Effect of diclofenac with B vitamins on the treatment of acute pain originated by lower-limb fracture and surgery.

The aim of this study was to compare the efficacy of diclofenac, for the treatment of acute pain originated by lower-limb fracture and surgery, with that of diclofenac plus B vitamins. This was a single-center, prospective, randomized, and double-blinded clinical trial. Patients with lower-limb closed fractures rated their pain on a 10 cm visual analog scale (VAS). Patients were then randomized to receive diclofenac or diclofenac plus B vitamins (thiamine, pyridoxine, and cyanocobalamin) intramuscularly twice daily. Patient evaluations of pain intensity were recorded throughout two periods: twenty-four hours presurgery and twenty-four hours postsurgical. One hundred twenty-two patients completed the study. The subjects' assessments of limb pain on the VAS showed a significant reduction from baseline values regardless of the treatment group. Diclofenac plus B vitamins combination was more effective to reduce the pain than diclofenac alone. The results showed that the addition of B vitamins to diclofenac increased its analgesic effect. The novelty of this paper consists in that diclofenac and diclofenac plus B vitamins were useful for treatment of acute pain originated by lower-limb fracture and surgery.

Effective analgesic between acetominophen + B vitamins vs. acetominophen in pediatric ambulatory surgery.

BACKGROUND: analgesics in pediatric ambulatory surgery must be safe and effective. Acetominophen is safe with moderate efficacy; therefore, we searched for other drugs. In preclinical trials, improved efficacy was reported with the combination of acetaminophen + B vitamins. The aim of this study was to determine the analgesic efficacy of acetaminophen + B vitamins in pediatric ambulatory surgery. METHODS: we conducted a clinical, comparative, randomized, double-blind study. We included 56 patients who were divided into four groups of 14 patients for each surgery (circumcision, tonsillectomy, inguinal hernioraphy, orchiopexy). Half of the patients received acetaminophen + B vitamins, and the remaining patients received acetaminophen alone. Variables were drugs, visual analogue scale and time of discharge. χ(2), Student t-test and analysis of variance (ANOVA) were used for statistical analysis. RESULTS: in children who received acetaminophen + B vitamins during the immediate postoperative period, 58% had a pain score <2 and 89% were discharged with a pain score %lt;1. Both schedules were effective and safe but acetaminophen + B vitamins showed a better pain score. CONCLUSIONS: the adjuvant effect of B vitamins was demonstrated with a better pain score in the immediate postoperative period and at the time of discharge.

Comparative bioavailability of two oral formulations of omeprazole.

Omeprazole is a very widely used proton-pump inhibitor. Currently, there are several branches available in Mexico, however, limited information about their bioavailabilities is available. The purpose of this study was to compare the bioavailability of two of them, Losec and Omelcid. Twenty-eight healthy volunteers were enrolled in this study that was carried out following the recommendations of the Declaration of Helsinki. Subjects read the protocol that was approved by the institutional research and ethics committees and gave written consent for participation. After an overnight fast, volunteers received an oral dose of 20 mg omeprazole (formulation A or B) and blood samples were obtained at selected times during 8 hours. Plasma was obtained by centrifugation and stored frozen until analyzed by a validated HPLC method. Pharmacokinetic parameters were obtained by non-compartmental analysis and values (+/- s.e.m.) obtained were as follows: Cmax 354.28 +/- 51.57 and 308.95 +/- 44.42 ng/ml, t(max) 2.26 +/- 0.22 and 2.63 +/- 0.24 h and AUC(8h) 701.01 +/- 109.34 and 774.13 +/- 132.84 ngh/ml for formulations A and B respectively. Log transformed Cmax and AUC(8h) were compared by analysis of variance and 90% confidence limits of the parameters ratios (B/A) were 72.73-106.34% and 90.32-124.96%, for Cmax and AUC(8h) respectively. As confidence intervals did not exceed the 70-142.9% limits for Cmax and 80-125% for AUC(8h), it is concluded that the formulations tested are bioequivalent.

Antinociceptive interaction between benfotiamine and resveratrol in capsaicin-induced licking.

In an attempt to provide more direct evidence concerning the possible antinociceptive effect of resveratrol-benfotiamine combination on neurogenic pain, we investigated whether resveratrol and benfotiamine administered alone or in combination decrease capsaicin induced nociception in mice. Before testing, the animals were placed individually in transparent glass cylinders, 20 cm in diameter, serving as observation chambers. After the adaptation period, 20 microL of capsaicin (1.6 microg/paw) were injected under the skin of the dorsal of the right hind paw. Animals were observed individually for 5 min after capsaicin injection. The amount of time spent licking the injected paw was timed with a chronometer and was considered as indicative of nociception. Animals were pretreated with resveratrol (56.2-177 mg/kg, i.p.), benfotiamine (100-1000 mg/kg, p.o.) and their combinations (11:1, 22:2, 44:4; 88:8 mg/kg benfotiamine:resveratrol). It was observed that resveratrol (ED50 = 104 +/- 8.2 mg/kg) was able to produce more important decrement of capsaicin-induced licking than benfotiamine (ED50 = 529.4 +/- 85.2 mg/kg). In addition, a synergistic interaction was observed between benfotiamine and resveratrol, suggesting that this combination could be useful in neurogenic nociception.

Synergistic antiallodynic interaction between gabapentin or carbamazepine and either benfotiamine or cyanocobalamin in neuropathic rats.

Anticonvulsants, including gabapentin and carbamazepine, have shown activity against several types of neuropathic pain; however, they have limiting side effects that may minimize their use. In this study the possible synergistic interaction between anticonvulsants and benfotiamine or cyanocobalamin on spinal nerve ligation-induced tactile allodynia was assessed. Oral administration of gabapentin (15-300 mg/kg), carbamazepine (10-300 mg/kg), benfotiamine (30-600 mg/kg) or cyanocobalamin (0.3-6.0 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with gabapentin 300 mg/kg (approximately 70%), carbamazepine 300 mg/kg (approximately 66%), benfotiamine 600 mg/kg (approximately 51%) and cyanocobalamin 6 mg/kg (approximately 59%). At the highest tested doses, gabapentin, but not carbamazepine, benfotiamine or cyanocobalamin, significantly reduced motor coordination. Coadministration of gabapentin or carbamazepine with benfotiamine or cyanocobalamin in a fixed ratio markedly reduced spinal nerve ligation-induced tactile allodynia, showing a synergistic interaction between anticonvulsants and B vitamins. Data indicate that combinations of anticonvulsants with benfotiamine or cyanocobalamin are able to reduce tactile allodynia without affecting motor coordination in rats, and suggest the possible clinical use of these combinations in the treatment of neuropathic pain in humans.

Pyritinol reduces nociception and oxidative stress in diabetic rats.

The purpose of this study was to assess the antinociceptive and antiallodynic effect of pyritinol as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral acute administration of pyritinol (50-200 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. Moreover, prolonged administration of pyritinol (12.5-50 mg/kg, every 2 days for 2 weeks) reduced formalin-induced nociception. 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, a guanylyl cyclase inhibitor, 2 mg/kg, i.p.), but not naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) or indomethacin (a non-selective cycloxygenase inhibitor, 5 mg/kg, i.p.), blocked the pyritinol-induced antinociception in diabetic rats. Given alone ODQ, naltrexone or indomethacin did not modify formalin-induced nociception in diabetic rats. Oral acute (200 mg/kg) or prolonged (25 mg/kg, every 2 days for 2 weeks) administration of pyritinol significantly reduced streptozotocin-induced changes in free carbonyls, dityrosine, malondialdehyde and advanced oxidative protein products. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of pyritinol (50-200 mg/kg) reduced tactile allodynia in diabetic rats. Results indicate that pyritinol is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that activation of guanylyl cyclase and the scavenger properties of pyritinol, but not improvement in glucose levels, play an important role in these effects.

A pilot study of the effect of diclofenac with B vitamins for the treatment of acute pain following lower-limb fracture and surgery.

The aim of this pilot study was to compare the efficacy and tolerability of the non-steroidal anti-inflammatory drug (NSAID), diclofenac (2-(2,6-dichloranilino) phenylacetic acid), for treatment of acute pain originated by lower-limb fracture and surgery, with that of diclofenac plus B vitamins. This clinical trial was single-center, prospective randomized and double-blinded. After giving informed consent, patients with lower-limb closed fractures rated their pain on a 10-cm visual analog scale (VAS). Patients were then randomized to receive 75 mg diclofenac or 75 mg diclofenac plus B vitamins (thiamine, pyridoxine and cyanocobalamin) twice daily (all intramuscularly). Patient evaluations of pain intensity were recorded throughout two periods: twenty-four hours pre-surgically and twenty-four hours postsurgical. Twenty-four hours after the first drug administration, patients underwent elective lower-limb surgery. Standardized general anesthetic techniques were used for all patients. Fourteen patients completed the study. The subjects' assessments of limb pain on the visual analog scale showed a significant reduction from baseline values regardless of the treatment group when surveyed at 12, 24, 36 and 48 hr post operation. All treatments showed a similar profile in pain reduction. There were reports of pain in the administration site, but in general, all the regimens were well tolerated.

Subcutaneous, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia in the rat.

The purpose of this study was to assess the possible antiallodynic effect of asimadoline ([N-methyl-N-[1S)-1-phenyl)-2-(13S))-3-hydroxypyrrolidine-1-yl)-ethyl]-2,2-diphenylacetamide HCl]) and ICI-20448 ([2-[3-(1-(3,4-Dichlorophenyl-N-methylacetamido)-2-pyrrolidinoethyl)-phenoxy]acetic acid HCl]), two peripheral selective kappa opioid receptor agonists, after subcutaneous, spinal and periaqueductal grey administration to neuropathic rats. Twelve days after spinal nerve ligation tactile allodynia was observed, along with an increase in kappa opioid receptor mRNA expression in dorsal root ganglion and dorsal horn spinal cord. A non-significant increase in periaqueductal grey was also seen. Subcutaneous (s.c.) administration of asimadoline and ICI-204448 (1-30 mg/kg) dose-dependently reduced tactile allodynia. This effect was partially blocked by s.c., but not intrathecal, naloxone. Moreover, intrathecal administration of asimadoline or ICI-204448 (1-30 mug) reduced tactile allodynia in a dose-dependent manner and this effect was completely blocked by intrathecal naloxone. Microinjection of both kappa opioid receptor agonists (3-30 mug) into periaqueductal grey also produced a naloxone-sensitive antiallodynic effect in rats. Our results indicate that systemic, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia. This effect may be a consequence of an increase in kappa opioid receptor mRNA expression in dorsal root ganglion, dorsal horn spinal cord and, to some extent, in periaqueductal grey. Finally, our data suggest that these drugs could be useful to treat neuropathic pain in human beings.

Bioequivalence of two oral formulations of glyburide (glibenclamide).

Glyburide (glibenclamide) is a sulfonylurea derivative that is very widely used in the treatment of type II diabetes mellitus. Currently, there are several pharmaceutical formulations available in Mexico containing this drug, however, very limited information about their bioavailabilities is known. The purpose of this study was to compare the bioavailability of two formulations of glyburide used in Mexico, Daonil and Gen-Glybe. Twenty-four Mexican healthy volunteers participated in this study that was carried out following the recommendations of the Declaration of Helsinki. Subjects received a dose of 10 mg of glyburide (two tablets of 5 mg) under fasting conditions in two separate sessions using a randomized crossover design with a one week washout period. Plasma samples were obtained at selected times over 24 hours and stored frozen until analyzed. Pharmacokinetic parameters were obtained and values (mean +/- S.E.M.) were as follows: Cmax 273.32 +/- 25.84 versus 294.83 +/- 27.12 ng/ml; tmax 3.03 +/- 0.23 versus 2.87 +/- 0.24 h; and AUC24h 1396.66 +/- 130.18 versus 1557.99 +/- 140.24 ng x h/ml, for Daonil and Gen-Glybe tablets, respectively. Pharmacokinetic parameters were compared using analysis of variance for a cross-over design and ratios of AUC24h and Cmax and 90% confidence intervals were obtained. As confidence intervals did not exceed the limits of acceptance (80--125%) for Cmax and AUC24h, it is concluded that the formulations tested are bioequivalent.

Comparison of antinociceptive efficacy and gastroprotection between celecoxib and diclofenac plus misoprostol in rats.

The present study was designed to assess the antinociceptive efficacy and gastroprotective activity of the mixture of diclofenac and misoprostol and its comparison with celecoxib in rats. The effect of diclofenac/misoprostol and celecoxib was assessed in the 1% formalin test. Female Wistar rats were fasted 12 hr before experiments and diclofenac (10 and 50 mg/kg), misoprostol (100 microg/kg), celecoxib (30 and 100 mg/kg), saline and the combination of diclofenac (50 mg/kg) plus misoprostol (25, 50 and 100 microg/kg) were administered orally. Nociceptive behavior was assessed during the following hr. Diclofenac and celecoxib dose-dependently reduced formalin-induced nociception reaching similar maximal effects. Moreover, misoprostol did not produce antinociception, but increased diclofenac-induced antinociception. Animals were sacrificed 3 hr following drug administration and stomachs examined to assess gastric damage. Misoprostol did not produce any damage to the stomach. However, diclofenac, but not celecoxib, produced significant gastric damage (number of stomach ulcers) in a dose-dependent fashion. Misoprostol dose-dependently reduced diclofenac-induced ulcers. Data show that diclofenac and celecoxib lead to similar antinociception, with diclofenac being more active to produce gastric damage. However, diclofenac-induced gastric damage can be markedly reduced by misoprostol. In addition to its gastroprotective effect, misoprostol showed a synergic effect on diclofenac-induced anti-nociception. Considering the cardiovascular effects of COX-2 selective inhibitors, the combination of diclofenac and misoprostol could represent a safer and effective alternative for patients with pain.

Comparative bioavailability of two oral suspensions of naproxen sodium.

The bioavailability of naproxen sodium (CAS 26159-34-2) after administration of two oral suspensions, reference or test (Pactens), was compared in 24 healthy subjects. The volunteers received an oral dose of 250 mg (10 ml) in two separate sessions under fasting conditions according to a randomized cross-over design and blood samples were obtained at selected times for a period of 72 h. Plasma samples were analyzed by a high-performance liquid chromatographic method for determination of naproxen. Individual plasma concentration against time curves were constructed and pharmacokinetic parameters were obtained by non-compartmental techniques. The parameters obtained (mean +/- S.E.M.) were: C(max) 43.93 +/- 1.83 and 44.91 +/- 2.15 microg/ml, t(max) 2.38 +/- 0.21 and 1.83 < or = 0.19 h, AUC(72 h) 721.73 +/- 18.47 and 722.55 +/- 19.07 microg x h/ml for reference and test formulations, respectively. Maximal concentration, AUC(72 h) and AUC(infinity). were log transformed and compared by analysis of variance and ratios; in addition, 90% confidence limits were obtained. As confidence limits were included in the 80-125% range and the probability of exceeding these intervals was always lower than 0.05, it is concluded that the formulations tested are bioequivalent.

Thiamine and cyanocobalamin relieve neuropathic pain in rats: synergy with dexamethasone.

Treatment of neuropathic pain is an area of largely unmet medical need. Therefore, this pain may require the development of novel drug entities. In the search for alternatives, B vitamins have been found to be a clinically useful pharmacological tool for patients with neuropathic pain. However, preclinical studies supporting this use are lacking. In this study, we assessed the possible antiallodynic effects of thiamine, pyridoxine, and cyanocobalamin as well as dexamethasone and their combination on spinal nerve ligation induced allodynia. Sub cutaneous administration of thiamine (75-600 mg/kg), pyridoxine (75-600 mg/kg), cyanocobalamin(0.75-6 mg/kg), and dexamethasone (4-32 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with 600 mg/kg of thiamine (approximately 58%), 600 mg/kg of pyridoxine (approximately 22%), 6 mg/kg of cyanocobalamin (approximately 73%), and 32 mg/kg of dexamethasone (approximately 68%). Since a small antiallodynic effect was observed with pyridoxine, this drug was not further analyzed in the combinations. Coadministration of thiamine or cyanocobalamin and dexamethasone remarkably reduced spinal nerve ligation induced allodynia (approximately 90%), showing a synergistic interaction between either thiamine or cyanocobalamin and dexamethasone. Our data indicate that thiamine and pyridoxine as well as the combination of B vitamins and dexamethasone are able to reduce tactile allodynia in rats and suggest the possible clinical use of these drugs in the treatment of neuropathic pain in human beings.

Comparative bioavailability of two oral formulations of ranitidine.

The current requirement of the Mexican Authorities to demonstrate the interchangeability of ranitidine formulations is to establish that the dissolution profile of the drug shows similarity. In order to establish if this requirement is adequate, the bioavailability of two formulations that did not meet this similarity were compared. Twenty-five female volunteers received 150 mg ranitidine (Azantac or Midaven) under fasting conditions in two separate sessions using a cross-over design. Plasma samples were obtained at selected times for a period of 12 h and stored frozen at -80 degrees C until analysed. Ranitidine plasma levels were determined and pharmacokinetic parameters were obtained. Values (mean+/-SEM) were: Cmax 528.85+/-25.34 and 563.03+/-33.25 ng/ml, tmax 2.76+/-0.19 and 2.79+/-0.18 h, and AUC12 h 2694.94+/-99.50 and 2648.51+/-133.38 ng.h/ml, for Azantac or Midaven, respectively. No statistically significant difference was obtained in the parameters evaluated. Moreover, 90% confidence limits were 96.6%-116.2% and 90.7%-105.1% for Cmax and AUC12 h ratios, respectively, indicating that the formulations tested are bioequivalent, despite the dissimilarity in the dissolution profile of the formulations. These results suggest that the comparative dissolution profile is not an adequate test to demonstrate the interchangeability of ranitidine formulations.

Benfotiamine relieves inflammatory and neuropathic pain in rats.

Benfotiamine has shown therapeutic efficacy in the treatment of painful diabetic neuropathy in human beings. However, so far there is no evidence about the efficacy of this drug in preclinical models of pain. The purpose of this study was to assess the possible antinociceptive and antiallodynic effect of benfotiamine in inflammatory and neuropathic pain models in the rat. Inflammatory pain was induced by injection of formalin in non-diabetic and diabetic (2 weeks) rats. Reduction of flinching behavior was considered as antinociception. Neuropathic pain was induced by either ligation of left L5/L6 spinal nerves or administration of streptozotocin (50 mg/kg, i.p.) in Wistar rats. Benfotiamine significantly reduced inflammatory (10-300 mg/kg) and neuropathic (75-300 mg/kg) nociception in non-diabetic and diabetic rats. Results indicate that oral administration of benfotiamine is able to reduce tactile allodynia from different origin in the rat and they suggest the use of this drug to reduce inflammatory and neuropathic pain in humans.

Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats.

The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5-50 microg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor, 1-50 microg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 microg), KT5823 (protein kinase G (PKG) inhibitor, 5-500 ng), charybdotoxin (large-conductance Ca2+-activated K+ channel blocker, 0.01-1 ng), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-3 ng) and glibenclamide (ATP-sensitive K+ channel blocker, 12.5-50 microg), but not N-D-nitro-arginine methyl ester (D-NAME, 50 microg) or saline, significantly diminished sildenafil (50 microg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not L-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO-cyclic GMP-PKG-K+ channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca2+-activated K+ channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain.

Further evidence for interethnic differences in the oral pharmacokinetics of meloxicam.

INTRODUCTION: Meloxicam is a nonsteroidal anti-inflammatory agent used widely in therapeutics. It is mainly metabolised by the cytochrome P450 enzyme (CYP) 2C9, with minor involvement of CYP3A4. So far, no information on the oral pharmacokinetics of this drug in adult Mexicans is available. The purpose of this study was to evaluate the oral pharmacokinetics of meloxicam in Mexican subjects. METHODS: Twenty-four healthy male subjects received an oral dose of meloxicam 7.5mg after fasting for 10 hours. Blood samples were drawn from a suitable forearm vein and plasma obtained. The meloxicam concentration was evaluated by a high-performance liquid chromatographic method and pharmacokinetic parameters were obtained by non-compartmental techniques. Pharmacokinetic parameters obtained in this study were compared with those reported under similar conditions in other populations in order to establish if interethnic differences in the pharmacokinetics of meloxicam exist. RESULTS: After administration of meloxicam, plasma levels increased to a maximum concentration (C(max)) of 0.702 +/- 0.027 (mean +/- SEM) microg/mL with a time to reach C(max) of 4.77 +/- 0.65h. The area under the plasma concentration versus time curve was 24.82 +/- 1.23 microg . h/mL. The clearance was about 4.8 mL/min and the volume of distribution 9.8 +/- 0.36L. When these parameters were compared with those reported in German and Indian subjects, a reduced clearance and volume of distribution were evident in Mexicans. However, clearance and volume of distribution obtained in this study were very similar to those reported in Chinese subjects. CONCLUSIONS: The oral pharmacokinetic parameters of meloxicam in healthy Mexican subjects compared with historic controls reported in other populations showed a reduced clearance and volume of distribution when compared with German subjects, whereas no differences between Mexican and Chinese subjects were observed. These results suggest that there are interethnic differences in the pharmacokinetics of meloxicam.

Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat.

Vitamin B2 (riboflavin) has been proposed as a prophylactic therapy of migraine. However, so far there are no preclinical studies about the analgesic properties of this vitamin. The current study was designed to investigate the possible antinociceptive, antihyperalgesic and antiallodynic effect of riboflavin in formalin, carrageenan-induced thermal hyperalgesia, and spinal nerve ligation models, respectively. Oral riboflavin produced a dose-related antinociceptive (6.25-50 mg/kg), antihyperalgesic (25-150 mg/kg) and anti-inflammatory (50-150 mg/kg) effect. Gabapentin (100 mg/kg, positive control), but not riboflavin (150-600 mg/kg), reduced tactile allodynia in neuropathic rats. Riboflavin-induced antinociception in the formalin test was reversed by pretreatment with NG-L-nitro-arginine methyl ester and glibenclamide, but not by NG-D-nitro-arginine methyl ester or naloxone. Our results indicate that riboflavin is able to produce antinociception and anti-inflammatory, but not antiallodynic, effect in the rat. The effect of riboflavin could be due to the activation of K+ channels or nitric oxide release, but not activation of opioid mechanisms.

Effect of K+ channel modulators on the antiallodynic effect of gabapentin.

The effect of K+ channel inhibitors on the antiallodynic activity induced by spinal gabapentin was assessed in rats. Ligation of L5 and L6 spinal nerves made the rats allodynic, whereas that intrathecal administration of gabapentin (25-200 microg) reduced tactile allodynia in a dose-dependent manner. Spinal pretreatment with glibenclamide (12.5-50 microg, ATP-sensitive K+ channel inhibitor), charybdotoxin (0.01-1 ng) or apamin (0.1-3 ng, large-and small-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (0.01-10 ng, voltage-dependent K+ channel inhibitor), significantly prevented gabapentin-induced antiallodynia. Pinacidil (1-30 microg, K+ channel opener) significantly reduced nerve ligation-induced allodynia. Intrathecal glibenclamide (50 microg), charybdotoxin (1 ng) and apamin (3 ng), but not margatoxin (10 ng), significantly reduced pinacidil-induced antiallodynia. K+ channel inhibitors alone did not modify allodynia produced by spinal nerve ligation. Results suggest that gabapentin and pinacidil may activate Ca2+-activated and ATP-sensitive K+ channels in order to produce part of its spinal antiallodynic effect in the Chung model.

Oral administration of B vitamins increases the antiallodynic effect of gabapentin in the rat.

The purpose of this study was to assess the possible synergistic interaction between gabapentin and B-vitamins (100:100:1 of vitamin B1, B6 and B12, respectively) in a neuropathic pain model in the rat. Neuropathic pain was induced by ligation of the left L5 and L6 spinal nerves of female Wistar rats. Tactile allodynia was determined by measuring paw withdrawal in response to probing with a series of calibrated von Frey filaments. Gabapentin (30-300 mg/kg), B-vitamins (75-600 mg/kg), or a combination of gabapentin and B-vitamins were administered orally and the antiallodynic effect was determined. Isobolographic analyses were used to define the nature of the functional interactions between gabapentin and B-vitamins in a fixed-dose ratio (0.5:0.5). Gabapentin (ED30 23.0+/-5.3 mg/kg), B-vitamins (ED30 524.0+/-97.0 mg/kg), or a fixed-dose ratio combination of gabapentin-B vitamins combinations dose-dependently reduced tactile allodynia. The theoretical ED30 value for the combination estimated from the isobologram was 273.5+/-48.6 mg/kg. This value was significantly higher than the experimental ED30 value which was 18.7+/-1.7 mg/kg. Results indicate that systemic administration of gabapentin and B vitamins can interact synergistically to reduce neuropathic pain in the rat and suggest the use of this combination to relieve neuropathy in humans.

Synergistic interaction between gabapentin and metamizol in the rat formalin test.

The purpose of this study was to assess the possible synergistic interaction between gabapentin and metamizol in the rat formalin test. Female Wistar rats were injected into the dorsal surface of the right hind paw with 50 microl of diluted formalin (1%). Formalin injection induced a typical flinching behavior indicating nociception. Reduction of the number of flinches was considered as antinociception. Gabapentin (10-300 mg/kg), metamizol (30-600 mg/kg), or the combination of gabapentin and metamizol were administered orally and the antinociceptive effect in the formalin test was determined. Isobolographic analyses were used to define the nature of the functional interaction between gabapentin and metamizol in a fixed-dose ratio (0.5:0.5). Gabapentin (ED30 18.3+/-7.9 mg/kg), metamizol (ED30 139.2+/-6.2 mg/kg) and fixed-dose ratio gabapentin-metamizol combinations dose-dependently reduced flinching behavior during second phase of the test. Theoretical ED30 value for the combination estimated from the isobologram was 78.8+/-5.5 mg/kg, whereas that experimental ED30 value was 15.0+/-1.2 mg/kg. Results indicate that oral administration of gabapentin and metamizol can interact synergistically to reduce inflammatory pain in the formalin test and suggest the use of this combination to relieve pain in humans.