Understanding general practitioners' prescribing choices to patients with chronic low back pain: a discrete choice experiment.

BACKGROUND: Although NSAIDs are recommended as a first line analgesic treatment, opioids are very commonly prescribed to patients with low back pain (LBP) despite risks of harms. AIM: This study aimed to determine factors contributing to general practitioners' (GPs') prescribing choices to patients with chronic LBP in a primary care setting. METHOD: This discrete choice experiment (DCE) presented 210 GPs with hypothetical scenarios of a patient with chronic LBP. Participants chose their preferred treatment for each choice set, either the opioid, NSAID or neither. The scenarios varied by two patient attributes; non-specific LBP or LBP with referred leg pain (sciatica) and number of comorbidities. The three treatment attributes also varied, being: the type of opioid or NSAID, degree of pain reduction and number of adverse events. The significance of each attribute in influencing clinical decisions was the primary outcome and the degree to which GPs preferred the alternative based on the number of adverse events or the amount of pain reduction was the secondary outcome. RESULTS: Overall, GPs preferred NSAIDs (45.2%, 95% CI 38.7-51.7%) over opioids (28.8%, 95% CI 23.0-34.7%), however there was no difference between the type of NSAID or opioid preferred. Additionally, the attributes of pain reduction and adverse events did not influence a GP's choice between NSAIDs or opioids for patients with chronic LBP. CONCLUSION: GPs prefer prescribing NSAIDs over opioids for a patient with chronic low back pain regardless of patient factors of comorbidities or the presence of leg pain (i.e. sciatica).

DGCR5 attenuates neuropathic pain through sponging miR-330-3p and regulating PDCD4 in CCI rat models.

Neuropathic pain caused by somatosensory nervous system dysfunction is a serious public health problem. Some long noncoding RNAs (lncRNAs) can participate in physiological processes involved in neuropathic pain. However, the effects of lncRNA DGCR5 in neuropathic pain have not been explored. Therefore, in our current study, we concentrated on the biological roles of DGCR5 in neuropathic pain. Here, it was observed that DGCR5 was significantly decreased in chronic sciatic nerve injury (CCI) rat models. DGCR5 overexpression was able to alleviate neuropathic pain development including mechanical and thermal hyperalgesia. In addition, the current understanding of miR-330-3p function in neuropathic pain remains largely incomplete. Here, we found that miR-330-3p was greatly increased in CCI rats and DGCR5 can modulate miR-330-3p expression negatively. Upregulation of DGCR5 repressed inflammation-correlated biomarkers including interleukin 6 (IL-6), tumor necrosis factor α, and IL-1ß in CCI rats by sponging miR-330-3p. The negative correlation between DGCR5 and miR-330-3p was confirmed in our current study. Inhibition of miR-330-3p suppressed neuropathic pain progression by restraining neuroinflammation in vivo. In addition, PDCD4 was predicted as a downstream target of miR-330-3p. Furthermore, PDCD4 was significantly increased in CCI rats and DGCR5 regulated PDCD4 expression through sponging miR-330-3p in CCI rat models. Taken these together, it was implied that DGCR5/miR-330-3p/PDCD4 axis participated in neuropathic pain treatment.

Kynurenic acid and zaprinast diminished CXCL17-evoked pain-related behaviour and enhanced morphine analgesia in a mouse neuropathic pain model.

BACKGROUND: The G protein-coupled receptor 35 (GPR35), is considered important for nociceptive transmission, as suggested by accumulating evidence. This receptor was discovered in 1998; however, a lack of pharmacological tools prevented a complete understanding of its function and how to exploit it therapeutically. We studied the influence of CXCL17, kynurenic acid and zaprinast on nociceptive transmission in naïve and neuropathic mice. Additionally, we investigated the influence of kynurenic acid and zaprinast on morphine effectiveness in neuropathic pain. METHODS: The chronic constriction injury (CCI) of the sciatic nerve in Swiss mice was performed. The CXCL17, kynurenic acid, zaprinast and morphine were injected intrathecally into naive and CCI-exposed mice at day 14. To evaluate tactile and thermal hypersensitivity, the von Frey and cold plate tests were used, respectively. RESULTS: Our results have shown, for the first time, that administration of CXCL17 in naïve mice induced strong pain-related behaviours, as measured by von Frey and cold plate tests. Moreover, we demonstrated that kynurenic acid and zaprinast diminished CXCL17-evoked pain-related behaviours in both tests. Kynurenic acid and zaprinast reduced thermal and tactile hypersensitivity developed by sciatic nerve injury and strongly enhanced the effectiveness of morphine in neuropathy. CONCLUSIONS: Our study highlights the importance of GPR35 as a receptor involved in neuropathic pain development. Therefore, these results suggest that the modulation of GPR35 could become a potential strategy for the treatment of neuropathic pain.

TNF-α contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury.

A large body of evidence has demonstrated that the ectopic discharges of action potentials in primary afferents, resulted from the abnormal expression of voltage gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons following peripheral nerve injury are important for the development of neuropathic pain. However, how nerve injury affects the expression of VGSCs is largely unknown. Here, we reported that selective injury of motor fibers by L5 ventral root transection (L5-VRT) up-regulated Nav1.3 and Nav1.8 at both mRNA and protein level and increased current densities of TTX-S and TTX-R channels in DRG neurons, suggesting that nerve injury may up-regulate functional VGSCs in sensory neurons indirectly. As the up-regulated Nav1.3 and Nav1.8 were highly co-localized with TNF-α, we tested the hypothesis that the increased TNF-α may lead to over-expression of the sodium channels. Indeed, we found that peri-sciatic administration of recombinant rat TNF-α (rrTNF) without any nerve injury, which produced lasting mechanical allodynia, also up-regulated Nav1.3 and Nav1.8 in DRG neurons in vivo and that rrTNF enhanced the expression of Nav1.3 and Nav1.8 in cultured adult rat DRG neurons in a dose-dependent manner. Furthermore, inhibition of TNF-α synthesis, which prevented neuropathic pain, strongly inhibited the up-regulation of Nav1.3 and Nav1.8. The up-regulation of the both channels following L5-VRT was significantly lower in TNF receptor 1 knockout mice than that in wild type mice. These data suggest that increased TNF-α may be responsible for up-regulation of Nav1.3 and Nav1.8 in uninjured DRG neurons following nerve injury.

Genetic deletion of synapsin II reduces neuropathic pain due to reduced glutamate but increased GABA in the spinal cord dorsal horn.

The synaptic vesicle protein synapsin II is specifically expressed in synaptic terminals of primary afferent nociceptive neurons and regulates transmitter release in the spinal cord dorsal horn. Here, we assessed its role in nerve injury-evoked molecular and behavioral adaptations in models of peripheral neuropathic pain using mice genetically lacking synapsin II. Deficiency of synapsin II resulted in reduced mechanical and cold allodynia in two models of peripheral neuropathic pain. This was associated with decreased glutamate release in the dorsal horn of the spinal cord upon sciatic nerve injury or capsaicin application onto the sciatic nerve and reduced calcium signals in spinal cord slices upon persistent activation of primary afferents. In addition, the expression of the vesicular glutamate transporters, VGLUT1 and VGLUT2, was strongly reduced in synapsin II knockout mice in the spinal cord. Conversely, synapsin II knockout mice showed a stronger and longer-lasting increase of GABA in lamina II of the dorsal horn after nerve injury than wild type mice. These results suggest that synapsin II is involved in the regulation of glutamate and GABA release in the spinal cord after nerve injury, and that a imbalance between glutamatergic and GABAergic synaptic transmission contributes to the manifestation of neuropathic pain.

Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy.

A painful neuropathy is frequently observed in people living with human immunodeficiency virus type 1 (HIV-1). The HIV coat protein, glycoprotein 120 (gp120), implicated in the pathogenesis of neurological disorders associated with HIV, is capable of initiating neurotoxic cascades via an interaction with the CXCR4 and/or CCR5 chemokine receptors, which may underlie the pathogenesis of HIV-associated peripheral neuropathic pain. In order to elucidate the mechanisms underlying HIV-induced painful peripheral neuropathy, we have characterised pathological events in the peripheral and central nervous system following application of HIV-1 gp120 to the rat sciatic nerve. Perineural HIV-1 gp120 treatment induced a persistent mechanical hypersensitivity (44% decrease from baseline), but no alterations in sensitivity to thermal or cold stimuli, and thigmotactic (anxiety-like) behaviour in the open field. The mechanical hypersensitivity was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. Immunohistochemical studies reveal: decreased intraepidermal nerve fibre density, macrophage infiltration into the peripheral nerve at the site of perineural HIV-1 gp120; changes in sensory neuron phenotype including expression of activating transcription factor 3 (ATF3) in 27% of cells, caspase-3 in 25% of cells, neuropeptide Y (NPY) in 12% of cells and galanin in 13% of cells and a spinal gliosis. These novel findings suggest that this model is not only useful for the elucidation of mechanisms underlying HIV-1-related peripheral neuropathy but may prove useful for preclinical assessment of drugs for the treatment of HIV-1 related peripheral neuropathic pain.

Propuesta de una vía de abordaje y técnica para el tratamiento de los síndromes de atrapamiento nervioso lumbar postcirugía (SANLPC), como alternativa a las técnicas de adhesiolisis o epidurolisis / Proposal for a new approach and technique for the treatment of post-surgery lumbar nerve entrapment syndromes, as an alternative to adhesiolysis or epidural lysis techniques

Objetivo: Describir una vía supracicatricial de abordaje y la técnica para la realización de epidurolisis, adhesiolisis y/o bloqueos repetidos radiculares, en síndromes dolorosos por atrapamiento nervioso cicatricial posterior a cirugías de columna lumbar, como alternativa a la epidurolisis caudal descrita en la literatura. Considerando que puede presentar menos complicaciones y puede presentar mejores resultados. Material y método: Ocho pacientes que presentan dolor posterior a cirugías de columna lumbar, con cuadros clínicos de lumbalgia, lumbociatalgia o ciática, con clínica y estudios de imagen (RNM, TAC, mieloTAC) sugerentes de fibrosis epidural, estudios de EMG y PESS que indicaban daño en raíces lumbares igual o más que en raíces sacras. Los pacientes no presentaban patología asociada o contraindicaciones para la realización de la técnica. En todos los casos se utilizo: antibioterapia previa, sedación y monitorización del paciente. Se coloca al paciente en decúbito prono, con apoyo abdominal para reducir la lordosis fisiológica posicional y se localiza el espacio interespinoso inmediatamente superior a la cicatriz, para abordar el espacio epidural. Se localiza el espacio epidural con una aguja RX Coudé Curva 8,75 cm 15 g de Epimed® con el bisel orientado caudalmente, confirmando con escopia de alta resolución, mediante la inyección de 0,5 mL de contraste. Se introduce el catéter Tun-L-Kath Epimed® de 19 g y 84,5 cm y se orienta caudalmente hacia el nivel y el lugar con mayor sintomatología con control radiológico directo, hasta la parada en la progresión del catéter y se inyecta contraste para verificar el obstáculo, con la difusión retrógrada del mismo, producida por la fibrosis cicatricial. Se intenta progresar comprobando que al hacerlo hay reproducción de las sensaciones del dolor del paciente. Se extrae la aguja y se vigila la inmovilidad de la punta del catéter con control radiológico. Se tuneli-za una sección de entre 10 y 15 cm del catéter y se verifica su permeabilidad. Finalmente se colocaron los filtros bacterianos del catéter. Con el catéter colocado y tunelizado se siguieron pautas de tratamiento con diferentes fármacos que se inyectaron a través del catéter 2 días a la semana durante 5 semanas, o sea, se realizaron 10 administraciones de fármacos. Después de la inyección de las dosis se lavó el catéter con 1 mL de lidocaína 1% s/a y se realizaron curas diarias de la inserción del catéter. Resultados: Los resultados del uso de la técnica presentan como única complicación en dos de los casos la salida del catéter, a lo largo del tiempo del tratamiento, sin complicaciones en el acto de colocación. Refieren mejoría subjetiva de 50% o más de disminución del dolor 5 de los 8 pacientes. Conclusiones: En nuestra experiencia, utilizando la técnica de abordaje caudal descrita en la literatura, se presentan múltiples complicaciones y resultados muy limitados. Especialmente se han producido complicaciones graves, una de ellas consistió en una severa afectación de las raíces S2 y S3, con parálisis de esfínter vesical y detrusor, así como afectación de esfínter rectal con abolición de sensibilidad. También se presentaron casos de anestesia en silla de montar, en uno de ellos con una evolución prolongada. Adicionalmente, los resultados del tratamiento con epidurolisis caudal, cuando presenta mejoría, son limitados temporalmente a pocos meses de mejoría de la sintomatología dolorosa (AU)

Aim: To describe a supra scar approach and technique for epi-dural lysis of adhesions and/or repeated radicular blocks in pain syndromes due to posterior nerve entrapment caused by scar tissue after low back surgery, as an alternative to caudal epidural lysis of adhesions as described in literature. Considering that it may present fewers complications and better outcomes. Material and method: 8 patients presenting pain after lumbar spine surgery, as lumbalgia, lumbosciatalgia or sciatica, with both clinical and imaging diagnostic confirmation (MRI, CT, myelo-CT) suggesting epidural fibrosis; EMG and SSEP indicating lumbar roots injury similar or bigger than in sacral roots. Patients did not present any concomitant condition or contraindication for this technique.In all cases, previous antibiotherapy, sedation and monitoring were applied. Patients were positioned in prone decubitus, with abdominal support to reduce physiological positional lordosis, to locate the interspinal space at the level of the scar. The epidural space is approached through an 8.75 cm/15 g curved needle (RX Coudé, Epimed International Inc.), the bevel oriented caudally, confirming the position by high-resolution radioscopy and the injection of 0.5 mL contrast. An 84.5/19 g catheter (Tun-L-Cath, Epimed International Inc.) is then introduced and steered towards the level and location with a higher symptomatology under direct radiologic control, until the catheter progression stops, and contrast is injected to verify the obstacle, with the retrograde diffusion produced by the scartissue fibrosis. An attempt is then made to progress, assessing that it evokes the patient's painful response. The needle is removed taking care that the catheter tip does not move from its location by RX control. A section of 10-15 cm of the catheter is then tunnelled, verifying its permeability. Finally an antibacterial filter is attached. With the catheter in place and tunnelled, treatment guidelines with different drugs were followed, being injected through the catheter two days a week during five weeks, i.e. ten doses in total. After each dose the catheter was flushed with 1 cc of lidocaine 1% (no epinephrine). Dressings of the catheter insertion were performed daily. Conclusions In our experience using the caudal approach technique as-described in the literature, we have found multiple complications and very limited results. Particularly serious complications, such as one severe affectation of the S2 and S3 roots with paralysis of the vesical and detrusor rectal sphincter with loss of sensitivity, have occurred. We also have had cases of perineal anesthesia, one of them with a long-term evolution. Additionally, when the outcomes with caudal epidural lysis are positive, improvements are limited in time, just a few months of relief of the painful symptoms (AU)

Snake venom phospholipase A2s (Asp49 and Lys49) induce mechanical allodynia upon peri-sciatic administration: involvement of spinal cord glia, proinflammatory cytokines and nitric oxide.

Snakebites constitute a serious public health problem in Central and South America, where species of the lancehead pit vipers (genus Bothrops) cause the majority of accidents. Bothrops envenomations are very painful, and this effect is not neutralized by antivenom treatment. Two variants of secretory phospholipases A2 (sPLA2), corresponding to Asp49 and Lys49 PLA2s, have been isolated from Bothrops asper venom. These sPLA2s induce hyperalgesia in rats following subcutaneous injection. However, venom in natural Bothrops bites is frequently delivered intramuscularly, thereby potentially reaching peripheral nerve bundles. Thus, the present series of experiments tested whether these sPLA2s could exert pain-enhancing effects following administration around healthy sciatic nerve. Both were found to produce mechanical allodynia ipsilateral to the injection site; no thermal hyperalgesia was observed. As no prior study has examined potential spinal mechanisms underlying sPLA2 actions, a series of anatomical and pharmacological studies were performed. These demonstrated that both sPLA2s produce activation of dorsal horn astrocytes and microglia that is more prominent ipsilateral to the site of injection. As proinflammatory cytokines and nitric oxide have each been previously implicated in spinally mediated pain facilitation, the effect of pharmacological blockade of these substances was tested. The results demonstrate that mechanical allodynia induced by both sPLA2s is blocked by interleukin-1 receptor antagonist, anti-rat interleukin-6 neutralizing antibody, the anti-inflammatory cytokine interleukin-10, and a nitric oxide synthesis inhibitor (L-NAME). As a variety of immune cells also produce and release sPLA2s during inflammatory states, the data may have general implications for the understanding of inflammatory pain.

Micromolar lidocaine selectively blocks propagating ectopic impulses at a distance from their site of origin.

Abnormal impulses caused by very slowly inactivating Na channels of peripheral nerve have been proposed to play a critical role in neuropathic pain. Low concentrations of local anesthetics, often effective in treating experimental and clinical neuropathic pain, are also known to potently suppress the long after-depolarizations induced by these persistently open Na channels. However, these drug actions on impulses that have propagated away from such sites are undetermined. In the present study, the focal application of anemone toxin II (ATX, 300 nM), which slows Na-channel inactivation, produced prolonged depolarizing after-potentials and, coincidentally, induced spontaneous bursting impulse activity that propagated away from the site of ATX application in the frog sciatic nerve in vitro. The application of low concentrations of lidocaine (1-10 microM), both at the site of ATX exposure and at a distant site, selectively and reversibly inhibited the spontaneous bursting, while having no effect on the electrically stimulated initial spike of the compound action potential. Inhibition occurred as a shortening of burst episodes rather than a reduction in frequency of impulses within a burst or a reduction of intraburst impulse amplitude. Tetrodotoxin also inhibited the induced spontaneous activity, but only at concentrations that also depressed the compound action potential spike. These findings show that low concentrations of lidocaine can restore normal firing patterns in nerve where hyperexcitability has been caused by delayed Na-channel inactivation, without acting directly at the site where ectopic impulses are generated. Thus, it appears that the pattern of abnormal activity rather than an abnormally gating Na channel per se can be a target for lidocaine's therapeutic action.

A new model of sciatic inflammatory neuritis (SIN): induction of unilateral and bilateral mechanical allodynia following acute unilateral peri-sciatic immune activation in rats.

Immune activation near healthy peripheral nerves may have a greater role in creating pathological pain than previously recognized. We have developed a new model of sciatic inflammatory neuritis to assess how such immune activation may influence somatosensory processing. The present series of experiments reveal that zymosan (yeast cell walls) acutely injected around the sciatic nerve of awake unrestrained rats rapidly (within 3h) produces low threshold mechanical allodynia in the absence of thermal hyperalgesia. Low (4 microg) doses of zymosan produce both territorial and extra-territorial allodynia restricted to the ipsilateral hindpaw. Higher (40-400 microg) doses of zymosan again produce both territorial and extra-territorial allodynia. However, allodynia is now expressed both in the ipsilateral as well as contralateral hindpaws. Several lines of evidence are provided that the appearance of this contralateral ('mirror') allodynia reflects local actions of zymosan on the sciatic nerve rather than spread of this immune activator to the general circulation. Since many clinical neuropathies result from inflammation/infection of peripheral nerves rather than frank physical trauma, understanding how immune activation alters pain processing may suggest novel approaches to pain control.

Influence of painful chronic neuropathy on neurogenic inflammation.

The effect of topical application of capsaicin cream on neurogenic inflammation was investigated in a neuropathic pain model in rat. The neuropathic state was induced by loose ligation of the sciatic nerve with a chromic gut suture. A marked thermal hyperalgesia was observed in response to heat stimulation applied to the operated side from 3 days through 2 weeks, followed by a gradual return to the control level 35 days after surgery. In sham-operated animals, topical application of capsaicin cream to both sides of the hind paw, the instep and sole, as well as antidromic stimulation of the sciatic nerve led to a significant increase in the amounts of Evans blue and substance P (SP) released into the perfusates. This stimulus-induced extravasation was significantly suppressed by pretreatment with RP67580, an NK1 antagonist. On day 7 after ligation, capsaicin- and antidromic stimulation-induced extravasation were significantly reduced. At this time, both amount of SP released immediately after application of capsaicin and during antidromic stimulation were almost similar to that in sham-operated rats, whereas the basal amount of SP release significantly increased in ligated animals. In particular a major release of SP was detected immediately after the start of the perfusion compared with that in sham-operated rats. Plasma extravasation evoked by SP (10(-4) M) applied to the subcutaneous perfusate was significantly less in ligated than in sham-operated rats. These results suggest that nerve injury with chronic pain may produce increase in basal SP release into the peripheral tissues, and then such enhanced SP release cause reduction of SP-induced extravasation.

Effects of phospholipase A2 on lumbar nerve root structure and function.

STUDY DESIGN: To investigate the effects of phospholipase A2 on the neurophysiology and histology of rat lumbar spinal nerves and the corresponding behavioral changes. OBJECTIVES: To study possible mechanisms of sciatica. SUMMARY OF BACKGROUND DATA: The pathophysiology of sciatica is uncertain, although mechanical, chemical, and ischemic factors have been proposed. METHODS: Phospholipase A2 was injected into the rat L4-L5 epidural space, and the rats were observed for 3 or 21 days. Behavioral studies were conducted daily during the survival period. On the 3rd or 21st day, extracellular nerve recordings were made from dorsal roots, to determine discharge properties and mechanical sensitivity. The nerve roots were then sectioned for a light-microscopic examination. RESULTS: Motor weakness of hind limbs and altered sensation were observed. In the 3-day phospholipase A2 groups, squeezing the dorsal roots at the L4-L5 disc level (force = 0.8 g) evoked sustained ectopic discharge that lasted approximately 8 minutes. Squeezing the roots distal to the L4-L5 area did not result in sustained discharges. In sham, control, and 21-day phospholipase A2 groups, squeezing the dorsal roots elicited only a transient firing that lasted approximately 0.1 second. Loss of myelin was seen in the nerve root cross sections in the 3-day group, and remyelination was observed in the 21-day group. No abnormality was found in the control groups. CONCLUSIONS: Based on these studies, it is hypothesized that phospholipase A2 causes demyelination that results in hypersensitive regions where ectopic discharge may be elicited by mechanical stimulation. These ectopic discharges may be a source of sciatica. We believe that, as long as these irritating factors are present, the hypersensitive nerve root nerve will continue to fire, and sciatic pain will persist.

Neurotoxicity of iohexol vs iopamidol in lumbar myelography. Clinical, electrophysiological and brain CT scan correlations.

The potential neurotoxicity of iohexol and iopamidol in lumbar myelography was investigated in 20 patients using three criteria: clinical symptoms, EEG recordings with spectral analysis and CT scans of the brain. There was no significant difference in clinical side-effects between the two groups (Iopaminol, Iohexol). In 10 patients (iopaminol 4, iohexol 6) CT scans revealed an important penetration of the contrast media into the subarachnoid spaces at 3 hours and into the cerebral cortex at 24 hours. This cerebral contamination was unrelated to the headaches experienced by the patients or to the electrophysiological disturbances observed. Spectral analysis in brain-contaminated subjects showed a reduction of delta, beta 1 and beta 2 bands with iohexol. This reduction suggests that EEG activation is less pronounced with this agent than with iopaminol.

Functional lumbar myelography with iohexol.

The results of 25 functional lumbar myelographies with iohexol are reported. The image quality was good or excellent in all. The side effects were mostly mild and showed the same frequency as reported in lumbar and thoracic myelographies with metrizamide. A slight increase in the frequency of side effects was found in 13 patients with spinal repuncture 6 or 24 hours after the myelography. Vacuolized monocytes in ultracentrifuged CSF following repuncture was found in 5 patients. No EEG changes or serious complications were found. Iohexol is considered safe in intrathecal use.

Documentation of a new contrast medium for the subarachnoid space. Demands, design and results from the first multicentre trial with iohexol.

The first clinical trial with the non-ionic contrast medium iohexol (Omnipaque) in lumbar myelography was performed as a multicentre investigation of a total of 88 included patients. The design of the comprehensive clinical trial program is presented and the necessity of using such an extensive clinical trial program in the early stage of the investigation is discussed. This comprehensive monitoring did not reveal any serious or persistent side effects. The documentation on the safety of the drug encourages further clinical trials.