Effect of preoperative gabapentin on pain intensity and development of chronic pain after carpal tunnel syndrome surgical treatment in women: randomized, double-blind, placebo-controlled study / Efeito da gabapentina pré-operatória na intensidade da dor e desenvolvimento de dor crônica após o tratamento cirúrgico da síndrome do túnel do carpo em mulheres: estudo randomizado duplo-cego controlado com placebo

ABSTRACT CONTEXT AND OBJECTIVES: Effective postoperative analgesia is important for reducing the incidence of chronic pain. This study evaluated the effect of preoperative gabapentin on postoperative analgesia and the incidence of chronic pain among patients undergoing carpal tunnel syndrome surgical treatment. DESIGN AND SETTINGS: Randomized, double-blind controlled trial, Federal University of São Paulo Pain Clinic. METHODS: Forty patients aged 18 years or over were randomized into two groups: Gabapentin Group received 600 mg of gabapentin preoperatively, one hour prior to surgery, and Control Group received placebo. All the patients received intravenous regional anesthesia comprising 1% lidocaine. Midazolam was used for sedation if needed. Paracetamol was administered for postoperative analgesia as needed. Codeine was used additionally if the paracetamol was insufficient. The following were evaluated: postoperative pain intensity (over a six-month period), incidence of postoperative neuropathic pain (over a six-month period), need for intraoperative sedation, and use of postoperative paracetamol and codeine. The presence of neuropathic pain was established using the DN4 (Douleur Neuropathique 4) questionnaire. Complex regional pain syndrome was diagnosed using the Budapest questionnaire. RESULTS: No differences in the need for sedation, control over postoperative pain or incidence of chronic pain syndromes (neuropathic or complex regional pain syndrome) were observed. No differences in postoperative paracetamol and codeine consumption were observed. CONCLUSIONS: Preoperative gabapentin (600 mg) did not improve postoperative pain control, and did not reduce the incidence of chronic pain among patients undergoing carpal tunnel syndrome surgery.

RESUMO CONTEXTO E OBJETIVOS: Analgesia pós-operatória eficaz é importante para reduzir a incidência de dor crônica. Este estudo avaliou o efeito da gabapentina pré-operatória na analgesia pós-operatória e na incidência de dor crônica em pacientes submetidos à cirurgia para tratamento da síndrome do túnel do carpo. DESENHO E LOCAL: Randomizado, duplo cego, Universidade Federal de São Paulo. MÉTODOS: Os 40 pacientes com 18 anos ou mais de idade foram distribuídos aleatoriamente em dois grupos: o Grupo Gabapentina recebeu 600 mg de gabapentina no pré-operatório uma hora antes da cirurgia, e o Grupo Controle recebeu placebo. Todos os pacientes receberam anestesia regional intravenosa com lidocaína a 1%. Midazolam foi utilizado para sedação, se necessário. Paracetamol foi administrado para analgesia pós-operatória, conforme necessário, e codeína, se o paracetamol fosse insuficiente. Foram avaliados: a intensidade da dor pós-operatória (durante seis meses), a incidência de dor neuropática pós-operatória (durante seis meses), a necessidade de sedação intra-operatória e o uso de paracetamol e codeína no pós-operatório. A presença de dor neuropática foi estabelecida utilizando-se o questionário DN4 (dor neuropática 4). Síndrome de dor regional complexa foi diagnosticada através do questionário Budapeste. RESULTADOS: Não foram observadas diferenças na necessidade de sedação, no controle da dor pós-operatória e na incidência de síndromes dolorosas crônicas (neuropáticas ou síndrome de dor regional complexa). Não foram observadas diferenças no consumo de paracetamol e codeína. CONCLUSÕES: Gabapentina pré-operatória (600 mg) não melhorou o controle da dor pós-operatória e não reduziu a incidência de dor crônica em pacientes submetidos à cirurgia para tratamento da síndrome do túnel do carpo.

Effects of preoperative gabapentin on postoperative nausea and vomiting after open cholecystectomy: a prospective randomized double-blind placebo-controlled study

To evaluate the effect of gabapentin on the incidence and severity of postoperative nausea and vomiting [PONV] after open cholecystectomy. A total of 90 patients scheduled for elective open cholecystectomy were randomly assigned to either a gabapentin group [600 mg, 2 h before surgery] or a placebo group. For the analysis, 1 patient was excluded from the gabapentin group and 2 patients from the placebo group. A standard technique was used for anesthesia. Pethidine and metoclopramide were used for postoperative management of pain and nausea/vomiting, respectively. The prevalence of PONV, its severity [measured on visual analogue scale, VAS], and total pethidine and metoclopramide use in the first 24 h after the operation were recorded. There were no demographic differences between the two groups. Of the 44 patients given gabapentin, 16 [36.6%] and 28 of 43 [65.2%] placebo patients developed PONV; the difference was statistically significant [p = 0.02]. However, there was no difference in the severity of PONV between the gabapentin and placebo groups [p = 0.12]. Gabapentin patients used less pethidine [28.33 +/- 129 mg] and metoclopramide [6.0 +/- 6.3 mg] than the placebo group [35.1 +/- 15.1 and 9.33 +/- 7.1 mg, respectively]. The differences were statistically significant [pethidine: p = 0.002, metoclopramide: p = 0.033]. However, gabapentin did not reduce postoperative pain significantly [p = 0.096]. Our data show that gabapentin not only reduced PONV after open cholecystectomy, but also reduced the need for additional postoperative analgesics

Protective Effects of Gabapentin on Allodynia and alpha2delta1-Subunit of Voltage-dependent Calcium Channel in Spinal Nerve-Ligated Rats

This study was designed to determine whether early gabapentin treatment has a protective analgesic effect on neuropathic pain and compared its effect to the late treatment in a rat neuropathic model, and as the potential mechanism of protective action, the alpha2delta1-subunit of the voltage-dependent calcium channel (alpha2delta1-subunit) was evaluated in both sides of the L5 dorsal root ganglia (DRG). Neuropathic pain was induced in male Sprague-Dawley rats by a surgical ligation of left L5 nerve. For the early treatment group, rats were injected with gabapentin (100 mg/kg) intraperitoneally 15 min prior to surgery and then every 24 hr during postoperative day (POD) 1-4. For the late treatment group, the same dose of gabapentin was injected every 24 hr during POD 8-12. For the control group, L5 nerve was ligated but no gabapentin was administered. In the early treatment group, the development of allodynia was delayed up to POD 10, whereas allodynia was developed on POD 2 in the control and the late treatment group (p<0.05). The alpha2delta1-subunit was up-regulated in all groups, however, there was no difference in the level of the alpha2delta1-subunit among the three groups. These results suggest that early treatment with gabapentin offers some protection against neuropathic pain but it is unlikely that this action is mediated through modulation of the alpha2delta1-subunit in DRG.

The Interaction of Gabapentin and N(6)-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA) on Mechanical Allodynia in Rats with a Spinal Nerve Ligation

We examined the antiallodynic interaction between gabapentin and adenosine A1 receptor agonist, N(6)-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), in a rat model of nerve ligation injury. Rats were prepared with ligation of left L5-6 spinal nerves and intrathecal catheter implantation for drug administration. Mechanical allodynia was measured by applying von Frey filaments. Gabapentin and R-PIA were administered to obtain the dose-response curve and the 50% effective dose (ED50). Fractions of ED50s were administered concurrently to establish the ED50 of the drug combination. The drug interaction between gabapentin and R-PIA was analyzed using the isobolographic method. Adenosine A1 receptor antagonist was administered intrathecally to examine the reversal of the antiallodynic effect. Locomotor function changes were evaluated by rotarod testing. Intrathecal gabapentin and R-PIA and their combination produced a dose-dependent antagonism against mechanical allodynia without severe side effects. Intrathecal gabapentin synergistically enhanced the antiallodynic effect of R-PIA when coadministered. There were no significant changes in rotarod performance time, except gabapentin 300 microgram. In the combination group, the maximal antiallodynic effect was reversed by A1 adenosine receptor antagonist. These results suggest that activation of adenosine A1 receptors at the spinal level is required for the synergistic interaction on the mechanical allodynia.

La insulinoterapia intensificada más antineuríticos es superior a antineurítico puro en neuropatía diabética dolorosa / Intensified insulin therapy plus antineuritic medication is more effective than antineuritics alone in painful diabetic neuropathy

Background: The basis of the treatment of painful diabetic neuropathy is the use of drugs that block the transmission of pain (antineuritics) and a good metabolic control of underlying disease. Aim: To describe the outcomes of 17 type-2 diabetics with painful neuropathy, treated between 1988 and 2005 with symptomatic therapy plus intensified insulin. Material and methods: Review of medical records of 17 type-2 diabetic patients, aged 63±11 years and a duration of diabetes of 15±8 years. All patients received intensified insulin therapy with 0.35 units/kg of NPH insulin (2/3 before breakfast and 1/3 evening meal), plus capillary glucose measurements and regular insulin (with sliding-scale centered in ~0.1 units/kg) before the 3 main meals. All patients were also treated with gabapentin, nortriptyline or clomipramine. Pain was assessed using a visual analog score of 10 points. Results: After 1 year, glycosilated hemoglobin decreased from 10.0±1.4 percent to 7.7±1.2 percent (p~=0.003). Pain decreased from 10 to 5.1±3.3 at one month, 2.3±3.2 at six months, and 3.1±3.6 at 1 year (p <0.01). There was a direct statistical correlation between the reduction of HbA1C and pain decline (r =0.736; p =0.037). Pain scores were lower than those reported elsewhere for Pregabalin (n =76; p =0.05), Lamotrigine (n =27; p <0.0005), Topiramate (n =208; p <0.005), and Gabapentin (n =84; p <0.025). The lack of difference to Sodium Valproate (n =21; p =0.07) had borderline significance. Conclusions: The addition of intensified insulin therapy to the symptomatic treatment of painful neuropathy in type-2 diabetics, significantly enhanced the reduction of pain. The lowering of glycosilated hemoglobin was a significant predictor of success in pain reduction.

Antinociceptive Interactions between Intrathecal Gabapentin and MK801 or NBQX in Rat Formalin Test

Antagonists for spinal N-methyl-D-aspartate (NMDA) and amino-hydroxy-methtyl-isoxazolepropionate (AMPA) receptors are effective in attenuating acute nociception or injury-induced hyperalgesia. The antinociception of spinal gabapentin is developed in injury-induced hyperalgesia without affecting acute nociception. The authors evaluated the effects of intrathecal gabapentin, NMDA antagonist (MK801) and AMPA antagonist (NBQX) in the formalin test which shows injury-induced hyperalgesia as well as acute pain. We further assessed the interactions between gabapentin and either MK801 or NBQX. Male Sprague-Dawley rats were implanted with intrathecal catheters. To evoke pain, 50 microliter of 5% formalin solution was injected into the hindpaw. The interaction was investigated by a fixed dose analysis or an isobolographic analysis. MK801 and NBQX suppressed flinching responses during phase 1 of the formalin test, while gabapentin had little effect on phase 1. All three agents decreased the phase 2 flinching response. A fixed dose analysis in phase 1 showed that gabapentin potentiated the antinociceptive effect of MK801 and NBQX. Isobolographic analysis in phase 2 revealed a synergistic interaction after coadministration of gabapentin-MK801 or gabapentin-NBQX. Correspondingly, spinal gabapentin with NMDA or AMPA antagonist may be useful in managing acute pain and injury-induced hyperalgesia.

Interaction between Intrathecal Gabapentin and Adenosine in the Formalin Test of Rats

Spinal gabapentin and adenosine have been known to display an antinociceptive effect. We evaluated the nature of the interaction between gabapentin and adenosine in formalin-induced nociception at the spinal level. Male Sprague-Dawley rats were prepared for intrathecal catheterization. Pain was evoked by injection of formalin solution (5%, 50 microliter) into the hindpaw. After examination of the effects of gabapentin and adenosine, the resulting interaction was investigated with isobolographic and fractional analyses. Neither gabapentin nor adenosine affected motor function. Gabapentin or adenosine decreased the sum of the number of flinches during phase 2, but not during phase 1 in the formalin test. Isobolographic analysis, in phase 2, revealed an additive interaction between gabapentin and adenosine. Taken together, intrathecal gabapentin and adenosine attenuated the facilitated state and interacted additively with each other.