Neuropathic Pain

Introduction

Pain is usually the natural consequence of tissue injury resulting in approximately forty million medical appointments per year. In general, as the healing process commences, the pain and tenderness associated with the injury will resolve. Unfortunately some individuals experience pain without an obvious injury or suffer protracted pain that persists for months or years after the initial insult. This pain condition is usually neuropathic in nature and accounts for a large number of patients presenting to pain clinics with chronic, nonñmalignant pain. Rather than the nervous system functioning properly to sound an alarm regarding tissue injury, in neuropathic pain the peripheral or central nervous systems are malfunctioning and become the cause of the pain.

Terminology

Acute pain and chronic pain differ in their etiology, pathophysiology, diagnosis and treatment. Acute pain is selfñlimiting and serves a protective biological function by acting as a warning of onñgoing tissue damage. It is a symptom of a disease process experienced in or around the injured or diseased tissue. Associated psychological symptoms are minimal and are usually limited to mild anxiety. Acute pain is nociceptive in nature, and occurs secondary to chemical, mechanical and thermal stimulation of Añdelta and Cñpolymodal pain receptors.

Chronic pain, on the other hand, serves no protective biological function. Rather than being the symptom of a disease process, chronic pain is itself a disease process. Chronic pain is unrelenting and not selfñlimiting and as stated earlier, can persist for years and even decades after the initial injury. Chronic pain can be refractory to multiple treatment modalities. If chronic pain is inadequately treated, associated symptoms can include chronic anxiety, fear, depression, sleeplessness and impairment of social interaction. Chronic, nonñmalignant pain is predominately neuropathic in nature and involves damage either to the peripheral or central nervous systems.

Nociceptive and neuropathic pain are caused by different neuroñphysiological processes, and therefore tend to respond to different treatment modalities. Nociceptive pain is mediated by receptors on Añdelta and Cñfibers 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, paroxysmal in nature and is usually described as deep, aching, squeezing and colicky in nature. Examples of nociceptive pain include: postñoperative pain, pain associated with trauma, and the chronic pain of arthritis. Nociceptive pain usually responds to opioids and nonñsteroidal antiñinflammatories (NSAIDS).

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 of Añdelta and Cñpolymodal pain receptors, by algogenic substances (eg. histamine bradykinin, substance P, etc.) neuropathic pain is produced by damage to, or pathological changes in the peripheral or central nervous systems.

Examples of pathological changes include prolonged peripheral or central neuronal sensitization, central sensitization related damage to nervous system inhibitory functions, and abnormal interactions between the somatic and sympathetic nervous systems. 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 (eg. light touch). Hyperalgesia is defined as an increased sensitivity to a normally painful stimuli. Primary hyperalgesia, caused by sensitization of Cñfibers, occurs immediately within the area of the injury. Secondary hyperalgesia, caused by sensitization of dorsal horn neurons, occurs in the undamaged area surrounding the injury.

Examples of neuropathic pain include: monoradiculopathies, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, complex regional pain syndromes and the various peripheral neuropathies. Neuropathic pain tends to be only partially responsive to opioid therapy.

Pathophysiology

The mechanisms involved in neuropathic pain are complex and involve both peripheral and central pathophysiologic phenomenon. The underlying dysfunction may involve deafferentation within the peripheral nervous system (eg. neuropathy), deafferentation within the central nervous system (eg. postñthalamic stroke) or an imbalance between the two (eg. phantom limb pain).

Peripheral Mechanisms:

Following a peripheral nerve injury (eg. crush, stretch, or axotomy) sensitization occurs which is characterized by spontaneous activity by the neuron, a lowered threshold for activation and increased response to a given stimulus. Should the injured nerve be a nociceptor then increased nervous discharge will equate to increased pain. Following nerve injury Cñfiber nociceptors can develop new adrenergic receptors and sensitivity, which may help to explain the mechanism of sympathetically maintained pain.

In addition to sensitization following damaged peripheral nerves, the formation of ectopic neuronal pacemakers can occur at various sites along the length of the nerve. Increased densities of abnormal or dysfunctional sodium channels are thought to be the cause of this ectopic activity.1,2,3 The sodium channels in damaged nerves differ pharmacologically and demonstrate different depolarization characteristics.4 This may explain the rationale of treatment with lidocaine, mexiletine, phenytoin, carbamazepine, and tricyclic antidepressants each of which blocks sodium channels. These ectopic pacemakers can occur in the proximal stump (eg. neuroma), in the cell bodies of the dorsal root ganglion, and in focal areas of demylenation along the axon. Neuromas are composed of abnormal sprouting axons and have a significant degree of sympathetic innervation.5 Neuromas have been reported to accumulate sodium channels at their distal ends which can modulate their sensitivity. They can acquire adrenergic sensitivity, as indicated by increased pain following injection of norepinephrine into the neuroma. Neuromas can also acquire sensitivity to catecholamines, prostanoids and cytokines.6 Novel ion channels or receptors, not found in normal nerves, appear to be expressed in the regenerating terminal/axon.4

Further animal investigations suggest that abnormal electrical connections can occur between adjacent demyelinated axons. These are referred to as ephapses. "Ephaptic cross talk" may result in the transfer of nerve impulses from one axon to another. Cross talk between A and C fibers develops in the dorsal root ganglion.7 Nerve growth trophic factors may be important in the elaboration of these changes.4 A similar event referred to as "crossed afterdischarge" has also been described whereby "the sprouts of primary afferents with damaged axons can be made to discharge at high frequencies by the discharge of other afferents."8 It is also theorized that injured nerves may contain ephapses between sensory and sympathetic fibers, and such crossñconnections may play a role in the pathogenesis of sympathetically mediated pain.

Neurogenic inflammation is a useful model for understanding pain and hyperalgesia.9 Neurogenic inflammation and the cascade of events following neural injury have been described.10 Inflammatory neuropeptides (substance P) and prostaglandins (PGE2) may be released from primary afferent nociceptors and sympathetic postganglionic neurons respectively,9,11 activating nearby receptors and triggering a process of spreading activation. These mechanisms may explain the clinical response of some neuropathic pain patients to topical nonsteroidal antiñinflammatory drugs, lidocaine, and capsaicin.9

The connective tissue sheath around peripheral nerves is innervated by the nervi nervorum. Injury, compression, and inflammation of the sheath may cause pain.12 In cancer patients, pain associated with tumor compression of neural structures is clinically indistinguishable from nonñmalignant neuropathic pain.9 This nervi nervorum related pain may resolve following tumor resection or treatment of tumor induced inflammation.9 Antiñinflammatory medications (NSAIDs and corticosteroids) have been shown to be effective in certain neuropathic pain conditions. The mechanism of pain relief may be decreased edema at the tumor or injury site.9 However these medications also have membranes stabilizing effects and central analgesic effects. Therefore it is extremely difficult to distinguish primary tumorñassociated inflammation and involvement of the nervi nervorum from other mechanisms of neuropathic pain.9

Central Mechanisms:

Following a peripheral nerve injury, anatomical and neuroñchemical changes can occur within the central nervous system (CNS) that can persist long after the injury has healed.13 This "CNS plasticity" may play an important role in the evolution of chronic, neuropathic pain. As is the case in the periphery, sensitization of neurons can occur within the dorsal horn following peripheral tissue damage and this is characterized by an increased spontaneous activity of the dorsal horn neurons, a decreased threshold and an increased responsivity to afferent input, and cell death in the spinal dorsal horn.14,15,16,17 In the nonñinjured state, A beta fibers (large myelinated afferents) penetrate the dorsal horn, travel ventrally, and terminate in lamina III and deeper. C fibers (small unmyelinated afferents) penetrate directly and generally terminate no deeper than lamina II. However, after peripheral nerve injury there is a prominent sprouting of large afferents dorsally from lamina III into laminae I and II.20 After peripheral nerve injury, these large afferents gain access to spinal regions involved in transmitting high intensity, noxious signals, instead of merely encoding low threshold information.18

Significant alterations have been shown in the dorsal horn ipsilateral to the injury. The mechanisms are likely related to the barrage of afferent impulses or the factors transported from the lesion site.4,9,21 Studies have revealed that peripheral nerve injury may lead to increased mRNA for specific neurotransmitters (e.g. substance P), differential temporal expression of mRNA and receptors,22 decreased levels of opiod binding sites,23,24,25 appearance of immediate early gene products (e.g. cñfos),26,27 of which the significance is that peripheral nerve injury is causing changes in the cell's synthesis of products, and alterations in the relative levels of neuropeptides/neuromodulators (e.g. increased galanin and VIP and reductions in sP and CGRP).4

Several forms of thermal or tactile hyperalgesia may involve the intercellular and intracellular messengers nitric oxide and arachidonic acid and metabolites.28,29,30 Cyclooxygenase inhibition appears to suppress tactile allodynia.4 Blockade of activation of protein kinase C has been shown to prevent behavioral neuropathic manifestations.31,32 Protein kinase C removes the voltage gating of the NMDA receptor, allowing activation of the receptor by glutamate.4 Protein kinase C may also modulate sodium channels.33

The injured axon may release factors which may be transported in a retrograde or orthograde fashion to initiate changes important to the development of a pain state.4,34 Thermal hyperalgesia has been prevented in the Bennett model of nerve injury by blocking axonal transport bidirectionally with colchicine.2,35 It has been shown also that colchicine blocks orthograde transport of tachykinins which may explain its ability to induce prolonged reductions in sciatic neurogenic extravasation at concentrations that spare Cñfiber nociceptor function.34

Repetitive noxious stimulation of unmyelinated Cñfibers can result in prolonged discharge of dorsal horn cells. This phenomenon which is termed "windñup", is a progressive increase in the number of action potentials elicited per stimulus that occurs in dorsal horn neurons.36 Repetitive episodes of "windñup" may precipitate longñterm potentiation (LTP), which involves a long lasting increase in the efficacy of synaptic transmission. Where "windñup" is thought to last only minutes, LTP by definition, lasts at least one hour and maybe even months. Both "windñup" and LTP are believed to be part of the sensitization process involved in many chronic pain states.

Animal studies suggest that expansion of receptive fields may also occur following tissue injury. Therefore, any peripheral stimulation would activate a greater number of dorsal horn cells because of an increased overlap of their receptive fields.

Evidence suggests that excessive nociceptive input to the dorsal horn can have excitotoxic consequences resulting in the death of inhibitory interneurons. This inhibition may contribute to spinal hyperñexcitability.

The allodynia and hyperalgesia associated with neuropathic pain may be best explained by: 1) the development of spontaneous activity of afferent input 2) the sprouting of large primary efferents (eg. Añbeta fibers from lamina 3 into lamina 1 and 2), 3) sprouting of sympathetic efferents into neuromas and dorsal root and ganglion cells, 4) elimination of intrinsic modulatory systems and 5) up regulation of receptors in the dorsal horn which mediate excitatory processes.

Recent animal studies have shown that dynamic and static hyperalgesia are probably mediated by different mechanisms,37 tactile allodynia and hyperalgesia are likely mediated by different mechanisms38,39 and repetitive thermal and mechanical stimuli are likely processed in different ways.40,41

On a cellular level, the central nervous system plastic changes appear to be associated with enhanced neurotransmission via the NMDA receptor. Under the appropriate conditions, appropriate Cñfiber stimulation can activate dorsal horn interñneurons, causing them to release excitatory amino acids (eg. aspartate and glutamate), which will excite wide dynamic range (WDR) neurons via the NMDA receptor. Hanai found that the C fiber response to stimulation of the superficial peroneal nerve consisted of three components: early, middle, and late.42 The separation into three components was found to be caused by asynchronous volleys in three different classes of C fibers in the superficial peroneal nerve.42 The phenomenon of wind up was observed to occur always in the late component, frequently in the middle component and to a far lesser extent in the early component.42 The NMDA antagonist, MK801 significantly suppressed the middle and late components of the C fiber response, although the effect on the early component was insignificant.42 NMDA receptor activation triggers a cascade of events leading to sensitization of dorsal horn wide dynamic range neurons then ensues. There is a significant increase in intracellular calcium and activation of protein kinases and phophorylating enzymes. NMDA receptor stimulation will also increase the production of spinal phospholipase and induce the production of nitric oxide synthetase. The prostaglandins and nitric oxide which are subsequently produced and released into the extracellular milieu can facilitate further release of excitatory amino acids and neuropeptides from primary afferent pain fibers. The NMDA receptor antagonists ketamine and dextromethorphan can block this cascade of events which contribute to sensitization.

Management of Neuropathic Pain

Early recognition and aggressive management of neuropathic pain is critical to successful outcome. Oftentimes, multiple treatment modalities are provided by an interdisciplinary management team. Numerous treatment modalities are available and include systemic medication, physical modalities (eg. physical rehabilitation), psychological modalities (eg. behavior modification, relaxation training), invasive procedures (eg. triggerñpoint injections, epidural steroids, sympathetic blocks), spinal cord stimulators, intrathecal morphine pump systems and various surgical techniques (eg. dorsal root entry zone lesions, cordotomy and sympathectomy). It should be noted that caution is warranted regarding the use of neuroablative techniques. Such approaches may produce deaffrentation and exacerbate the underlying neuropathic mechanisms. The focus of this review will be on pharmacological interventions.

As previously mentioned, most neuropathic pain responds poorly to NSAIDS and opioid analgesics. The mainstay of treatment are predominantly the tricyclic antidepressants (TCA's), the anticonvulsants and the systemic local anesthetics. Other pharmacological agents that have proven efficacious include the corticosteroids, topical therapy with substance P depletors, autonomic drugs and NMDA receptor antagonists.

The TCA's have been successfully used for the treatment of neuropathic pain for some 25 years. The mechanism of action for the alleviation of neuropathic pain is thought to be due to the inhibition of reñuptake of serotonin and norepinephrine within the dorsal horn,49 however, other possible mechanisms of action include alphañadrenergic blockade, sodium channel effects and NMDA receptor antagonism.

Amitriptyline is the prototypical tertiary amine. Other tertiary amines include imipramine, doxepine, clomipramine and trimipramine. Unlike the dosing regimen utilized for the treatment of depression doses of TCA's for treatment of neuropathic pain are considerably less. The typical dosing schedule for amitriptyline may be simply 10 mg orally at bedtime with a gradual escalation every three days, in 10 mg increments, to a maximum to 30 to 50 mg orally at bedtime. Furthermore, the onset analgesia usually occurs over several days versus the two weeks that are required for the onset of the antidepressant effects of the drugs.

The side effect profile of the TCA's include sedation and anticholinergic effects. Since these side effects are more prominent with the tertiary amines prudence would dictate the use of a secondary amine such as nortriptyline or desipramine, particularly in the elderly population who are more sensitive to the side effects.

The recently introduced selective serotonin reuptake inhibitors (SSRI's) have not proven to be as effective against neuropathic pain as anticipated. Fluoxetine (Prozac) only appears to relieve pain in patients with coñmorbid depression. Paroxetine (Paxil) has found some utility in the treatment of chronic, daily headaches. In general, the SSRI's are partially effective in the treatment of diabetic neuropathy, but not to the extent of the TCA's. Venlafaxine (Effexor) may have some analgesic effects since, like the TCA's, it inhibits the reuptake of both serotonin and norepinephrine. Its side effect profile is similar to the other SSRI's and can include agitation, insomnia, or somnolence, gastrointestinal distress and inhibition of sexual functioning. Anticholinergic side effects are less bothersome than with the TCA's.

The antiñconvulsant medications can be particularly effective treatment for neuropathic pain that is described as burning and lancinating in nature. Commonly used medications in this category include phenytoin, carbamazepine, valproic acid, clonazepam, and gabapentin.

Carbamazepine has proven to be particularly effective against glossopharyngeal neuralgia, post herpetic neuralgia, trigeminal neuralgia, and diabetic neuropathies. Should carbamazepine prove ineffective, it can be replaced with phenytoin. Unlike the other anticonvulsants, valproic acid has found some success in treating migraine headaches. The combination of an anticonvulsant with a TCA can be synergistic.

The mechanism of action of the anticonvulsant medications is thought to involve membrane stabilization. Evidence also suggests that some of the agents, such as carbamazepine and phenytoin can depress both segmental and descending excitatory pathways in the CNS and at the same time facilitate inhibitory mechanisms. For example, carbamazepine has been shown to inhibit the electrical C and A fiber evoked neuronal responses of spinal nerve ligated rats.50 Valproic acid, on the other hand, has been reported to increase gammañamino butyric acid (GABA) levels in the substantia nigra and corpus striatum. Gabapentin, which we will be discussing subsequently, reportedly increases extracellular GABA levels throughout the brain, including the thalamus and causes the release of GABA from glial cells. However it is unlikely that Gabapentin increases GABAergic tone because neither GABAa nor GABAb antagonists reverse the analgesic effects of Gabapentin.48

Because of the significant risks of the blood dyscrasias and liver dysfunction, baseline and periodic monitoring of blood chemistries and liver function tests are highly recommended when prescribing phenytoin, carbamazepine, or valproic acid.

Although clonazepam, a benzodiazepine, is usually used for the treatment of petite mal and myoclonic seizures, it has been successfully utilized to treat the lancinating and pain associated with phantom limb pain.51 Its mechanism of action may be associated with its reputed ability to enhance the inhibitory action of GABA within the CNS, and also possibly secondary to increased serotonin levels.

Gabapentin (Neurontin), 1ñ(aminomethyl) cyclohexaneñacetic acid, is an antiñepileptic drug which was introduced in 1993 and was originally approved for the treatment of partial seizures with or without secondary generalization. Recently, however, reports have documented its efficacy in the treatment of various neuropathic pain states such as complex regional pain syndrome, deafferentation neuropathy of the face, postherpetic neuralgia, sciatic type pain, and HIVñrelated neuropathy.52 The effective dose range is 30ñ300 mg/kg (systemic) and >37.5 mg/kg (IT).48 Gabapentin is reportedly completely ineffective in altering threshold responses to acute nociceptive stimuli at doses up to 300 mg/kg.53ñ56 Presently the mechanism of action as either an anticonvulsant or an analgesic is unknown. The antinociceptive effects are likely to be due to actions within the spinal cord, because 1000 times the IT dose is required to produce equianalgesic effects when given intraperitoneally.53,57 Gabapentin binds to the alpha 2 delta calcium channel subunit.48 However, the relationship between binding at this site and the analgesic properties of gabapentin have not been determined. The NMDA receptor complex may be a potential spinal locus for neuropathic pain relief , but it has not been conclusively found that this is the major site of action.48 Gabapentin has a relatively benign side effect profile and is well tolerated if dosing proceeds in a gradually escalating manner. It has few if any drug interactions and is primarily renally excreted. Although expensive, it does not require the routine monitoring of blood chemistries and liver functions tests like carbamazepine and phenytoin. To date, little evidence suggests the efficacy of felbamate or lamotrogine in the treatment of neuropathic pain. Further investigation is necessary.

The systemic local anesthetics which are commercially available include lidocaine, tocainide, and mexiletine. The assumed mechanism of action to effect analgesia is the acute blocking of sodium channels. Phenytoin, carbamazepine and tricyclic antidepressants also act as sodium channel blockers. Following the use of the TCA's and anticonvulsants, local anesthetics tend to be third line drugs. Lidocaine has proven effective for noncancer patients58 but not for those with cancer.59 In cancer patients tumor involvement of nervi nervorum with "nociceptive neuropathic pain" (as discussed earlier) may represent a different mechanism with variable response to therapy.9 The predictive value of lidocaine in determining the expected benefits of drugs such as mexilitene remains important in allowing us to move more efficiently through therapeutic trials.9 Recent studies have suggested that the duration and pattern of spontaneous discharge is dependent on the level and kinetics of Na+ slow channel inactivation.60 Slow inactivation of voltageñgated ion channels could be major factors in the induction and treatment of neuropathic pain.60 QXñ314, a positively charged lidocaine derivative which is frequently assumed to be membrane impermeant, has recently been shown to acutely block Na+ channels at nerve injury sites in rats.61 We avoid the use of tocainide because of unacceptable side effects which include blood dyscrasis and pulmonary fibrosis. Dosing of mexiletine is begun at 150 mg po qd and is slowly escalated by 150 mg q 72 hours to a maximum of 10 mg/kg/day as tolerated.62 The only absolute contraindication to the use of mexiletine is preñexisting second or third degree AV block or known allergy to the medication.

Autonomic drugs which are proven beneficial in the treatment of neuropathic pain include the alphañ2 agonists (eg. Clonidine) and alphañ1 antagonists (eg. prazosin, terazosin). The role of the 2 adrenergic system in neuropathic pain has been studied using various pharmacologic interventions and animal models.63 In animal studies, alpha 2 adrenergic agonists produce analgesia by actions in the periphery, supraspinal CNS, and in the spinal cord.64 Spaulding et al studies in mice suggested a primary spinal site of action.65 Clonidine is believed to produce analgesia at the spinal level in part through stimulation of cholinergic interneurons in the spinal cord. This cholinergic mediation of analgesia, as reflected by CSF acetylcholine concentration is activated by intrathecal, but not IV, injection of clonidine.66 However, clonidine has been shown to produce analgesia to experimental pain stumuli after systemic67 and epidural68 injection. Yet, clinical studies of systemic clonidine for analgesia have yielded conflicting results.64 Alpha 2 adrenergic agonists produce sedation and reduced blood pressure in addition to analgesia small doses (ie 50 mg) clonidine may reduce blood pressure more after an intrathecal than IV injection.64 Clonidine has also been shown to potentiate the neuropathic pain relieving action of NMDA antagonist MKñ801 while preventing its neurotoxic and hyperactivity side effects.69 Clonidine is available in several different dosage forms and can be administered orally, transdermally70 or spinally. Conversely, systemic Dexmedetomidine, another alpha 2 adrenergic agonist, has been shown neither to prevent nor attenuate neuropathic pain behavior in rats.63 Dexmedetomidine has affinity to all three alpha 2ñ adrenergic subtypes.71 The role of the different subtypes of alpha 2 adrenoreceptors is unclear. Subtypeñselective alpha 2ñadrenergic agonists are needed for further studies.

Several other pharmacological treatments which have proven beneficial in the treatment of neuropathic pain include the corticosteroids, and capsaicin cream. Corticosteroids are believed to provide longñterm pain relief because of their ability to inhibit the production of phospholipaseñAñ2 and through membrane stabilizing effects, hence their utility for epidural steroid injections.1 Topical capsaicin cream (Zostrix, 0.025% and 0.075%) is a substance P depletor, and has on occasion provided relief for both acute herpetic neuralgia (shingles) and postñherpetic neuralgia. Capsaicin is known for its selectivity for and effect on Cñfiber nociceptors and heat receptors.72 Studies have shown its ability to trigger membrane depolarization and to open non selective cation channels,73 which may be either reversible or lytic. Capsaicin is theorized to cause a neurotoxic cellular degeneration of primary afferent nociceptors.74 Basically, exposure to capsaicin results in activation, desensitization, and under certain conditions, the destruction of lightly myelinated or unmyelinated primary afferent fibers.75 A recent preliminary study proposes a clinical role for topical capsaicin at doses of 5%ñ10% in patients with intractable pain.72 A recent animal study suggests that an orally bioavailable capsaicin analogue, civamide (cisñ8ñmethylñNñvanillylñ6ñnonenamide) possessed analgesic activity with respect to several noxious stimuli, including nerve injuryñinduced tactile allodynia.39 Compliance may be a problem with this medication, since it needs to be applied 4ñ5 times a day for several weeks before any significant benefit is appreciated and it has intense initial burning effects.76 A recent study demonstrated that if famciclovior (Famvir) is administered within 72 hours of the onset of the vesicles of shingles then damage to peripheral nerves can be minimized and therefore, the subsequent pain of postñherpetic neuralgia attenuated.77 The dose of famciclovior is 500 mg orally, three times a day for seven days.77

If a chronic neuropathic pain condition is already well established, treatment is more difficult. Sensitization (eg. "windñup") is presumed to have already occurred, so the ideal medication would include an NMDA receptor antagonist. Two agents are currently available. Ketamine is an injectable anesthetic that nonñcompetitively antagonizes NMDA receptors.78 Although it has proven beneficial in the treatment of neuropathic pain, side effects tend to be unacceptable.79 NMDA receptor antagonists are known to induce psychomimetic reactions in adult humans and induce behavioral disturbances such as learning and memory impairments, sensorimotor disturbances, stereotypical behavior and hyperactivity and pathomorphological changes in neurons of the posterior cingulate/retrosplenial (PC/RS) cortex of the adult rat.69 Recent animal studies have reported that preemptive intrathecal ketamine delayed mechanical hyperalgesia but did not prevent it.41 Also, a case report suggests that epidural administration of a "very low dose" of Ketamine is sufficient to block activated NMDA receptors and is an effective choice for the management of neuropathic pain without undesirable side effects.80 We occasionally will prescribe dextromethorphan, a readily available overñtheñcounter antitussive, to supplement the medication regimen of some of our patients with neuropathic pain. Like Ketamine, it is a nonñcompetitive antagonist at the NMDA receptor. However in humans, doses may be so high that unacceptable side effects occur. MK801, an antagonist for the NñmethylñDñaspartate receptor for glutamate, has been shown to reverse mechanical hyperalgesia in streptozotocin/diabetic rats81 and conversely to have no effect on tactile allodynia in nerveñinjured rats.82 Amantadine, an antiviral and anti Parkinsonian agent, was shown to act as a nonñcompetitive NMDA antagonist.83 Unlike other NMDA antagonists amantadine is clinically available for chronic use in humans and its level of toxicity is low. Case reports84 and a preliminary double blind, controlled trial85 show that acute administration of amantadine significantly reduces surgical neuropathic pain in cancer patients. Investigational NMDA receptor antagonists are currently undergoing clinical trials.

Activation of NMDA receptors leads to calcium entry into the cell and initiates a series of central sensitization. This sensitization may be blocked not only with NMDA receptor antagonists, but also with calcium channel blockers that prevent Ca2+ entry into cells. A double blind study revealed that epidural verapamil and bupivacaine reduced the amount of self administered post op analgesic versus epidural bupivacaine alone. The authors suggest that epidural verapamil may prevent central sensitization by surgical trauma.86

Clinical experience with the use of opioids for chronic nonñmalignant pain which is neuropathic in character suggests that there may be a subñpopulation of chronic pain patients who may clearly benefit from maintenance with opioid analgesics.87 Many studies have shown that neuropathic pain is only slightly responsive or not responsive at all to opioid treatments.88 Yet others have shown that neuropathic pain responds to high doses of opioids.89ñ91 Portenoy has stated that opioid responsiveness is partly a matter of dosage and that satisfactory outcomes can be obtained following dose escalation to an endpoint determined by either adequate analgesia or intolerable side effects. Benedetti et al suggest that postop neuropathic pair responds to opioid, opioid responsiveness of neuropathic pain is partly a matter of dosage and higher doses of opioids that are necessary to relieve neuropathic pain may be not a characteristic of neuropathic pain per se but a general feature related to the individual.88 A randomized doubleñblind activeñplaceboñcontrolled crossover trial suggested that fentanyl may relieve nonñcancer neurapathic pain by its intrinsic analgesic effect.92 The indiscriminate prescribing of chronic opioids, seductive hypnotics and muscle relaxants, however, is without justification, especially if patients are not experiencing decreased pain and increased function.

Agents that may soon be available for the treatment of neuropathic pain include: 1) butylñparañaminobensoate (ButambenÆ), an ester local anesthetic, 2) bupivacaine microspheres,and 3) SNXñIII, a selective calcium channel blocker. Nicotinic acetylcholine receptor agonists such as ABTñ594, which may also prove efficacious, are in preliminary research stages. Animal studies have revealed the following as potential therapies in neuropathic pain 1) electroconvulsive treatment93 2) intrathecal injection of chromaffin cells94ñ96 3) inrathecal injection of Nitric oxide synthase inhibitor LñNññGñnitro arginine methyl ester (LñNAME)97 4) intrathecal neostigmine.98 A clinically available agent which is currently being investigated for the treatment of neuropathic pain is levodopa.99

Conclusion:

Clearly, numerous pharmacological agents are available for the treatment of neuropathic pain. The definitive drug therapy has however remained elusive. Oftentimes triple drug therapy with tricyclic antidepressants, antiñconvulsants and a systemic local anesthetic is necessary. Occasionally, there is the patient who requires chronic opioid therapy in conjunction with the above medications. When patients fail systemic treatments implantable systems, such as a spinal cord stimulator, or intrathecal morphine pumps are available. Recently, the spinal cord stimulator has been shown to attenuate the augmented dorsal horn release of excitatory amino acids via a GABAergic mechanism in rats.100 Rarely, surgical intervention is required.

References:

1. Devor M, et al, Corticosteroids suppress ectopic neuronal discharge in experimental neurons. Pain 22:127-137, 1985.

2. Devor M, Govrin - Lippmann R: Axoplasmic transport block reduces ectopic impulse generation in injured peripheral nerves. Pain 16:73-85, 1983.

3. England JD, Gamboni F, Levinson SR. Immunocytochemical localization of sodium channels form along demyelinated axons. Brain Research 1991; 548:334-337.

4. Yaksh TL, Chaplan SR. Physiology and pharmacology of neuropathic pain. Anesthesiology Clinics of North America Vol 15 Number 2 pp 335-352, 1997

5. Chung K, Kim HJ, Na HS, et al: Abnormalities of sympathetic innervation in the area of an injured peripheral nerve in a rat model of neuropathic pain. Neurosci Lett 162:85-88,1993.

6. Devor M. Neuropathic pain and injured nerve - peripheral mechanisms. Br Med Bull 47: 619-630, 1991.

7. Devor M, Wall PD: Cross - excitation in dorsal root ganglia of nerve - injured and intact rats. J Neurophysiol 64: 1733-1746, 1990.

8. Bennett, GF, Neuropathic pain. In Textbook of Pain, P.D. Wall and R. Melzack (ed.), Churchill Livingstone, New York third ed. 1994.

9. Allen R. Neuropathic Pain: Mechanisms and Clinical Assessment. Assessment and Treatment of Cancer Pain, Progress in Pain Research and Management, Vol. 12 (1998) 159-173.

10. Fields HL. Pain. New York: McGraw - Hill, 1987, pp 13-16.

11. Levine JD, Fields HL, Basbaum AI. Peptides and the primary afferent nociceptor. J Neurosci 1993; 13:2273-2286.

12. Asbury AK, Fields HL. Pain due to peripheral nerve damage; an hypothesis. Neurology 1984; 34:1587-1590.

13. Tasker RR. Central Pain Syndromes. In Principles and Practice of Pain Management, Warfield, CA (ed.) McGraw Hill, Inc. New York, 1993.

14. Johnson BW, Parris WCV. Mechanisms of Neuropathic Pain. In Current Review of Pain, Raj PP, (ed.) Current Medicine, 1994.

15. Cameron AA, Cliffer KD, Dougherty PM, et al: Changes in lectin, GAP-43 and neuropeptide staining in the rat dorsal horn following experimental peripheral neuropathy. Neurosci Lett 131:249-252, 1991.

16. Garrison CJ, Dougherty PM, Kajander KC, et al: Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res 565:1-7, 1991.

17. Sugimoto T, Bennett GJ, Kajander KC. Transsynaptic degeneration in the superficial dorsal horn after sciatic nerve injury: Effects of a chronic constriction injury, transection and strychnine. Pain 42:205-213, 1990.

18. Todd AJ, Sullivan AC. Light microscope study of the coexistence of GABA-like and glycine-like immunoreactivities in the spinal cord of the rat. J Comp Neurol 296:496-505, 1990.

19. Fields HL, Basbaum AI. Central nervous system mechanisms of pain modulation. In: Wall PD, Melzack R (Eds). Textbook of Pain, 3rd ed. Edinburgh: Churchhill Livingstone, 1994, pp 243-257.

20. Yaksh TL: The spinal pharmacology of facilitation of afferent processing evoked by high-threshold afferent input of the post injury pain state Curr Opin Neurol Neurosurg 6:250-256, 1993.

21. Woolf CL, Chong MS. Preemptive analgesia: treating postoperative pain by preventing the establishment of central sensitization. Anesth. Analg. 1993; 77:362-379.

22. Ito Y, Yamamoto M, Li M, Doyu M, Tanaka F, Mutch T, Mitsuma T, Sobue G. Differential temporal expression of mRNAs for ciliary neutotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFR , LIFR , IL-6R and gp130) in injured peripheral nerves. Brain Research 793 (1998) 321-327.

23. Besse D, Lombard MC, Besson JM: Time related decreases in mu and delta opioid receptors in the superficial dorsal horn of the rat spinal cord following a large unilateral dorsal rhizotomy. Brain Res 578:115-127, 1992.

24. Besse D, Lombard MC, Perrot S, etal: Regulation of opioid binding sites in the superficial dorsal horn of the rat spinal cord following loose ligation of the sciatic nerve: Comparison with sciatic nerve section and lumbar dorsal rhizotomy. Neuroscience 50:921-933, 1992.

25. Stevens CW, Kajander KC, Bennett GJ, et al: Bilateral and differential changes in spinal mu, delta and kappa opioid binding in rats with a painful, unilateral neuropathy. Pain 46:315-326, 1991.

26. Presley RW, Menetry D, Levine JD, et al, Systemic morphine suppresses noxious stimulus-evoked Fos protein-like immuno reactivity in the rat spinal cord. J Neurosci 10:323-335, 1990.

27. Tolle TR, Castro-Lopes JM, Coimbra A, et al: Opiates modify induction of c-fos proto-oncogene in the spinal cord of the rat following noxious stimulation. (published erratum appears in Neurosci Letters 114:239, 1990). Neursci Lett 111:46-51, 1990.

28. Coderre TJ, Yashpal K. Intracellular messengers contributing to persistent nociception and hyperalgesia induced by L-glutamate and substance P in rat formalin pain model. Eur J Neurosci 6:1328-1334, 1994.

29. Malmberg AB, Basbaum AI. Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain 76 (1998) 215-222.

30. Malmberg AB, Yaksh TL: Spinal nitric oxide synthesis inhibition blocks NMDA-induced thermal hyperalgesia and produces antinociception in the formalin test in rats. Pain 54:291-300, 1993.

31. Ahlgren SC, Levine JD: Protein Kinase C inhibitors decrease hyperalgesia and C fiber hyperexcitability in the streptozotocin - diabietic rat. J Neurophysiol 72: 684-692, 1994.

32. Yashpal K, Pitcher GM, Parent A, et al: Noxious thermal and chemical stimulation induce increases in 3H-phorbol 12, 13-dibutyrate binding in spinal cord dorsal horn as well as persistent pain and hyperalgesia, which is reduced by inhibition of protein kinase C. J Neuroscience 15:3263-3272, 1995.

33. Thio CL, Sontheimer H: Differential modulation of TTX-sensitive and TTX-resistant Na+ channels in spinal cord astrocytes following activation of protein kinase C. J Neurosci 13:4889-4897, 1993.

34. Kingery WS, Guo TZ, Poree LR, Maze M. Colchicine treatment of the sciatic nerve reduces neurogenic extravasation, but does not affect nociceptive thresholds or collateral sprouting in neuropathic or normal rats. Pain 74 (1998) 11-20.

35. Yamamoto T, Yaksh TL: Effects of colchicine applied to the peripheral nerve on the thermal hyperalgesia evoked with chronic nerve constriction. Pain 55:227-233, 1993.

36. Pockett S. Spinal cord sympathetic plasticity and chronic pain. Anesth. Annalg., 80:173-179, 1995.

37. Gottrup H, Nielsen J, Arendt-Nielsen L, Jensen TS. The relationship between sensory thresholds and mechanical hyperalgesia in nerve injury. Pain 75 (1998), 321-329.

38. Jett MF, McGuirk J, Waligora D, Hunter JC. The effects of mexiletine, desipramine and fluoxetine in rat models involving central sensitization. Pain 69 (1997) 161-169.

39. Hua XY, Chen P, Hwang J, Yaksh TL. Antinociception induced by civamide, an orally active capsaicin analogue. Pain (1997) 313-322.

40. Attal N, Brasseur L, Chauvin M, Bouhassira D. A case of pure dynamic mechano-allodynia due to a lesion of the spinal cord: pathophysiological considerations. Pain 75 (1998) 399-404.

41. Hartrick CT, Wise JJ, Patterson JS. Preemptive intrathecal ketamine delays mechanical hyperalgesia in the neuropathic rat. Anesth Analg 1997;86:557-560.

42. Hanai F. C Fiber responses of wide dynamic range neurons in the spinal dorsal horn. Clinical Orthopaedics and Related Research No. 349(1998), pp 256-267.

43. Yaksh TL: Pharmacology of the Pain Processing System In: Waldman SD, Winnie AP (Eds.). Interventional Pain Management, 1st ed. Philadelphia; WB Saunders, 1996, 19-32.

44. Yezierski RP, Liu S, Ruenes GL, Kajander KJ, Brewer KL. Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model. Pain 75 (1998) 141-155.

45. Jasmin L, Kohan L, Franssen M, Janni G, Goff JR. The cold plate as a test of nociceptive behaviors: description and application to the study of chronic neuropathic and inflammatory pain models. Pain 75 (1998) 367-382.

46. Malmberg AB, Yaksh TL: The effect of morphine on formalin-evoked behavior and spinal release of excitatory amino acids and prostaglandin E2 using microdialysis in conscious rats. Br J Pharmacol 114:1069-1075, 1995.

47. Yaksh TL. Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: Effects of modulatory receptor systems and excitatory amino antagonists. Pain 37 (1989) 111-123.

48. Gillin S, Sorkin L. Gabapentin reverses the allodynia produced by the administration of anti-GD2 ganglioside, an immunotherapeutic drug. Anesth Analg 1998;86:111-116.

49. Goodkind K, et al, On the putative efficacy of antidepressants in chronic benign pain syndromes: an update. Pain Forum 4:237-247, 1995.

50. Chapman V, Suzuki R, Chamarette HLC, Rygh LJ, Dickenson AH. Effects of systemic carbamazepine and gabapentin on spinal neuronal responses in spinal nerve ligated rats. Pain 75 (1998) 261-272.

51. Bartusch, SL, et al, Clonazepam for the Treatment of Lancinating Phantom Limb Pain. 12:59-62, 1996.

52. Rosner H, et al, Gabapentin Adjunct Therapy in Neuropathic Pain States. 12:56-58, 1996.

53. Xiao W-H, Bennett GJ. Gabapentin has an anti-nociceptive effect mediated via a spinal site of action in a rat model of painful peripheral neuropathy. Analgesia 1997; 2:267-273.

54. Hunter JC, Goas KR, Hedley LR, et al. The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain. Eur J Pharmaco 1997; 324:153-160.

55. Singh L, Field MJ, Ferris P, et al. The anti-epileptic agent gabapentin possesses anxiolytic-like and antinociceptive actions that are reversed by D-serine. Psychopharmacology 1996; 127:1-9.

56. Stanfa LC, Singh L, Williams RG, Dickerson AH. Gabapentin, ineffective in normal rats, markedly reduces C-fiber evoked responses after inflammation. Neuroreport 1997; 8:587-590.

57. Hwang JH, Yaksh TL. The effect of intrathecal gabapentin on tactile-evoked allodynia in a surgically-induced neuropathic pain model in the rat. Reg Anesth 1997; 22:249-256.

58. Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of post herpetic neuralgia. Neurology 1991;41:1024-1028.

59. Bruera E, Ripamonti C, Brennis C, Macmillan K, Hanson J. A randomized double-blind crossover trial of intravenous lidocaine in the treatment of neuropathic pain. J Pain Symptom Manage 1992; 7(3):138-140.

60. Elliott JR. Slow Na+ channel inactivation and bursting discharge in a simple model axon: implications for neuropathic pain. Brain Research 754 (1997) 221-226.

61. Omana-Zapata I, Khabbaz MA, Hunter JC, Bley KR. QX-314 inhibits ectopic nerve activity associated with neuropathic pain. Brain Research 771 (1997) 228-237.

62. Glazer S, Portenoy RK, Systemic local anesthetics in pain control, J. Pain Sympt Mgmt 6:30-39, 1991.

63. Kontinen VK, Paananen S, Kalso E. The effects of the - 2 -adrenergic agonist, Dexmedetomidine, in the Spinal Nerve Ligation Model of Neuropathic Pain. Anesth Analg 1998;86:355-360.

64. Eisenach JC, Hood DD, Curry R. Intrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers. Anesth Analg 1998; 87:591-596.

65. Spaulding TC, Venafro JJ, MaMG, Fielding, S. The dissociation of the antinociceptive effect of clonidine from supraspinal structures. Neuro pharamacol 1979; 18:103-105.

66. De Kock M, Eisenach J, Tong C, et al. Analgesic doses of intrathecal but not intravenous clonidine increase acetylcholine in cerebrospinal fluid in humans. Anesth Analg 1997; 84:800-803.

67. Porchet HC, Piletta P, Dayer P. Pharmacokinetics pharmacodynamic modeling of the effects of clonidine on pain threshold, blood pressure, and salivary flow. Eur J Clin Pharmac 1992; 42:655-661.

68. Eisenach J, Detweiler D, Hood D. Hemodynamic and analgesic actions of epidurally administered clonidine. Anesthesiology 1993; 78:277-287.

69. Jevtovic-Todorovic V, Wozniak DF, Powell S, Nardi A, Olney JW. Clonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects. Brain Research 781 (1998) 202-211.

70. Ziegler D, Lynch SA, Muir J, et al, Transdermal clonidine vs placebo in painful diabetic neuropathy. Pain 48:403-408, 1992.

71. Mac Donald E, Scheinin M. Distribution and pharmacology of alpha 2-adrenoreceptors in the central nervous system. J Physiol pharmacol 1995; 46:241-258.

72. Robbins WR, Staats PS, Levine J, et al. Treatment of intractable pain with topical large-dose capsaicin: preliminary report. Anesth Analg 1998;86:579-583.

73. Dray A. Mechanism of action of capsaicin - like molecules on sensory neurons. Life Sci 1992; 51:1759-1765.

74. Chung JM, Paik KS, Kim JS, et al. Chronic effects of topical application of capsaicin to the sciatic nerve on responses of primate spinothalamic neurons. Pain 1993; 53:311-321.

75. Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Review, 43 (1991) 143-201.

76. Cotton P. Compliance problems, placebo effect cloud trials of topical analg. JAMA 1990;264:13-14.

77. Tyring S, Barbarsh RA, et al, Famciclovir for the treatment of acute herpes zoster: effects on acute disease and post-herpetic neuralgia. Arch. Inern. Med. 123:89-96, 1995.

78. Mao J, Price DD, Hayes RL, et al, Intrathecal treatment with dextrorphan or ketamine potently reduces pain related behaviors in a rat model of mononeuropathy. Brain 5:164-168, 1993.

79. Dickenson AH, NMDA receptor antagonists as analgesics. In Progress in Pain Research and Management, vol. 1, Fields, HL, Liebeskind, JC (ed.), IASP Press, Seattle, 1994.

80. Takahashi H, Miyazaki M, Nanbu T, et al. The NMDA-receptor antagonist ketamine abolishes neuropathic pain after epidural administration in a clinical case. Pain 75 (1998) 391-394.

81. Malcangio M, Tomlinson DR. A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain 76 (1998) 151-157.

82. Wegert S, Ossipov MH, Nichols ML, et al. Differential activities of intrathecal MK-801 or morphine to alter responses to thermal and mechanical stimuli in normal or nerve-injured rats. Pain 71 (1997) 56-64.

83. Kohrenhuber J, Quack G, Danysz W, Jellinger K, Danielczyk W, Gsell W and Riederer P. Therapeutic brain concentration of the NMDA antagonist Amantadine, Neuropharmacology, 34 (1995) 713-721.

84. Eisenberg E, Pud D. Can patients with chronic neuropathic pain be cured by acute administration of the NMDA receptor antagonist amantadine? Pain 74 (1998) 337-339.

85. Pud D, Eisenberg E, Spitzer A, et al. The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial. Pain 75 (1998) 349-354.

86. Choe H, Kim JS, Ko SH, Kim DC, Han YJ, Song HS. Epidural verapamil reduces analgesic consumption after lower abdominal surgery. Anesth Analg 1998;86:786-90.

87. Stein C. Opioid treatment of Chronic Non-malignant Pain. Anesth. Analg. 84:912-914, 1997.

88. Benedetti F, Vighetti S, Amanzio M, et al. Dose-response relationship of opioids in nociceptive and neuropathic postoperative pain. Pain 74 (1998) 205-211.

89. Jadad AR, Carroll D, Glynn CJ, Moore RA and McQuay, HJ. Morphine responsiveness of chronic pain: double blind randomised crossover study with patient-controlled analgesia. Lancet, 339 (1992) 1367-1371.

90. Portenoy RK and Foley KM. Chronic use of opioid analgesics in non-malignant pain: report of 38 cases. Pain 25 (1986) 171-186.

91. Portenoy RK, Foley KM and Inturrisi CE. The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain 43 (1990) 273-286.

92. Dellemijn P, Vanneste J. Randomised double-blind active-placebo-controlled crossover trial of intravenous fentanyl in neuropathic pain. Lancet 1997; 349: 753-758.

93. Shibata M, Wakisaka S, Inoue T, et al. The effect of electroconvulsive treatment on thermal hyperalgesia and mechanical allodynia in a rat model of peripheral neuropathy. Anesth Analg 1998;86:584-587.

94. Brewer K, Yezierski RP. Effects of adrenal medullary transplants on pain-related behaviors following excitotoxic spinal cord injury. Brain Research 798, 1998, pp 83-92.

95. Decosterd I, Buchser E, Gilliard N, Saydoff J, Zurn AD, Aebischer P. Intrathecal implants of bovine chromaffin cells alleviate mechanical allodynia in a rat model of neuropathic pain. Pain 76 (1998) 159-166.

96. Yu W, Hao JX, Saydoff J, Haegeeerstrand A. Long term alleviation of allodynia-like behaviors by intrathecal implantation of bovine chromaffin cells in rats with spinal cord injury. Pain 74 (1998) 115-122.

97. Wong CS, Cherng CH, Tung CS. Intrathecal administration of excitatory amino acid receptor antagonists or nitric oxide synthase inhibitor reduced autotomy behavior in rats. Anesth Analg 1998;87:605-608.

98. Lavand'homme P, Pan HL, Eisenach JC. Intrathecal neostigmine, but not sympathectomy, relieves mechanical allodynia in a rat model of neuropathic pain. Anesthesiology, Vol 89, No 2, Aug 1998.

99. Ertas M, Sagduyu A, Arac N, Uludag B, Ertekin C. Use of levodopa to relieve pain from painful symmetrical diabetic polyneuropathy. Pain 75 (1998) 257-259.

100. Cui JG, O'Connor WT, Ungerstedt U, Linderoth B, Meyerson BA. Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism. Pain 73 (1997) 87-95.

101. Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 42 (1990) 135 - 144.

102. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the Treatment of Postherpetic Neuralgia. JAMA 280 (1998) 1837 - 1842.

103. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the Symptomatic Treatment of Painful Neuropathy in Patients with Diabetes Mellitus. JAMA 280 (1998) 1831 - 1836.

 

For more information contact http://www.spineuniverse.com/