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PubMed1997

Spinal gabapentin is antinociceptive in the rat formalin test.

Gabapentin is a novel anticonvulsant that may be of value for the relief of clinical pain. To determine whether gabapentin is antinociceptive after spinal administration, the drug was given via an intrathecal catheter in doses from 6 to 200 micrograms/rat 10 min prior to intraplantar formalin. Five percent formalin injected subcutaneously in the right hind paw produced a biphasic reaction consisting of flinching and licking behaviors (phase 1, 0-10 min; phase 2, 10-60 min). Gabapentin dose-dependently reduced the numbers of flinches and the duration of licking during phase 2 of the formalin test. The highest dose of gabapentin (200 micrograms/rat) did not affect the tail-flick response. These results demonstrate that spinal gabapentin is antinociceptive in the formalin test.

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PubMed1999

Gabapentin prevents hyperalgesia during the formalin test in diabetic rats.

The anticonvulsant agent gabapentin exhibits antihyperalgesic properties in animal models of neuropathic pain. Diabetic rats display increased nocifensive behavior during the formalin test of persistent chemical irritation to the paw, suggesting the presence of abnormal pain processing mechanisms. We therefore, investigated the efficacy of gabapentin on formalin-evoked behavior in diabetic rats. Diabetic rats showed increased (P < 0.05) flinching during the normally quiescent phase of the 5.0% formalin test. Gabapentin (50 mg/kg i.p. 30 min pre-test) suppressed flinching during phases 1 and 2 of the formalin test in both control and diabetic rats but not the increased flinching of diabetic rats during the quiescent phase. When 0.5% formalin was used, diabetic rats exhibited increased flinching during both the quiescent phase and phase 2. Gabapentin was without effect in controls but suppressed (P < 0.01) the increased flinching in diabetic rats. Gabapentin displays efficacy against abnormal sensory processing in diabetic rats and may be of benefit for treating painful diabetic neuropathy.

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PubMed2001

The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat.

We have examined the effects of a novel GABA(B) agonist, CGP35024, in models of chronic neuropathic (partial sciatic ligation) and inflammatory (Freund's complete adjuvant) pain in the rat, and its inhibitory action on spinal transmission in vitro. The effects of CGP35024 were compared with L-baclofen and gabapentin. CGP35024 and L-baclofen reversed neuropathic mechanical hyperalgesia following single subcutaneous or intrathecal administration, but did not affect inflammatory mechanical hyperalgesia. Gabapentin only moderately affected neuropathic hyperalgesia following a single administration by either route, but produced significant reversal following daily administration for 5 days. It was only weakly active against inflammatory hyperalgesia following single or repeated administration. The antihyperalgesic effects of L-baclofen and CGP35024, but not gabapentin, were blocked by the selective GABA(B) receptor antagonist CGP56433A. CGP35024 was seven times more potent against neuropathic hyperalgesia than in the rotarod test for motor co-ordination, whilst L-baclofen was approximately equipotent in the two tests. In the isolated hemisected spinal cord from the rat, CGP35024, L-baclofen and gabapentin all inhibited capsaicin-evoked ventral root potentials (VRPs). CGP35024 and L-baclofen, but not gabapentin, also inhibited the polysynaptic and monosynaptic phases of electrically-evoked VRPs, as well as the 'wind-up' response to repetitive stimulation. These data indicate that CGP35024 and L-baclofen modulate nociceptive transmission in the spinal cord to inhibit neuropathic hyperalgesia, and that CGP35024 has a therapeutic window for antihyperalgesia over spasmolysis.

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PubMed2001

Effect of gabapentin and lamotrigine on mechanical allodynia-like behaviour in a rat model of trigeminal neuropathic pain.

Injury to the trigeminal nervous system may induce severe pain states. This study examined the antinociceptive effect of the novel anticonvulsants, gabapentin and lamotrigine, in a rat model of trigeminal neuropathic pain produced by chronic constriction of one infraorbital nerve. Responsiveness to von Frey filament stimulation of the vibrissal pad was evaluated 2 weeks post-operation. Hyper-responsive rats received acute and repeated (five injections separated by the half-life of the compound) injections with gabapentin and lamotrigine. 76% of the nerve-injured rats displayed pronounced hyper-responsiveness (median 0.217 g (lower-upper percentiles 0.217-0.217) vs. 12.5 g pre-operative), that was resistant to both single (5-100 mg/kg) and repeated (5-30 mg/kg) injections with i.p. lamotrigine. Repeated (30 and 50 mg/kg), but not single (30-100 mg/kg) injections of i.p. gabapentin partially alleviated the mechanical allodynia-like behaviour. Repeated injections of gabapentin at 50 but not at 30 mg/kg produced motor deficits. The results indicate that gabapentin rather than lamotrigine may be a better therapeutic approach for the clinical management of some trigeminal neuropathic pain disorders.

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PubMed2001

Gabapentin inhibits the substance P-facilitated K(+)-evoked release of [(3)H]glutamate from rat caudial trigeminal nucleus slices.

The effect of gabapentin on the release of the spinal sensory neurotransmitter glutamate has been investigated in an in vitro model using a perfused thin slice preparation from the rat brainstem containing the spinal trigeminal caudal subnucleus (Sp5C) and pre-incubated with [(3)H]glutamate. Addition of excess K(+) to the perfusing solution increased the content of tritium in the perfusate. The prior addition of substance P increased this index of glutamate release in a concentration-dependent manner, with the mean maximum of around 50% increase obtained at 1-3 microM. The action of substance P to increase the evoked release of glutamate was blocked by the antagonist CP-99994, suggesting a specific involvement of the NK(1) receptor in mediating the facilitatory effect. On its own, gabapentin at up to 100 microM did not modify the baseline level of K(+)-evoked release of glutamate; however, gabapentin caused a concentration-dependent decrease of the facilitatory effect of substance P (EC(50)=6.49 microM). The R-(-)- and S-(+)-isomers of 3-isobutylgaba were then tested against the increase in K(+)-evoked release of glutamate by substance P. S-(+)-3-isobutylgaba (pregabalin) at 30 microM acted like gabapentin to reduce the substance P-mediated increase of release almost to the baseline level of K(+)-evoked release, while in contrast the R-(-)-isomer at this concentration produced no reduction, and rather a trend towards a further enhancement of the potentiating effect of substance P. In conclusion, we have found and characterized an effect of gabapentin that is of possible mechanistic relevance to the anti-hyperalgesic/allodynic actions of this compound.

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PubMed1999

Automated microanalysis of gabapentin in human serum by high-performance liquid chromatography with fluorometric detection.

An automated high-performance liquid chromatographic method for the determination of gabapentin, 1-(amino-methyl)cyclohexaneacetic acid, in serum is described. The procedure involves protein precipitation with methanol followed by using a robotized derivatization with o-phthaldialdehyde reagent and automated high-performance liquid chromatography. The analog of gabapentin, 1-(aminomethyl)cycloheptaneacetic acid, was used as the internal standard. Blank serum was fortified with gabapentin (0.1-10.0 microg/ml) and internal standard. Separation was achieved on a Waters 5-microm reversed-phase column (10 cmx4.6 mm) with mobile phase consisting of 0.02 M phosphate buffer (pH 4.5)-acetonitrile (50:50, v/v). Eluents were monitored by fluorescence spectroscopy with excitation and emission wavelengths of 230 and 420 nm, respectively. The calibration curve for gabapentin in serum was linear (r=0.999) over the concentration range 0.1-10.0 microg/ml. The inter- and intraassay variations for three different gabapentin concentrations were < or =10% throughout. The lower limit of quantitation was found to be 0.1 microg/ml. Chromatography was unaffected by a range of commonly employed antiepileptic drugs or selected amino acids.

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PubMed2004

Sample preparation and determination of gabapentin in venous and capillary blood using liquid chromatography-tandem mass spectrometry.

An analytical method for the determination of gabapentin in serum obtained from venous blood samples has been developed using high-performance liquid chromatography (HPLC)-tandem mass spectrometry. In addition, a comparative study between capillary plasma samples and venous serum samples was carried out. This demonstrates the potential for the use of the described analytical system using very small amounts of blood. As internal standard (S)-(+)-alpha-amino-cyclohexane-propionic acid hydrate was used. Gabapentin and the internal standard are structural isomers, but have different m/z values for the fragments after collision induced dissolution. Gabapentin has 172-->154 and 172-->136 transitions and amino-cyclohexane-propionic acid hydrate has a 172-->126 transition which can be detected in tandem MS. Analysis of gabapentin was carried out on a C8 HPLC column using an isocratic mobile phase consisting of ammonium acetate (pH 3.0; 5mM)-methanol (96:4, v/v). The analytical method was validated for venous serum samples. Limit of detection was 1.6ng/ml and lower limit of quantification was 7.5ng/ml. R.S.D. values and bias values were within the range of acceptance for all concentration levels. The method developed for venous serum samples is being used in a gabapentin monitoring study using population pharmacokinetic modeling.

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PubMed2000

The effects of gabapentin in the rat hippocampus are mimicked by two structural analogs, but not by nimodipine.

Gabapentin has been shown to reduce paired-pulse inhibition in the dentate gyrus of the urethane-anesthetized rat and has been shown to block calcium channels, but its not known how these possible mechanisms relate to its antiepileptic effect. Here, we tested two structural analogs of gabapentin for the ability to reduce seizure duration and to alter paired-pulse inhibition in the dentate gyrus in urethane anesthetized adult Sprague-Dawley rats. We compared with our results to those with diazepam, an anxiolytic and GABA(A) positive modulator and with nimodipine, a specific blocker of L-type Ca2+ channels. Both structural analogs of gabapentin caused a dose-dependent loss of paired-pulse inhibition and blocked the lengthening of the duration of the seizure discharge. Nimodipine also blocked the increase in duration of the seizure discharge, but increased paired-pulse inhibition. The effects of the GABA derivatives on paired-pulse inhibition and on seizure duration may have a common mechanism. Furthermore, our results indicate that gabapentin's postulated block of L-type calcium channels is not responsible for reducing paired-pulse inhibition. However, calcium channel block could still be the basis for the antiepileptic effect of gabapentin and its analogs.

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PubMed2002

Gabapentin and vigabatrin increase GABA in the human neocortical slice.

The effects of antiepileptic drugs, gabapentin and vigabatrin, on gamma-aminobutyric acid (GABA) concentrations were studied in human (n=14) and rat (n=6) neocortical slice preparations. In this study, neocortical slices were incubated with gabapentin, vigabatrin or no drugs for 3 h in an oxygenated environment. Proton magnetic resonance spectroscopy (MRS) of perchloric acid (PCA) extracts was used to measure GABA concentrations. Vigabatrin increased cellular GABA concentrations in both human and rat neocortical slices by 62% (P<0.001) and 88% (P<0.03), respectively. Gabapentin significantly increased GABA concentrations by 13% (P<0.02) in human neocortical slices made from tissue resected during epilepsy surgery. However, in the rat neocortical slice exposed to the same conditions as the human tissue, gabapentin did not increase GABA significantly. These results confirm our MRS studies in vivo that gabapentin increases GABA levels in epileptic patients, but has minimal or no effect in a healthy rodent model. Caution must be used in extrapolating negative results obtained in rodent models to the human condition.

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PubMed1997

Comparison of the preclinical anticonvulsant profiles of tiagabine, lamotrigine, gabapentin and vigabatrin.

Tiagabine is a novel antiepileptic drug which has clinical efficacy against complex refractory and myoclonic seizures. The anticonvulsant mechanism of action of tiagabine results from its blockade of neuronal and glial GABA-uptake, thereby increasing GABA levels in the synaptic cleft. Here we present a comparison of the preclinical anticonvulsant profile of tiagabine with that of lamotrigine, gabapentin and vigabatrin in the following tests (all antiepileptic drugs were administered i.p.): seizures induced by pentylentetrazol (PTZ), 6,7-dimethoxy-4-ethyl-b-carboline-3-carboxylate (DMCM) and maximal electroshock (MES); sound induced seizures in DBA/2 mice and finally acute amygdala kindled seizures. Tiagabine was the most potent drug in antagonizing tonic convulsions induced by PTZ, DMCM and sound induced seizures in DBA/2 mice with ED50 values of 2, 2 and 1 mumol/kg, respectively, followed by lamotrigine with ED50 values of 9, 43 and 6 mumol/kg, respectively. Gabapentin and vigabatrin had ED50 values in the same tests of 185, 452, 66 mumol/kg and 2322, > 7740, 3883 mumol/kg, respectively. Tiagabine was the only drug capable of blocking PTZ-induced clonic convulsions (ED50 = 5 mumol/kg), an effect seen at low but not high doses of tiagabine. Lamotrigine was the only drug which antagonized tonic convulsions in the MES test (ED50 = 36 mumol/kg). Therapeutic index (TI) of antiepileptic drugs in NMRI- and DBA/2-mice ranked with decreasing TI lamotrigine > gabapentin > vigabatrin > tiagabine. All drugs reduced the generalized seizures in amygdala kindled rats, but tiagabine and gabapentin furthermore attenuated afterdischarge duration of amygdala kindled seizures. However, an ED50 value against amygdala kindled focal seizures was only obtained for tiagabine (36 mumol/kg). The data here presented show that tiagabine, lamotrigine, gabapentin and vigabatrin possess different preclinical anticonvulsant profiles which is of relevance to the clinical anticonvulsant profiles of the drugs.

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PubMed2000

Adjunctive gabapentin treatment of bipolar disorder.

INTRODUCTION: The aim of this study was to analyze the effectiveness of gabapentin administration to bipolar patients who had an incomplete response to other mood stabilizers. SUBJECTS AND METHODS: Twenty-two RDC bipolar 1 and II patients were assessed by means of the SADS and entered if they gave their consent to participate. All them had suffered from frequent relapses, subsyndromal features (mostly depressive) and incomplete response to other drugs. They all received open-label increasing doses of gabapentin until clinical response. The patients were assessed through the CGI-BP and a specific questionnaire at baseline and at 12 weeks of follow-up. RESULTS: Six out of the 22 patients dropped out for various reasons (four because of relapse, one because of side effects and one more because of poor compliance). Eight of the 16 patients that completed the 12-week follow-up showed at least two stages of improvement in the CGI. Using the last observation-carried forward analysis, the improvement was statistically significant for the depression subscale, and apparently related to social functioning, irritability and anxiety. Only one patient dropped out because of intolerance (mild rash). The mean dose of gabapentin was 1,310 mg/day. CONCLUSION: Gabapentin may be a useful drug for the add-on treatment of bipolar patients with poor response to other mood stabilizers. Gabapentin may improve depressive residual symptoms such as irritability, social withdrawal or anxiety. These results should be confirmed in randomized clinical trials.

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PubMed2003

Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations.

The effects of antiepileptic drugs, gabapentin, pregabalin and vigabatrin, on brain gamma-aminobutyric acid (GABA), glutamate and glutamine concentrations were studied in Long Evans rats using proton magnetic resonance spectroscopy (MRS) of perchloric acid extracts. Cellular glutamate concentrations significantly decreased by 7% (P<0.05) 2 hours after intraperitoneal injection of 100mg/kg gabapentin and 4% (P<0.05) with 1000 mg/kg. No differences were observed in cellular GABA and cellular glutamine concentrations in rats treated with gabapentin. Pregabalin, an analogue of gabapentin, significantly decreased cellular glutamate concentrations by 4% (P<0.05), while no effect was observed on cellular GABA or glutamine concentrations in the healthy rat forebrain. Vigabatrin, used as a positive control to increase GABA levels, produced a 50% increase in cellular GABA compared to saline treated rats (P<0.003). Although, gabapentin and pregabalin are anticonvulsants designed to mimic GABA, these drugs do not raise cellular GABA levels acutely but modestly decreased cellular glutamate levels in our healthy rat forebrain model.

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PubMed1998

Effects of gabapentin on cognition and quality of life in patients with epilepsy.

The effect of gabapentin on cognition and quality of life (QoL) in patients with epilepsy was investigated using a controlled pre- and post-treatment design. Thirty patients with chronic epilepsy were administered a battery of cognitive tests and QoL measures at baseline (pre-treatment) and again following 1-2 months of treatment (post-treatment). All patients were receiving anticonvulsant medication at baseline. Following baseline assessment, 15 patients were started on gabapentin as add-on therapy (gabapentin group), and 15 patients remained on stable medication (control group). No between-group treatment effects were demonstrated on any of the mood measures. A significant between-group treatment effect was demonstrated on one cognitive measure, in favour of the gabapentin group. Results do not suggest any adverse short-term effects of gabapentin on cognition or QoL in patients with chronic epilepsy.

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PubMedDate not supplied

Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat.

BACKGROUND AND OBJECTIVES: Spinal gamma-aminobutyric acid (GABA) receptors have been shown to modulate post-nerve injury-induced allodynia. This study sought to examine the antiallodynic effects of a GABA analog gabapentin [1-(aminomethyl)cyclohexaneacetic acid], given by subarachnoid injection in a rat neuropathic pain model. METHODS: The rats were prepared with lumbar subarachnoid catheters, and allodynia was induced in rats by ligation of the L5-6 nerve roots (Chung model). RESULTS: Spinal injection of gabapentin resulted in a dose-dependent (10-1,000 microg) antagonism of the allodynia at doses that had no detectable effect on motor function. Subarachnoid injection of either the GABA A antagonist bicuculline (0.3 microg), or the GABA B antagonist CGP 35348 (30 microg) 5 minutes before or 60 minutes after injection of GABA receptor agonist did not reverse the antiallodynic effects produced by gabapentin. CONCLUSIONS: Gabapentin shows antiallodynic effect, but its mechanism is not known. The failure to reverse this effect by GABA A or B antagonists at doses that reverse the effects of the respective agonists suggests that gabapentin is involved in the modulation of spinal systems by mechanisms that do not involve either a GABA A or a GABA B site.

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PubMed2001

Mucosal uptake of gabapentin (neurontin) vs. pregabalin in the small intestine.

PURPOSE: To compare the mucosal membrane transport of gabapentin and pregabalin in animal small intestine. METHODS: Uptake of the two drugs by brush-border membrane vesicles (BBMV) from rat and rabbit small intestine was studied as a function of temperature, uptake-medium sodium content, and intestinal region. Amino acid inhibition studies were conducted with pregabalin. RESULTS: Gabapentin uptake by rat and rabbit jejunal BBMV was sodium independent, whereas pregabalin uptake was sodium dependent. Uptake of both drugs in rabbit small intestinal vesicles was greater at 25 degrees C than at 4 degrees C in the absence of sodium and an additional increase in uptake was observed for pregabalin at 25 degrees C in the presence of sodium. Pregabalin uptake in rabbit duodenal, jejunal, and ileal BBMV was equivalent, whereas gabapentin uptake was greater in duodenal and ileal BBMV, compared with jejunal BBMV. Although inhibition is weak, a decrease in BBMV uptake of pregabalin is observed with coincubation of high concentrations of both neutral and basic amino acids. CONCLUSIONS: Amino acid carriers mediate the apical uptake of both drugs in the small intestine. Although gabapentin and pregabalin are structurally similar, their small intestinal mucosal uptake differs in sodium dependence and region dependence. Gabapentin uptake is likely mediated by system b0,+, whereas pregabalin uptake is also mediated by B0 and/or B0,+.

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PubMed1997

A pilot trial of adjunctive gabapentin in the treatment of bipolar disorder.

Several antiepileptic drugs (AEDs) have documented efficacy in the manic phase of bipolar disorder. To investigate the efficacy, tolerability, and safety of the new AED, gabapentin, in mania, we treated nine consecutive outpatients with bipolar I or II disorder by DSM-IV criteria who were experiencing hypomanic, manic, or mixed states inadequately responsive to standard mood stabilizers with open-label, adjunctive gabapentin. Response of manic symptoms was assessed monthly as none, minimal, moderate, or marked. Of the nine patients, seven displayed a moderate or marked reduction in manic symptoms by 1 month after addition of gabapentin, and an additional patient displayed moderate improvement after 3 months. Of these eight patients, six displayed continued antimanic responses for follow-up periods ranging from 1 to 7 months. Side effects were most commonly neurological, mild, and transient. Adjunctive gabapentin may have antimanic and mood-stabilizing effects in some patients with bipolar disorder and is generally well tolerated. Controlled studies of gabapentin in bipolar disorder appear to be warranted.

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PubMed1999

Gabapentin in the acute treatment of refractory bipolar disorder.

BACKGROUND: Gabapentin, a new anti-epileptic agent, has been anecdotally reported to be effective in the treatment of mania. We systematically assessed the response rate in bipolar patients being treated adjunctively with gabapentin for manic symptoms, depressive symptoms, or rapid cycling not responsive to standard treatments. METHOD: Twenty-eight bipolar patients experiencing manic (n = 18), depressive (n = 5), or rapid-cycling (n = 5) symptoms inadequately responsive to at least one mood stabilizer were treated in an open fashion with adjunctive gabapentin. Illness response was assessed using the Clinical Global Impression Scale modified for bipolar disorder (CGI-BP). A 'positive response' was operationalized as a CGI response of much or very much improved. RESULTS: Fourteen of the 18 (78%) treated for hypomania or mania had a positive response to a dosage range of 600-3,600 mg/day. Patients with hypomania responded fastest, with a positive response achieved in 12.7 +/- 7.2 days. Patients with classic mania had a mean time to positive response of 25 +/- 12 days, and in patients with mixed mania it was 31.8 +/- 20.9 days. All of the five patients treated for depression had a positive response within 21 +/- 13.9 days. Only one of five patients with rapid cycling had a positive response. Gabapentin was well tolerated by all patients, with the most common side-effect being sedation. CONCLUSIONS: Gabapentin appears to have acute anti-manic and anti-depressant properties as an adjunctive agent for refractory bipolar illness. Prospective double-blind studies are needed to further delineate its acute efficacy when used as monotherapy and its prophylactic efficacy as monotherapy or in conjuction with other mood stabilizers.

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PubMed1997

Gabapentin for the treatment of spasticity in patients with spinal cord injury.

Our serendipitous observations suggested that some patients with spasticity appeared to have improved following the administration of the anticonvulsant drug gabapentin. As some patients with spasticity are either refractory to or intolerant of established medical treatments, we conducted this study to investigate the effect of gabapentin on spasticity in patients with spinal cord injury. Twenty-five patients with spinal cord injury and spasticity received oral gabapentin (2400 mg over 48 h) in a randomized, double blind, placebo-controlled crossover study. We assessed responses by measuring the Ashworth spasticity scale, muscle stretch reflexes, presence of clonus and reflex response to noxious stimuli. Patient ratings were obtained using a Likert Scale. Administration of gabapentin, but not placebo, was associated with an 11% reduction in spasticity as measured by the Ashworth Scale (P = 0.04) and by a 20% reduction in the Likert Scale (P = 0.0013). Significant changes were not obtained for the other measures. The data obtained suggest that gabapentin may be useful in the management of spasticity associated with spinal cord injury.

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