Neuromodulación eléctrica en el tratamiento del dolor neuropático refractario. Colocación del primer estimulador medular en Cuba / Electric neuromodulation in the treatment of refractory pain. Placement of the first spinal stimulator in Cuba

El dolor es una causa importante de sufrimiento físico y emocional. El tratamiento médico de los pacientes con dolor crónico refractario es un gran reto. Se presenta el caso de una paciente de 19 años con un cuadro radicular compresivo secundario a Hernia discal L5-S1 derecha, que se le aplicó una discectomía L5-S1 por técnica de Caspar. Al mes de evolución regresa con igual sintomatología. A pesar de múltiples terapias farmacológicas y procederes intervencionistas, el dolor neuropático no mejora, después de múltiples estudios y discusiones en colectivo se determina la posibilidad de la colocación de un neuroestimulador medular, proceder que se lleva a cabo con mejoría considerable de su cuadro doloroso(AU)

Pain is a major cause of physical and emotional suffering. The management of patients with refractory chronic pain is a great challenge. The case is presented of a 19-year-old female patient with compressive radicular symptoms secondary to right L5-S1 disc herniation, who underwent L5-S1 discectomy with Caspar technique. After one month of evolution, she returned with the same symptoms. Despite multiple pharmacological therapies and interventional procedures, the neuropathic pain did not improve. After multiple studies and collective discussions, the possibility of placing a spinal neurostimulator was decided. After the procedure, the patient improved considerably with respect to her painful symptoms(AU)

Effect and Mechanism of Dexmedetomidine Hydrochloride on Neuropathic Pain / 医药导报

Objective To establish neuropathic pain models,explore the effects and mechanisms of dexmedetomidine on neuropathic pain.Methods Wistar rats were randomly divided into four groups (n =9):0.9％ sodium chloride solution CCI group (N),dexmedetomidine CCI group (D),ZD7288 CCI group (Z) and sham-operated group (Sham).Sciatic nerve ligation was performed in group N,D and Z.The sciatic nerve in group Sham was exposured without ligation.7 d after surgery,the rats in group D were intraperitoneal injected with dexmedetomidine (40 μg· kg-1),and the rats in group Z were intraperitoneal injected with ZD7288 (10 mg·kg-1)once a day for 3 d.The same volume of 0.9％ sodium chloride solution was given at the same time in group N.The behavioral test was performed before and 7 d after operation,as well as 3 d after injection treatment.Mechanical allodynia was assessed by paw withdrawal mechanical threshold (PWMT) to von Frey filaments.Thermal hyperalgesia was assessed by paw thermal withdrawal latency (TWL) to radiant heat.Dexmedetomidine block of HCN channels in dorsal root ganglion (DRG) neurons were confirmed by whole-cell recording.Results 7 d after surgery,the PWMT and TWL of rats in group N,D and Z were decreased significantly (P ＜ 0.05).The PWMT and TWL in group Sham were no significant difference before and after operation.Dexmedetomidine significantly increased the levers of PWMT and TWL in group D and Z after treatment for 3 d,and group Z was greater than group D (P ＜ 0.05).Dexmedetomidine (0.1,1,10 μmol· L-1) caused a concentration-dependent decrease in the amplitude of Ih in DRG neurons from (-844.43 ± 386.34) to (-215.99 ± 63.90) pA (P ＜ 0.05),and the inhibition rate of Ih was (11.87 ± 1.80) ％,(35.26 ± 3.65) ％ and (52.02 ± 5.56) ％,respectively(P ＜0.05).Dexmedetomidine produced a dose-related shift to the left of the Ih activation,and a negative shift in V1/2 (P ＜ 0.05).V1/2 shifted from (-86.21 ± 1.68) to (-103.54 ± 2.01) mV (P ＜ 0.05).The slope values were not altered by dexmedetomidine.Conclusion Dexmedetomidine produces a dose-dependently analgesic effect on neuropathic pain after peripheral never injury,which is likely due to the inhibition of Ih and reduction of ectopic spontaneous discharge in DRG neurons.

Research Progress in the Mechanism of Neuropathic Pain and the Intervention Effect of Electroacupuncture / 上海针灸杂志

Neuropathic pain is a chronic pain caused by primary nervous system damage and nerve dysfunction. Its pathogenesis is complex and diverse. It is difficult to treat clinically. In recent years, researchers used electroacupuncture to treat neuropathic pain and obtained a desirable effect. This article summarizes recent years’ studies on the main mechanisms of neuropathic pain and the intervention effect of electroacupuncture to provide reference for following studies on electroacupuncture treatment of neuropathic pain.

The Antinociceptive Effect of Perineural Capsaicin to the Injured Nerve in Neuropathic Rats / 대한마취과학회지

BACKGROUND: We designed this study to evaluate the antinociceptive effect and changes in amounts of substance P in the spinal cord after perineural application of capsaicin to the injured nerve in rats in neuropathic pain. METHODS: Male Sprague-Dawley rats (200-250 g) were prepared with the tight ligation of the left L5, 6 spinal nerves or with the sham operation. They were divided into 3 groups according to the solution treated to the left sciatic nerve and pre-treated condition, group I (capsaicin treatment after ligation; n = 10), group II (solvent treatment after ligation; n = 10), group III (capsaicin treatment after sham operation; n = 10). The withdrawal threshold to touch with von Frey filaments and the withdrawal time to thermal stimulus by plantar tester were measured and percent maximum possible effects (%MPE) were calculated, respectively, at 1, 2, 3 and 4 weeks after treatment. The area and integrity optical density (IOP) of substance P stained immunohistochemically in the lumbar dorsal horn were quantified with an image analyzer in group I. RESULTS: In the capsaicin-treated groups (I, III), withdrawal time to thermal stimulus was prolonged significantly during the 4 weeks as compared with baseline values before treatment (P < 0.05), but withdrawal time to touch didn't change. The %MPE of capsaicin to thermal stimulus in group I was significantly higher than that in group III (P < 0.05). In group II, withdrawal responses to touch and thermal stimulus didn't change. The area and IOP of substance P in the left lumbar dorsal horn at the 1st and 4th week didn't change, compared with the baseline before capsaicin treatment, except for theIOP at the 4th week in group I. CONCLUSIONS: Perineural application of capsaicin to the injured nerve in neuropathic rats does not inhibit hypersensitivity to touch but inhibit reaction to thermal stimulus. Its effect does not depend on the changes in amounts of substance P in the ipsilateral lumbar dorsal horn.

Gabapentin for the Management of Various Neuropathic Pain Syndromes / 대한마취과학회지

BACKGROUND: Anticonvulsant agents have been used and found to be effective for the treatment of neuropathic pain. Even though it is rare, they can have very serious side effects and therefore the search for more selective drugs with fewer side effects is justified. This study was conducted to evaluate the newly introduced anticonvulsants, gabapentin, for various neuropathic pain syndromes in the Korean population. METHODS: According to individual diagnostic group as diabetic neuropathy, postherpetic neuralgia, chronic back pain with radiating pain, there were 20 patients per group. Patients have been stabilized in their analgesic regimen at least four weeks prior to enrollment in the study. An anticonvulsant, if taken, was discontinued for four weeks for wash-out. Pretreatment baseline pain scores (visual analog scale and a pain intensity score) were obtained. Oral administration of gabapentin 300 mg was initiated in all groups and doses were given from 300 mg per day with gradual titration over two weeks 1) to the maximum of 2400 mg per day, 2) to the onset of intolerable side effects, and 3) to the onset of analgesic effect. At two weeks follow-up visit, visual analog scale, pain intensity scores, pain improvement scores judged by family, drug efficacy, tolerability and overall evaluation were assessed. The incidence of side effects, cell blood count and chemistry were also obtained. RESULTS: After two weeks of treatment, the visual analog scale and pain intensity scores improved in all study groups and no patients experienced aggravation. These findings were objectively reflected in pain improvement scores observed by family members. In drug efficacy, tolerability and overall evaluation, the majority of patients scored as good or excellent. There were no reports of serious side effects. Minor side effects were spontaneously subsided even with continuation. CONCLUSIONS: Gabapentin, a newer anticonvulsant, appears to be effective as an adjunctive analgesic for the management of various neuropathic pain syndromes with minimal side effects.

Effects of Cervical Sympathectomy on Mechanical Allodynia and Cold Allodynia in a Rat Model of Neuropathic Pain / 대한마취과학회지

BACKGROUND: The pathophysiologic mechanism of the neuropathic pain is still unclear. We designed this study to evaluate the effect of bilateral cervical sympathectomy on allodynia and the relationship of neuropathic pain with sympathetic nerve system of supraspinal level in rats experiencing neuropathic pain. METHODS: Neuropathic pain was produced by tight ligating the left 5th and 6th lumbar spinal nerves of male Sprague-Dawley rats. Mechanical allodynia was quantified by measuring the foot withdrawal frequency to stimuli with two von Frey filaments of 14.5 mN and 53.9 mN applied to the affected left hind paw, and cold allodynia was quantified with the same manner using 100% acetone. We divided the neuropathic pain models into experimental group (bilateral cervical sympathectomy) and control group (sham operation), and then measured the foot withdrawal frequency 1, 3, 5, 7, 14, 21 and 28 days postoperatively. RESULTS: In experimental group, the foot withdrawal frequency to mechanical stimuli with 14.5 and 53.9 mN of von Frey filament and cold stimuli with 100% acetone was significantly lower than that of control group for all postoperative observation points. Also, the experimental group showed decrease in foot withdrawal frequency compared with preoprative value over the course of the study. CONCLUSIONS: Bilateral cervical sympathectomy reduced mechanical allodynia and cold allodynia in the rat model of neuropathic pain suggesting that neuropathic pain, although the lesions are localized in low extremities, may be correlated with functional disturbance of sympathetic nerve fibers of supraspinal or brain level and help explain the mechanism of neuropathic pain.

Interaction between Neostigmine and Morphine in the Neuropathic Pain Model / 대한마취과학회지

BACKGROUND: Spinally administered neostigmine, but not morphine, has been well known to reverse the mechanical allodynia in human and animal studies. The efficacy of morphine in neuropathic pain state is somewhat controversial. Using an isobolographic analysis, we examine the spinal interaction between neostigmine and morphine in a rat model of neuropathic pain. METHODS: Male Sprague Dawley rats were prepared with tight ligation of left lumbar 5th and 6th spinal nerves and chronic lumbar intrathecal catheter. Intrathecal dose response curves were established for the antiallodynic effect of neostigmine (0.3, 1.0, 3.0, and 10 microgram) and morphine (0.3, 1.0, 3.0, and 10 microgram) alone to obtain the ED50 for each agent. ED50 fractions (1/2, 1/4, 1/8, and 1/16) of drug combination of neostigmine-morphine were administered. Allodynic thresholds for left hindpaw withdrawal to von Frey hairs application were assessed and converted to %MPE. The ED50 of neostigmine-morphine combinations was established and isobolographic analysis of the drug interaction was carried out. RESULTS: Intrathecal neostigmine and morphine alone produced dose-dependent reductions of tactile allodynia. ED50 values are 0.43 microgram (0.21~0.86 microgram) for neostigmine and 0.39 microgram (0.07~2.01 microgram) for morphine. The log dose responses were plotted from the peak effect of %MPE in each group of neostigmine and morphine. The experimental ED50 1.34E-2 microgram (2.1E-4-0.85 microgram) for neostigmine and morphine combination was found to be significantly below the theoretical additive ED50 value 0.41 microgram (P<0.05). CONCLUSION: The results suggest that intrathecal neostigmine and morphine alone produce a dose dependent antagonism on touch evoked allodynia and intrathecal neostigmine is synergistic at the spinal level when combined with intrathecal morphine in a rat model of neuropathy.

The Effect of Selective Muscarinic Receptor Antagonists on Antiallodynic Action in a Rat Model of Neuropathic Pain / 대한마취과학회지

BACKGROUND: Peripheral nerve injury may produce a syndrome consisting of spontaneous pain, allodynia and hyperpathia. In previous study, we examined the antiallodynic action produced by intrathecal (i.t.) cholinesterase inhibitors (ChEi) in a neuropathic pain rat model and the reversal of antiallodynic state by i.t. atropine, muscarinic antagonist, but not by nicotinic antagonist mecamylamine. The purpose of this study was to determine the selective antagonistic action of four subtypes of muscarinic receptor on antiallodynic state by i.t. ChEi in a rat model of neuropathic pain. METHODS: Sprague Dawley rats were prepared with tight ligation of left L5/L6 spinal nerves with 6-0 black silk and chronic lumbar intrathecal catheters. After obtaining the baseline hindpaw withdrawal scores, edrophonium (100 microgram) or neostigmine (10 microgram) was administered intrathecally. Tactile allodynia was measured using von Frey filaments and allodynic threshold was calculated by the up-down method. Allodynic changes were tested at 15, 30, 45, 60, 90, 120 and 180 minutes. To examine the reversal of antiallodynia and to compare the antagonizing action of antiallodynic state produced by i.t. administration of ChEi, non-selective muscarinic receptor antagonists atropine (10 microgram), M1 antagonist pirenzepine (3 microgram), M2 antagonist methoctramine (3 microgram), M3 antagonist 4-DAMP (3 microgram) and M4 antagonist tropicamide (3 microgram) were injected intrathecally respectively 5 minutes prior to the injection of edrophonium or neostigmine. RESULTS: Antiallodynia produced by i.t. edrophonium was reversed by pretreatment with i.t. methoctramine, 4-DAMP, tropicamide and pirenzepine (P<0.05). On the contrary, antiallodynic state made by i.t. neostigmine was not antagonized by methoctramine, 4-DAMP and tropicamide. M1 antagonist pirenzepine had a moderate, statistically significant (P<0.05) effect on reversal of increased allodynic threshold while atropine showed a complete antagonism. CONCLUSION: These experiments suggest that antialllodynic action of cholinesterase inhibitors is likely due to mediation of spinal muscarinic system and M1 receptor subtype is more likely involved in this mechanism.

The Effects of NMDA Antagonists and Sympathectomy on the c-Fos mRNA Expression in the Neuropathic Rat / 대한마취과학회지

BACKGROUND: Neuropathic pain produced by nerve injury has the characteristics of enhanced pain responses - allodynia. To understand the pathophysiology of the neuropathic pain, We evaluated the effect of NMDA antagonists and chemical sympathectomy on the c-fos mRNA expression. METHODS: We have divided rats(Sprague-Dawley, N=24) that their left L5 and L6 nerve were tightly ligated into two groups. In NMDA antagonist group(N=17), We injected 10 g MK801 and 10 g 5-amino-phosphonovalerate in three ways, intrathecally before the ligation, after ligation and subcutaneous continuously. Then behavioral tests for mechanical allodynia and cold allodynia were performed. After the test of allodynia,the expression of c-fos were assessed by Northern blot hybridization. In chemical sympathectomy group(N=7), We injected 70 mg/kg guanethidine into the peritoneum in two ways, before the ligation and after ligation. Then same methods were performed in NMDA antagonist group as well. RESULTS: Intrathecal NMDA antagonists before the ligation supressed the elevation of c-fos mRNA expression. Intrathecal NMDA antagonists on the 7 days after the ligation reduced the c-fos mRNA expression and neuropathic pain. Continuous treatment of subcutaneous NMDA antagonists supressed the development of neuropathic pain and the elevation of c-fos mRNA expression. Chemical sympathectomy before the ligation did not supress the elevation of c-fos mRNA expression. Chemical sympathectomy on the 7 days after the ligation reduced neuropathic pain and the elevation of c-fos mRNA expression. CONCLUSIONS: NMDA receptor is related to the induction and maitenance of neuropatic pain, and sympathetic nervous system has a main role in the already induced neuropathic pain.

Drug Interactions of Intrathecal Carbachol and Clonidine in Neuropathic Pain Model of the Rats / 대한마취과학회지

BACKGROUND: After peripheral nerve injury in human, a syndrome of events (spontaneous pain, allodynia and hyperalgesia) may be observed that includes no response of morphine and dependency of this pain state on intact sympathetic function. Spinally delivered 2-adrenoceptor agonist and cholinergic agonist or cholinesterase inhibitors have been shown to have actions attenuating the hyperalgesia in rat models of nerve injury-induced pain. Using a fixed-dose analysis and an isobolographic paradigm, the spinal interaction between the 2-adrenoreceptor agonist, clonidine and cholinergic agonist, carbachol is characterized in rat model of nerve injury-induced tactile hyperalgesia. METHODS: Male Sprague Dawely rats were anesthetized with halothane, and the left L5 and L6 spinal nerve were ligated (Chung model). After recovery, a polyethylene tubing catheter was implanted into lumbar intrathecal space. After recovery from catheter implantation, intrathecal dose-response curves were established for the antiallodynic effect of carbachol (0.1, 0.3, 1.0, 3.0 microgram) and clonidine (0.3, 1.0, 3.0, 10 microgram) alone to obtain the ED50 for each agent. ED50 fractions (1/2, 1/4, 1/8, 1/16) of drug combinations of carbachol-clonidine were administered and thresholds for left hind limb paw withdrawal to von Frey hair application were assessed. The ED50 of carbachol-clonidine combination was established and isobolographic analysis of the drug interactions was carried out.c RESULTS: Intrathecal carbachol and clonidine alone produced dose-dependent reductions of tactile allodynia: ED50 of 66 ng (12~367 ng) and 39 ng (1~1452 ng), respectively. With the fixed dose analysis, the log dose-response curves showed a left shift that considerably exceeds the theoretical curves made by a simple sum of the effects of carbachol alone and clonidine. With the isobolographic analysis, ED50 of mixture was found to be statistically less than the theoretical additive ED50 of mixture. CONCLUSION: The experiments suggest that intrathecal carbachol and clonidine alone produce a dose dependent antagonism on touch evoked allodynia and intrathecal carbachol is synergistic when combined with intrathecal clonidine.

Response to Capsaicin and Changes in Sodium Currents in Dorsal Root Ganglion Neurons of Neuropathic Rats / 대한마취과학회지

BACKGROUND: Allodynia, one of the most debilitating symptoms of neuropathic pain syndromes, can be defined as `pain due to a stimulus that does not normally provoke pain'. Subsets of dorsal root ganglion (DRG) neurons involved in nociception are characteristically expressed capsaicin sensitivity and high proportion of tetrodotoxin resistant sodium current (TTX-R INa). We performed an experiment to elucidate whether nerve injury induced mechanical allodynia could be resulted from elctrophysiological modulation of large, nonnociceptive afferent neurons to nociceptors. METHODS: Whole cell patch clamp recordings were made from acutely dissociated dorsal root ganglion (DRG) neurons of normal and experimental neuropathic rats. We compared the proportion of capsaicin sensitive neurons which responded to capsaicin (1micrometer) with an inward current > or = 100 pA in amplitude and the proportion of sodium channel subtypes measured in the absence and presence of tetrodotoxin (1micrometer), in small and large DRG neurons. RESULTS: The proportion of capsaicin sensitive cells to total number of cells tested was not changed by nerve injury in both small and large cell populations. In large cell population of nerve injured rats, the proportion of TTX-R INa was significantly increased as compared with normal group (p <0.05), and in small cell population of nerve injured rats, TTX-S INa was increased, but there was no statistical significance. CONCLUSIONS: These data indicate that expression of the sensitivity to capsaicin in DRG neurons would not be altered by nerve injury and increased TTX-R INa in large cell population of nerve injured DRG may underlie increased excitability.

The Antiallodynic Effect of Edrophonium and Neostigmine in a Neuropathic Pain Model / 대한마취과학회지

BACKGROUND: Peripheral nerve injury may produce a syndrome consisting of spontaneous pain, allodynia and hyperpathia. Cholinesterase inhibitors are known to have an antinociceptive effect in hot plate and tail flick tests and to be mediated by spinal muscarinic system. The purpose of the current study was to determine the effect of intrathecally (i.t.) administered edrophonium and neostigmine on the touch-evoked allodynia and to identify the antagonism of antiallodynia in a rat model of neuropathic pain. METHODS: Sprague Dawley rats were prepared with tight ligation of left L5/L6 spinal nerves with 6~0 black silk and chronic lumbar intrathecal catheters. After obtaining the baseline hindpaw withdrawal scores, edrophonium (3~100ug) or neostigmine (0.3~10ug) was administered intrathecally. Tactile allodynia was measured using von Frey filaments and allodynic threshold was calculated by updown method. Motor dysfunction was assessed by observing righting/stepping reflex responses and abnormal weight bearing. To examine the reversal of antiallod ynia, muscarinic receptor antagonist atropine (10ug) or nicotinic receptor antagonist mecamylamine (10ug) was injected intrathecally 5 min. prior to injection of edrophonium or neostigmine. RESULTS: I.t. edrophonium and i.t. neostigmine produced a dose dependent antagonism of allodynic state but had moderate to severe effect on motor weakness at doses of 3 and 10 g of neostigmine. Pretreatment with i.t. atropine yielded a complete antagonism of antiallodynia in both drugs, but i.t. mecamylamine did not significantly reverse incresed allodynic threshold. CONCLUSIONS: These experiments suggest that i.t. edrophonium or i.t. neostigmine produces a dose dependent antagonism on touch-evoked allodynia at the spinal level and this antagonism is likely due to spinal muscarinic system.