RESUMO
OBJECTIVES: Conflicting data regarding the efficacy of high-frequency spinal cord stimulation (HF SCS) has prompted the issue of the possible importance of the shape of the stimulating pulses. The aim of this pilot study was to compare HF SCS applied with monophasic and biphasic pulses of two different durations with conventional SCS in a rat model of neuropathic pain. MATERIALS AND METHODS: Rats were operated with lesions of sciatic nerve branches according to the spared nerve injury procedure (SNI). Animals, which developed pathological tactile hypersensitivity after surgery, were implanted with four-polar miniature SCS leads. SCS was applied during 60 min with either conventional current parameters (monophasic pulse width [PW]: 200 µsec; 50 Hz and amplitude 80% of the motor threshold [MT]), or with high-frequency SCS (1 kHz) with monophasic or biphasic pulses, the latter with pulse widths of either 24 (12 + 12) or 48 (24 + 24) µsec. The outcomes were examined regarding change of tactile hypersensitivity during the one-hour SCS period and with two tests of thermal sensitivity. RESULTS: Conventional monophasic SCS, as well as HF SCS applied with monophasic PW = 24 µsec or with biphasic PW = 48 (24 + 24) µsec, had similar suppressive effects on tactile hypersensitivity. Solely, HF SCS applied with biphasic pulses with a total PW of 24 (12 + 12) µsec demonstrated no effect. Thermal hypersensitivity was unaffected by HF SCS with all pulse varieties. CONCLUSIONS: There is no significant difference in efficacy between HF SCS applied with low amplitude ("subparesthetic") monophasic and biphasic pulses. However, short PWs providing only 12 µsec of cathodal stimulation was ineffective, presumably because of insufficient electric charge transfer from the lead contacts to the nervous tissue.
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Fenômenos Biofísicos/fisiologia , Neuralgia/terapia , Limiar da Dor/fisiologia , Medula Espinal/fisiologia , Análise de Variância , Animais , Modelos Animais de Doenças , Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Masculino , Neuralgia/fisiopatologia , Medição da Dor , Estimulação Física , Projetos Piloto , Psicofísica , Ratos , Ratos Wistar , Estimulação da Medula Espinal , Resultado do TratamentoRESUMO
OBJECTIVES: The aim was to compare the effects of high-frequency spinal cord stimulation (HF-SCS) at subparesthetic intensity with conventional SCS in rat models of different types of pain. In addition, microrecordings of afferent activity in the dorsal columns during both types of SCS were performed to elucidate their mode of action. MATERIALS AND METHODS: Miniature SCS electrodes were implanted in all rats. One group was submitted to the spared nerve injury procedure (SNI) and another to inflammatory pain after carrageenan injection into a hind paw. All animals were tested for hypersensitivity to normally innocuous tactile and thermal stimuli. One group of normal healthy rats was submitted to acute nociceptive (pinch, heat) pain. Microrecording of afferent activity in the gracile nucleus (GN) was performed in a group of nerve-lesioned rats responding to conventional SCS. RESULTS: HF-SCS at 500, 1,000, or 10,000 Hz at subparesthetic amplitudes produced similar reductions in hypersensitivity due to nerve lesion as did conventional SCS at 50 Hz. HF-SCS showed no effect on thermal pain. A trial to rescue non-responders to conventional SCS using HF-SCS was not successful. There were no effects either of conventional or of HF-SCS on acute or inflammatory pain. Conventional SCS produced massive activation in the GN but no activation during HF-SCS, though normal peripherally evoked afferent activity remained. CONCLUSIONS: Conventional SCS proved equally effective to HF-SCS in various pain models. As no activity is conveyed rostrally in subparesthetic HF-SCS, we hypothesize that its mechanisms of action are primarily segmental.
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Modelos Animais de Doenças , Manejo da Dor/métodos , Dor/fisiopatologia , Estimulação da Medula Espinal/métodos , Vias Aferentes/fisiopatologia , Animais , Carragenina/toxicidade , Temperatura Baixa/efeitos adversos , Denervação , Eletrodos Implantados , Pé , Temperatura Alta/efeitos adversos , Hiperalgesia/induzido quimicamente , Hiperalgesia/terapia , Inflamação/fisiopatologia , Masculino , Bulbo/fisiopatologia , Microeletrodos , Dor/classificação , Dor/etiologia , Pressão/efeitos adversos , Ratos , Ratos Wistar , Nervo Isquiático/fisiopatologia , Nervo Isquiático/cirurgia , Corno Dorsal da Medula Espinal/fisiopatologiaRESUMO
OBJECTIVES: The effects of spinal cord stimulation (SCS) on the spinal γ-amino butyric acid (GABA) system have previously been studied in animal models of neuropathic pain. These studies, confirming the pivotal role of segmental GABA actions for the efficacy of SCS, have led to the question if the disturbance of the GABA inhibitory system as demonstrated both in basal and clinical studies also encompasses malfunction of the GABA synthesis. METHODS: Rat models of neuropathic pain were submitted to SCS applied with "clinical SCS parameters." The levels of the GABA-synthesizing enzymes, glutamic acid decarboxylase (GAD) 65 and GAD 67, in the spinal dorsal horns (DHs) were analyzed using Western blot and immunohistochemistry comparing responders and nonresponders to SCS, with and without SCS, as well as controls. RESULTS: There were no significant differences in general DH GAD levels between hypersensitive, nonhypersensitive, and intact control animals. Although SCS did not significantly influence these levels, there was a significant local augmentation of GAD 65 expression in lamina II in SCS responders subjected to SCS immediately prior to tissue collection as compared with SCS nonresponders. CONCLUSIONS: Although GABAergic mechanisms are closely related to the effects of SCS, the presence of neuropathic signs and their suppression by SCS are not associated with changes of the general levels of the spinal DH GABA-synthesizing enzymes. However, in SCS responding animals, there was a significant increased expression of GAD 65 in lamina II, presumably reflecting an augmented GABA synthesis following SCS.
Assuntos
Neurônios GABAérgicos/fisiologia , Neuralgia/terapia , Estimulação da Medula Espinal , Medula Espinal/enzimologia , Ácido gama-Aminobutírico/metabolismo , Análise de Variância , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/fisiologia , Glutamato Descarboxilase/metabolismo , Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Masculino , Medição da Dor , Limiar da Dor/fisiologia , Ratos , Ratos Wistar , Medula Espinal/citologiaRESUMO
In order to reconcile the present resurgence of psychiatric neurosurgery with the not-too-distant historic transgressions in the field, one needs to examine the era of transition from crude art to regulated science. In large part, this transition took place in the 1970s with the continued development and widespread acceptance of stereotactic techniques in functional neurosurgery and several hard-fought ideological and academic victories by proponents of the much-maligned field. Established in 1970, the International Society for Psychiatric Surgery (ISPS) sought to gather like-minded surgeons, psychiatrists and other neuroscientists to counter the rising pressure from special interest groups, as well as some in the public and medical realm, who attempted to abolish all forms of surgical management of psychiatric disease. We reviewed the archives of the ISPS, including letters from its founding members and active participants, conference proceedings and minutes from organizational meetings, from throughout its existence from 1970 to 1983. The archives provide a unique insight into the organization and objectives of the society that kept psychiatric surgery alive in the face of persistent and staunch opposition. We also outline the lessons that current and future functional neurosurgeons can learn from the ISPS, whose key figures, structure and communication, in the non-electronic era, were instrumental for the survival of psychiatric surgery during that critical period.
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Cooperação Internacional/história , Transtornos Mentais/história , Procedimentos Neurocirúrgicos/história , Psicocirurgia/história , Sociedades Médicas/história , História do Século XX , Humanos , Transtornos Mentais/cirurgia , Técnicas Estereotáxicas/históriaRESUMO
BACKGROUND: Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. On the basis of our previous studies on the mode of action of SCS, intrathecal administration of subeffective doses of certain drugs has been shown to enhance the pain-relieving effect in patients with SCS. Antidepressants have a well-established beneficial effect in neuropathic pain. We performed the present study to examine potential synergistic or antagonistic effects on SCS of antidepressants: amitriptyline (tricyclic antidepressant), fluoxetine (selective serotonin reuptake inhibitor), and milnacipran (selective serotonin/noradrenaline reuptake inhibitor). METHODS: In rats, the effect of SCS on mechanical hypersensitivity after peripheral nerve injury was assessed in awake, freely moving animals. Antidepressants were administered intrathecally. RESULTS: When combining SCS with subeffective doses of amitriptyline or milnacipran, the suppressive effect of SCS on the mechanical hypersensitivity was enhanced in comparison with that obtained with SCS alone. There was no detectable effect of fluoxetine. No signs of an antagonistic effect of the drugs on the SCS effect were observed. CONCLUSIONS: These findings suggest a possible clinical application with a combination of SCS and a tricyclic antidepressant or selective serotonin/noradrenaline reuptake inhibitor drug in cases in which SCS per se has proven inefficient.
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Antidepressivos/uso terapêutico , Manejo da Dor/métodos , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/terapia , Medula Espinal/fisiologia , Estimulação Elétrica Nervosa Transcutânea , Amitriptilina/uso terapêutico , Animais , Antidepressivos Tricíclicos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Ciclopropanos/uso terapêutico , Eletrodos Implantados , Fluoxetina/uso terapêutico , Ligadura , Masculino , Milnaciprano , Medição da Dor/efeitos dos fármacos , Estimulação Física , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/terapia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. Our previous animal experiments performed on rat models of SCS and ensuing clinical trials have demonstrated that intrathecal (i.t.) administration of subeffective doses of certain drugs may enhance the pain relieving effect of SCS in cases with unsatisfactory SCS outcome. Recently, an augmented release of spinal acetylcholine acting on muscarinic receptors has been shown to be one of the mechanisms involved in SCS. The present study was performed to examine whether cold hypersensitivity and heat hyperalgesia in rats with partial sciatic nerve injuries can be attenuated by SCS in the same way as tactile hypersensitivity and to explore a possibly synergistic effect of SCS and a muscarinic receptor agonist, oxotremorine. Rats with signs of neuropathy were subjected to SCS applied in awake, freely moving condition. Oxotremorine was administered intrathecally. Tactile, cold and heat sensitivities were assessed by using von Frey filaments, cold spray and focused radiant heat, respectively. Oxotremorine i.t. dose-dependently suppressed the tactile hypersensitivity. SCS markedly increased withdrawal thresholds (WTs), withdrawal latencies and cold scores. When combining SCS with a subeffective dose of oxotremorine i.t., the suppressive effect of SCS on the pain-related symptoms was dramatically enhanced in rats failing to obtain a satisfactory effect with SCS alone. In conclusion, the combination of SCS and a drug with selective muscarinic receptor agonistic properties could be an optional therapy, when SCS per se has proven inefficient.
Assuntos
Terapia por Estimulação Elétrica , Mononeuropatias/terapia , Agonistas Muscarínicos/administração & dosagem , Neuralgia/terapia , Oxotremorina/administração & dosagem , Medula Espinal/metabolismo , Animais , Temperatura Baixa , Terapia Combinada , Eletrodos Implantados , Temperatura Alta , Hiperestesia/terapia , Injeções Espinhais , Masculino , Mononeuropatias/complicações , Neuralgia/etiologia , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Nervo Isquiático/lesões , Medula Espinal/efeitos dos fármacosRESUMO
BACKGROUND/AIMS/METHODS: In order to explore the usefulness and long-term result of subthalamic nucleus (STN) stimulation for the treatment of essential tremor (ET), we evaluated 3 groups of patients undergoing deep brain stimulation (DBS) for ET. RESULTS: Group 1 consisted of 3 patients who 9 years ago at intra-operative testing had good tremor reduction from STN stimulation. The second group consisted of 10 patients treated with DBS in the ventral intermediate (Vim) nucleus of the thalamus. The third group comprised 9 patients subjected to STN stimulation for ET with 1-3 years of follow-up. The 3 ET patients with STN stimulation in group 1 have continued to have excellent tremor reduction for up to 9 years. The second group, with Vim stimulation, showed less favourable long-term results. All of the recent STN stimulation group experienced good tremor reduction, but some of the patients above 70 years of age reported troublesome side effects. CONCLUSION: Provided that intra-operative test stimulation produces satisfactory tremor control, STN is a good target for long-term treatment of ET. For patients above the age of 70 years, however, the Vim is a preferable target.
Assuntos
Estimulação Encefálica Profunda/métodos , Tremor Essencial/fisiopatologia , Tremor Essencial/terapia , Núcleo Subtalâmico/fisiologia , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Pessoa de Meia-Idade , Monitorização Intraoperatória/psicologia , TempoRESUMO
Substantial evidence has established that activation of the NMDA receptor in the spinal dorsal horn is essential for central sensitization-a phenomenon which comprises various pathophysiological mechanisms underlying neuropathic pain-like signs in animal models. In the present study, a partial sciatic nerve ligation in the rat was used to produce a model of nerve injury-induced pain represented by hypersensitivity to innocuous stimuli ("allodynia"). The aim was to assess whether alteration of NMDA receptor expression correlates with the presence of neuropathic signs. Our approach was to compare spinal NMDA receptor subunit expression and especially subunit 1 phosphorylation, assessed with immunohistochemistry and Western blot at late postoperative times, between nerve-injured rats with marked signs of neuropathy in terms of mechanical and cold hypersensitivity and nerve-injured rats that lacked robust behavioral signs of neuropathy. Quantification of receptor expression was based on comparisons between the dorsal horns ispi- and contralateral to the nerve lesion. The phosphorylated NR1 subunit of the NMDA receptor was found to be significantly increased in the ipsilateral dorsal horn in hypersensitive, but not in non-hypersensitive nerve-injured rats. We did not detect any differences in immunoreactivity in any of the non-phosphorylated NR1, NR2A, NR2B, NR2C or the NR2D subunits. These data suggest that phosphorylation of the NMDA receptor 1 subunit is correlated to the presence of signs of neuropathy (stimulus evoked pain-like behavior) and possibly also to persistent pain following nerve injury. This may represent a mechanism involved in spinal sensitization.
Assuntos
Dor/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/metabolismo , Animais , Temperatura Baixa , Imuno-Histoquímica , Masculino , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Fosforilação , Células do Corno Posterior/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/biossíntese , Nervo Isquiático/lesões , TatoRESUMO
Spinal cord stimulation (SCS) is a treatment given to patients with drug-resistant neuropathic pain, in particular pain resulting from peripheral nerve injury. However, the reasons why some patients develop neuropathic pain and why SCS is not effective in all patients with this chronic pain are not fully understood. The present study compares the response to SCS and the yield of neuropathic animals in variants of the spared nerve injury (SNI) model introduced by Decosterd and Woolf (I. Decosterd, C.J. Woolf, Spared nerve injury: an animal model of persistent peripheral neuropathic pain, Pain 87 (2000) 149-158). Sprague-Dawley rats were prepared with various types of lesions of different branches of the sciatic nerve and then tested for paw mechanical hypersensitivity. A miniature electrode system for SCS was implanted at the T10-T11 vertebral level. Stimulation was applied in awake, freely moving animals with parameters comparable to those employed clinically. Suppression of paw hypersensitivity was considered a positive response to SCS. The incidence of mechanical hypersensitivity ("allodynia") in the different models was: SNI 53%; peroneal axotomy 45%; tibial axotomy 68%; tibial tight ligation 73% and partial tibial tight ligation 50%. "Mirror phenomena" with contralateral paw hypersensitivity was present in about 20% of the animals. The response to SCS differed between models with the lowest response rate in the original SNI model (8%) while the others demonstrated rates in the order of 40-50%. There was a tendency that the efficacy of SCS in suppressing allodynia was inversely related to the severity of hypersensitivity. In conclusion, modifications of the SNI model provide a reproducible incidence of neuropathic hypersensitivity and an increased responsiveness to SCS. These variants may prove suitable for future research on the mechanisms involved in pain relief with SCS.
Assuntos
Modelos Animais de Doenças , Estimulação Elétrica/métodos , Ciática/terapia , Medula Espinal/efeitos da radiação , Animais , Axotomia/métodos , Masculino , Medição da Dor/métodos , Limiar da Dor/fisiologia , Limiar da Dor/efeitos da radiação , Ratos , Ratos Sprague-Dawley , Ciática/etiologia , Medula Espinal/fisiopatologia , Fatores de TempoRESUMO
Spinal cord stimulation emerged as a spin-off from the classical gate-control theory, which, however, does not suffice to explain its clinical effects. Whether or not nociceptive forms of pain may be attenuated remains a controversial issue. Previous experimental studies aiming at elucidating the underlying mechanisms were performed on intact, anesthetized animals and were therefore of limited clinical relevance. Not until recent years have some data on the mode of action accumulated providing evidence that gamma-aminobutyric acid (GABA) ergic as well as adenosine-related mechanisms are involved in the pain amelioration. It appears that the effects are exerted mostly via segmental spinal levels, but recent evidence suggests that a supraspinal loop may also be of importance; this issue remains to be resolved. It should be emphasized that most experimental data pertaining to the mode of action are derived from so-called animal models of neuropathic pain. However, caution must be exercised in the translation of such data from bench to bedside, because some behavioral signs interpreted as "pain" in such models may be misleading. We still need animal studies to generate basic data but these findings should also be confirmed in humans.
Assuntos
Terapia por Estimulação Elétrica/métodos , Modelos Neurológicos , Neuralgia/fisiopatologia , Neuralgia/terapia , Limiar da Dor , Medula Espinal/fisiopatologia , Animais , Doença Crônica , Humanos , Neuralgia/diagnóstico , RatosRESUMO
Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug's spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics.
RESUMO
OBJECTIVE: The objective of the present study was to evaluate the long-term efficacy and safety of capsulotomy in patients with anxiety disorders. METHOD: Twenty-six patients who had undergone bilateral thermocapsulotomy were followed up 1 year after the procedure and after a mean of 13 years. Primary diagnoses were generalized anxiety disorder (N=13), panic disorder (N=8), and social phobia (N=5). Measures of psychiatric status included symptom rating scales and neuropsychological testing. Ratings were done by psychiatrists not involved in patient selection or postoperative treatment. A quantitative magnetic resonance imaging (MRI) evaluation was conducted to search for common anatomic denominators. Seventeen of the 23 patients who were alive at long-term follow-up were followed up in person, and one was interviewed by telephone; the relatives of these 18 patients were interviewed. RESULTS: The reduction in anxiety ratings was significant both at 1-year and long-term follow-up. Seven patients, however, were rated as having substantial adverse symptoms; the most prominent adverse symptoms were apathy and dysexecutive behavior. Neuropsychological performance was significantly worse in the patients with adverse symptoms. No common anatomic denominator could be found in responders in the analysis of MRI scans. CONCLUSIONS: Thermocapsulotomy is an effective treatment for selected cases of nonobsessive anxiety but may carry a significant risk of adverse symptoms indicating impairment of frontal lobe functioning. These findings underscore the importance of face-to-face assessments of adverse symptoms.
Assuntos
Transtornos de Ansiedade/cirurgia , Cápsula Interna/cirurgia , Adulto , Transtornos de Ansiedade/diagnóstico , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Eletrocoagulação/efeitos adversos , Eletrocoagulação/métodos , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtorno de Pânico/diagnóstico , Transtorno de Pânico/cirurgia , Transtornos Fóbicos/diagnóstico , Transtornos Fóbicos/cirurgia , Escalas de Graduação Psiquiátrica , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
The clinical results of electrical stimulation in medial thalamic regions for cancer pain have been correlated with the exact location of the stimulation sites. Five brains were examined by post-mortem histology. Chronic implantation of enamel coated platinum-iridium electrodes for up to 17 months caused relatively mild glial and neuronal reactions and no significant haemorrhage or infarction. The anatomical verifications showed that the electrodes were close to, but not exactly in, the regions defined by the stereotactic coordinates. From the clinico-anatomical correlations it appears that good pain relief can be obtained by electrical stimulation in the periventricular gray region of the posterior thalamus.
Assuntos
Terapia por Estimulação Elétrica , Dor Intratável/terapia , Tálamo/anatomia & histologia , Idoso , Estimulação Elétrica , Eletrodos Implantados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naloxona/uso terapêutico , Neoplasias/terapia , Técnicas Estereotáxicas , Tálamo/fisiologiaRESUMO
Thirty-eight consecutive patients with neuralgia after peripheral nerve injury were treated with one or two series of peripheral local anesthetic blocks. All patients experienced an initial total relief of ongoing pain for 4-12 h. Evoked pain (hyperalgesia or allodynia), which occurred in 17 patients, was blocked simultaneously with the spontaneous pain. In 18 patients the analgesia outlasted the conduction block and there was a period of complete pain relief of 12-48 h in 13 patients and of 2-6 days in the other 5. In 8 patients there was a second phase of analgesia of 4 h to 6 days duration occurring within 12 h of pain recurrence. Thus, mono- or biphasic prolonged complete analgesia occurred in 25 out of 38 patients. A prolonged analgesia may be the result of a central action of the local anesthetic at the spinal level after intra-axonal incorporation and centripetal axoplasmic transport. To test this hypothesis, an experimental study with [3H]lidocaine was performed in 6 rats. The radioactive local anesthetic was injected into one hind limb foot with the other side serving as a control. Tissue samples from the peripheral nerve, nerve root and the lumbosacral spinal cord segment were analyzed for radioactivity using a scintillation counter technique at various time intervals after the [3H]lidocaine injection. There was a low grade of activity in all samples and no difference between the test side and the control side. Thus these experiments provided no evidence in support of this hypothesis. Various alternative peripheral and central mechanisms are discussed. Further studies specifically directed to these alternatives and with longitudinal controls are prompted.
Assuntos
Anestesia Local , Bloqueio Nervoso , Neuralgia/terapia , Cuidados Paliativos , Adolescente , Adulto , Idoso , Animais , Feminino , Humanos , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Lidocaína/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neuralgia/fisiopatologia , Medição da Dor , Ratos , Ratos Endogâmicos , Fatores de Tempo , TocainideRESUMO
Peripheral hypersensitivity (hyperalgesia and allodynia) are common phenomena both in inflammatory and in neuropathic pain conditions. Several rat models of mononeuropathy (Bennett, Seltzer and Gazelius models) display such symptoms following partial injury to the sciatic nerve. Using immunohistochemistry and behavioral tests, we investigated inflammatory cell and cytokine responses in the sciatic nerve 14 days after injury created in these different models as well as after axotomy. Tactile hypersensitivity ('allodynia') was present in all Gazelius model rats whereas only 38 and 29% of the Bennett and Seltzer models, respectively, displayed this sign of neuropathy. The inflammatory reactions in rats with and without tactile allodynia were compared. Monocytes/macrophages (ED-1), natural killer cells, T lymphocytes, and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), were significantly upregulated in all nerve injured rats in comparison to sham-operated controls. Interestingly, ED-1-, TNF-alpha- and IL-6-positive cells increased more markedly in allodynic Bennett and Seltzer rats than in non-allodynic ones. The magnitude of the inflammatory response does not seem to relate to the extent of damage to the nerve fibers because axotomized rats displayed much lower upregulation. Our findings indicate that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of IL-6 and TNF-alpha. This may relate to the generation of tactile allodynia/hyperalgesia, since there was a clear correlation between the number of ED-1 and IL-6-positive cells and the degree of allodynia. It is possible that measures to reduce monocyte/macrophage recruitment and the release of pro-inflammatory interleukins after nerve damage could influence the development of neuropathic pain.
Assuntos
Hiperalgesia/metabolismo , Mediadores da Inflamação/metabolismo , Mononeuropatias/metabolismo , Limiar da Dor/fisiologia , Nervo Isquiático/metabolismo , Animais , Axotomia , Masculino , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Nervo Isquiático/cirurgia , TatoRESUMO
Only about 60-70% of well selected patients with neuropathic pain syndromes of peripheral origin enjoy sufficient pain relief with spinal cord stimulation (SCS). Since recent animal experiments have demonstrated that the GABA-B receptor is pivotal in the effect of SCS on certain neuropathic symptoms, the use of baclofen as an adjunct to stimulation emerged as an option in patients not responding satisfactorily to SCS. Forty-eight patients with neuropathic pain of peripheral origin responding poorly to SCS were enrolled in a study with intrathecal baclofen; in a few cases adenosine was also tried. Twenty patients reported significant pain reduction at bolus trials and were offered implantation of a drug pump. Seven patients subsequently had pumps implanted together with SCS and four had pumps alone. Three patients had only peroral baclofen therapy as an adjunct to SCS. The 14 patients continuing with baclofen therapy as an adjunct to SCS, or alone, were followed for an average of 35 months after pump implant. The group with SCS+pump n=5; 2 explanted) reported an average decrease of pain ratings from VAS 82 to 33. The group with i.t. baclofen only had a pain decrease from VAS 63 to 33, while the three patients with peroral baclofen+SCS had less benefit from drug therapy. Adjunctive drug therapy for patients with unsatisfactory pain relief by SCS may offer a possibility to enhance pain alleviation.
Assuntos
Baclofeno/administração & dosagem , Terapia por Estimulação Elétrica/estatística & dados numéricos , Neuralgia/terapia , Dor Intratável/terapia , Doenças do Sistema Nervoso Periférico/terapia , Medula Espinal/efeitos dos fármacos , Administração Oral , Adulto , Idoso , Analgésicos/administração & dosagem , Feminino , Agonistas GABAérgicos/administração & dosagem , Agonistas dos Receptores de GABA-B , Humanos , Bombas de Infusão , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Neuralgia/fisiopatologia , Dor Intratável/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Projetos Piloto , Receptores de GABA-B/metabolismo , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Resultado do TratamentoRESUMO
Spinal cord stimulation (SCS) is an effective tool in alleviating neuropathic pain. However, a number of well-selected patients fail to obtain satisfactory pain relief. Previous studies have demonstrated that i.t. baclofen and/or adenosine can enhance the SCS effect, but this combined therapy has been shown to be useful in less than half of the cases and more effective substances are therefore needed. The aim of this experimental study in rats was to examine whether gabapentin or pregabalin attenuates tactile allodynia following partial sciatic nerve injury and whether subeffective doses of these drugs can potentiate the effects of SCS in rats which do not respond to SCS. Mononeuropathy was produced by a photochemically induced ischaemic lesion of the sciatic nerve. Tactile withdrawal thresholds were assessed with von Frey filaments. Effects of increasing doses of gabapentin and pregabalin (i.t. and i.v.) on the withdrawal thresholds were analysed. These drugs were found to reduce tactile allodynia in a dose-dependent manner. In SCS non-responding rats, i.e. where stimulation per se failed to suppress allodynia, a combination of SCS and subeffective doses of the drugs markedly attenuated allodynia. In subsequent acute experiments, extracellular recordings from wide dynamic range neurones in the dorsal horn showed prominent hyperexcitability. The combination of SCS and gabapentin, at the same subeffective dose, clearly enhanced suppression of this hyperexcitability. In conclusion, electrical therapy and pharmacological therapy in neuropathic pain can, when they are inefficient individually, become effective when combined.
Assuntos
Acetatos/farmacologia , Aminas , Analgésicos/farmacologia , Anticonvulsivantes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Ácidos Cicloexanocarboxílicos , Mononeuropatias/tratamento farmacológico , Dor/tratamento farmacológico , Nervo Isquiático/lesões , Medula Espinal/efeitos dos fármacos , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacologia , Animais , Quimioterapia Combinada , Estimulação Elétrica , Eletrofisiologia , Gabapentina , Injeções , Isquemia , Masculino , Mononeuropatias/terapia , Manejo da Dor , Células do Corno Posterior/efeitos dos fármacos , Pregabalina , Ratos , Ratos Sprague-Dawley , TatoRESUMO
OBJECTIVE: To optimize the technique of implanting laminotomy plate electrodes for spinal cord stimulation and to minimize the discomfort of the patients during surgery. This operation is often performed while the patient is under local anesthesia, which is very stressful for the patient, or under general anesthesia, which precludes the use of test stimulation. An alternative approach is to perform the implantation with a spinal anesthetic and to examine whether stimulation-induced paresthesiae can still be evoked to guide the positioning of the electrode. METHODS: Spinal anesthesia was induced by bupivacaine (12.5-20 mg), which produced complete motor block and anesthesia up to a midthoracic level. After a single-level laminotomy (thoracic vertebrae 9-11) a four-pole plate electrode was inserted into the epidural space. Stimulation was applied with commonly used parameters, and the electrode was positioned so that the paresthesiae covered the painful region. RESULTS: In 19 patients (20 procedures) with different forms of neuropathic pain, implantation of laminotomy plate electrodes could be performed under spinal anesthesia without problems. In all patients, it was possible to evoke paresthesiae, the distribution of which could be reproduced postoperatively. The paresthesia thresholds during surgery were only moderately higher than those recorded after implantation (mean, 3.1 versus 2.1 V, respectively). During an interview after the intervention, no patient reported that he or she had experienced surgery as painful or uncomfortable. CONCLUSION: Implantation of laminotomy electrodes can be performed conveniently with spinal anesthesia because it minimizes discomfort for the patient and enables the use of intraoperative test stimulation to guide the positioning of the electrode. In spite of the total motor block and anesthesia, paresthesiae representing the activation of the dorsal columns can be evoked and are well perceived, and the thresholds are not abnormally high. This observation supports the notion that the subarachnoidal anesthetic agent acts predominantly on the spinal rootlets rather than on the spinal afferent pathways.