Clinical Studies on Epidural and Spinal Postoperative Analgesia : With Special Reference to Continuous Techniques of Administration and Adjuvant Drugs

Continuous epidural analgesia (CEA) and continuous spinal postoperative analgesia (CSPA) provided by a mixture of local anaesthetic and opioid are widely used for postoperative pain relief. E.g., with the introduction of so-called microcatheters, CSPA found its way particularly in orthopaedic surgery. These techniques, however, may be associated with dose-dependent side-effects as hypotension, weakness in the legs, and nausea and vomiting. At times, they may fail to offer sufficient analgesia, e.g., because of a misplaced catheter. The correct position of an epidural catheter might be confirmed by the supposedly easy and reliable epidural stimulation test (EST). The aims of this thesis were to determine a) whether the efficacy, tolerability, and reliability of CEA might be improved by adding the α2-adrenergic agonists adrenaline and clonidine to CEA, and by the repeated use of EST during CEA; and, b) the feasibility of CSPA given through a microcatheter after vascular surgery. Studies I IV were double-blinded, randomized, and controlled trials; Study V was of a diagnostic, prospective nature. Patients underwent arterial bypass surgery of the legs (I, n=50; IV, n=46), total knee arthroplasty (II, n=70; III, n=72), and abdominal surgery or thoracotomy (V, n=30). Postoperative lumbar CEA consisted of regular mixtures of ropivacaine and fentanyl either without or with adrenaline (2 µg/ml (I) and 4 µg/ml (II)) and clonidine (2 µg/ml (III)). CSPA (IV) was given through a microcatheter (28G) and contained either ropivacaine (max. 2 mg/h) or a mixture of ropivacaine (max. 1 mg/h) and morphine (max. 8 µg/h). Epidural catheter tip position (V) was evaluated both by EST at the moment of catheter placement and several times during CEA, and by epidurography as reference diagnostic test. CEA and CSPA were administered for 24 or 48 h. Study parameters included pain scores assessed with a visual analogue scale, requirements of rescue pain medication, vital signs, and side-effects. Adrenaline (I and II) had no beneficial influence as regards the efficacy or tolerability of CEA. The total amounts of epidurally-infused drugs were even increased in the adrenaline group in Study II (p=0.02, RM ANOVA). Clonidine (III) augmented pain relief with lowered amounts of epidurally infused drugs (p=0.01, RM ANOVA) and reduced need for rescue oxycodone given i.m. (p=0.027, MW-U; median difference 3 mg (95% CI 0 7 mg)). Clonidine did not contribute to sedation and its influence on haemodynamics was minimal. CSPA (IV) provided satisfactory pain relief with only limited blockade of the legs (no inter-group differences). EST (V) was often related to technical problems and difficulties of interpretation, e.g., it failed to identify the four patients whose catheters were outside the spinal canal already at the time of catheter placement. As adjuvants to lumbar CEA, clonidine only slightly improved pain relief, while adrenaline did not provide any benefit. The role of EST applied at the time of epidural catheter placement or repeatedly during CEA remains open. The microcatheter CSPA technique appeared effective and reliable, but needs to be compared to routine CEA after peripheral arterial bypass surgery.

Paracetamol metabolism in postoperative patients

Introduction: Despite being available for more than 50 years, there is still much to learn about paracetamol. Postoperative analgesic regimens that maintain good pain control while minimising exposure to opiates are beneficial and paracetamol has had a resurgence in this role since an IV formulation came to market. However there is evidence to suggest currently licensed doses are sub-therapeutic, especially when administered orally or rectally. Higher, unlicensed doses are now being advocated but, prior to this study, there was little evidence of their safety in surgical patients. When assessing drug safety in surgical patients a number of surgery and patient related factors influence results, and these must be considered. Methods: Major and intermediate surgical patients were recruited from two hospitals in Ireland. They were administered IV paracetamol at either 9g or 4g daily doses. In addition they received daily sub therapeutic doses of four other medicines to indicate the activity of their CYP450 enzymes that are involved in paracetamol metabolism. Urine and blood samples were collected to determine paracetamol pharmacokinetics, CYP450 activity, inflammatory cytokine concentration and for evidence of hepatotoxicity. Results: There were 33 patients that participated in the study. There was no evidence of clinically significant hepatotoxicity occurring in any patient during the study period, but there could have been changes following this time. Paracetamol disposition was shown to change, however half-life remained relatively constant. There were a number of changes to the way paracetamol was metabolised following surgery that maintained this rate of elimination. Conclusion: Doses of up to 9g per day given to major surgical patients for up to five days postoperatively produced no evidence of hepatotoxicity. Further research is warranted to determine the clinical utility of these higher doses

Lack of evidence for ectopic sprouting of genetically labeled Aβ touch afferents in inflammatory and neuropathic trigeminal pain.

BACKGROUND: Mechanical and in particular tactile allodynia is a hallmark of chronic pain in which innocuous touch becomes painful. Previous cholera toxin B (CTB)-based neural tracing experiments and electrophysiology studies had suggested that aberrant axon sprouting from touch sensory afferents into pain-processing laminae after injury is a possible anatomical substrate underlying mechanical allodynia. This hypothesis was later challenged by experiments using intra-axonal labeling of A-fiber neurons, as well as single-neuron labeling of electrophysiologically identified sensory neurons. However, no studies have used genetically labeled neurons to examine this issue, and most studies were performed on spinal but not trigeminal sensory neurons which are the relevant neurons for orofacial pain, where allodynia oftentimes plays a dominant clinical role. FINDINGS: We recently discovered that parvalbumin::Cre (Pv::Cre) labels two types of Aβ touch neurons in trigeminal ganglion. Using a Pv::CreER driver and a Cre-dependent reporter mouse, we specifically labeled these Aβ trigeminal touch afferents by timed taxomifen injection prior to inflammation or infraorbital nerve injury (ION transection). We then examined the peripheral and central projections of labeled axons into the brainstem caudalis nucleus after injuries vs controls. We found no evidence for ectopic sprouting of Pv::CreER labeled trigeminal Aβ axons into the superficial trigeminal noci-receptive laminae. Furthermore, there was also no evidence for peripheral sprouting. CONCLUSIONS: CreER-based labeling prior to injury precluded the issue of phenotypic changes of neurons after injury. Our results suggest that touch allodynia in chronic orofacial pain is unlikely caused by ectopic sprouting of Aβ trigeminal afferents.

Neonatal pain in relation to postnatal growth in infants born very preterm

Procedural pain is associated with poorer neurodevelopment in infants born very preterm (= 32 weeks gestational age), however, the etiology is unclear. Animal studies have demonstrated that early environmental stress leads to slower postnatal growth; however, it is unknown whether neonatal pain-related stress affects postnatal growth in infants born very preterm. The aim of this study was to examine whether greater neonatal pain (number of skin-breaking procedures adjusted for medical confounders) is related to decreased postnatal growth (weight and head circumference [HC] percentiles) early in life and at term-equivalent age in infants born very preterm. Participants were n=78 preterm infants born = 32 weeks gestational age, followed prospectively since birth. Infants were weighed and HC measured at birth, early in life (median: 32 weeks [interquartile range 30.7-33.6]) and at term-equivalent age (40 weeks [interquartile range 38.6-42.6]). Weight and HC percentiles were computed from sex-specific British Columbia population-based data. Greater neonatal pain predicted lower body weight (Wald ?(2)=7.36, P=0.01) and HC (Wald ?(2)=4.36, P=0.04) percentiles at 32 weeks postconceptional age, after adjusting for birth weight percentile and postnatal risk factors of illness severity, duration of mechanical ventilation, infection, and morphine and corticosteroid exposure. However, later neonatal infection predicted lower weight percentile at term (Wald ?(2)=5.09, P=0.02). Infants born very preterm undergo repetitive procedural pain during a period of physiological immaturity that appears to impact postnatal growth, and may activate a downstream cascade of stress signaling that affects later growth in the neonatal intensive care unit.

Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU

Data from animal models indicate that neonatal stress or pain can permanently alter subsequent behavioral and/or physiological reactivity to stressors. However, cumulative effects of pain related to acute procedures in the neonatal intensive care unit (NICU) on later stress and/or pain reactivity has received limited attention. The objective of this study is to examine relationships between prior neonatal pain exposure (number of skin breaking procedures), and subsequent stress and pain reactivity in preterm infants in the NICU. Eighty-seven preterm infants were studied at 32 (+/-1 week) postconceptional age (PCA). Infants who received analgesia or sedation in the 72 h prior to each study, or any postnatal dexamethasone, were excluded. Outcomes were infant responses to two different stressors studied on separate days in a repeated measures randomized crossover design: (1) plasma cortisol to stress of a fixed series of nursing procedures; (2) behavioral (Neonatal Facial Coding System; NFCS) and cardiac reactivity to pain of blood collection. Among infants born

Perceptions of the Nurse Practitioner Role in Facilitating the Implementation of an Onsite Pain Management Team in Long Term Care

Background: One strategy to improve pain management in long term care (LTC) is to optimize the emerging role of the nurse practitioner (NP) in LTC. The purpose of this sub study was to learn about the NP role in implementing an onsite, interdisciplinary Pain Team in the LTC home setting.

Methods: We used a case study design that included two NPs who worked at separate LTC homes. Each of the NPs completed a weekly questionnaire of pain-related activities that they engaged in over a one-year implementation period; and a diary, using critical reflection, about their experiences and strategies used to implement the Pain Team. Descriptive statistics and thematic content analysis were used to analyze the case study data.

Findings: NPs tended to be most engaged in pain assessment and collaborated more with licensed nurses and personal support workers; less with pharmacists. NPs were more involved in organizational level activities, such as participating in committee work or assisting with the development of policies and procedures about pain. NPs created palliative care and pain service protocols; engaged in policy development, in-servicing, quality assurance and advocacy; and encouraged best practices. NPs were challenged with time constraints for pain management and balancing other role priorities and felt that increased scope of practice for them was needed.

Conclusions: The results of this study highlight how NPs implemented a Pain Team in LTC which may be helpful to others interested in implementing a similar strategy to reduce residents’ pain.

Pain expressiveness and altruistic behavior

Predictions which invoke evolutionary mechanisms ar e hard to test. Agent-based modeling in artificial life offers a way to simulate behaviors and interac tions in specific physical or social environments o ver many generations. The outcomes have implications fo r understanding adaptive value of behaviors in context. Pain-related behavior in animals is communicated to other animals that might protect or help, or might exploit or predate. An agent-based model simulated the effects of displaying or not displaying pain (expresser/non-expresser strategies) when injured, and of helping, ignoring or exploiting another in pain (altruistic/non-altruistic/selfish strategies) . Agents modeled in MATLAB interacted at random while foraging (gaining energy); random injury inte rrupted foraging for a fixed time unless help from an altruistic agent, who paid an energy cost, speeded recovery. Environmental and social conditions also varied, and each model ran for 10,000 iterations. Findings were meaningful in that, in general, conti ngencies evident from experimental work with a variety of mammals, over a few interactions, were r eplicated in the agent-based model after selection pressure over many generations. More energy-demandi ng expression of pain reduced its frequency in successive generations, and increasing injury frequ ency resulted in fewer expressers and altruists. Allowing exploitation of injured agents decreased e xpression of pain to near zero, but altruists remained. Decreasing costs or increasing benefits o f helping hardly changed its frequency, while increasing interaction rate between injured agents and helpers diminished the benefits to both. Agent- based modeling allows simulation of complex behavio urs and environmental pressures over evolutionary time.

Descending pain modulation in a Kaolin-induced hydrocephalus rat model

Pain transmission at the spinal cord is modulated by descending actions that arise from supraspinal areas which collectively form the endogenous pain control system. Two key areas involved of the endogenous pain control system have a circunventricular location, namely the periaqueductal grey (PAG) and the locus coeruleus (LC). The PAG plays a crucial role in descending pain modulation as it conveys the input from higher brain centers to the spinal cord. As to the LC, it is involved in descending pain inhibition by direct noradrenergic projections to the spinal cord. In the context of neurological defects, several diseases may affect the structure and function of the brain. Hydrocephalus is a congenital or acquired disease characterized by an enlargement of the ventricles which leads to a distortion of the adjacent tissues, including the PAG and LC. Usually, patients suffering from hydrocephalus present dysfunctions in learning and memory and also motor deficits. It remains to be evaluated if lesions of the periventricular brain areas involved in pain control during hydrocephalus may affect descending pain control and, herein, affect pain responses. The studies included in the present thesis used an experimental model of hydrocephalus (the rat injected in the cisterna magna with kaolin) to study descending modulation of pain, focusing on the two circumventricular regions referred above (the PAG and the LC). In order to evaluate the effects of kaolin injection into the cisterna magna, we measured the degree of ventricular dilatation in sections encompassing the PAG by standard cytoarquitectonic stanings (thionin staining). For the LC, immunodetection of the noradrenaline-synthetizing enzyme tyrosine hydroxylase (TH) was performed, due to the noradrenergic nature of the LC neurons. In general, rats with kaolin-induced hydrocephalus presented a higher dilatation of the 4th ventricle, along with a tendency to a higher area of the PAG. Due to the validated role of detection the c-fos protooncogene as a marker of neuronal activation, we also studied neuronal activation in the several subnuclei which compose the PAG, namely the dorsomedial, dorsolateral, lateral and ventrolateral (VLPAG) parts. A decrease in the numbers of neurons immunoreactive for Fos protein (the product of activation of the c-fos protooncogene) was detected in rats injected with kaolin, whereas the remaining PAG subnuclei did not present changes in Fos-immunoreactive nuclei. Increases in the levels of TH in the LC, namely at the rostral parts of the nucleus, were detected in hydrocephalic animals. The following pain-related parameters were measured, namely 1) pain behavioural responses in a validated pain inflammatory test (the formalin test) and 2) the nociceptive activation of spinal cord neurons. A decrease in behavioral responses was detected in rats with kaolin-induced hydrocephalus was detected, namely in the second phase of the test (inflammatory phase). This is the phase of the formalin test in which the motor behaviour is less important, which is important since a semi-quantitative analysis of the motor performance of rats injected with kaolin indicates that these animals may present some motor impairments. Collectively, the results of the behavioral studies indicate that rats with kaolin-induced hydrocephalus exhibit hypoalgesia. A decrease in Fos expression was detected at the superficial dorsal layers of the spinal cord in rats with kaolin-induced hydrocephalus, further indicating that hydrocephalus decreases nociceptive responses. It remains to be ascertained if this is due to alterations in the PAG and LC in the rats with kaolin-induced hydrocephalus, which may affect descending pain modulation. It remains to be evaluated what are the mechanisms underlying the increased pain inhibition at the spinal dorsal horn in the hydrocephalus rats. Regarding the VLPAG, the decrease in neuronal activity may impair descending modulation. Since the LC has higher levels of TH in rats with kaolininduced hydrocephalus, which also appears to increase the noradrenergic innervation in the spinal dorsal horn, it is possible that an increase in the release of noradrenaline at the spinal cord accounts for pain inhibition. Our studies also determine the need to study in detail patients with hydrocephalus namely in what concerns their thresholds to pain and to perform imaging studies focused on the structure and function of pain control areas in the brain.

Partner behavioral responses to pain mediate the relationship between partner pain cognitions and pain outcomes in women with provoked vestibulodynia.

Partner behavioral responses to pain can have a significant impact on patient pain and depression, but little is known about why partners respond in specific ways. Using a cognitive-behavioral model, the present study examined whether partner cognitions were associated with partner behavioral responses, which prior work has found to predict patient pain and depressive symptoms. Participants were 354 women with provoked vestibulodynia and their partners. Partner pain-related cognitions were assessed using the partner versions of the Pain Catastrophizing Scale and Extended Attributional Style Questionnaire, whereas their behavioral responses to pain were assessed with the Multidimensional Pain Inventory. Patient pain was measured using a numeric rating scale, and depressive symptoms were assessed using the Beck Depression Inventory–II. Path analysis was used to examine the proposed model. Partner catastrophizing and negative attributions were associated with negative partner responses, which were associated with higher patient pain. It was also found that partner pain catastrophizing was associated with solicitous partner responses, which in turn were associated with higher patient pain and depressive symptoms. The effect of partner cognitions on patient outcomes was partially mediated by partner behavioral responses. Findings highlight the importance of assessing partner cognitions, both in research and as a target for intervention. Perspective The present study presents a cognitive-behavioral model to partially explain how significant others' thoughts about pain have an effect on patient pain and depressive symptoms. Findings may inform cognitive-behavioral therapy for couples coping with PVD.

Estudio Costo-Efectividad de Lidocaína tópica como adyuvante a Pregabalina y Gabapentina en dolor neuropático periférico en una I.P.S de Bogotá 2011.

Introducción: el dolor neuropático es una patología de considerable prevalencia e impacto socio-económico en la población latinoamericana, la evidencia clínica sugiere que los ligandos de canales de calcio y el parche de Lidocaína pueden tratar exitosamente el dolor neuropático periférico y localizado. Metodología: se realizo una evaluación económica tipo costo-efectividad, observacional y retrospectiva con datos extraídos de las historias clínicas de pacientes atendidos en la clínica de dolor de la IPS. La variable primaria de efectividad fue la mejoría del dolor medida mediante escala visual análoga. Resultados: se estudiaron 94 pacientes tratados con: Gabapentina (G) 21, Pregabalina (P) 24, Gabapentina+ lidocaína (G/P) 24, Pregabalina + Lidocaína (P/L) 25, los costos asociados al tratamiento son los siguientes COP$114.070.835, COP$105.855.920, COP$88.717.481 COP$89.854.712 respectivamente, el número de pacientes con mejoría significativa de dolor fue: 8,10,9 y 21 pacientes respectivamente. El ICER de G/L con respecto a G fue: COP$ -25.353.354. El ICER de P/L con respecto a P fue: COP$ -1.454.655. Conclusiones: la adición del parche de lidocaína a la terapia regular con P/L represento una disminución de consumo de recursos en salud como uso de medicamentos co-analgésicos, analgésicos de rescate y fármacos para controlar reacciones adversas, de la misma forma que consultas a profesionales de la salud. Cada paciente manejado con P/L representa un ahorro de COP $1.454.655 al contrario si se manejase con el anticonvulsivante de manera exclusiva, en el caso de G/L este ahorro es de COP $ 25.353.354 frente a G sola.

Efectos del consumo de cigarrillo en la presentación y severidad de la dismenorrea

Introducción: La dismenorrea se presenta como una patología cada vez más frecuente en mujeres de 16-30 años. Dentro de los factores asociados a su presentación, el consumo de tabaco ha revelado resultados contradictorios. El objetivo del presente estudio es explorar la asociación entre el consumo de cigarrillo y la presentación de dismenorrea, y determinar si los trastornos del ánimo y la depresión, alteran dicha asociación. Materiales y métodos: Se realizó un estudio de prevalencia analítica en mujeres de la Universidad del Rosario matriculadas en pregrado durante el primer semestre de 2013, para determinar la asociación entre el consumo de tabaco y la presentación de dismenorrea. En el estudio se tuvieron en cuenta variables tradicionalmente relacionadas con dismenorrea, incluyendo las variables ansiedad y depresión como potenciales variables de confusión. Los registros fueron analizados en el programa Estadístico IBM SPSS Statistics Versión 20.0. Resultados: Se realizaron 538 cuestionarios en total. La edad promedio fue 19.92±2.0 años. La prevalencia de dismenorrea se estimó en 89.3%, la prevalencia de tabaquismo 11.7%. No se encontró una asociación entre dismenorrea y tabaquismo (OR 3.197; IC95% 0.694-14.724). Dentro de las variables analizadas, la depresión y la ansiedad constituyen factores de riesgo independientes para la presentación de dismenorrea con una asociación estadísticamente significativa p=0.026 y p=0.024 respectivamente. El análisis multivariado encuentra como factor determinante en la presentación de dismenorrea, la interacción de depresión y ansiedad controlando por las variables tradicionales p<0.0001. Sin embargo, esta asociación se pierde cuando se analiza en la categoría de dismenorrea severa y gana relevancia el uso de métodos de anticoncepción diferentes a los hormonales, mientras que el hecho de haber iniciado la vida sexual presenta una tendencia limítrofe de riesgo. Conclusiones: No se puede demostrar que el tabaco es un factor asociado a la presentación de dismenorrea. Los trastornos del ánimo y la ansiedad constituyen factores determinantes a la presentación de dismenorrea independientemente de la presencia de otros concomitantes. Las variables de asociación se modifican cuando la variable dependiente se categoriza en su estado más severo. Se necesitan estudios más amplios y detallados para establecer dicha asociación.

Evaluación e intervención interdisciplinaria del dolor en Unidades de Cuidado Intensivo

El dolor es un problema importante para los pacientes hospitalizados en las UCI porque genera malestar y distrés. Además, la investigación ha demostrado que en algunos pacientes críticos el dolor agudo puede persistir después de alta y convertirse en crónico. La gestión eficaz del dolor en pacientes críticos requiere un enfoque interdisciplinario, que incorpore la visión y trabajo de expertos que representan una amplia variedad de especialidades clínicas. Así, la utilización de la intervención psicológica en el tratamiento del dolor es una parte integral de un enfoque global. Basado en una revisión de la evidencia científica, se identifican y señalan: (1) los tipos de dolor más comunes; (2) las características del dolor; (3) las patologías más frecuentes asociadas con la presencia de dolor; (4) los procedimientos que generan dolor en la UCI; (5) los métodos de evaluación del dolor; (6) la intervención del mismo y; (7) la contribución del psicólogo en la evaluación y manejo del dolor con el paciente, los familiares y los profesionales de la salud. La revisión realizada indica que los procesos psicológicos influyen tanto en la experiencia del dolor como en los resultados del tratamiento, por lo tanto la integración de los principios psicológicos en el tratamiento del dolor parecen tener potencial mejora de los resultados beneficiando la salud del paciente.

4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1

TRPA1 is an excitatory ion channel expressed by a subpopulation of primary afferent somatosensory neurons that contain substance P and calcitonin gene-related peptide. Environmental irritants such as mustard oil, allicin, and acrolein activate TRPA1, causing acute pain, neuropeptide release, and neurogenic inflammation. Genetic studies indicate that TRPA1 is also activated downstream of one or more proalgesic agents that stimulate phospholipase C signaling pathways, thereby implicating this channel in peripheral mechanisms controlling pain hypersensitivity. However, it is not known whether tissue injury also produces endogenous proalgesic factors that activate TRPA1 directly to augment inflammatory pain. Here, we report that recombinant or native TRPA1 channels are activated by 4-hydroxy-2-nonenal (HNE), an endogenous alpha,beta-unsaturated aldehyde that is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress. HNE provokes release of substance P and calcitonin gene-related peptide from central (spinal cord) and peripheral (esophagus) nerve endings, resulting in neurogenic plasma protein extravasation in peripheral tissues. Moreover, injection of HNE into the rodent hind paw elicits pain-related behaviors that are inhibited by TRPA1 antagonists and absent in animals lacking functional TRPA1 channels. These findings demonstrate that HNE activates TRPA1 on nociceptive neurons to promote acute pain, neuropeptide release, and neurogenic inflammation. Our results also provide a mechanism-based rationale for developing novel analgesic or anti-inflammatory agents that target HNE production or TRPA1 activation.

Non-pain goal pursuit inhibits attentional bias to pain

Although dealing with pain is a vital goal to pursue, most individuals are also engaged in the pursuit of other goals. The aim of the present experiment was to investigate whether attentional bias to pain signals is inhibited when one is pursuing a concurrent salient but nonpain task goal. Attentional bias to pain signals was measured in pain-free volunteers (n=63) using a spatial cueing task with pain cues and neutral cues. The pursuit of a concurrent goal was manipulated by including additional trials in which a digit appeared at the middle of the screen. Half of the participants (goal group) were instructed to name these additional stimuli aloud. In order to increase the affective-motivational value of this non-pain-related goal, monetary reward and punishment were made contingent upon the performance of this task. Participants of the control group did not perform the additional task. As predicted, the results show attentional bias to pain signals in the control group, but not in the goal group. This indicates that attentional bias to signals of impending pain is inhibited when one is engaged in the pursuit of another salient but nonpain goal. The results of this study underscore a motivational view on attention to pain, in which the pursuit of multiple goals, including nonpain goals, is taken into account.

HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain

Histone deacetylase inhibitors (HDACIs) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models of chronic inflammatory pain. The aim of this study was to determine whether these compounds could also affect neuropathic pain. Different class I HDACIs were delivered intrathecally into rat spinal cord in models of traumatic nerve injury and antiretroviral drug-induced peripheral neuropathy (stavudine, d4T). Mechanical and thermal hypersensitivity was attenuated by 40% to 50% as a result of HDACI treatment, but only if started before any insult. The drugs globally increased histone acetylation in the spinal cord, but appeared to have no measurable effects in relevant dorsal root ganglia in this treatment paradigm, suggesting that any potential mechanism should be sought in the central nervous system. Microarray analysis of dorsal cord RNA revealed the signature of the specific compound used (MS-275) and suggested that its main effect was mediated through HDAC1. Taken together, these data support a role for histone acetylation in the emergence of neuropathic pain.