Analgésicos Tópicos

Background and objectives: Pain treatment involves the usage of common and opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and adjuvant analgesics. Traditionally, these drugs are administered systemically or into the neuraxis. However, when analgesics are applied through these pathways, they are associated with significant side effects, which can hinder its use. Topical administration of analgesics is an alternative. The objective of this paper is to discuss topical analgesics, the mechanisms of action and clinical efficacy. Content: This is a review paper addressing the usage of the topical local anesthetics: capsaicin, clonidine, tricyclic antidepressants, ketamine, opioids and cannabinoids, discussing mechanism of action and effectiveness. Conclusions: Topical analgesics are promising as a strategy for pain treatment, as they are associated with lower incidence of side effects. The benefit of local anesthetics, NSAID's and capsaicin is well established. However, the efficacy of clonidine, tricyclic antidepressants, ketamine, opioids and cannabinoids is still questionable. Studies have shown that the multimodal approach is an alternative, but studies are needed to confirm this hypothesis. © 2012 Elsevier Editora Ltda.

Efeitos determinados pela amitriptilina, administrada pela via subaracnóidea, sobre a medula e as meninges: estudo experimental em cães

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Serotonergic modulation in neuropathy induced by oxaliplatin: Effect on the 5HT(2C) receptor

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Leg Amputation for an Extensive, Severe and Intractable Sickle Cell Anemia Ulcer in a Brazilian Patient

A 35-year-old African Brazilian patient had sickle cell anemia complicated with recurrent vasoocclusive (VOC) crises and refractory painful leg ulcers for 16 years. The ulcers started over both medial malleoli and expanded gradually. The ulcer on the left leg spread from the foot to the knee circumferentially and was refractory to all forms of therapy within the frame work of multi-disciplinary care. The patient agreed to a below the knee amputation of the left leg. He felt much better after the amputation but developed severe neuropathic phantom pain that was well controlled medically. He could differentiate the sickle cell anemia and ulcer pain from the neuropathic pain. About 6 months after the amputation he had dengue fever with fatal outcome. This is the first report of treatment of refractory sickle cell anemia leg ulcer with amputation and probably the first report of a Brazilian patient with sickle cell anemia and dengue fever.

Synaptic plasticity and sensory-motor improvennent following fibrin sealant dorsal root reimplantation and mononuclear cell therapy

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Investigação da participação de adrenoceptores α1 no efeito antinociceptivo da amitriptilina em um modelo de dor neuropática

Tricyclic antidepressants, such as amitriptyline, are inhibitors of serotonin and norepinephrine neuronal reuptake and this action has been implied in changes in pain threshold supporting its use to alleviate neuropathic pain. Although is known that 1 adrenoceptors participate in the antinociceptive effect of amitriptyline it is unclear which receptor subtype is the target for the increased synaptic levels of norepinephrine resultant from the inhibition of neuronal uptake. Paradoxically, several tricyclic antidepressants including amitriptyline also behave as antagonists of 1 adrenoceptors with different affinities for its subtypes: these drugs have 10 to 100-fold higher affinities for 1A than for 1B and 1D adrenoceptors. This work investigated the involvement of 1 adrenoceptors subtypes in the antinociceptive effect of the amitriptyline in a constriction of the sciatic nerve in rats by determining the effects of subtype selective 1 adrenoceptors antagonists. Fifteen days later, mechanical hyperalgesia was analyzed in a Randall-Selitto test. The 1A-selective antagonist RS100329 was the most potent antagonist of the contractions of the rat prostate, whereas the 1D-selective antagonist BMY 7378 (up to 100g/Kg) was unable to affect these contractions. The antagonist prazosin, BMY 7378 and 5-methyl urapidil inhibited the antinociceptive effect of the amitriptyline. However, the highly selective 1A adrenoceptor antagonist RS100329 was unable to affect the antinociception induced by amitriptyline. These results point out that 1B and/or 1D adrenoceptors, but not 1A, are involved in the antinociceptive effects of amitriptyline

Avaliação do efeito do citral na dor neuropática e na inflamação

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Métodos de avaliação da eficácia dos tratamentos para a dor

Pain is a subjective condition and, thus, difficult to measure. The best tools to assess pain are the pain evaluation questionnaires, which provide either diagnostic, pain evolution or pain intensity information. To provide information which could help differentiate between nociceptive pain and neuropathic pain is one of the most important functions of these questionnaires. The questionnaires can measure pain intensity, quality of life, or sleep quality. Quality of life and sleep are two really important characteristics to assess the pain impact on patients' life. Pain intensity assessing questionnaires combine physical evaluations with questions, providing information either from the patient sensations or clinical assessment of pain manifestations as well as the underlying biological mechanisms (such as hyperalgesia or allodynia). For example, the Pain Detect questionnaire has two parts: the patient form (intuitive, with pictures and easy understandable) and the physician form. Thus, in this questionnaire, subjective information is provided by the patient and the objective one is provided by the physician. Other pain intensity questionnaires are NPSI, DN4, LANSS or StEP. Quality of life questionnaires are versatile (can be used in different pathologies). These questionnaires include functional self-evaluation questions, and other ones associated to physical and mental health. Two of such quality of life questionnaires are SF-36 and NHP. Sleep evaluation questionnaires include quantitative features such as the number of sleep interruptions, sleep latency or sleep duration as well as qualitative characteristics such as rest sensation, mood and dreams. One of the most used sleep evaluation questionnaires is PSQI, which includes patient questions and bed-partner questions, providing information from two points of view.

12 item Allodynia Symptom Checklist/Brasil: cross-cultural adaptation, internal consistency and reproducibility

Since there was no Portuguese questionnaire to evaluate cutaneous allodynia, which has been pointed out as a risk factor of migraine, we aimed to perform the cross-cultural adaptation of the 12 item Allodynia Symptom Checklist for the Brazilian population and to test its measurement properties. It consisted in six stages: translation, synthesis, back translation, revision by a specialist committee, pretest and submission the documents to the committee. In the pretest stage, the questionnaire was applied to 30 migraineurs of both sexes, who had some difficulty in understanding it. Thus, a second version was applied to 30 additional subjects, with no difficulties being reported. The mean filling out time was 3'36", and the internal consistency was 0.76. To test reproducibility, 15 other subjects filled out the questionnaire at two different times, it was classified as moderate (weighted kappa=0.58). We made available to Brazilian population an easy, quick and reliable questionnaire.

Enantioselective analysis of unbound tramadol, O-desmethyltramadol and N-desmethyltramadol in plasma by ultrafiltration and LC-MS/MS: Application to clinical pharmacokinetics

This study describes the enantioselective analysis of unbound and total concentrations of tramadol and its main metabolites O-desmethyltramadol (M1) and N-desmethyltramadol (M2) in human plasma. Sample preparation was preceded by an ultrafiltration step to separate the unbound drug. Both the ultrafiltrate and plasma samples were submitted to liquid/liquid extraction with methyl t-butyl ether. Separation was performed on a Chiralpak (R) AD column and tandem mass spectrometry consisting of an electrospray ionization source, positive ion mode and multiple reaction monitoring was used as the detection system. Linearity was observed in the following ranges: 0.2-600 and 0.5-250 ng/mL for analysis of total and unbound concentrations of the tramadol enantiomers, respectively, and 0.1-300 and 0.25-125 ng/mL for total and unbound concentrations of the M1 and M2 enantiomers, respectively. The lower limits of quantitation were 0.2 and 0.5 ng/mL for analysis of total and unbound concentration of each tramadol enantiomer, respectively, and 0.1 and 0.25 ng/mL for total and unbound concentrations of M1 and M2 enantiomers, respectively. Intra- and interassay reproducibility and inaccuracy did not exceed 15%. Clinical application of the method to patients with neuropathic pain showed plasma accumulation of (+)-tramadol and (+)-M2 after a single oral dose of racemic tramadol. Fractions unbound of tramadol, M1 or M2 were not enantioselective in the patients investigated. (C) 2011 Elsevier B.V. All rights reserved.

Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: Possible pathways for antinociception

Motor cortex stimulation is generally suggested as a therapy for patients with chronic and refractory neuropathic pain. However, the mechanisms underlying its analgesic effects are still unknown. In a previous study, we demonstrated that cortical stimulation increases the nociceptive threshold of naive conscious rats with opioid participation. In the present study, we investigated the neurocircuitry involved during the antinociception induced by transdural stimulation of motor cortex in naive rats considering that little is known about the relation between motor cortex and analgesia. The neuronal activation patterns were evaluated in the thalamic nuclei and midbrain periaqueductal gray. Neuronal inactivation in response to motor cortex stimulation was detected in thalamic sites both in terms of immunolabeling (Zif268/Fos) and in the neuronal firing rates in ventral posterolateral nuclei and centromedian-parafascicular thalamic complex. This effect was particularly visible for neurons responsive to nociceptive peripheral stimulation. Furthermore, motor cortex stimulation enhanced neuronal firing rate and Fos immunoreactivity in the ipsilateral periaqueductal gray. We have also observed a decreased Zif268, delta-aminobutyric acid (GABA), and glutamic acid decarboxylase expression within the same region, suggesting an inhibition of GABAergic interneurons of the midbrain periaqueductal gray, consequently activating neurons responsible for the descending pain inhibitory control system. Taken together, the present findings suggest that inhibition of thalamic sensory neurons and disinhibition of the neurons in periaqueductal gray are at least in part responsible for the motor cortex stimulation-induced antinociception. (C) 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting cannabinoid receptors

Pharmacological activation of cannabinoid CB(1) and CB(2) receptors is a therapeutic strategy to treat chronic and inflammatory pain. It was recently reported that a mixture of natural triterpenes α- and β-amyrin bound selectively to CB(1) receptors with a subnanomolar K(i) value (133 pM). Orally administered α/β-amyrin inhibited inflammatory and persistent neuropathic pain in mice through both CB(1) and CB(2) receptors. Here, we investigated effects of amyrins on the major components of the endocannabinoid system.

Effects of local continuous release of brain derived neurotrophic factor (BDNF) on peripheral nerve regeneration in a rat model

The purpose of this study was to evaluate the effect of continuously released BDNF on peripheral nerve regeneration in a rat model. Initial in vitro evaluation of calcium alginate prolonged-release-capsules (PRC) proved a consistent release of BDNF for a minimum of 8 weeks. In vivo, a worst case scenario was created by surgical removal of a 20-mm section of the sciatic nerve of the rat. Twenty-four autologous fascia tubes were filled with calcium alginate spheres and sutured to the epineurium of both nerve ends. The animals were divided into 3 groups. In group 1, the fascial tube contained plain calcium alginate spheres. In groups 2 and 3, the fascial tube contained calcium alginate spheres with BDNF alone or BDNF stabilized with bovine serum albumin, respectively. The autocannibalization of the operated extremity was clinically assessed and documented in 12 additional rats. The regeneration was evaluated histologically at 4 weeks and 10 weeks in a blinded manner. The length of nerve fibers and the numbers of axons formed in the tube was measured. Over a 10-week period, axons have grown significantly faster in groups 2 and 3 with continuously released BDNF compared to the control. The rats treated with BDNF (groups 2 and 3) demonstrated significantly less autocannibalization than the control group (group 1). These results suggest that BDNF may not only stimulate faster peripheral nerve regeneration provided there is an ideal, biodegradable continuous delivery system but that it significantly reduces the neuropathic pain in the rat model.

Mechanical modeling of Intraneural Ganglion Cyst

Intraneural Ganglion Cyst is a 200 year old mystery related to nerve injury which is yet to be solved. Current treatments for the above problem are relatively simple procedures related to removal of cystic contents from the nerve. However, these treatments may result into neuropathic pain and recurrence of the cyst. The articular theory proposed by Spinner et al., (Spinner et al. 2003) takes into consideration the neurological deficit in Common Peroneal Nerve (CPN) branch of the sciatic nerve and affirms that in addition to the above treatments, ligation of articular branch results into foolproof eradication of the deficit. Mechanical Modeling of the Affected Nerve Cross Section will reinforce the articular theory (Spinner et al. 2003). As the cyst propagates, it compresses the neighboring fascicles and the nerve cross section appears like a signet ring. Hence, in order to mechanically model the affected nerve cross section; computational methods capable of modeling excessively large deformations are required. Traditional FEM produces distorted elements while modeling such deformations, resulting into inaccuracies and premature termination of the analysis. The methods described in this Master’s Thesis are effective enough to be able to simulate such deformations. The results obtained from the model adequately resemble the MRI image obtained at the same location and shows an appearance of a signet ring. This Master’s Thesis describes the neurological deficit in brief followed by detail explanation of the advanced computational methods used to simulate this problem. Finally, qualitative results show the resemblance of mechanical model to MRI images of the Nerve Cross Section at the same location validating the capability of these methods to study this neurological deficit.

Determination of ajulemic acid and its glucuronide in human plasma by gas chromatography-mass spectrometry

A method using gas chromatography-mass spectrometry (GC-MS) and solid-phase extraction (SPE) was developed for the determination of ajulemic acid (AJA), a non-psychoactive synthetic cannabinoid with interesting therapeutic potential, in human plasma. When using two calibration graphs, the assay linearity ranged from 10 to 750 ng/ml, and 750 to 3000 ng/ml AJA. The intra- and inter-day precision (R.S.D., %), assessed across the linear ranges of the assay, was between 1.5 and 7.0, and 3.6 and 7.9, respectively. The limit of quantitation (LOQ) was 10 ng/ml. The amount of AJA glucuronide was determined by calculating the difference in the AJA concentration before ("free AJA") and after enzymatic hydrolysis ("total AJA"). The present method was used within a clinical study on 21 patients suffering from neuropathic pain with hyperalgesia and allodynia. For example, plasma levels of 599.4+/-37.2 ng/ml (mean+/-R.S.D., n=9) AJA were obtained for samples taken 2 h after the administration of an oral dose of 20 mg AJA. The mean AJA glucuronide concentration at 2h was 63.8+/-127.9 ng/ml.