Population pharmacokinetics of gabapentin in patients with neuropathic pain: Lack of effect of diabetes or glycaemic control.

AIMS: Gabapentin (GBP) is widely used to treat neuropathic pain, including diabetic neuropathic pain. Our objective was to evaluate the role of diabetes and glycaemic control on GBP population pharmacokinetics. METHODS: A clinical trial was conducted in patients with neuropathic pain (n = 29) due to type 2 diabetes (n = 19) or lumbar/cervical disc herniation (n = 10). All participants were treated with a single oral dose GBP. Blood was sampled up to 24 hours after GBP administration. Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm. Weight, body mass index, sex, biomarkers of renal function and diabetes, and genotypes for the main genetic polymorphisms of SLC22A2 (rs316019) and SLC22A4 (rs1050152), the genes encoding the transporters for organic cations OCT2 and OCTN1, were tested as potential covariates. RESULTS: GBP drug disposition was described by a 1-compartment model with lag-time, first-order absorption and linear elimination. The total clearance was dependent on estimated glomerular filtration rate. Population estimates (between-subject variability in percentage) for lag time, first-order absorption rate, apparent volume of distribution and total clearance were 0.316 h (10.6%), 1.12 h-1 (10.7%), 140 L (7.7%) and 14.7 L/h (6.97%), respectively. No significant association was observed with hyperglycaemia, glycated haemoglobin, diabetes diagnosis, age, sex, weight, body mass index, SLC22A2 or SLC22A4 genotypes. CONCLUSION: This population pharmacokinetics model accurately estimated GBP concentrations in patients with neuropathic pain, using estimated glomerular filtrationrate as a covariate for total clearance. The distribution and excretion processes of GBP were not affected by hyperglycaemia or diabetes.

Cetirizine Reduces Gabapentin Plasma Concentrations and Effect: Role of Renal Drug Transporters for Organic Cations.

Gabapentin (GBP) is an organic cation mainly eliminated unchanged in urine, and active drug secretion has been suggested to contribute to its renal excretion. Our objective was to evaluate the potential drug-drug interaction between GBP and cetirizine (CTZ), an inhibitor of transporters for organic cations. An open-label, 2-period, crossover, nonrandomized clinical trial was conducted in patients with neuropathic pain to evaluate the effect of CTZ on GBP pharmacokinetics. Twelve participants were treated with a single dose of 300 mg GBP (treatment A) or with 20 mg/d of CTZ for 5 days and 300 mg GBP on the last day of CTZ treatment (treatment B). Blood sampling and pain intensity evaluation were performed up to 36 hours after GBP administration. The interaction of GBP and CTZ with transporters for organic cations was studied in human embryonic kidney (HEK) cells expressing the organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and OCTN1. CTZ treatment resulted in reduced area under the concentration-time curve and peak concentration compared with treatment A. In treatment B, the lower plasma concentrations of GBP resulted in reduced pain attenuation. GBP renal clearance was similar between treatments. GBP has low apparent affinity for OCT2 (concentration of an inhibitor where the response [or binding] is reduced by half [IC50 ] 237 µmol/L) and a high apparent affinity for hMATE1 (IC50 1.1 nmol/L), hMATE2-K (IC50 39 nmol/L), and hOCTN1 (IC50 2.1 nmol/L) in HEK cells. At therapeutic concentrations, CTZ interacts with hMATE1 and OCTN1. In summary, CTZ reduced the systemic exposure to GBP and its effect on neuropathic pain attenuation. However, CTZ × GBP interaction is not mediated by the renal transporters.

Pharmacogenomics in chronic pain therapy: from disease to treatment and challenges for clinical practice.

Pharmacogenomics (PGx) has emerged as an encouraging tool in chronic pain therapy. Genetic variations associated with drug effectiveness or adverse reactions (amitriptyline/nortriptyline/codeine/oxycodone/tramadol-CYP2D6, amitriptyline-CYP2C19, carbamazepine-HLA-A, carbamazepine/oxcarbazepine-HLA-B) can be used to guide chronic pain management. Despite this evidence, many obstacles still need to be overcome for the effective clinical implementation of PGx. To translate the pharmacogenetic testing into actionable clinical decisions, the Clinical Pharmacogenetics Implementation Consortium has been developing guidelines for several drug-gene pairs. This review will show the applicability of PGx in chronic pain from disease to treatment; report the drug-gene pairs with strongest evidences in the clinic; and the challenges for the clinical implementation of PGx.

Chronic visceral pain secondary to ventral disc herniation: Development of visceral complex regional pain syndrome.

When an organ disease is ruled out as the origin of pelvic pain, the superior hypogastric plexus (SHP) injury and consequent dysfunction could be the mechanism of visceral chronic pain perpetuation. As much as a dorsal discus herniation may harm the dorsal or ventral roots, a ventral discus herniation at L4-L5 or L5-S1 may result in direct physical trauma to the SHP, maintaining chronic visceral pain mediated by sympathetic dysfunction, conceivably also afferent fibers dysfunction. We propose that similarly to nociceptive somatic dysfunction named complex regional pain syndrome, the maintained sympathetic pelvic pain secondary to straight physical damage to the SHP characterize in fact the same disease, but in nociceptive visceral tissue, named visceral complex regional pain syndrome, a concept constructed based on the International Association for the Study of Pain criteria (1994).

The evolution of spinal/epidural neostigmine in clinical application: Thoughts after two decades.

Since the first clinical application of analgesia following spinal anticholinesterase by 1940's, several clinical double-blind studies have been conducted to date, where intrathecal doses of neostigmine in humans ranged from 750 to 1 µg, due to side-effects. Conversely, epidural neostigmine has been evaluated in proportionally higher doses and represents an alternative, but still deserves more investigation concerning both acute and chronic pain, as it seems devoid of important side-effects.

Low-dose spinal neostigmine further enhances the analgesic effect of spinal bupivacaine combined with epidural dexamethasone, following orthopedic surgery.

BACKGROUND: Opioids are considered mainstream for combined spinal-epidural anesthesia, but frequently limited by adverse effects. The aim of this study was to examine whether low-dose spinal neostigmine, epidural dexamethasone or their combination enhances analgesia from spinal bupivacaine without adverse effects. MATERIALS AND METHODS: A total of 60 patients undergoing orthopedic surgery were randomized to one of four groups and evaluated for 24-h after surgery for analgesia (time to first rescue analgesic) and rescue analgesic consumption. Patients received 15 mg bupivacaine plus the test drug intrathecally (saline or 1 microgram (µg) neostigmine). The epidural test drug was either saline or 10 mg dexamethasone. The Control group (CG) received spinal and epidural saline. The Neostigmine group (NG), spinal neostigmine and epidural saline; the Dexamethasone group (DG), spinal saline and epidural dexamethasone; and the Neostigmine-dexamethasone group (NDG), spinal neostigmine and epidural dexamethasone. RESULTS: The CG (282 ± 163 min) and NG (524 ± 142 min) were similar in their times to first rescue analgesic and analgesic consumption. The time to first rescue analgesic was longer for the DG (966 ± 397 min) compared with CG and NG (P < 0.0002), and the DG had less ketoprofen consumption and lower overall visual analogue scale-pain sores compared with CG and NG (P < 0.0005). Addition of 1 mg-neostigmine (NDG) resulted in longer time to rescue analgesic (1205 ± 303 min; P < 0.02) and lower ketoprofen consumption (P < 0.05) compared to DG. Sporadic cases of vesical catheterization and emesis were observed, however adverse effects were similar among groups. CONCLUSION: Spinal 1 microgram (µg) neostigmine further enhanced analgesia from spinal bupivacaine combined with epidural dexamethasone, without increasing the incidence of adverse effects.

Comparison between the intravenous and caudal routes of sufentanil in children undergoing orchidopexy and further evaluation of the association of caudal adrenaline and neostigmine.

BACKGROUND: The aim of this study was to compare the intravenous (IV) and caudal routes of administration of sufentanil for children undergoing orchidopexy and also to evaluate the effects on addition of caudal adrenaline and neostigmine. MATERIALS AND METHODS: SIXTY PATIENTS SCHEDULED FOR ORCHIDOPEXY WERE DIVIDED INTO THE FOLLOWING GROUPS: 1) Group IVSu received IV 0.5 µg/kg sufentanil and caudal saline; 2) Group CSu received caudal 0.5 µg/kg sufentanil and IV saline; 3) Group CSuAdr received caudal sufentanil plus adrenaline 5 µg/ml (1:200,000) and IV saline; 4) Group CSuNeo received caudal sufentanil plus neostigmine, and IV saline; and 5) Group CSuNeoAdr received caudal sufentanil plus neostigmine plus adrenaline, and IV saline. Heart rate and mean blood pressure >15% was treated with increasing isoflurane concentration. Consumption of isoflurane, side effects, quality of sleep, time to first administration of analgesic, and number of doses of 24-h rescue analgesic were recorded. RESULTS: Groups were demographically similar. Isoflurane consumption showed the following association: Group IVSu = Group CSuNeo = Group CSuNeoAdr < Group CSu = Group CSuAdr (P < 0.02). VAS for sedation on reversal of anesthesia showed the following association: Group CSuNeo = Group CSuNeoAdr < Group CSu = Group CSuAdr = Group IVSu (P < 0.005). Time to the first administration of dipyrone showed the following association: Group IVSu = Group CSu = Group CSuAdr (3-4 h) < Group CSuNeo = Group CSuNeoAdr (10-11 h) (P < 0.05). Number of doses of rescue analgesic showed the following association: Group IVSu = Group CSu = Group CSuAdr > Group CSuNeo = Group CSuNeoAdr (P < 0.005). Incidence of adverse effects was similar among groups. CONCLUSION: Caudal sufentanil alone was no better than when administered in the IV route, and would just be justified by the association of neostigmine, but not adrenaline. Neostigmine association resulted in better perioperative analgesia.

Effects of type 1 and type 2 diabetes on the pharmacokinetics of tramadol enantiomers in patients with neuropathic pain phenotyped as cytochrome P450 2D6 extensive metabolizers.

OBJECTIVES: The aim of this study was to evaluate the influence of poorly controlled type 1 (T1DM) and type 2 diabetes mellitus (T2DM) on the pharmacokinetics and metabolism of tramadol enantiomers in patients with neuropathic pain. METHODS: Nondiabetic patients (control group, n = 12), patients with T1DM (n = 9) or T2DM (n = 9), all with neuropathic pain and phenotyped as cytochrome P450 2D6 extensive metabolizers, received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected over a 24-h period. KEY FINDINGS: Patients with T1DM showed reduced Cmax of both tramadol enantiomers. The plasma concentrations of the active (+)-M1 were significantly reduced in T1DM (area under the curve plasma concentration versus time (AUC∞ ): 313.1 ng·h/ml) when compared with nondiabetic patients (AUC∞ : 1246.6 ng·h/ml). The fraction unbound of (+)-M1 was increased in patients with T1DM. Patients with T1DM and T2DM showed reduced AUC and increased fraction unbound of (-)-M1. CONCLUSIONS: The reduced total plasma concentrations of the active (+)-M1 in patients with T1DM may not be of clinical relevance because they are counterbalanced by the increased fraction unbound.

Analysis of rocuronium in human plasma by liquid chromatography-tandem mass spectrometry with application in clinical pharmacokinetics.

Rocuronium (ROC) is a neuromuscular blocking agent used in surgical procedures which is eliminated primarily by biliary excretion. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for analysis of ROC in human plasma. Separation of ROC and IS (verapamil) was performed using an endcapped C-18 column and a mixture of water:acetonitrile:trifluoracetic acid (50:50:0.1, v/v) as mobile phase. Aliquots of 100 µL of human plasma were extracted at pH 3, using dichloromethane. The lower limit of quantification of 5 ng/mL shows the high sensitivity of this method. Intra- and inter-assay precision (as relative standard deviation) was all ≤14.2% and accuracy (as relative standard error) did not exceed 10.1%. The validated method was successfully applied to quantify ROC concentrations in patients under surgical procedures up to 6h after the administration of the 0.4-0.9 mg/kg ROC. The pharmacokinetic parameter estimations of ROC showed AUC/dose of 563 µg min/mL, total clearance of 2.5 mL/min/kg, volume of distribution at steady state of 190 mL/kg and mean residence time of 83 min.

Efficacy of the use of two simultaneously TENS devices for fibromyalgia pain.

Fibromyalgia is characterized by a range of symptoms that include muscle pain, fatigue and sleep disorders. Transcutaneous electrical nerve stimulation (TENS) is an established method for pain relief. The purpose of the study was to evaluate the effectiveness and safety of the use of two simultaneously new TENS devices for fibromyalgia pain. After Ethics approval and informed consent, 39 patients were prospectively divided into three groups to evaluate TENS device, applied simultaneously in each patient: (1) at the lower back (perpendicular to the vertebrae canal, at the level of the 5th lumbar vertebrae) and (2) centrally above and below the space between the C7 and T1 spinous processes. The devices were applied for 20 min at 12-h interval during 7 consecutive days. For the placebo group (PG), the devices did not transmitted electrical stimulus. The single-TENS group (STG) (n = 13) had one active and one placebo TENS. The DTG applied both active TENS devices at the low back and cervical areas. Diclofenac was used as rescue analgesic. The efficacy measures were pain relief, reduction in use of daily analgesic tablets, quality of sleep and fatigue. The evaluation within groups revealed that patients from DPG refereed no pain relief when compared to their previous VAS pain score (8 cm, p > 0.05), while patients from the STG refereed improvement of 2.5 cm in the pain VAS (previous 8.5 cm compared to 6 cm after treatment) (p < 0.05), and the DPG refereed daily maintained reduction of 4 cm in the VAS pain (previous 8.5-4.3 cm) (p < 0.02). Concurrent daily consumption of analgesic tablets was reduced in both STG (p < 0.05) and DTG (p < 0.02). Comparison among groups revealed that analgesia, as well as quality of sleep and disposition, was DTG > STG > PG (p < 0.05). Participants subjectively found the active device useful. While the application of a single active TENS improved pain relief in fibromyalgia pain, pain and fatigue were further improved when two active devices were simultaneously applied at the low back and cervical area, with no side effects.

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(®) 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.

Quarta idade e velhice extrema: substituição da polifarmácia por um comprimido de hidromorfona de liberação controlada para o controle da dor crônica / Fourth age and extreme old age: replacement of polypharmacy by a controlled-release hydromorphone tablet to control chronic pain

JUSTIFICATIVA E OBJETIVOS: Cerca de 4,5 milhões de pessoas terão idade superior a 80 anos até 2020.Frequentemente, esta população necessita de polifarmácia para o controle da dor. O objetivo deste estudo foi avaliar a eficácia, custo e segurança da administração única, diária de hidromorfona de liberação controlada em pacientes com idade > 80 anos.MÉTODO: Oito pacientes (82 a 89 anos, quarta idade), e dois pacientes (93 e 99 anos, velhice extrema) foram avaliados.Todos utilizavam opioides, antidepressivos, anti--inflamatórios não esteroides, paracetamol e anticonvulsivantes para o controle da dor. Todos os fármacos com finalidade analgésica foram substituídos por um comprimido diário de 8 mg de hidromorfona de liberação controlada(OROS). Dor e efeitos adversos foram avaliados.RESULTADOS: O número de comprimidos diários para controle da dor diminuiu de 6-7 para um de hidromorfona.Houve diminuição da sensação de mal estar gástrico matinal, secundária à ingestão de grande número de comprimidos. Não foram relatadas náusea ou indisposição.Não foi relatada sonolência diária, sendo que os pacientes referiram melhor padrão de sono.CONCLUSÃO: A substituição da polifarmácia por um comprimido diário de hidromorfona melhorou o padrão analgésico, com baixa incidência de efeitos adversos em pacientes idosos, portadores de dor crônica, podendo ser considerada como uma boa alternativa para o controle da dor e a melhora da qualidade de vida desta população.

BACKGROUND AND OBJECTIVES: Approximately 4.5 million people will have more than 80 years of age by 2020. Very often, this population needs polypharmacy to control pain. This study aimed at evaluating the effectiveness,cost and safety of a single daily dose of controlled-release hydromorphone in patients aged > 80 years.METHOD: Eight patients (82 to 89 years old, fourth age) and two patients (93 and 99 years old, extreme old age) were evaluated. All were under opioids, antidepressants,non-steroid anti-inflammatory drugs, paracetamol and anticonvulsants to control pain. All analgesic drugs were replacedby a daily 8 mg tablet of controlled-release hydromorphone (OROS). Pain and adverse effects were evaluated.RESULTS: The number of daily tablets to control pain was decreased from 6-7 to one hydromorphone tablet. The morning gastric malaise sensation, secondary to the ingestion of a large number of tablets has decreased.There were no nausea or distemper. There were no reports on daily sleepiness and patients have referred abetter sleeping pattern.CONCLUSION: Replacing polypharmacy by a daily hydromorphone tablet has improved the analgesic pattern,with low incidence of adverse effects in elderly patients with chronic pain and it may be considered a good alternative to control pain and improve quality of life of this population.

Spinal and intravenous midazolan anesthetic effects on fentanyl/ ligdocaine regional anesthesia following back minor orthopedic surgery / Midazolan por via espinal ou endovenosa como coadjuvante da anestesia regional com lidocaína/fentanil em pacientes submetidos a procedimentos cirúrgicos lombares de pequeno porte / Midazolan por vía espinal o endovenosa como coadyuvante de la anestesia regional con lidocaína/fentanil en pacientes sometidos a procedimientos quirúrgicos lumbares de pequeño porte

OBJECTIVES: the present study was designed to evaluate the usefulness of intravenous and intrathecal midazolan as an adjunct to intrathecal ligdocaine, with or without intrathecal fentanyl. METHODS: double-blind study, institutional approval and informed consent; 40 patients scheduled for minor lumbar orthopedic surgery were randomly assigned to one of five groups (n=8). Patients were premedicated with a 4 mL final intravenous volume (saline or midazolan). Spinal anaesthesia was administered to a 3 mL final volume - 75 mg of lidocaina plus either 33 mg fentanyl or 500 mg midazolan diluted in saline (0,9 percent) - with the patient in sitting position. The latency time for onset of the block (LT), time to progress to T10 sensory level (TT10), duration of the block (Bl), duration of effective analgesia (An), the subjective degree of intraoperative sedation, level of alertness, concentration level and degree of anxiety were specifically measured. P<0.05 was considered significant. RESULTS: the addition of midazolan to the intrathecal injection in the absence of fentanyl was the only procedure which caused a statistically significant reduction in LT (p<0.002) and TT10 (p<0.001). Intrathecal midazolan increased the blockade time both with (p<0.05) and without (p<0.02) intrathecal fentanyl, but, when given intravenously, this effect failed to reach statistical significance (p>0,05). Both intrathecal fentanyl and midazolan increased the duration of analgesia (p<0.01). With respect to the subjective measures, group 1 served as the control group, demonstrating an alert, fully awake patient who was able to concentrate but showed some anxiety. CONCLUSIONS: while all additional treatments resulted in a relaxed patient, only those given intrathecal midazolan remained fully awake, alert and able to concentrate. Intrathecal fentanyl with saline premedication or intravenous midazolan premedication resulted in decreased alertness and inability to concentrate, ...

OBJETIVOS: o presente estudo visa avaliar a utilidade da administração do benzodiazepínico midazolan, por via venosa ou espinal, em pacientes submetidos a procedimentos cirúrgicos de pequeno porte sob anestesia regional com lidocaína e fentanil. MÉTODOS: após aprovação do Comitê de Ética em pesquisa e consentimento formal, 40 pacientes foram avaliados de forma duplamente encoberta e prospectiva, sendo divididos aleatoriamente a um dos cinco grupos do estudo (n=8). Os pacientes foram premedicados com midazolan ou solução fisiológica (volume final de 4 mL) por via venosa. A anestesia espinal foi administrada com o paciente sentado, utilizando-se 75 mg de lidocaína, 33 mg de fentanil ou 500 mg de midazolan, diluídos em solução fisiológica (0,9 por cento), sendo o volume final (3 mL) administrado por via intratecal. Foram avaliados: tempo de latência, tempo de bloqueio motor, tempo de analgesia, grau de sedação, nível de alerta, nível de concentração e grau de ansiedade. Foi considerado significante p<0,05. RESULTADOS: a adição de midazolan por via intratecal na ausência de fentanil foi o único procedimento que resultou em redução do tempo de latência para início do bloqueio (p<0,002). Midazolan por via intratecal aumentou o tempo de bloqueio motor, com (p<0,05) ou sem (p<0,02) a associação de fentanil intratecal, enquanto que, ao serem administrado por via venosa, não alterou o tempo de bloqueio motor (p>0,05). Tanto a administração de fentanil ou midazolan intratecais resultaram em aumento do tempo de analgesia (p<0,01). Em relação aos resultados subjetivos, enquanto o grupo 1 atuou como controle, sendo os pacientes alertas, porém com certo grau de ansiedade, os pacientes que receberam midazolan estavam alertas e não ansiosos. CONCLUSÕES: os pacientes que receberam midazolan intratecal permaneceram acordados, alertas e com capacidade de concentração, apresentaram menor latência para anestesia e maior tempo de analgesia.

OBJETIVOS: el presente estudio visa evaluar la utilidad de la administración del benzodiazepínico midazolan por vía venosa o espinal en pacientes sometidos a procedimientos quirúrgicos de pequeño porte sobre anestesia regional con lidocaína y fentanil. MÉTODOS: después de la aprobación del Comité de Ética en Investigación Formal, 40 pacientes fueron evaluados de forma doble-ciego y prospectivo, siendo divididos de forma aleatoria uno de los cinco grupos del estudio (n=8). Los pacientes fueron pre-medicados con midazolan o solución fisiológica (volumen final 4 mL) por vía venosa. La anestesia espinal fue administrada con el paciente sentado, utilizándose 75 mg de lidocaína, 33 mg de fentanil o 500 mg de midazolan diluidos en solución fisiológica (0.9 por ciento), siendo el volumen final administrado por vía intratecal 3 mL. Fueron evaluados: el tiempo de latencia, el de bloqueo motor, el de analgesia, lo grado de sedación y de ansiedad. El p<0.05 fue considerado significativo. RESULTADOS: la adición de midazolan por vía intratecal en la ausencia de fentanil fue el único procedimiento que resultó en reducción del tiempo de latencia para inicio del bloqueo (p<0.002). Midazolan por vía intratecal aumentó el tiempo de bloqueo motor con (p<0.05) o sin (p<0.02) la asociación de fentanil intratecal, mientras que administrado por vía venosa no cambió el tiempo de bloqueo motor (p>0.05). Tanto la administración de fentanil intratecal o midazolan intratecal resultaron en aumento del tiempo de analgesia (p<0.01). En relación a los resultados subjetivos, el Grupo 1 actuó como Control, siendo los pacientes alertas, pero con cierto grado de ansiedad, mientras los pacientes que recibieron midazolan estuvieron alertas y no ansiosos. CONCLUSIONES: los pacientes que recibieron midazolan intratecal permanecieron alertas y con capacidad de concentración, presentaron menor latencia para anestesia y mayor tiempo de analgesia.

Avaliação do efeito antinociceptivo do fentanil transdérmico no controle da dor lombar pós-operatória / Evaluación del efecto antinociceptivo del fentanil transdérmico en el control del dolor lumbar postoperatorio / Efficacy of fentanyl transdermal delivery system for acute postoperative pain after posterior laminectomyEvaluación del efecto antinociceptivo del fentanil transdérmico en el control del dolor lumbar postoperatorio

OBJETIVO: pacientes submetidos à laminectomia por via posterior geralmente reclamam de dor severa. A aplicação por via transdérmica de fentanil resulta em sua liberação contínua e poderia ser útil no controle da dor. Este estudo visou avaliar a eficácia do fentanil (F) transdérmico em dor aguda pós-operatória secundária à laminectomia por via posterior. MÉTODOS: após aprovação do Comitê de Ética em Pesquisa e consentimento adquirido, 24 pacientes foram distribuídos de forma aleatória e duplamente encoberta em dois grupos, sendo que 12 pacientes receberam o adesivo de F transdérmico (25 mcg/h) e outros 12 receberam o adesivo placebo. Todos os pacientes foram submetidos à laminectomia posterior, sob anestesia geral padronizada. Os adesivos transdérmicos foram colocados nos pacientes dez horas antes do início da cirurgia e removidos 24 horas após o término dessa. Cetoprofeno por via venosa foi administrado no início da cirurgia, dipirona estava disponível para analgesia de resgate, se necessário, a intervalos mínimos de seis horas. RESULTADOS: os pacientes que receberam F transdérmico apresentaram redução de 60 por cento no consumo de dipirona no período pós-operatório (p<0,05); e menor VAS para dor após a 12ª hora, o que se manteve até a 36ª hora de avaliação (p<0,02). Os parâmetros fisiológicos variaram dentro dos limites de normalidade e foram semelhantes entre os grupos. A incidência de efeitos adversos foi similar entre os grupos, sendo constatado apenas eritema local no Grupo F transdérmico (30 versus 5 por cento, p<0,05). CONCLUSÃO: o adesivo transdérmico de F associado ao cetoprofeno foi efetivo em controlar a dor pós-operatória após laminectomia por via posterior, com tolerância e segurança semelhante ao Grupo Placebo.

Objectives: patients who are submitted to posterior laminectomy often complain of severe pain that is difficult to treat. The transdermal application of the potent opioid fentanyl results in its continuous liberation and consequently could be useful in controlling the pain. This study evaluated the efficacy of transdermal fentanyl (F) delivery system for acute postoperative pain after posterior laminectomy. METHODS: the study was approved by the local Ethic Committee and conducted in the Teaching Hospital. After the patient's consent, 24 patients were randomized to either transdermic F 25 mg/h (n=12) or transdermic placebo (n=12). All patients were submitted to posterior laminectomy under a standard general anesthesia. Transdermic systems were placed during 10 hours preoperatively and removed 24 hours later; 20 minute IV ketoprofen, 2.5 mg/kg was administered following traqueal intubation with propofol, alfentanil and atracurium. IV 20 mg/kg dipyrone act as rescue at a minimum six hours interval. Data was recorded for 36 hours. RESULTS: the transdermic F Group showed 60 percent of reduction in the rescue dipyrone consumption (p<0.05); and displayed lesser VAS scores after the 12th hour, which was maintained until the 36th hour (p<0.02). All physiological parameters fluctuated within normal range and no differences were observed between the treatments. The incidence of adverse events was similar between the groups, there was local erythema in the transdermic F (30 versus 5 percent, p<0.05). CONCLUSION: transdermic F combined with IV ketoprofen was effective in controlling postoperative pain after posterior laminectomy. Additionally, the safety and tolerability of this regimen were similar to the Placebo Group

OBJETIVO: pacientes sometidos a laminectomía por vía posterior generalmente reclaman de dolor severo. La aplicación por vía transdérmica de fentanil resulta en su liberación continua y podría ser útil en el control del dolor. Este estudio visó evaluar la eficacia del fentanil (F) transdérmico en el dolor agudo postoperatorio, secundario a la laminectomía por vía posterior. MÉTODOS: después de la aprobación por el Comité de Ética en investigación y consentimiento adquirido, 24 pacientes fueron distribuidos de forma aleatoria y duplamente ciegos en dos grupos, siendo que 12 pacientes recibieron el adhesivo de F transdérmico (25 mcg/h) y 12 pacientes recibieron el adhesivo de placebo. Todos los pacientes fueron sometidos a la laminectomía posterior sobre anestesia general estandarizada. Los adhesivos transdérmicos fueron colocados en los pacientes diez horas antes del inicio de la cirugía y removidos 24 horas después de haber terminado la misma. Cetoprofeno por vía venosa fue administrado por vía venosa en el inicio de la cirugía. Dipirona estaba disponible para analgesia de rescate, si era necesario, a intervalos mínimos de seis horas. RESULTADOS: los pacientes que recibieron F transdérmico presentaron reducción de 60 por ciento en el consumo de dipirona en el periodo postoperatorio (p<0,05); y menor VAS para dolor después de la 12ª hora, lo que se mantuvo hasta la 36ª hora de evaluación (p<0,02). Los parámetros fisiológicos variaron dentro de los límites de normalidad y fueron semejantes entre los grupos. La incidencia de efectos adversos fue similar entre los grupos, siendo constatado únicamente eritema local en el Grupo F transdérmico (30 versus 5 por ciento, p<0,05). CONCLUSIÓN: el adhesivo transdérmico de F asociado al cetoprofeno fue efectivo en controlar el dolor postoperatorio después de la laminectomía por vía posterior, con tolerancia y seguridad semejante al Grupo Placebo.

Avaliação clínica e laboratorial da cetamina transdérmica, do fentanil transdérmico, da clonidina transdérmica ou suas associações na dor lombar crônica / Evaluación clínica y de laboratorio de cetamina transdérmica, del fentanyl transdérmico, de la clonidina transdérmica o de sus asociaciones en el dolor lumbar crónico / The clinical and laboratorial evaluation of transdermal ketamine, fentanyl, clonidine or their combination in chronic low back pain

OBJECTIVES: chronic low back pain may result in central sensitization, with involvement of different receptors. The aim of this study was to evaluate the analgesic action of transdermal (T) ketamine (a NMDA antagonist), clonidine (an x2-agonist), fentanyl (an opioid agonist), or their combination in chronic low back pain. METHODS: after the institutional approval and informed consent signature, 54 patients were prospectively randomized into 6 groups. Each patient had two of the T preparations applied in different arms. The effect of either T ketamine (1 mg/h), T clonidine (25 µg/h) or T fentanyl (25 µg/h), combined with T placebo (CloG, KetG and FenG); or the combination of T ketamine and clonidine (Ket-CloG), T fentanyl and ketamine (Fen-KetG), or T fentanyl and clonidine (Fen-CloG) was searched for pain and adverse effects. Pain was evaluated by: 1) VAS pain scores, and 2) noradrenaline plasma levels at 0-h (just prior to T application), 3- and 6-h after the T application of two medications, by HPLC. RESULTS: clinically, the pain VAS score at 6-h was smaller in comparison to the 0-h in all groups (p<0.02), and lower when compared to the Fen-CloG and Fen-KetG at the 6-h in relation to the administration of each correspondent T drug alone (p<0.05). The laboratorial data revealed that administration of T fentanyl alone (FenG) resulted in plasma noradrenaline decrease at 6-h (p<0.01), while the association of T fentanyl with clonidine resulted in plasma noradrenaline decrease at 3- and 6-h as compared to the others (p<0.01). The combination of both T ketamine and clonidine (Ket-CloG) did not result in a better analgesic profile and resulted in excessive sedation during the evaluation (p<0.02). CONCLUSIONS: all the studied drugs resulted in clinical analgesia (VAS) at 6-h. However, T fentanyl analgesia was corroborated by lower plasma noradrenaline levels at 6-h when applied alone or at 3-h when combined with T clonidine.

OBJETIVOS: a dor lombar crônica pode resultar em sensibilização central, com a participação de diferentes tipos de receptores. O objetivo deste estudo foi avaliar a ação analgésica por via transdérmica (T) do fentanil, cetamina, clonidina ou suas associações para o alívio da dor lombar crônica. MÉTODOS: após aprovação do Comitê de Ética em Pesquisa e assinatura do termo de consentimento livre e esclarecido, 54 pacientes foram avaliados de forma prospectiva, aleatória e duplamente-encoberta, sendo divididos em 6 grupos. Cada paciente recebeu duas preparações por via transdérmica, aplicadas em braços diferentes (T cetamina (1 mg/h), T clonidina (25 µg/h) ou T fentanil (25 µg/h), associados a T placebo (CloG, CetG and FenG); ou a associação de T cetamina e clonidina (Cet-CloG), T fentanil e cetamina (Fen-CetG), ou T fentanil e clonidina (Fen-CloG). A analgesia e a incidência de efeitos adversos foram avaliadas. A analgesia foi avaliada com: 1) VAS-cm, e 2) níveis plasmáticos de noradrenalina às 0-h (antes da aplicação T), 3- e 6-h após a aplicação T, com HPLC. RESULTADOS: clinicamente, os valores de VAS as 6-h foram menores comparados ao tempo de 0-h para todos os grupos (p<0,02), e menores para o Fen-CloG e Fen-CetG às 6-h em relação à administração de cada droga T isolada (p<0,05). A administração de fentanil T (FenG) resultou em diminuição dos níveis de noradrenalina plasmática às 6-h (p<0,01), enquanto a associação de fentanil T com clonidina T resultou em diminuição de noradrenalina plasmática às 3-h e 6-h em comparação aos demais grupos (p<0.01). A combinação de cetamina e clonidina (Cet-CloG) não ofereceu melhor perfil analgésico e resultou em sedação excessiva (p<0,02). CONCLUSÕES: todos os grupos apresentaram melhora clínica (VAS) da dor às 6-h. Entretanto, somente quem recebeu fentanil T apresentou níveis plasmáticos de noradrenalina mais baixos às 6-h (quando combinado com placebo) e às 3-h quando associado à clonidina T.

OBJETIVOS: el dolor lumbar crónico puede resultar en sensibilización central, con la participación de diferentes tipos de receptores. El objetivo de este estudio fue evaluar la acción analgésica por vía transdérmica (T) del fentanyl, cetamina, clonidina o sus asociaciones en dolor lumbar crónico. MÉTODOS: después de la aprobación por el Comité de Ética en Investigación y Consentimiento, 54 pacientes fueron evaluados de forma prospectiva, aleatoria e duplamente-ciego siendo divididos en seis grupos. Cada paciente recibió dos preparaciones por vía transdérmica, aplicadas en brazos diferentes (T cetamina (1 mg/h), T clonidina (25 µg/h) o T fentanyl (25 µg/h), asociados a T placebo (CloG, CetG y FenG); o la asociación de T cetamina y clonidina (Cet-CloG), T fentanyl y cetamina (Fen-CetG), o T fentanyl y clonidina (fen-CloG). La analgesia y la incidencia de efectos adversos fueron evaluadas. La analgesia fue evaluada con: 1) VAS-cm, y 2) niveles plasmáticos de noradrenalina a las 0 hora (antes de la aplicación T), tres y seis horas después de la aplicación T, con HPLC. RESULTADOS: clínicamente los valores de VAS a las seis horas fueron menores comparados a 0 hora para todos los grupos (p<0,02), y menores para el Fen-CloG y Fen-CetG a las seis horas después de la administración de cada droga T aislada (p<0,05). La administración de fentanyl T (Feng) resultó en disminución de los niveles de noradrenalina plasmática a las seis horas (p<0,01). La combinación de cetamina y clonidina (Cet-CloG) no ofreció mejor perfil analgésico y resultó en sedación excesiva (p<0,02). CONCLUSIONES: todos los grupos presentaron mejoría clínica (VAS) del dolor a las seis horas. Sin embargo, solamente quien recibió fentanyl T presentó menores niveles plasmáticos de noradrenalina a las seis horas (cuando combinado con placebo) y a las tres horas cuando asociado con clonidina T.

High and low frequency TENS reduce postoperative pain intensity after laparoscopic tubal ligation: a randomized controlled trial.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is an effective adjunctive therapy for postoperative pain; however, effects of different frequencies of stimulation have not been systematically investigated. Laparoscopic sterilization (LS) causes significant pain in the early postoperative period and requires substantial postoperative medication. Therefore, we studied the effects of TENS on postoperative pain after LS through placement of Yoon fallopian rings in a prospective, randomized, double-blinded, and placebo-controlled study. METHODS: Sixty-four patients undergoing LS for uterine tube ligation were randomly allocated to receive either active TENS or placebo TENS. Postoperative pain was evaluated using a standard 11-point numeric rating scale and the McGill Pain Questionnaire (MPQ)-pain rating index and number of words chosen. Both high frequency (100 Hz) and low frequency (4 Hz) TENS, at strong, but comfortable sensory intensity, were applied for 20 minutes through 4 electrodes placed around the surgical incision immediately after surgery. Pain was assessed before and after application of TENS when patients were at postanesthesia care unit (PACU). RESULTS: Both high and low frequency TENS significantly decreased postoperative pain intensity when compared with before administration of TENS using the numeric rating scale (P=0.001), pain rating index (P=0.001), and number of words chosen (P=0.001) compared with placebo TENS (P=0.001). TENS in combination with standard pharmacologic analgesic treatment was efficacious for postoperative pain relief after LS. CONCLUSIONS: We recommend regular use of multimodal therapy with TENS and analgesic drugs after LS with placement of Yoon rings.

Mecanismos envolvidos na analgesia da lidocaína por via venosa / Mechanisms of analgesia of intravenous lidocaine

JUSTIFICATIVA E OBJETIVOS: A lidocaína é utilizada por via venosa desde a década de 1960 para diversas finalidades. Seu mecanismo de ação multimodal foi o objetivo principal dessa revisão. CONTEÚDO: Foram revisados mecanismos de ação divergentes do clássico bloqueio do canal de Na+, a ação diferencial da lidocaína venosa na sensibilização central, sua ação analgésica e citoprotetora, assim como as diferentes doses da lidocaína utilizadas por via venosa. CONCLUSÕES: A ação analgésica final da lidocaína por via venosa reflete seu aspecto multifatorial de ação. Em relação à sensibilização central, sugere-se uma ação anti-hiperalgésica periférica da lidocaína na dor somática e central na dor neuropática, com resultante bloqueio da hiperexcitabilidade central. A dose por via venosa não deve exceder a concentração plasmática tóxica de 5 µg.mL-1, sendo consideradas seguras doses inferiores 5 mg.kg-1, administradas lentamente (30 minutos), com monitoração.

BACKGROUND AND OBJECTIVES: Intravenous lidocaine has been used for several indications since the decade of 1960. Its multimodal mechanism of action was the objective of this review. CONTENTS: Mechanisms of action that diverge from the classical Na+ channel blockade, the differential action of intravenous lidocaine in central sensitization, and the analgesic and cytoprotective actions, as well as the different doses of intravenous lidocaine were reviewed. CONCLUSIONS: The final analgesic action of intravenous lidocaine is a reflection of its multifactorial action. It has been suggested that its central sensitization is secondary to a peripheral anti-hyperalgic action on somatic pain and central on neuropathic pain, which result on the blockade of central hyperexcitability. The intravenous dose should not exceed the toxic plasma concentration of 5 µg.mL-1; doses smaller than 5 mg.kg-1, administered slowly (30 minutes), under monitoring, are considered safe.

JUSTIFICATIVA Y OBJETIVOS: La lidocaína se utiliza por vía venosa desde la década de 60 para diversas finalidades. Su mecanismo de acción multimodal fue el objetivo principal de esta revisión. CONTENIDO: Se revisaron mecanismos de acción divergentes del clásico bloqueo del canal de Na+, la acción diferencial de la lidocaína venosa en la sensibilización central, su acción analgésica y citoprotectora, como también las diferentes dosis de la lidocaína utilizadas por vía venosa. CONCLUSIONES: La acción analgésica final de la lidocaína por vía venosa refleja su aspecto multifactorial de acción. Con relación a la sensibilización central, se sugiere una acción antihiperalgésica periférica de la lidocaína en el dolor somático y central en el dolor neuropático, con el resultante bloqueo de la hiperexcitabilidad central. La dosis de por vía venosa no debe exceder la concentración plasmática tóxica de 5 µg.mL-1, siendo consideradas seguras dosis inferiores 5 mg.kg-1, administradas lentamente (30 minutos), con monitorización.

Mechanisms of analgesia of intravenous lidocaine.

BACKGROUND AND OBJECTIVES: Intravenous lidocaine has been used for several indications since the decade of 1960. Its multimodal mechanism of action was the objective of this review. CONTENTS: Mechanisms of action that diverge from the classical Na+ channel blockade, the differential action of intravenous lidocaine in central sensitization, and the analgesic and cytoprotective actions, as well as the different doses of intravenous lidocaine were reviewed. CONCLUSIONS: The final analgesic action of intravenous lidocaine is a reflection of its multifactorial action. It has been suggested that its central sensitization is secondary to a peripheral anti-hyperalgic action on somatic pain and central on neuropathic pain, which result on the blockade of central hyperexcitability. The intravenous dose should not exceed the toxic plasma concentration of 5 microg mL(-1); doses smaller than 5 mg kg(-1), administered slowly (30 minutes), under monitoring, are considered safe.

Highlights in opioid agonists and antagonists.

This review highlights new insights in to opioid agonists and antagonists, focusing on their mechanism of action with spinal and systemic administration, chronic use and main adverse effects. Short-cuts on some opioid agonists and antagonists of clinical interest are also presented, revealing potential clinical implications and future clinical directions as part of multimodal analgesia.

Reabilitação funcional e analgesia com uso de toxina botulínica A na síndrome dolorosa regional complexa tipo I do membro superior: relato de casos / Functional rehabilitation and analgesia with botulinum toxin A in upper limb complex regional pain syndrome type I: case reports

JUSTIFICATIVA E OBJETIVOS: Freqüentemente, soma-se ao quadro de alodínia e hiperalgesia em pacientes portadores de Síndrome Dolorosa Regional Complexa (SDRC) tipo I a incapacidade funcional do segmento acometido. Relatam-se dois casos de SDRC em que a aplicação de toxina botulínica-A como fármaco coadjuvante contribuiu na recuperação funcional motora do membro acometido. RELATO DOS CASOS: Duas pacientes portadoras de SDRC tipo I foram inicialmente avaliadas para controle da dor no membro superior direito. Ambas apresentavam incapacidade para abrir a mão e dor pela escala analógica numérica (EAN) de 10 em repouso ou quando a mão ou os dedos eram passivamente manipulados. Iniciou-se seqüência de 5 bloqueios, do gânglio estrelado ipsilateral a intervalos semanais, com clonidina e lidocaína. Simultaneamente, durante a realização do terceiro bloqueio do gânglio estrelado, foram administrados 75 UI de toxina botulínica-A nos músculos flexores das falanges e da articulação do punho. Uma semana após a aplicação da toxina botulínica-A, as pacientes apresentavam relaxamento das falanges e punho, relatavam facilidade para execução da fisioterapia passiva e a dor classificada foi como 2 (EAN) à manipulação passiva. Ao término da realização da seqüência de bloqueios do gânglio estrelado, as pacientes foram submetidas a 3 sessões semanais de administração por via venosa regional de clonidina, lidocaína e parecoxib. Após 8 meses de avaliação, as pacientes apresentaram 70 por cento e 80 por cento de recuperação motora e funcional do membro acometido. CONCLUSÕES: A aplicação por via muscular de toxina botulínica A resultou em melhora da movimentação do membro acometido, analgesia auxiliando na sua recuperação funcional.