamanaka H, Obata K, Fukuoka T, Dai Y, et al. Induction of plasminogen activator inhibitor-1 and -2 in dorsal root ganglion neurons after peripheral nerve injury. Neuroscience 2005;132: 183-191.

(87.) Kirwin JL, Goren JL. Duloxetine: a dual serotonin-norepinephrine reuptake inhibitor for treatment of major depressive disorder. Pharmacotherapy 2005;25:396-410.

(88.) Obata H, Saito S, Koizuka S, Nishikawa K, et al. The monoamine-mediated antiallodynic effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a rat model of neuropathic pain. Anesth Analg 2005;100:1406-1410.

(89.) Jahnel R, Dreger M, Gillen C, Bender O, et al. Biochemical characterization of the vanilloid receptor 1 expressed in a dorsal root ganglia derived cell line. Eur J Biochem 2001;268:5489-5496.

(90.) El-Kouhen O, Lehto SG, Pan JB, Chang R, et al. Blockade of mG1uR 1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mG1uR1 receptor antagonist. Br J Pharmacol 2006;149: 761-774.

(91.) Valenzano KJ, Sun Q. Current perspectives on the therapeutic utility of VRl antagonists. Curr Med Chem 2004;11:3185-3202.

(92.) Tender GC, Walbridge S, Olah Z, Karai L, et al. Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation. J Neurosurg 2005;102:522-525.

(93.) Karai L, Brown DC, Mannes AJ, Connelly ST, et al. Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. J Clin Invest 2004;113:1344-1352.

(94.) Ruiz G, Banos JE. The effect of endoneurial nerve growth factor on calcitonin gene-related peptide expression in primary sensory neurons. Brain Res 2005;1042:44-52.

(95.) McLachlan EM, Hu P. Axonal sprouts containing calcitonin gene-related peptide and substance P form pericellular baskets around large diameter neurons after sciatic nerve transection in the rat. Neuroscience 1998;84:961-965.

(96.) Ma W, Bisby MA. Increase of calcitonin gene-related peptide immunoreactivity in the axonal fibers of the gracile nuclei of adult and aged rats after complete and partial sciatic nerve injuries. Exp Neurol 1998;152:137-149.

(97.) Sevcik MA, Ghilardi JR, Peters CM, Lindsay TH, et al. Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization. Pain 2005;115:128-141.

(98.) Zhou XF, Deng YS, Xian CJ, Zhong JH. Neurotrophins from dorsal root ganglia trigger allodynia after spinal nerve injury in rats. Eur J Neurosci 2000;12:100-105.

(99.) Yajima Y, Narita M, Usui A, Kaneko C, et al. Direct evidence for the involvement of brain-derived neurotrophic factor in the development of a neuropathic pain-like state in mice. J Neurochem 2005;93:584-594.

(100.) Boucher TJ, Okuse K, Bennett DL, Munson JB, et al. Potent analgesic effects of GDNF in neuropathic pain states. Science 2000;290:124-127.

(101.) Pezet S, Krzyzanowska A, Wong LF, Grist J, et al. Reversal of neurochemical changes and pain-related behavior in a model of neuropathic pain using modified lentiviral vectors expressing GDNF. Mol Ther 2006;13:1101-1109.

(102.) Hoke A, Cheng C, Zochodne DW. Expression of glial cell line-derived neurotrophic factor family of growth factors in peripheral nerve injury in rats. Neuroreport 2000;11:1651-1654.

(103.) Dong ZQ, Ma F, Xie H, Wang YQ, et al. Changes of expression of glial cell line-derived neurotrophic factor and its receptor in dorsal root ganglions and spinal dorsal horn during elec troacupuncture treatment in neuropathic pain rats. Neurosci Lett 2005;376:143-148.

(104.) Lee HL, Lee KM, Son SJ, Hwang SH, et al. Temporal expression of cytokines and their receptors mRNAs in a neuropathic pain model. Neuroreport 2004;15:2807-2811.

(105.) Ignatowski TA, Sud R, Reynolds JL, Knight PR, et al. The dissipation of neuropathic pain paradoxically involves the presence of tumor necrosis factor-alpha (TNF). Neuropharmacology 2005;48:448-460.

(106.) Choi BH, Zhu SJ, Kim SH, Kim BY, et al. Nerve repair using a vein graft filled with collagen gel. J Reconstr Microsurg 2005;21:267-272.

(107.) Zhu SS, Zeng YM, Wang JK, Yan R, et al. Inhibition of thermal hyperalgesia and tactile allodynia by intrathecal administration of gamma-aminobutyric acid transporter-1 inhibitor NO-711 in rats with chronic constriction injury. Sheng Li Xue Bao 2005;57: 233-239.

(108.) Tamai H, Sawamura S, Takeda K, Orii R, et al. Anti-allodynic and anti-hyperalgesic effects of nociceptin receptor antagonist, JTC-801, in rats after spinal nerve injury and inflammation. Eur J Pharmacol 2005;510:223-228.

(109.) Corradini L, Briscini L, Ongini E, Bertorelli R. The putative OP(4) antagonist, [Nphe(1)]nociceptin(1-13)NH(2), prevents the effects of nociceptin in neuropathic rats. Brain Res 2001;905:127-133.

(110.) Wang S, Lim G, Yang L, Sung B, et al. Downregulation of spinal glutamate transporter EAACl following nerve injury is regulated by central glucocorticoid receptors in rats. Pain 2006;120:78-85.

(111.) Binns BC, Huang Y, Goettl VM, Hackshaw KV, et al. Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat spinal nerve ligation model. Brain Res 2005;1041:38-47.

(112.) Sung B, Lim G, Mao J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 2003;23:2899-2910.

(113.) Sotgiu ML, Bellomi P, and Biella GE. The mG1uR5 selective antagonist 6-methyl-2-(phenylethynyl)-pyridine reduces the spinal neuron pain-related activity in mononeuropathic rats. Neurosci Lett 2003;342:85-88.

(114.) Simmons RM, Webster AA, Ka1raAB, Iyengar S. Group II mGluR receptor agonists are effective in persistent and neuropathic pain models in rats. Pharmacol Biochem Behav 2002;73:419-427.

(115.) Niederberger E, Schmidtko A, Rothstein JD, Geisslinger G, et al. Modulation of spinal nociceptive processing through the glutamate transporter GLT-1. Neuroscience 2003;116:81-87.

(116.) Neugebauer V, Canton SM. Peripheral metabotropic glutamate receptors as drug targets for pain relief. Expert Opin Ther Targets 2002;6:349-361.

(117.) Rueter LE, Kohlhaas KL, Curzon P, Surowy CS, et al. Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain. Pain 2003;103:269-276.

(118.) Mense S. Neurobiological basis for the use of botulinum toxin in pain therapy. J Neuro12004;251(Suppl 1):Il-7.

(119.) Dube GR, Kohlhaas KL, Rueter LE, Surowy CS, et al. Loss of functional neuronal nicotinic receptors in dorsal root ganglion neurons in a rat model of neuropathic pain. Neurosci Lett 2005;376:29-34.

(120.) Kim SK, Min BI, Kim JH, Hwang BG, et al. Effects of alpha1- and alpha2-adrenoreceptor antagonists on cold allodynia in a rat tail model of neuropathic pain. Brain Res 2005;1039: 207-210.

(121.) Yamanaka K, Inaba T, Nomura E, Hurwitz D, et al. Basic fibroblast growth factor treatment for skin ulcerations in scleroderma. Cutis 2005;76:373-376.

(122.) Yamanaka H, Obata K, Fukuoka T, Dai Y, et al. Tissue plasminogen activator in primary afferents induces dorsal horn excitability and pain response after peripheral nerve injury. Eur J Neurosci 2004;19:93-102.

(123.) Zhang J, Hoffert C, Vu HK, Groblewski T, et al. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci 2003;17: 2750-2754.

(124.) Sanderson JE, Ibrahim B, Waterhouse D, Palmer RB. Spinal electrical stimulation for intractable angina--long-term clinical outcome and safety. Eur Heart J 1994;15:810-814.

(125.) Valenzano KJ, Tafesse L, Lee G, Harrison JE, et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 2005;48:658-672.

(126.) Liang YC, Huang CC, Hsu KS. Therapeutic potential of cannabinoids in trigeminal neuralgia. err Drug Targets CNS Neurol Disord 2004;3:507-514.

(127.) Kingery WS, Fields RD, Kocsis JD. Diminished dorsal root GABA sensitivity following chronic peripheral nerve injury. Exp Neurol 1988;100:478-490.

(128.) Millheiser LS, Chen B. Severe vaginal pain caused by a neuroma in the rectovaginal septum after posterior colporrhaphy. Obstet Gynecol 2006;108:809-811.

(129.) Marcol W, Kotulska K, Larysz-Brysz M, Bierzynska-Macyszyn G, et al. Prevention of painful neuromms by oblique transection of peripheral nerves. J Neurosurg 2006;104:285-289.

(130.) Dellon AL, Kim J, Ducic I. Painful neuroma of the posterior cutaneous nerve of the forearm after surgery for lateral humeral epicondylitis. J Hand Surg Am 2004;29:387-390.

(131.) Won R, Lee BH, Park S, Kim SH, et al. Role of different peripheral components in the expression of neuropathic pain syndrome. Yonsei Med J 2000;41:354-361.

(132.) Sindou M, Jeanmonod D. Microsurgical DREZ-otomy for the treatment of spasticity and pain in the lower limbs. Neurosurgery 1989;24:655-670.

(133.) Sindou M, Rosati C, Millet MF, Beneton C. Selective posterior rhizotomy at the posterior radiculomedullary junction in the treatment of hyperspasticity and pain in the lower limbs. Neurochinurgie 1987;33:433-454.

(134.) Whitworth LA, Feler CA. Application of spinal ablative techniques for the treatment of benign chronic painful conditions: history, methods, and outcomes. Spine 2002;27:2607-2613.

(135.) Spaic M, Markovic N, Tadic R. Microsurgical DREZotomy for pain of spinal cord and Cauda equina injury origin: clinical characteristics of pain and implications for surgery in a series of 26 patients. Acta Neurochir (alien) 2002;144:453-462.

(136.) Meyerson BA. Neurosurgical approaches to pain treatment. Acta Anaesthesiol Scand 2001;45:1108-1113.

(137.) Danshaw CB. An anesthetic approach to amputation and pain syndromes. Phys Med Rehabil Clin N Am 2000;11:553-557.

(138.) Hargraves WA, Hentall ID. Analgesic effects of dietary caloric restriction in adult mice. Pain 2005;114:455-461.

(139.) Goroszeniuk T, Kothari S, Hamann W. Subcutaneous neuromodulating implant targeted at the site of pain. Reg Anesth Pain Med 2006;31:168-171.

(140.) Ainsworth L, Budelier K, Clinesmith M, Fiedler A, et al. Transcutaneous electrical nerve stimulation (TENS) reduces chronic hyperalgesia induced by muscle inflammation. Pain 2006;120:182-187.

(141.) Sluka KA, Vance CG, Lisi TL. High-frequency, but not low-frequency, transcutaneous electrical nerve stimulation reduces aspartate and glutamate release in the spinal cord dorsal horn. J Neurochem 2005;95:1794-1801.

(142.) Reichstein L, Labrenz S, Ziegler D, Martin S. Effective treatment of symptomatic diabetic polyneuropathy by high-frequency external muscle stimulation. Diabetologia 2005;48:824-828.

(143.) Miranda-Cardenas Y, Rojas-Piloni G, Martinez-Lorenzana G, Rodriguez-Jimenez J, et al. Oxytocin and electrical stimulation of the paraventricular hypothalamic nucleus produce antinociceptive effects that are reversed by an oxytocin antagonist. Pain 2006;122:182-189.

(144.) Villarreal CF, Kina VA, Prado WA. Antinociception induced by stimulating the anterior pretectal nucleus in two models of pain in rats. Clin Exp Pharmacol Physiol 2004;31:608-613.

(145.) Rushton DN. Electrical stimulation in the treatment of pain. Disabil Rehabil 2002;24:407-415.

(146.) Stanik-Hutt JA. Management options for angina refractory to maximal medical and surgical interventions. AACN Clin Issues 2005;16:320-332.

(147.) Bueno EA, Mamtani R, Frishman WH. Alternative approaches to the medical management of angina pectoris: acupuncture, electrical nerve stimulation, and spinal cord stimulation. Heart Dis 2001;3:236-241.

(148.) Mailis-Gagnon A, Furlan AD, Sandoval JA, Taylor R. Spinal cord stimulation for chronic pain. Cochrane Database Syst Rev 2004;CD003783.

(149.) Vijayan R, Ahmad TS. Spinal cord stimulation for treatment of failed back surgery syndrome--two case reports. Med J Malaysia 1999;54:509-513.

(150.) Bosi E, Conti M, Vermigli C, Cazzetta G, et al. Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy. Diabetologia 2005;48:817-823.

(151.) Daousi C, Benbow SJ, MacFarlane IA. Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabet Med 2005;22:393-398.

(152.) Sundaraj SR, Johnstone C, Noore F, Wynn P, et al. Spinal cord stimulation: a seven-year audit. J Clin Neurosci 2005;12:264-270.

(153.) Kemler MA, Barendse GA, van Kleef M, de Vet HC, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 2000;343:618-624.

(154.) Senapati AK, Huntington PJ, Peng YB. Spinal dorsal horn neuron response to mechanical stimuli is decreased by electrical stimulation of the primary motor cortex. Brain Res 2005;1036:173-179.

(155.) Henderson LP, Kuffler DP, Nicholls J, Zhang R. Structural and functional analysis of synaptic transmission between identified leech neurones in culture. J Physiol 1983;340:347-358.

(156.) McDougall S, Dallon J, Sherratt J, Maini P. Fibroblast migration and collagen deposition during dermal wound healing: mathematical modelling and clinical implications. Philos Transact A Math Phys Eng Sci 2006;364:1385-1405.

(157.) Spilker MH, Yannas IV, Kostyk SK, Norregaard TV, et al. The effects of tubulation on healing and scar formation after transection of the adult rat spinal cord. Restor Neurol Neurosci 2001;18:23-38.

JOSE SANTIAGO-FIGUEROA, MD *; DAMIEN P. KUFFLER, Ph D ([dagger])

* Department of Orthopedic Surgery, ([dagger]) Institute of Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico

Address correspondence to: Damien Kuffler, Institute of Neurobiology, 201 Blvd. del Valle, San Juan, PR 00901. Tel: 787-721-1235 * Fax: 787-725-1289 * Email: dkuffler@hotmail.com
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