Cognitive side effects of anticonvulsants.
Anticonvulsant efficacy of gabapentin on kindling in the immature brain.
Oxcarbazepine in focal epilepsy and hepatic porphyria: a case report.
Comparative cognitive effects of carbamazepine and gabapentin in healthy senior adults.
Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: How valid is the GABAergic hypothesis?
Gabapentin actions on N-methyl-D-aspartate receptor channels are protein kinase C-dependent.
The anticonvulsant, antihyperalgesic agent gabapentin is an agonist at brain gamma-aminobutyric acid type B receptors negatively coupled to voltage-dependent calcium channels.
Behavioral effects of agents active at the gamma-aminobutyric acid receptor complex in the staircase paradigm.
Single-dose gabapentin pharmacokinetics and safety in healthy infants and children.
Gabapentin treatment of the non-refractory bipolar spectrum: an open case series.
Gabapentin and gabapentin monohydrate.
Using gabapentin to treat failed back surgery syndrome caused by epidural fibrosis
Antiepileptic drugs and neuropathic pain.
The effect of gabapentin and gabapentin-lactam on retinal ganglion cell survival.
Calcium channel alpha(2)delta subunits-structure and Gabapentin binding.
Differential effect of gabapentin on neuronal and muscle calcium currents.
Gabapentin for treatment of behavioral and psychological symptoms of dementia.
Adjunctive gabapentin in patients with intellectual disability and bipolar spectrum disorders.
Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis.
Gabapentin quantification in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study.
Effects of antimanic mood-stabilizing drugs on fetuses, neonates, and nursing infants.
Rapid initiation of gabapentin: a randomized, controlled trial.
Oral gabapentin (neurontin) treatment of refractory genitourinary tract pain.
Determination of the antiepileptics vigabatrin and gabapentin in dosage forms and biological fluids using Hantzsch reaction.
Progressive encephalomyelitis with rigidity.Clinical and electrophysiological aspects.
Gabapentin therapy for pain.
Efficacy of gabapentin in migraine prophylaxis.
The effects of gabapentin on different ligand- and voltage-gated currents in isolated cortical neurons.
Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review.
Function of leucine in excitatory neurotransmitter metabolism in the central nervous system.
Gabapentin in the treatment of cocaine dependence: a case series.
Gabapentin for the treatment of tinnitus: a case report.
Pharmacotherapy of spasticity: oral medications and intrathecal baclofen.
Gabapentin in phantom limb pain management in children and young adults: report of seven cases.
Gabapentin--yet another antiepileptic agent for the treatment of neuropathic pain?
Benzodiazepines and anticonvulsants for social phobia (social anxiety disorder).
The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat.
Gabapentin antinociception in mice with acute herpetic pain induced by herpes simplex virus infection.
Gamma-aminobutyric acid type B receptors with specific heterodimer composition and postsynaptic actions in hippocampal neurons are targets of anticonvulsant gabapentin action.

J Clin Psychiatry 2001;62 Suppl 14:27-33
Cognitive side effects of anticonvulsants.
Goldberg JF, Burdick KE. Weill Medical College of Cornell University and the Bipolar Disorders Research Clinic, Payne Whitney Clinic-New York Presbyterian Hospital, New York, USA. JFGoldbe@mail.med.cornell.edu
The increasing use of anticonvulsant drugs in psychiatry has prompted greater awareness of their effects on a range of psychiatric domains, including cognition. Older versus newer antiepileptic drugs have been reported to either worsen or enhance cognitive performance in clinical populations, and the extent to which cognitive disturbances may reflect iatrogenic factors versus psychopathology is subject to debate. We review current information about the role of anticonvulsants in cognition, with particular emphasis on newer compounds (such as lamotrigine, gabapentin, and topiramate), the cognitive dimensions of affective illness, and the clinical approach to evaluating cognition in psychiatric patients taking anticonvulsant drugs over time.
Publication Types:

Review

Review, tutorial

PMID: 11469672

Epilepsia 2001 Apr;42(4):458-63
Anticonvulsant efficacy of gabapentin on kindling in the immature brain.
Lado FA, Sperber EF, Moshe SL. Department of Neurology, Albert Einstein College of Medicine, Montefiore Medical Center Epilepsy Management Center, Bronx, NY 10461, USA. ladof@ix.netcom.com
The anticonvulsant and motor effects of gabapentin (GBP) were evaluated in rat pups aged 16-17 days. Fourteen-day-old rat pups received an implanted stimulating electrode in the amygdala unilaterally. Kindled seizures were produced on day 16 of life by repeatedly applying an electrical current stimulus to the amygdala electrode. Animals received kindling stimulation until they achieved three consecutive generalized convulsions. On day 17, rat pups received one of four doses of GBP 10, 25, 50, or 100 mg/kg. After receiving GBP, rat pups again received electrical stimulation to the amygdala electrode to determine the extent to which GBP prevented the kindled seizure. Anticonvulsant effects were found at doses as low as 10 mg/kg. A separate group of naive rats received GBP to determine the motor effects of each treatment dose. Impaired motor performance, quantified as time on a balance beam, occurred at doses of >or=50 mg/kg. In summary, our data indicate that in immature rats, GBP exerts an anticonvulsant effect against kindled seizures at doses that do not significantly impair motor performance.
PMID: 11440340

Epilepsia 2001 Jun;42(6):793-5
Oxcarbazepine in focal epilepsy and hepatic porphyria: a case report.
Gaida-Hommernick B, Rieck K, Runge U. Department of Neurology, Ernst-Moritz-Arndt-University, Ellernholzstrasse 1-2, 17487 Greifswald, Germany.
PURPOSE: Despite the development of new antiepileptic agents (AEDs), the therapy of epilepsies along with hepatic porphyrias remains difficult. Most AEDs such as carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) may precipitate clinically latent porphyria by inducing hepatic metabolism and increasing hepatic heme synthesis. Actually, only gabapentin (GBP), an AED without any hepatic metabolism, is known as a potential therapy for partial seizures in patients having hepatic forms of porphyria. METHODS: We present the case of a 28-year-old man with porphyria cutanea tarda (PCT) who has had pharmacoresistant epilepsy with complex partial and secondarily generalized seizures since early childhood. Despite having undergone several AED therapies over the years, no seizure-free interval had been observed. Only CBZ could cause a seizure reduction, but this treatment had to be discontinued as an elevation of the transaminases as well as pruritus and erythema were noted. The patient was then started on oxcarbazepine (OCBZ), a ketoanalogue of CBZ similar in its pharmacologic mechanism as well as its clinical use, but which, in contrast to CBZ, has only a low hepatic induction of microsomal enzymes. A final maintenance dose four times higher than that of CBZ was prescribed. RESULTS: In the follow-up, the patient stopped having seizures, and his liver functions became normal. CONCLUSIONS: It can be concluded that OCBZ can successfully be administered to patients with hepatic porphyria and focal epilepsy who did not respond to treatment with GBP.
PMID: 11422339

Epilepsia 2001 Jun;42(6):764-71
Comparative cognitive effects of carbamazepine and gabapentin in healthy senior adults.
Martin R, Meador K, Turrentine L, Faught E, Sinclair K, Kuzniecky R, Gilliam F. Department of Neurology, UAB Epilepsy Center, University of Alabama at Birmingham, 1719 6th Avenue South, Birmingham, AL 35294-0021, U.S.A.
PURPOSE: This study compared the cognitive effects of carbamazepine (CBZ) and gabapentin (GBP) in healthy senior adults by using a randomized, double-blind crossover design. METHODS: Thirty-four senior adults were randomized to receive one of the two drugs followed by a 5-week treatment period. A 4-week washout phase preceded initiation of the second drug. Antiepileptic drugs (AEDs) were titrated to target doses of either CBZ (800 mg/day) or GBP (2,400 mg/day). Primary outcome measures were standardized neuropsychological tests of attention/vigilance, psychomotor speed, motor speed, verbal and visual memory, and the Profile of Mood State (POMS), yielding a total of 17 variables. Each subject received cognitive testing at predrug baseline, end of first drug phase, end of second drug phase, and 4 weeks after completion of the second drug phase. RESULTS: Fifteen senior adults (mean age, 66.5 years; range, 59-76 years) completed the study. Seniors completing the study did not differ significantly from noncompleting seniors in terms of demographic features or baseline cognitive performances. Fifteen of the 19 seniors not completing the study dropped out while receiving CBZ. Adverse events were frequently reported for both AEDs, although they were more common for CBZ. Mean serum levels for the completers were within midrange clinical doses (CBZ, 6.8 microg/ml; GBP, 7.1 microg/ml). Significant differences between CBZ and GBP were found for only one of 11 cognitive variables, with better attention/vigilance for GBP, although the effect was modest. Performances on the nondrug average were significantly better on 45% of cognitive variables compared with CBZ and 36% compared with GBP. The overall pattern of means favored GBP over CBZ on 15 of 17 (p < 0.001), nondrug over CBZ on 17 of 17 (p < 0.0000), and nondrug over GBP on eight of 17 (NS). CONCLUSIONS: Mild cognitive effects were found for both AEDs compared with the nondrug average condition. The magnitude of difference between the two AEDs across the cognitive variables was modest. Self-reported mood was not significantly affected by either AED. However, overall tolerability and side-effect profile of CBZ were poorer than those of GBP in senior adults at doses and titration rates reported in this study.
Publication Types:

Clinical trial

Randomized controlled trial

PMID: 11422333

J Neurol Neurosurg Psychiatry 2001 Jul;71(1):107-10
Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: How valid is the GABAergic hypothesis?
Bandini F, Castello E, Mazzella L, Mancardi GL, Solaro C. Department of Neurological Sciences and Vision, University of Genoa, via De Toni 5, 16132 Genoa, Italy. fbandini@neurologia.unige.it
Acquired nystagmus occurs frequently in patients with multiple sclerosis and is often the cause of illusory motion of the environment (oscillopsia), and blurring of vision. Based primarily on the beneficial effect of gabapentin on acquired pendular nystagmus (APN), a GABAergic mechanism in controlling nystagmus has been hypothesised. If increasing GABA concentrations in the CNS are critical for the treatment of nystagmus, then a selective GABAergic drug should be highly successful. However, as gabapentin is not a selective GABAergic agent, vigabatrin, a "pure" GABAergic medication, and gabapentin, were compared in a single blind cross over trial in eight patients with definite multiple sclerosis.Patients were randomly assigned to begin with gabapentin (1200 mg daily) or vigabatrin (2000 mg daily). Neuro-ophthalmological and electro-oculographic (EOG) evaluations were performed four and three times, respectively. Treatment efficacy was based on improving visual acuity and EOG indices (amplitude or frequency of nystagmus, or both) by at least 50% of pretreatment values. Three out of eight patients dropped out due to adverse effects.In the remaining five patients gabapentin improved symptomatic pendular or gaze evoked jerk nystagmus in four. Three patients decided to continue gabapentin therapy. Importantly, vigabatrin proved useful in only one out of five patients, suggesting that gabapentin effectiveness may be related to additional non-GABAergic mechanisms of action. Interaction with cerebral glutamate transmission by inhibition of NMDA receptor might be an alternative hypothesis for the therapeutic action of gabapentin.
PMID: 11413274

Pain 2001 Jul;93(1):85-92
Gabapentin actions on N-methyl-D-aspartate receptor channels are protein kinase C-dependent.
Gu Y, Huang LM. Marine Biomedical Institute, University of Texas Medical Branch, 77555-1069, Galveston, TX, USA
Gabapentin (Neurontin((R))) (GBP) is a widely prescribed analgesic used in treating pain patients with peripheral nerve injuries, diabetic neuropathy and cancer. To understand the mechanism of its action, we used the whole-cell patch recording technique to study the effects of GBP on N-methyl-D-aspartate (NMDA)-evoked currents in single dorsal horn neurons isolated from normal rats and from rats with inflammation induced by the injection of complete Freund adjuvant (CFA) to the hindpaw. We found that GBP enhanced NMDA currents in normal neurons only when protein kinase C (PKC) was added to these cells. The enhancement resulted from an increase in the affinity of glycine for NMDA receptors by GBP. In contrast, in neurons isolated from CFA-treated rats, GBP enhanced NMDA responses without any PKC treatment. Since endogenous PKC in inflamed tissue is elevated, these results suggest that GBP exerts its effects only on those cells affected by inflammatory injuries. Thus, the effects of GBP on NMDA receptors are plastic; they depend on the phosphorylation states of cells or receptors. These observations point to a new strategy for drug design. A chemical whose action depends on the state of cells would maximize its effectiveness while keeping its side-effects to a minimum.
PMID: 11406342

J Pharmacol Exp Ther 2001 Jul;298(1):15-24
The anticonvulsant, antihyperalgesic agent gabapentin is an agonist at brain gamma-aminobutyric acid type B receptors negatively coupled to voltage-dependent calcium channels.
Bertrand S, Ng GY, Purisai MG, Wolfe SE, Severidt MW, Nouel D, Robitaille R, Low MJ, O'Neill GP, Metters K, Lacaille JC, Chronwall BM, Morris SJ. Centre de Recherche en Sciences Neurologiques et Departement de Physiologie, Universite de Montreal, Montreal, Province of Quebec, Canada.
Gabapentin (Neurontin, Pfizer Global R & D) is a novel anticonvulsant, antihyperalgesic, and antinociceptive agent with a poorly understood mechanism of action. In this study, we show that gabapentin (EC50 2 microM) inhibited up to 70 to 80% of the total K+-evoked Ca2+ influx via voltage-dependent calcium channels (VD-CCs) in a mouse pituitary intermediate melanotrope clonal mIL-tsA58 (mIL) cell line. mIL cells endogenously express only gamma-aminobutyric acid type B (GABA(B)) gb1a-gb2 receptors. Moreover, activity of the agonist gabapentin was dose dependently and completely blocked with the GABA(B) antagonist CGP55845 and was nearly identical to the prototypic GABA(B) agonist baclofen in both extent and potency. Antisense knockdown of gb1a also completely blocked gabapentin activity, while gb1b antisense and control oligonucleotides had no effect, indicating that gabapentin inhibition of membrane Ca2+ mobilization in mIL cells was dependent on a functional GABA(B) (gb1a-gb2) heterodimer receptor. In addition, during combined whole cell recording and multiphoton Ca2+ imaging in hippocampal neurons in situ, gabapentin significantly inhibited in a dose-dependent manner subthreshold soma depolarizations and Ca2+ responses evoked by somatic current injection. Furthermore, gabapentin almost completely blocked Ca2+ action potentials and Ca2+ responses elicited by suprathreshold current injection. However, larger current injection overcame this inhibition of Ca2+ action potentials suggesting that gabapentin did not predominantly affect L-type Ca2+ channels. The depressant effect of gabapentin on Ca2+ responses was coupled to the activation of neuronal GABA(B) receptors since they were blocked by CGP55845, and baclofen produced similar effects. Thus gabapentin activation of neuronal GABA(B) gb1a-gb2 receptors negatively coupled to VD-CCs can be a potentially important therapeutic mechanism of action of gabapentin that may be linked to inhibition of neurotransmitter release in some systems.
PMID: 11408520

Brain Res 2001 May 18;901(1-2):137-42
Behavioral effects of agents active at the gamma-aminobutyric acid receptor complex in the staircase paradigm.
Weizman R, Paz L, Peter Y, Toren P, Pick CG. Tel Aviv Community Mental Health Center, Tel Aviv, Israel.
This study examined the behavioral effects of agents active at the gamma-aminobutyric acid (GABA(A)) receptor complex in the mouse staircase paradigm. The neuroactivesteroids dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were compared with the benzodiazepine agonist clonazepam, the non-benzodiazepine hypnotic compound zopiclone, and the antiepileptic agent gabapentin. Clonazepam, zopiclone and gabapentin reduced rearing activity at doses that did not affect climbing. The rearing-suppression effect of clonazepam and zopiclone, but not of gabapentin, was blocked by the benzodiazepine antagonist flumazenil, suggesting that the added effect of gabapentin is not mediated by the benzodiazepine receptor on the GABA complex. DHEA suppressed rearing behavior at doses that did not reduce climbing, but analysis with the Bonferroni post hoc test yielded no statistically significant difference. This inhibitory effect was attenuated by flumazenil. By contrast, DHEA-S suppressed, in a dose-dependent manner, both rearing and climbing behavior to the same extent. The findings support the potential value of the mouse staircase paradigm for demonstrating behaviorally relevant anxiolysis of test compounds shown to interact in vitro with the GABA(A) receptor complex.
PMID: 11368960

J Clin Pharmacol 2001 May;41(5):507-14
Single-dose gabapentin pharmacokinetics and safety in healthy infants and children.
Haig GM, Bockbrader HN, Wesche DL, Boellner SW, Ouellet D, Brown RR, Randinitis EJ, Posvar EL. Department of Clinical Pharmacology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Gabapentin (Neurontin) is a gamma-aminobutyric acid analogue indicated in adults for adjunctive treatment of partial seizures with or without secondary generalization. Two studies were conducted to determine the single-dose pharmacokinetics of gabapentin in healthy subjects age 1 month to 12 years and to guide dose selection in safety and efficacy trials in pediatric patients. Forty-eight subjects were given single oral doses of gabapentin (10 mg/kg) while fasting. Enrollment was homogeneously distributed throughout the age range. Plasma samples were drawn predose and then serially for 24 hours postdose. Single doses of gabapentin were well tolerated by healthy pediatric subjects. Plots of pharmacokinetic parameters versus age suggested significant differences between younger (1 month to < 5 years) and older (> or =5 to 12 years) subjects. Mean area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) was 25.6 microg x h/mL in younger subjects and 36.0 microg x h/mL in older subjects (p < 0.001). Corresponding mean peak plasma concentrations (Cmax) were 3.74 and 4.52 microg/ml (p < 0.05). Oral clearance (normalized for body weight) was 7.40 and 4.41 mL/min/kg in younger subjects and older subjects, respectively (p < 0.001). It was concluded that children between 1 month and < 5 years of age require approximately 30% higher daily doses of gabapentin than those > or =5 to 12 years of age.
PMID: 11361047

J Affect Disord 2001 Jul;65(2):167-71
Gabapentin treatment of the non-refractory bipolar spectrum: an open case series.
Ghaemi SN, Goodwin FK. Psychopharmacology Program, Cambridge Hospital, Consolidated Department of Psychiatry, Harvard Medical School, Cambridge, MA, USA. ghaemi@hms.harvard.edu
OBJECTIVE: To determine if gabapentin is effective in monotherapy or add-on treatment of non-refractory bipolar disorder in open prospective treatment. METHODS: Charts of 21 outpatients meeting DSM-IV criteria for bipolar spectrum disorder (type I, type II, NOS, and cyclothymia) and who were treated with gabapentin were reviewed and clinical response was assessed based on prospective application of the Hamilton Depression Rating Scale (HDRS), the Young Mania Rating Scale (YMRS), the Clinical Global Impression scale (CGI), and the Global Assessment of Functioning scale (GAF). Also, response was rated retrospectively using the Clinical Global Impression scale for Bipolar Disorder (CGI-BP). RESULTS: Eight patients received gabapentin monotherapy and 13 received adjunctive therapy. Similar improvement in depression was noted in the monotherapy group, without induction of mania. Gabapentin was associated with a 43.8% improvement in manic symptoms and a 27.6% improvement in depressive symptoms in the overall sample. In the depressed subsample (n=10), there was a 57.5% improvement in depressive symptoms (P=0.10). Using the CGI-BP, gabapentin was moderately to markedly effective in 43% of patients for overall bipolar illness, 38% for depressive symptoms, and 25% for manic symptoms. Of those in the study, 62% reported side effects, mainly sedation and nausea, with 14% of the total sample discontinuing treatment due to adverse events. CONCLUSIONS: Gabapentin, either alone or as an adjunct, appeared moderately effective in treating depression in this small, uncontrolled, heterogeneous sample of non-refractory bipolar spectrum illness. Coupled with the earlier clinical literature, these data suggest the need for prospective double-blind studies of depressive illness in the bipolar spectrum.
PMID: 11356240

Acta Crystallogr C 2001 May;57(Pt 5):641-3
Gabapentin and gabapentin monohydrate.
Ibers JA. Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA. ibers@chem.northwestern.edu
Gabapentin [1-(aminomethyl)cyclohexaneacetic acid, C9H17NO2] is a zwitterion in the solid state. Its crystal structure involves extensive hydrogen bonding between the NH3(+) and COO(-) groups of neighboring molecules. The structure of gabapentin monohydrate [1-(aminomethyl)cyclohexaneacetic acid monohydrate, C9H17NO2-H2O] also involves such hydrogen bonding and, in addition, has a hydrogen-bonding network comprising the water molecules and both the NH3(+) and COO(-) groups.
PMID: 11353278

Arch Phys Med Rehabil 2001 May;82(5):691-3
Using gabapentin to treat failed back surgery syndrome caused by epidural fibrosis: A report of 2 cases.
Braverman DL, Slipman CW, Lenrow DA. Department of Rehabilitation Medicine, University of Pennsylvania School of Medicine, University of Pennsylvania Health System, Philadelphia, PA, USA.
Failed back surgery syndrome (FBSS) is a long-lasting, often disabling, and relatively frequent (5%-10%) complication of lumbosacral spine surgery. Epidural fibrosis is among the most common causes of FBSS, and it is often recalcitrant to treatment. Repeated surgery for fibrosis has only a 30% to 35% success rate, whereas 15% to 20% of patients report worsening of their symptoms. Long-term outcome studies focusing on pharmacologic management of chronic back pain secondary to epidural fibrosis are lacking in the literature. This report presents 2 cases of severe epidural fibrosis managed successfully with gabapentin monotherapy. In both cases, functional status improved markedly and pain was significantly diminished. Gabapentin has an established, favorable safety profile and has been shown to be effective in various animal models and human studies of chronic neuropathic pain. Clinicians should consider gabapentin as a pharmacologic treatment alternative in the management of FBSS caused by epidural fibrosis.
PMID: 11346850

Rev Neurol 2001 Feb 16-28;32(4):345-50
[Antiepileptic drugs and neuropathic pain].
Martinez-Salio A, Porta-Etessam J, Berbel-Garcia A, Garcia-Morales I, de la Pena-Mayor P, Vicente-Fatela L. Servicio de Neurologia; Hospital Universitario 12 de Octubre, Madrid, 28041, Espana. amsalio@yahoo.com
INTRODUCTION: This article is a bibliographic review of the part currently played by antiepileptic drugs in the treatment of neuropathic pain, and knowledge of their specific actions according to the different physiopathogenic mechanisms suspected of being involved in this type of pain. DEVELOPMENT: Neuropathic pain, the result of neurological damage in part of the nerve transmission system for pain, is one of the commonest painful syndromes in clinical practice and is a challenge for both neurologists and pain specialists. In recent years there has been increasing interest in the antiepileptic drugs, which were already used in this context in the sixties. Interest has increased with new drugs and better understanding of the physiopathogenic mechanisms of pain. The poor, variable response of these conditions to different treatments and the complex relationship between aetiologies, mechanisms and symptoms make it advisable to modify the traditional approach to the treatment of these conditions, passing form the aetiology and topographical distribution to the probable mechanisms involved in each individual patient, adapting the treatment to the individual concerned. CONCLUSIONS: The antiepileptic drugs are one of the most promising approaches to the drug treatment of neuropathic pain. Their use as the sole treatment, or in combination with other treatment, in individual patients depends on better understanding of the mechanisms involved in the genesis and maintenance of neuropathic pain and how antiepileptic drugs act on these mechanisms.
PMID: 11333392

Ophthalmologe 2001 Mar;98(3):237-41
[The effect of gabapentin and gabapentin-lactam on retinal ganglion cell survival. Situation after acute retinal ischemia in animal models].
Jehle T, Feuerstein TJ, Lagreze WA. Neurologische Universitatsklinik Freiburg, Klinische Neuropharmakologie.
BACKGROUND: Reduction in the excitatory and potentially toxic neurotransmitter glutamate can protect retinal ganglion cells. What are the effects of the antiepileptic drug gabapentin, for which antiglutamatergic effects have been described, and the new substance gabapentin-lactam (GBP-L) on retinal ganglion cell survival after retinal ischemia? METHODS: In 3 groups of 10 rats each, ischemia was induced by elevating the intraocular pressure of the left eye to 120 mmHg for 1 h. Saline, gabapentin (2 x 50 mg/kg intraperitoneally) and GBP-L (2 x 50 mg/kg intraperitoneally) were injected before and 5 h after ischemia. Two weeks later ischemic damage was quantified histologically by counting the number of neurons in the ganglion cell layer. In vitro transmitter release experiments were performed to obtain information on the effect of gabapentin and GBP-L on ischemia-induced glutamate release and the mechanism of action of GBP-L. RESULTS: In the control group 17% of the retinal ganglion cells survived ischemia. GBP-L doubled the number of the surviving cells while gabapentin was not effective in these experiments. In vitro gabapentin and GBP-L reduced ischemia-induced glutamate release by 35.7% and 42.5%, respectively. The blockade of ATP-sensitive potassium channels antagonized the effect of GBP-L completely. CONCLUSION: GBP-L is neuroprotective in retinal ischemia and diminishes the release of the excitatory neurotoxic amino acid glutamate. The effect of GBP-L might be mediated by ATP-sensitive potassium channels. Also gabapentin reduced glutamate release but was not neuroprotective in vivo.
PMID: 11320809

Mol Pharmacol 2001 May;59(5):1243-8
Calcium channel alpha(2)delta subunits-structure and Gabapentin binding.
Marais E, Klugbauer N, Hofmann F. Institut fur Pharmakologie und Toxikologie der Technischen Universitat Munchen, Munchen, Germany.
High-voltage activated calcium channels are modulated by a series of auxiliary proteins, including those of the alpha(2)delta family. Until recently, only a single alpha(2)delta subunit was known, but two further members, alpha(2)delta-2 and -3, have since been identified. In this study, the structure of these two novel subunits has been characterized and binding of the antiepileptic drug gabapentin investigated. Using antibodies directed against the amino terminal portion of the proteins, the gross structure of the subunits could be analyzed by Western blotting. Similar to alpha(2)delta-1, both alpha(2)delta-2 and -3 subunits consist of two proteins-a larger alpha(2) and a smaller delta that can be separated by reduction. The subunits are also highly N-glycosylated with approximately 30 kDa of their mass consisting of oligosaccharides. alpha(2)delta-1 was detected in all mouse tissues studied, whereas alpha(2)delta-2 was found at high levels in brain and heart. The alpha(2)delta-3 subunit was observed only in brain. alpha(2)delta-1 and alpha(2)delta-2, but not alpha(2)delta-3, were found to bind gabapentin. The K(d) value of gabapentin binding to alpha(2)delta-2 was 153 nM compared with the higher affinity binding to alpha(2)delta-1 (K(d) = 59 nM).
PMID: 11306709

J Pharmacol Exp Ther 2001 May;297(2):727-35
Differential effect of gabapentin on neuronal and muscle calcium currents.
Alden KJ, Garcia J. Department of Physiology & Biophysics, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60607, USA.
Calcium channels modulate cell function by controlling Ca(2+) influx. A main component of these proteins is the alpha 2/delta subunit. Nevertheless, how this subunit regulates channel activity in situ is unclear. Gabapentin (GBP), an analgesic and anti-epileptic agent with an unknown mechanism of action, specifically binds to the alpha 2/delta subunit. Using the patch clamp technique, we tested the effects of GBP on Ca(2+) currents from dorsal root ganglion (DRG) cells, the mediators of pain perception, to determine how GBP binding modifies channel activity. In DRGs, GBP significantly reduced whole cell Ca(2+) current amplitude at positive membrane potentials when a pulse preceded the test pulses or when cells were stimulated with a train of pulses. In control cells, neither prepulse depolarization nor pulse trains reduced Ca(2+) currents at positive potentials. GBP did not reduce the low-voltage activated Ca(2+) current under any experimental condition. Similar to DRG cells, GBP attenuated Ca(2+) current in skeletal myotubes at positive membrane potentials in the presence of a depolarizing prepulse. However, GBP did not significantly alter Ca(2+) currents in cardiac myocytes. Reverse transcription-polymerase chain reaction was used to confirm expression of the alpha 2/delta subunit in these cells. Each cell type expressed multiple isoforms of alpha 2/delta. Muscle cells showed a more variable expression of alpha 2/delta subunits than did DRG cells. Our results suggest a possible participation of the alpha 2/delta subunit in the action of GBP. Our data also indicate that GBP inhibits Ca(2+) channels in a use- and voltage-dependent manner at a therapeutically relevant concentration.
PMID: 11303064

Ann Pharmacother 2001 Apr;35(4):427-31
Gabapentin for treatment of behavioral and psychological symptoms of dementia.
Miller LJ. Memorial Hermann Southwest Hospital, Houston, TX 77074-1802, USA. lisa_miller@MHHS.org
OBJECTIVE: To report the use of gabapentin in the treatment of behavioral and psychological symptoms of dementia (BPSD) and to review the available literature relating to the use of gabapentin in this population. CASE SUMMARY: A 62-year-old white man was admitted to the hospital due to a worsening state of confusion, anxiety, depressed mood, insomnia, and verbal and physical aggressiveness toward his wife. He had a past medical history significant for vascular dementia. He had been intolerant of or had failed to respond to numerous antidepressants, benzodiazepines, and neuroleptics. The addition of gabapentin to the patient's medication regimen resulted in reduced agitation, sexual inappropriateness, and lability. He was discharged to his home on a dose of gabapentin 300 mg three times daily. DATA SOURCES: A MEDLINE search (1966-August 2000) was performed to identify case reports and clinical trials discussing the efficacy of gabapentin in the treatment of BPSD. DISCUSSION: Gabapentin, like other anticonvulsants, has been used with success in several psychiatric illnesses. Available literature indicates that the drug may have some efficacy in the treatment of BPSD. It has a favorable adverse effect profile in the elderly, which makes it an attractive altemative to standard therapies, including benzodiazepines and neuroleptics. Optimal dosing remains unclear. CONCLUSIONS: This case suggests that gabapentin is a reasonable alternative therapy for patients whose behavioral symptoms do not respond to conventional agents.
PMID: 11302405

J Intellect Disabil Res 2001 Apr;45(Pt 2):139-45
Adjunctive gabapentin in patients with intellectual disability and bipolar spectrum disorders.
Carta MG, Hardoy MC, Dessi I, Hardoy MJ, Carpiniello B. Psychiatric Unit, Department of Public Health, University of Cagliari, Cagliari, Italy. mgcarta@tiscalinet.it
The aim of the present study was to assess the efficacy of adjunctive gabapentin (GBP) in the treatment of patients with intellectual disability (ID) and bipolar spectrum disorders. Ten affected subjects with demonstrable increases in symptomatology during 'significant' life events which had interfered with or induced the interruption of their rehabilitation programmes were chosen for this study. The meaning of 'significant' was defined for each patient as a frequently repeated life event which had elicited a marked increase in symptoms on at least two occasions. Gabapentin (300-900 mg day-1) was added to the standard therapy. The subjects' psychopathological conditions during the significant life event were assessed by means of standardized tools both before and after adjunctive therapy with GBP. A positive response to therapy was observed, with subsequent improvement of psychopathological conditions, particularly for anxiety and depressive symptoms. The promising results obtained with GBP suggest the need for further trials. Adjunctive GBP may become an alternative treatment approach for patients with ID in whom traditional mood-stabilizing agents have frequent contraindications.
PMID: 11298253

Neurology 2001 Apr 10;56(7):843-8
Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis.
Miller RG, Moore DH 2nd, Gelinas DF, Dronsky V, Mendoza M, Barohn RJ, Bryan W, Ravits J, Yuen E, Neville H, Ringel S, Bromberg M, Petajan J, Amato AA, Jackson C, Johnson W, Mandler R, Bosch P, Smith B, Graves M, Ross M, Sorenson EJ, Kelkar P, Parry G, Olney R; Western ALS Study Group. Department of Neurology, California Pacific Medical Center, San Francisco, USA. rmiller@cooper.cpmc.org
BACKGROUND: Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial. METHODS: Patients were randomly assigned, in a double-blinded fashion, to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations. RESULTS: Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin. CONCLUSION: These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS.
Publication Types:

Clinical trial

Clinical trial, phase iii

Randomized controlled trial

PMID: 11294919

J Mass Spectrom 2001 Feb;36(2):188-94
Gabapentin quantification in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study.
Ifa DR, Falci M, Moraes ME, Bezerra FA, Moraes MO, de Nucci G. Cartesius Analytical Unit, Department of Pharmacology, ICB-University of Sao Paulo, 05508-900, Sao Paulo, Brazil. ifa@usp.br
A rapid, sensitive and specific analytical method was developed and validated to quantify gabapentin in human plasma using acetaminophen as an internal standard. The method employs a single plasma protein precipitation. The analytes are chromatographed on a C4 reversed-phase chromatographic column and analyzed by mass spectrometry in the multiple reaction monitoring (MRM) mode. The method has a chromatographic run time of 4 min and a linear calibration curve over the range 50-10 000 ng x ml(-1) (r > 0.999). The between-run precision, based on the relative standard deviation for replicate quality controls, was < or = 4.8 % (200 ng x ml(-1)), 6.0% (1000 ng x ml(-1)) and 4.4% (5000 ng x ml(-1)). The between-run accuracy was +/-2.6, 4.4 and 0.5% for the above-mentioned concentrations, respectively. This method was employed in a bioequivalence study of two gabentin capsule formulations (Progresse from Biosintetica, Brazil, as a test formulation, and Neurotin from Parke-Davis, as a reference formulation) in 24 healthy volunteers of both sexes who received a single 300 mg dose of each formulation. The study was conducted using an open, randomized, two-period crossover design with a 7-day washout interval. The 90% confidence interval (CI) of the individual ratio geometric mean for Progresse/Neurotin was 87.9-115.6% for AUC(0-36 h) and 88.6-111.7% for Cmax. Since both 90% CI for AUC(0-36 h) and Cmax were included in the 80-125% interval proposed by the US Food and Drug Administration, Progresse was considered bioequivalent to Neurotin according to both the rate and extent of absorption.
PMID: 11288201

South Med J 2001 Mar;94(3):304-22
Effects of antimanic mood-stabilizing drugs on fetuses, neonates, and nursing infants.
Iqbal MM, Gundlapalli SP, Ryan WG, Ryals T, Passman TE. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham School of Medicine, 35294-0017, USA.
Pregnancy presents a special problem to the clinician treating bipolar disorders in women. Since the first episode of mania typically occurs before the age of 30, many women in their prime childbearing years may be exposed to potentially teratogenic mood-stabilizing agents. This exposure may also continue for the nursing infant during lactation. Pregnancy itself can exacerbate bipolar symptoms and also alter the pharmacokinetics of mood-stabilizing drugs. Risks to mother and fetus can be reduced with a number of simple strategies, including monotherapy with the lowest effective dose of a drug for the shortest period necessary, periconceptional use of multivitamins with folate, prescription of drugs with established safety records, and avoidance of exposure to antimanic agents during the first trimester of pregnancy. In this article, we review existing evidence on the risks to fetuses and nursing infants of mothers taking specific mood-stabilizing agents, and we present appropriate management guidelines designed to minimize these risks.
Publication Types:

Review

Review, tutorial

PMID: 11284518

Neurology 2001 Mar 27;56(6):743-8
Rapid initiation of gabapentin: a randomized, controlled trial.
Fisher RS, Sachdeo RC, Pellock J, Penovich PE, Magnus L, Bernstein P. Epilepsy Center, Stanford Medical School, CA 94305-5235, USA. rfischer@stanford.edu
OBJECTIVE: To compare the tolerability of two different dose-initiation regimens of gabapentin for the adjunctive treatment of partial seizures. BACKGROUND: Patient compliance is a key feature of successful outpatient pharmacologic therapy for epilepsy, and one aspect of compliance is simplicity of initiation. By using a rapid titration rate, leading to a rapid therapeutic gabapentin dose, perhaps there could be an improvement with compliance. METHODS: Male or female patients, at least 12 years old, with a recent history of partial seizures with or without secondary generalization, were randomized to receive gabapentin (following a blinded placebo period of an undisclosed number of days) as either a Slow initiation (300 mg day 1, 600 mg day 2, then 900 mg/day) or a Rapid initiation (900 mg/day immediately following the placebo lead-in). RESULTS: Starting gabapentin therapy at an initial therapeutic dosage of 900 mg/day is well tolerated by patients with epilepsy and is as safe as initiating with a titration schedule over 3 days. Of the four most common adverse events (somnolence, dizziness, ataxia, fatigue), only one, dizziness, occurred more often in the nontitrated (Rapid initiation) group than in the titrated (Slow initiation) group. CONCLUSION: Initiation of gabapentin at 900 mg/day is as well tolerated as is a 3-day titration, except for a higher incidence of dizziness.
Publication Types:

Clinical trial

Randomized controlled trial

PMID: 11274308

Tech Urol 2001 Mar;7(1):47-9
Oral gabapentin (neurontin) treatment of refractory genitourinary tract pain.
Sasaki K, Smith CP, Chuang YC, Lee JY, Kim JC, Chancellor MB. Department of Urology, University of Pittsburgh School of Medicine, Pennsylvania, USA.
PURPOSE: Refractory genitourinary pain is a common but difficult condition to treat. Examples of chronic genitourinary pain include orchalgia, interstitial cystitis, pain after bladder suspension surgery, nonbacterial prostatitis, and genital pain related to lumbosacral neuropathy. We report our experience with oral gabapentin treatment for this condition. Gabapentin is an anticonvulsant with unclear but therapeutic effects on neurologic pain. MATERIALS AND METHODS: Twenty-one patients referred with refractory genitourinary pain were treated with oral gabapentin. There were 9 men and 12 women. In the male patients, the location of pain was testicle (4), bladder (2), penis (1), or prostate (2). In female patients, the pain was located in the urethra (4), bladder (6), vulva (1), or vagina (1). The dose of gabapentin was titrated from 300 up to 2,100 mg/day. Subjective pain severity and 10-cm visual pain scale was used before and 6 months after therapy. RESULTS: The mean dose of gabapentin was 1,200 mg/day (range 300-2,100 mg). Ten of 21 patients reported subjective improvement of their pain. The remaining patients did not perceive any improvement. Gabapentin was well tolerated; only 4 patients dropped out due to side effects. The most common adverse effects were dizziness and drowsiness. Five of 8 patients with interstitial cystitis reported improvement. CONCLUSIONS: Although only 10 of 21 patients improved with gabapentin, this cohort included only patients with refractory genitourinary pain that failed a wide range of prior treatments. Gabapentin belongs in the armaterium of the urologist who treats genitourinary pain.
Publication Types:

Clinical trial

PMID: 11272678

Arzneimittelforschung 2001 Feb;51(2):97-103
Determination of the antiepileptics vigabatrin and gabapentin in dosage forms and biological fluids using Hantzsch reaction.
al-Zehouri J, al-Madi S, Belal F. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
A selective and sensitive method was developed for the determination of the anticonvulsants vigabatrin (I) (CAS 60643-86-9) and gabapentin (II) (CAS 60142-96-3). The method is based on the condensation of the drugs through their amino groups with acetylacetone and formaldehyde according to Hantzsch reaction yeilding the highly fluorescent dihydropyridine derivatives. The yellowish-orange color was also measured spectrophotometrically at 410 nm and 415 nm for I and II, respectively. The absorbance-concentration plots were rectilinear over the ranges 10-70 micrograms/ml and 20-140 micrograms/ml for I and II, respectively. As for the fluorescence-concentration plots, they were linear over the ranges 0.5-10 micrograms/ml and 2.5-20 micrograms/ml with minimum detection limits (S/N = 2) of 0.05 microgram/ml (approximately 2.1 x 10(-8) mol/l) and 0.1 microgram/ml (approximately 5.8 x 10(-7) mol/l) for I and II, respectively. The spectrophotometric method was applied to the determination of I and II in their tablets. The percentage recoveries +/- SD (n = 6) were 99.45 +/- 0.13 and 98.05 +/- 0.53, respectively. The spectrofluorimetric method was successfully applied to the determination of I and II in spiked human urine and plasma. The % recoveries +/- SD (n = 5) were 98.77 +/- 0.29 and 98.39 +/- 0.53 for urine and 99.32 +/- 0.74 and 98.90 +/- 0.96 for plasma, for I and II, respectively. No interference was encountered with the co-administered drugs: valproic acid (CAS 99-66-1), diphenylhydantoin (CAS 57-41-0), phenobarbital (CAS 50-06-6), carbamazepine (CAS 298-46-4), clonazepam (CAS 1622-61-3), clobazam (CAS 22316-47-8) or cimetidine (CAS 51481-61-9). A proposal of the reaction pathway is suggested. The advantages of the proposed methods over existing method are discussed.
PMID: 11258050

Neurologia 2001 Feb;16(2):85-8
[Progressive encephalomyelitis with rigidity. Clinical and electrophysiological aspects].
Gazulla Abio J, Benavente Aguilar I, Capablo Liesa JL. Unidad de Neurologia, Hospital San Jorge, Huesca.
A 72-year-old man presented with a chronic illness constituted by muscle rigidity affecting his lower limbs, trunk and neck, either spontaneous or triggered by stimuli, together with a spastic paraparesis, manual amyotrophy and pseudobulbar syndrome. The electrophysiologic study showed continuous motor unit activity integrated by normal motor unit potentials. Biochemical and imaging results were normal. These data suggest the diagnosis of idiopathic progressive encephalomyelitis with rigidity. Following administration of gabapentin (2000 mg daily), muscle rigidity and electromyographic continuous motor unit activity were suppressed. Transient drowsiness was the only side effect. The authors have tried to relate these findings to those found in the literature.
PMID: 11257936

Nervenarzt 2001 Feb;72(2):69-77
[Gabapentin therapy for pain].
Block F. Neurologische Klinik der RWTH Aachen. fblock@post.klinkum.rwth-aachen.de
Gabapentin, which has been approved for add-on therapy of focal seizures, is increasingly used for treatment of neuropathic pain. Its analgesic effect is supposed to be due to reduction of glutamatergic transmission, improvement of GABAergic transmission and to binding to voltage-dependent calcium channels. Experimental studies demonstrated an ameliorating effect of gabapentin on neuropathic pain. Placebo-controlled studies revealed an efficacy of gabapentin against pain in diabetic neuropathy and postherpetic neuralgia and in prophylaxis of migraine. Case reports show an analgesic effect of gabapentin in trigeminus neuralgia and in reflex sympathetic dystrophy. The main adverse events are dizziness, ataxia and somnolence. Controlled studies, which compare the efficacy of gabapentin with that of the respective reference drug, are needed to evaluate its importance in treatment of pain.
Publication Types:

Review

Review, tutorial

PMID: 11256157

Headache 2001 Feb;41(2):119-28
Efficacy of gabapentin in migraine prophylaxis.
Mathew NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, Stacey B, Tepper S. Houston Headache Clinic, 1213 Hermann Drive, Suite 350, Houston, TX 77004, USA.
OBJECTIVE: To compare gabapentin with placebo for use as a prophylactic agent in patients with migraine (with or without aura). STUDY DESIGN AND TREATMENT: After screening, a 4-week, single-blind, placebo baseline period was followed by a 12-week, double-blind, treatment period. The 12-week treatment period consisted of a 4-week titration phase and an 8-week stable-dosing phase. During the 4-week titration phase, patients were started on one 300-mg capsule of gabapentin or matching placebo. Patients were titrated weekly from 900 mg/day (end of week 1) to 2400 mg/day (end of week 4) and had to be receiving a stable dose of study medication by the end of the titration period. Study medication was to be given on a three-times-a-day dosing regimen. METHODS: The study hypothesis was defined a priori as a lower 4-week migraine rate during the second stabilization period for the gabapentin-treated patients as compared with the placebo-treated patients. The analyses were performed with the 4-week migraine rate at baseline as a covariate and center as a blocking factor. RESULTS: At seven participating centers, 143 patients with migraine were randomized in a 2:1 ratio and received either gabapentin (n = 98) or matching placebo (n = 45). Thirty-three patients (24.1%) discontinued prematurely from the study, including 24 (24.5%) of 98 gabapentin-treated patients and 9 (20.0%) of 45 placebo-treated patients; the majority of patients discontinued due to adverse events (16 [16.3%] of 98 gabapentin-treated patients; 4 [8.9%] of 45 placebo-treated patients). Patients included in the analysis were evenly balanced for age, sex, race, weight, and height. The majority of these patients were white (80 [92.0%] of 87) and women (72 [82.8%] of 87), with a mean age of approximately 39.4 years and a history of migraine episodes for a mean of about 21 years. At the end of the 12-week treatment phase, the median 4-week migraine rate was 2.7 for the gabapentin-treated patients maintained on a stable dose of 2400 mg/day and 3.5 for the placebo-treated patients (P =.006), compared with 4.2 and 4.1, respectively, during the baseline period. Additionally, 26 (46.4%) of 56 patients receiving a stable dose of 2400 mg/day gabapentin and 5 (16.1%) of 31 patients receiving placebo showed at least a 50% reduction in the 4-week migraine rate (P =.008). The average number of days per 4 weeks with migraine was also statistically significant and favored gabapentin (P =.006) during stabilization period 2. The median change in 4-week headache rate was statistically significant as well (P =.013). The most frequently reported adverse events for both treatment groups were asthenia, dizziness, somnolence, and infection. Adverse events determined by the investigator to be associated with study drug resulted in patient withdrawal in 13 (13.3%) of 98 gabapentin-treated patients and 3 (6.7%) of 45 placebo-treated patients. Somnolence and dizziness accounted for many of the premature withdrawals among those taking gabapentin. CONCLUSION: Gabapentin is an effective prophylactic agent for patients with migraine. In addition, gabapentin appears generally well tolerated with mild to moderate somnolence and dizziness.
Publication Types:

Clinical trial

Multicenter study

Randomized controlled trial

PMID: 11251695

Epilepsy Res 2001 Mar;43(3):239-48
The effects of gabapentin on different ligand- and voltage-gated currents in isolated cortical neurons.
Stefani A, Spadoni F, Giacomini P, Lavaroni F, Bernardi G. Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy. stefani@uniroma2.it
A clear picture of the mechanisms of action of the anti-epileptic agent gabapentin is far from being accomplished. We have analyzed the effects of gabapentin on ligand- and voltage-gated currents in isolated adult rat cortical neurons. Gabapentin failed to modify glutamate currents and produced a slight reduction of GABA responses. Negligible inhibition of sodium, but consistent inhibition of high-voltage-activated calcium conductance was promoted by gabapentin. In addition, gabapentin reduced calcium current sensitivity to dihydropyridine agonist and antagonists. Interestingly, gabapentin also decreased a not-inactivating, cadmium-sensitive, potassium current. These unconventional effects might underlie its efficacy in a variety of diseases which involve periodic discharge patterns as neuropathic pain or essential tremor.
PMID: 11248535

J Affect Disord 2001 Mar;63(1-3):243-7
Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review.
Yasmin S, Carpenter LL, Leon Z, Siniscalchi JM, Price LH. Mood Disorders Program, Butler Hospital, Department of Psychiatry and Human Behavior, Brown University School of Medicine, 345 Blackstone Blvd., Providence, RI 02906, USA.
BACKGROUND: Previous studies in predominantly bipolar patients have suggested that gabapentin may be useful in treating mood disorders. This report describes its efficacy and tolerability as an adjunctive agent in treatment-resistant depression. METHODS: A chart review was conducted on 27 outpatients presenting with a depressive disorder in whom gabapentin was added to ongoing treatment with a conventional antidepressant to which patients had not responded after at least 6 weeks. The majority of patients had either prominent anxiety or a history of soft bipolar features, but patients with bipolar I disorder were excluded. Clinical state and adverse effects were assessed retrospectively at each visit. RESULTS: Mean gabapentin trial duration was 15.2+/-7.8 weeks, with a mean final dose of 904+/-445 mg/day (range, 300-1800 mg/day). Clinician-rated measures of clinical state improved significantly from baseline to endpoint. Overall, 37.0% (n=10) of patients were responders at endpoint; another 18.5% (n=5) manifested a transient response not sustained to endpoint. Gabapentin was well tolerated; the most common adverse effects were fatigue, sedation, dizziness, and gastrointestinal symptoms. LIMITATIONS: Treatment was uncontrolled and efficacy assessments were retrospective. CONCLUSION: These findings suggest that gabapentin may be of adjunctive benefit in the management of treatment-resistant depression.
PMID: 11246103

J Nutr 2001 Mar;131(3):846S-850S
Function of leucine in excitatory neurotransmitter metabolism in the central nervous system.
Hutson SM, Lieth E, LaNoue KF. Wake Forest University School of Medicine, Department of Biochemistry, Medical Center Boulevard, Winston-Salem, NC 27157, USA. shutson@wfubmc.edu
A novel hypothesis for the role of branched-chain amino acids (BCAA) in regulating levels of the major excitatory neurotransmitter glutamate in the central nervous system is described. It is postulated that the branched-chain aminotransferase (BCAT) isoenzymes (mitochondrial BCATm and cytosolic BCATc) are localized in different cell types and operate in series to provide nitrogen for optimal rates of de novo glutamate synthesis. BCAA enter the astrocyte where transamination is catalyzed by BCATm, producing glutamate and branched-chain alpha-keto acids (BCKA). BCKA, which are poorly oxidized in astrocytes, exit and are taken up by neurons. Neuronal BCATc catalyzes transamination of the BCKA with glutamate. The products, BCAA, exit the neuron and return to the astrocyte. The alpha-ketoglutarate product in the neurons may undergo reductive amination to glutamate via neuronal glutamate dehydrogenase. Operation of the shuttle in the proposed direction provides a mechanism for efficient nitrogen transfer between astrocytes and neurons and synthesis of glutamate from astrocyte alpha-ketoglutarate. Evidence in favor of the hypothesis is: 1) The two BCAT isoenzymes appear to be localized separately in the neurons (BCATc) or in the astroglia (BCATm). 2) Inhibition of the shuttle in the direction of glutamate synthesis can be achieved by inhibiting BCATc using the neuroactive drug gabapentin. Although gabapentin does not inhibit BCATm, it does block de novo glutamate synthesis from alpha-ketoglutarate. 3) Conversely, gabapentin stimulates oxidation of glutamate. Inhibition of BCATc may allow BCKA to accumulate in the astroglia, thus facilitating conversion of glutamate to alpha-ketoglutarate.
PMID: 11238772

J Clin Psychiatry 2001 Jan;62(1):19-23

Gabapentin in the treatment of cocaine dependence: a case series.
Myrick H, Henderson S, Brady KT, Malcolm R. Department of Psychiatry, Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, USA.
BACKGROUND: Although multiple medications have been studied for the treatment of cocaine dependence, no medication has been shown to have a robust effect on craving and use. This pilot project was designed to evaluate the safety and tolerability of gabapentin in subjects with cocaine dependence. METHOD: Thirty cocaine-dependent subjects (DSM-IV criteria) were enrolled in an 8-week, open-label trial of 1,200 mg/day of gabapentin in divided doses. Urine drug screens, subjective measures of craving, and cocaine use interviews were conducted at each weekly visit. RESULTS: Baseline rating of amount and frequency of craving decreased significantly by week 8 (78% vs. 25% for amount, p = .000; 74% vs. 23% for frequency, p = .004). Positive urine drug screens for cocaine decreased from 86% at baseline to 29% at weeks 4 and 8. There were no reports of significant side effects or adverse events. CONCLUSION: This pilot study indicates that gabapentin is safe and well tolerated and may be beneficial in the treatment of cocaine dependence. A placebo-controlled trial would be of interest.
Publication Types:

Clinical trial

PMID: 11235923

Ear Nose Throat J 2001 Feb;80(2):114-6
Gabapentin for the treatment of tinnitus: a case report.
Zapp JJ. Pain Institute of Northeast Florida, 2021 Kingsley Ave., Suite 102, Orange Park, FL 32073, USA.
The objective of this article is to discuss the clinically effective use of gabapentin in patients with tinnitus. The author describes the case of a man who came to the office complaining of tinnitus of 10 months' duration. The patient was started on gabapentin and maintained on a regimen of 500 mg/day in divided doses. Subsequently, he reported that he was free of tinnitus approximately 23 days a month and that he experienced a 75% decrease in symptoms during the remaining days. At 2 years' follow-up, he remains noise- and pain-free on 500 mg/day of gabapentin.
PMID: 11233342

J Child Neurol 2001 Jan;16(1):31-6
Pharmacotherapy of spasticity: oral medications and intrathecal baclofen.
Krach LE. Gillette Children's Specialty Healthcare, St. Paul, MN 55101, USA. lkrach@gillettechildrens.com
Spasticity is a common problem in children with neurologic impairment, particularly in those with cerebral palsy. Clinicians commonly make use of oral medications to attempt to reduce spasticity and increase function. Little has been published in the literature concerning the use of these medications in children and their effects on both muscle tone and function. This article is a review of the sites of action, side effects, and efficacy of benzodiazepines, baclofen, dantrolene sodium, alpha2-adrenergic agonists, and gabapentin. A brief review of intrathecal baclofen is included as well.
Publication Types:

Review

Review, tutorial

PMID: 11225954

J Pain Symptom Manage 2001 Jan;21(1):78-82
Gabapentin in phantom limb pain management in children and young adults: report of seven cases.
Rusy LM, Troshynski TJ, Weisman SJ. Department of Anesthesiology, Medical College of Wisconsin-Children's Hospital of Wisconsin, Milwaukee, WI 53201, USA.
Seven children and young adults with phantom limb pain (PLP) were treated with gabapentin. PLP resolved in six patients within two months. One patient still had symptoms to a lesser degree. Mean follow up time was 1.74 years. Gabapentin may be a useful adjunct to pain management in patients with PLP symptoms.
PMID: 11223317

Ugeskr Laeger 2001 Jan 22;163(4):454-8
[Gabapentin--yet another antiepileptic agent for the treatment of neuropathic pain]?
Kamp-Jensen M, Werner MU. H: S Hvidovre Hospital, smerteklinikken og akut smerteenhed, anaestesiologisk afdeling 532.
Gabapentin is a recently introduced anti-epileptic drug used as an adjuvant in partial and secondarily generalised tonic-clonic seizures. Its mechanism of action has not been fully elucidated, but it seems that gabapentin may regulate voltage-dependent calcium channels, presumably on a spinal level, in the nociceptive system. Two large, controlled clinical trials of painful diabetic neuropathy and postherpetic neuralgia have demonstrated its analgesic efficacy. The adverse effects associated with gabapentin treatment are relatively harmless, mild to moderate in severity, and usually transient, with tolerance developing 2-3 weeks after start of treatment. Gabapentin and tricyclic antidepressants are efficacious in the treatment of painful diabetic neuropathy and postherpetic neuralgia.
Publication Types:

Review

Review, tutorial

PMID: 11218787

J Clin Psychiatry 2001;62 Suppl 1:50-3
Benzodiazepines and anticonvulsants for social phobia (social anxiety disorder).
Jefferson JW. Madison Institute of Medicine, Inc., and the University of Wisconsin Medical School, USA. JeffJ@healthtechsys.com
Both benzodiazepines and conventional anticonvulsants have been evaluated as treatments for social phobia (social anxiety disorder). Among the benzodiazepines, clonazepam is the best studied, although there is reason to expect that all benzodiazepine anxiolytics would be effective for this condition. Among the anticonvulsants, gabapentin and pregabalin, an analogue of gamma-aminobutyric acid (GABA), have been shown to be more effective than placebo in double-blind studies. Other than a small negative open study of valproic acid for social phobia, there is a paucity of information on whether other anticonvulsants might be useful for this condition.
PMID: 11206035

Pain 2001 Feb 15;90(3):217-26
The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat.
Patel S, Naeem S, Kesingland A, Froestl W, Capogna M, Urban L, Fox A. Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BN, UK.
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.
PMID: 11207393

J Pharmacol Exp Ther 2001 Feb;296(2):270-5
Gabapentin antinociception in mice with acute herpetic pain induced by herpes simplex virus infection.
Takasaki I, Andoh T, Nojima H, Shiraki K, Kuraishi Y. Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan.
The effects of systemic and local injections of gabapentin, a novel anticonvulsant agent, were tested on nociceptive behaviors in mice with acute herpetic pain. Transdermal infection with herpes simplex virus type-1 (HSV-1) produced nociceptive hypersensitivity of the infected hind paw to innocuous (allodynia) and noxious mechanical stimulation (hyperalgesia) with von Frey filaments. Systemic administration of gabapentin (10-100 mg/kg, peroral) produced a dose-dependent inhibition of both allodynia and hyperalgesia; gabapentin (30-300 mg/kg) did not affect locomotor activity. Intrathecal injection of gabapentin (10-100 microg/animal) also attenuated dose dependently both nociceptive hypersensitivities. In contrast, intraplantar, intracisternal, and intracerebroventricular administration of gabapentin (10-100 microg/animal) had no effect on the HSV-1-induced nociceptive hypersensitivities. Pretreatment with naltrexone (1 mg/kg) inhibited antinociceptive effect of morphine (5 mg/kg), but not gabapentin (100 mg/kg). Repeated administration of morphine (5 mg/kg, four times) led to tolerance of antinociceptive action, whereas gabapentin (100 mg/kg, four times) had antinociceptive effect even after the forth administration. The present results suggest that gabapentin is effective in the treatment of acute herpetic pain without apparent adverse effects, and analgesic action of gabapentin is mainly mediated by actions on the spinal cord.
PMID: 11160607

Mol Pharmacol 2001 Jan;59(1):144-52
Gamma-aminobutyric acid type B receptors with specific heterodimer composition and postsynaptic actions in hippocampal neurons are targets of anticonvulsant gabapentin action.
Ng GY, Bertrand S, Sullivan R, Ethier N, Wang J, Yergey J, Belley M, Trimble L, Bateman K, Alder L, Smith A, McKernan R, Metters K, O'Neill GP, Lacaille JC, Hebert TE. Merck Frosst Center for Therapeutic Research, Kirkland, Canada. gordon_ng@merck.com
Gamma-aminobutyric acid (GABA) activates two qualitatively different inhibitory mechanisms through ionotropic GABA(A) multisubunit chloride channel receptors and metabotropic GABA(B) G protein-coupled receptors. Evidence suggests that pharmacologically distinct GABA(B) receptor subtypes mediate presynaptic inhibition of neurotransmitter release by reducing Ca2+ conductance, and postsynaptic inhibition of neuronal excitability by activating inwardly rectifying K+ (Kir) conductance. However, the cloning of GABA(B) gb1 and gb2 receptor genes and identification of the functional GABA(B) gb1-gb2 receptor heterodimer have so far failed to substantiate the existence of pharmacologically distinct receptor subtypes. The anticonvulsant, antihyperalgesic, and anxiolytic agent gabapentin (Neurontin) is a 3-alkylated GABA analog with an unknown mechanism of action. Here we report that gabapentin is an agonist at the GABA(B) gb1a-gb2 heterodimer coupled to Kir 3.1/3.2 inwardly rectifying K+ channels in Xenopus laevis oocytes. Gabapentin was practically inactive at the human gb1b-gb2 heterodimer, a novel human gb1c-gb2 heterodimer and did not block GABA agonism at these heterodimer subtypes. Gabapentin was not an agonist at recombinant GABA(A) receptors as well. In CA1 pyramidal neurons of rat hippocampal slices, gabapentin activated postsynaptic K+ currents, probably via the gb1a-gb2 heterodimer coupled to inward rectifiers, but did not presynaptically depress monosynaptic GABA(A) inhibitory postsynaptic currents. Gabapentin is the first GABA(B) receptor subtype-selective agonist identified providing proof of pharmacologically and physiologically distinct receptor subtypes. This selective agonism of postsynaptic GABA(B) receptor subtypes by gabapentin in hippocampal neurons may be its key therapeutic advantage as an anticonvulsant.
PMID: 11125035