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PubMed2006

The nitric oxide-cyclic GMP-protein kinase G-K+ channel pathway participates in the antiallodynic effect of spinal gabapentin.

The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway on gabapentin-induced spinal antiallodynic activity was assessed in spinal nerve injured rats. Intrathecal gabapentin, diazoxide or pinacidil reduced tactile allodynia in a dose-dependent manner. Pretreatment with NG-L-nitro-arginine methyl ester (L-NAME, non-specific inhibitor of NO synthase NOS), 7-nitroindazole (neuronal NO synthase inhibitor), 1H-[1,2,4] -oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor), but not NG-D-nitro-arginine methyl ester (D-NAME) or okadaic acid (protein phosphatase 1 and 2 inhibitor) prevented gabapentin-induced antiallodynia. Pinacidil activity was not blocked by L-NAME, D-NAME, 7-nitroindazole, ODQ, KT-5823 or okadaic acid. Moreover, KT-5823, glibenclamide (ATP-sensitive K+ channel blocker), apamin and charybdotoxin (small- and large-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (voltage-gated K+ channel blocker), L-NAME, 7-nitroindazole, ODQ or okadaic acid, reduced diazoxide-induced antiallodynia. Data suggest that gabapentin-induced spinal antiallodynia could be due to activation of the NO-cyclic GMP-PKG-K+ channel pathway.

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PubMed2004

Effects of the suppression of acute herpetic pain by gabapentin and amitriptyline on the incidence of delayed postherpetic pain in mice.

The inoculation of mice with herpes simplex virus type-1 (HSV-1) causes herpes zoster-like skin lesions and pain-related responses (tactile allodynia and mechanical hyperalgesia) from day 5 after inoculation. Skin lesions completely heal by day 15 after inoculation, but about half of mice with acute herpetic pain show pain-related responses long after the lesions heal. Using this mouse model, we examined the effects of repeated administration of gabapentin and amitriptyline on the acute herpetic pain and the incidence of postherpetic pain. Gabapentin and amitriptyline were administered three times daily from day 5 to 11 after inoculation. Postherpetic pain-related responses were assessed on day 30 after inoculation. Gabapentin (10-100 mg/kg) produced the dose-dependent inhibition of acute herpetic pain-related responses. This medication produced marked reduction in the incidence of delayed postherpetic pain and the dose of 100 mg/kg produced the complete inhibition. Amitriptyline (10 mg/kg) did not affect the acute pain-related responses in the initial 3- and 2-day periods and then gradually inhibited them. This dosage produced a substantial but non-significant decrease in the incidence of postherpetic pain-related responses. Amitriptyline (1 and 3 mg/kg) was without effects on acute herpetic and postherpetic pain-related responses. The results strongly support the idea that the severity of the acute herpetic pain is a risk factor of postherpetic neuralgia. It may be worth testing the effects of gabapentin on acute herpetic pain and the incidence of postherpetic neuralgia in human subjects.

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PubMed2006

The P/Q-type voltage-dependent calcium channel as pharmacological target in spinocerebellar ataxia type 6: gabapentin and pregabalin may be of therapeutic benefit.

Voltage-dependent calcium channels (VDCCs) are heteromultimeric complexes that mediate calcium influx into cells in response to changes in membrane potential. The alpha1A subunit, encoded by the CACNA1A gene, is the pore-forming subunit specific to the neuronal P/Q-type VDCCs. These are implicated in fast excitatory and inhibitory neurotransmission. Their highest levels of expression are found in the Purkinje cell layer of the cerebellum, and in the hippocampus. Spinocerebellar ataxia type 6 (SCA 6) is an autosomal dominant cerebellar degeneration that shares neuropathological findings with late-onset cortical cerebellar atrophy (CCA). It is caused by an abnormal expansion of a trinucleotide (CAG) repeat in exon 47 of CACNA1A, on chromosome 19p13. This translates into a polyglutamine (polyQ) tract of prolonged length in the carboxyl terminal of the alpha1A subunit. Heterologous expression of mutated alpha1A subunits results in increased channel inactivation in electrophysiological tests. No treatment is known to improve SCA 6 at present, as none of the available drugs is able to reverse alpha1A dysregulation, nor disturbed protein aggregation, transport and localization in this disease. The drugs gabapentin and pregabalin interact with the alpha2delta subunit of the P/Q-type VDCCs. Gabapentin and pregabalin slow the rate of inactivation in recombinant P/Q-type VDCCs, expressed in Xenopus oocytes. These drugs improve ataxia in cases of CCA, olivopontocerebellar atrophy and ataxia-telangiectasia. On the basis of the neuropathological identity of SCA 6 with CCA, and given the capacity of gabapentin and pregabalin to decrease P/Q-type VDCCs inactivation, in this paper the authors put forward the hypothesis that the administration of gabapentin and pregabalin might prove beneficial in SCA 6 as the ataxia caused by this disease would be expected to improve. The authors hope that researchers working with this illness will be inspired and encouraged to undertake the appropriate clinical and experimental work.

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PubMed2004

Use of gabapentin for attenuation of symptoms following rapid opiate detoxification (ROD)--correlation with neurophysiological parameters--.

Rapid opiate detoxification (ROD) is a technique whereby the opiate-dependent patient is withdrawn acutely, under anesthesia, from the opioid. Following detoxification, patients experience severe back pain and restlessness often accompanied by a restless-leg-syndrome. We evaluated gabapentin given immediately following detoxification to attenuate these symptoms. In addition, we evaluated the use of the somatosensory-evoked potential (SEP) as a parameter to quantitate pain responses. Patients (n=21; mean age 32.5 +/- 7 SD; 12 males, 9 females) underwent ROD with naltrexone (2 x 50 mg) during propofol anesthesia and artificial ventilation (IPPV). Sympathetic overshoot was attenuated by clonidine, and increased bowl movement was managed by continuous i.v. somatostatin. Back pain, restlessness, and restless-leg-syndrome were treated with gabapentin (1200 mg) in the ICU. Efficacy was assessed by the patient's subjective ratings of restlessness (0-4). In addition, measurements of amplitude (microV), latency (ms) of late N100-peak of the somatosensory evoked potential (SEP), and tolerance to an increased electrical nociceptive stimulus (mA) to the forearm were performed. Data were compared to pre-treatment control and to the period shortly after detoxification. From a mean of 8.4 +/- 2.5 microV, N100-peak increased to a mean of 12.3 microV +/- 3.3 (p < 0.005) following opioid detoxification. Gabapentin reduced amplitude height to a mean of 3.5 +/- 1.5 microV. Also, tolerance to nociceptive stimulus, which had dropped to 4.4 mA, increased to 12.5 mA (p < 0.01), while intensity for restlessness and thrashing of limbs dropped from 3.2 to 1.2 (p < 0.05). The sudden displacement of the opiate from its receptor site induced by naltrexone, resulted in a post inhibitory SEP overshoot with an increase in nociceptive afferent volleys, and a lowering in pain threshold. This was associated with back pain, limb thrashing and a restless-leg-syndrome, all of which could be attenuated by gabapentin. The amplitude of late N100-peak parameter appears to be a potential candidate to quantify the increase of nociception in such patients.

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PubMed2004

Gabapentin relieves mechanical, warm and cold allodynia in a rat model of peripheral neuropathy.

Although recent studies demonstrated the relieving effect of gabapentin on neuropathic pain, the effect has not been sufficiently examined. In the present study, we investigated the effect of gabapentin on mechanical, warm and cold allodynia in a rat model of peripheral neuropathy. Under enflurane anesthesia, animals were subjected to the partial injury of the nerves innervating the tail. Behavioral tests for mechanical, cold and warm allodynia on the tail were performed by von Frey hair (2.0 g) stimulation, 4 and 40 degrees C water immersion, respectively. Intraperitoneal injection of gabapentin (30, 100, 300 mg/kg) significantly alleviated mechanical, warm and cold allodynia in a dose-dependent manner. Our results suggest that gabapentin is an effective agent against mechanical, warm and cold allodynia in a rat model of peripheral neuropathy.

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PubMed2002

Gabapentin attenuates superior oblique myokymia.

PURPOSE: To investigate therapeutic effects of oral gabapentin therapy on superior oblique myokymia. DESIGN: Observational case series with measurement of visual acuity and eye movements before, during, and after therapy. METHODS: Two adult patients with superior oblique myokymia, refractory to other therapies, were treated with gabapentin orally after informed consent was obtained. Eye movements were measured using the magnetic search coil technique. RESULTS: Superior oblique myokymia completely resolved after starting gabapentin. CONCLUSION: Gabapentin may be an effective treatment for superior oblique myokymia; a double-blind study seems justified.

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PubMed2000

Gabapentin effect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial.

OBJECTIVE: To investigate the effect of gabapentin on subject self-report and physician-administered spasticity scales in individuals with multiple sclerosis. DESIGN: Prospective, double-masked, placebo-controlled, crossover design. SETTING: The Multiple Sclerosis Center at the Denver Veterans Affairs Medical Center. INTERVENTION: Subjects were titrated to either 900 mg gabapentin orally three times a day or placebo over a 6-day period. Subjects underwent a 14-day washout and then were crossed over. No other changes were made to their medication regimen. MAIN OUTCOME MEASURES: The outcome measures were divided into two categories: subject self-report scales physician-administered scales. Subject self-report scales included the spasm frequency scale, spasm severity scale, interference with function scale, painful spasm scale, and global assessment scale. Physician-administered scales included the Modified Ashworth Scale, clonus scale, deep tendon reflexes, plantar stimulation response, and the Kurtzke Expanded Disability Status (EDSS) Scale. Digit Span and Digit Symbol subtests of the WAIS-R Intelligence Scale were administered to assess for possible impaired concentration. The Fatigue Impact Scale was administered to assess for changes in fatigue. The adjective generation technique was administered to assess for alterations in mood. RESULTS: A statistically significant reduction in the impairment of spasticity was found in the gabapentin-treated subjects compared with placebo as measured by the self-report scales of the spasm severity scale, interference with function scale, painful spasm scale, and global assessment scale and by the physician-administered scales of the Modified Ashworth and plantar stimulation response. No significant difference was noted in the Digit Span, Digit Symbol, adjective generation technique, and EDSS. CONCLUSION: Gabapentin reduces the impairment of spasticity, compared with placebo, without the side effects of worsening concentration and fatigue.

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PubMed1997

Gabapentin for relief of upper motor neuron symptoms in multiple sclerosis.

OBJECTIVE: To examine the efficacy of gabapentin in the treatment of spasticity and painful muscle spasms in patients with multiple sclerosis. DESIGN: Double-blind, placebo-controlled crossover study. SETTING: Free-standing, 93-bed, university-affiliated rehabilitation hospital. PARTICIPANTS: There were 15 patients between the ages of 18 and 50 who had laboratory-supported definite multiple sclerosis with spasticity and leg cramps severe enough to interfere with daily activities, including sleep. INTERVENTION: The patients received the placebo or 400mg gabapentin orally three times a day for 48 hours with an 11-day washout period. If the patients were on currently accepted modes of therapy, including oral baclofen, their current medication was not changed. MAIN OUTCOME MEASURES: The outcome measures were Visual Faces Scale rating, Kurtzke Disability Scale, quantitative surface electromyography, Ashworth Scale, presence or absence of clonus in response to rapid ankle dorsiflexion and wrist extension, presence or absence of reflex withdrawal in response to nailbed pressure to the first finger, and assessment of Babinski response. RESULTS: Statistically significant improvements for the gabapentin treated patients were found in the Ashworth Scale, Visual Faces Scale, and Kurtzke Disability Scale. CONCLUSIONS: At a dose of 400mg orally three times a day, gabapentin may be of value in the treatment of the spasticity and painful muscle cramping experienced by patients with multiple sclerosis.

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PubMed1996

Efficacy of gabapentin therapy in children with refractory partial seizures.

Thirty-two children with refractory partial epilepsy received open-label gabapentin as an additional medication to their antiepileptic drug regimen. Gabapentin was given in a dose ranging from 10 to 50 mg/kg per day (mean dose, 26.7 mg/kg daily). All patients had partial seizures with or without secondary generalization. Compared with baseline, 11 patients (34.4%) had a greater than 50% decrease in seizure frequency, and 4 (12.5%) had a 25% to 50% decrease in seizure frequency. Of the seven children who received the medication for 6 months or longer, two were seizure free and four were almost seizure free (having one seizure every few months). Mean gabapentin concentration was 4.8 micrograms/ml, and mean apparent clearance was 372 ml/kg per hour. The major reported side effects were behavioral. These consisted of hyperactivity, irritability, and agitation that occurred in patients with baseline mental retardation with attention deficit. We conclude that gabapentin can be a useful adjunctive medication in the treatment of refractory partial epilepsy in children.

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PubMed2003

Effect of gabapentin on nausea induced by chemotherapy in patients with breast cancer.

In an anecdotal report, complete resolution of chemotherapy-induced nausea was seen in a patient with breast cancer, after she was placed on the anticonvulsant gabapentin. On this basis, we did an open-label study in which oral gabapentin 300 mg thrice daily was given for every other chemotherapy treatment in nine patients with breast cancer. Six of the nine reported at least a three-point improvement in peak delayed nausea (on an eight-point nausea scale), and three patients had complete resolution of nausea when taking gabapentin. This preliminary evidence shows that gabapentin might have a role in treatment of chemotherapy-induced nausea.

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PubMed2002

Treatment of alcohol withdrawal with gabapentin.

Gabapentin is an anticonvulsant agent, also effective in the treatment of mood disorders and anxiety disorders. Three cases of alcohol withdrawal treated with gabapentin are presented. All patients received gabapentin 400 mg tid for 3 days, 400 mg bid for 1 day, and finally 400 mg for 1 day. Withdrawal symptoms subsided and no adverse effects were observed. The possible effectiveness of gabapentin in the treatment of alcohol withdrawal warrants further investigation by systematic and well-designed studies.

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PubMed2003

Gabapentin reduces the mechanosensitivity of fine afferent nerve fibres in normal and inflamed rat knee joints.

The antiepileptic drug gabapentin has been shown to have an antihyperalgesic effect following central administration. This electrophysiological investigation examined whether peripherally administered gabapentin could modulate the mechanosensitivity of primary afferents innervating normal and kaolin/carrageenan inflamed rat knee joints. Close intraarterial injection of gabapentin (0.01, 1 and 100mg/kg) dose-dependently reduced afferent firing rate in both normal and acutely inflamed rat knees in response to normal and hyper-rotation of the joint. Thus, in addition to its central mode of action, peripheral administration of gabapentin reduces nociception locally and this may prove to be beneficial in the treatment of various pain syndromes including inflammatory arthritis.

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PubMed2003

Genotype-dependence of gabapentin and pregabalin sensitivity: the pharmacogenetic mediation of analgesia is specific to the type of pain being inhibited.

The antiepileptic drug, gabapentin, and another structurally related compound, pregabalin, are increasingly employed in the pharmacotherapy of chronic pain states, although their primary mechanism of action remains a topic of active study. A genomic approach to the study of these drugs may elucidate their potentially novel mechanisms. We examined the heritability of sensitivity to analgesia from gabapentin and pregabalin as a precursor to linkage mapping efforts. Accordingly, 11 inbred mouse strains were tested for inhibition of nociception by gabapentin or pregabalin (50-300 mg/kg, i.p.) in two different preclinical assays of inflammatory pain, the formalin test (5% formalin; 20 microl) and zymosan thermal hyperalgesia on the paw-withdrawal test (3 mg/ml zymosan; 20 microl). Significant strain-dependence of drug action was noted in each case, indicating that sensitivity to these analgesics is heritable. Furthermore, the pattern of strain sensitivities to gabapentin and pregabalin were mostly similar, supporting the notion that they act via similar genetic and physiological mechanisms. However, there was virtually no correlation between strain sensitivities to pregabalin inhibition of formalin nociception and zymosan thermal hyperalgesia. In light of previous data from our laboratory and others regarding morphine analgesia, we now establish and empirically demonstrate the general principle that pharmacogenetic mechanisms underlying analgesic sensitivity are specific to the type of pain being inhibited. This has considerable implications for ongoing pharmacogenetic investigations and, more generally, for the choices of preclinical models of pain used in drug development.

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PubMed1999

Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat.

A single injection of streptozocin (50 mg/kg, i.p.) led to the development of static and dynamic allodynia in the rat. The two responses were detected, respectively, by application of pressure using von Frey hairs or lightly stroking the hind paw with a cotton bud. Static allodynia was present in the majority of the animals within 10 days following streptozocin. In contrast, dynamic allodynia took almost twice as long to develop and was only present in approximately 60% of rats. Morphine (1-3 mg/kg, s.c.) and amitriptyline (0.25-2.0 mg/kg, p.o.) dose-dependently blocked static allodynia. However, neither of the compounds was effective against dynamic allodynia. In contrast, gabapentin (10-100 mg/kg, p.o.) and the related compound pregabalin (3-30 mg/kg, p.o.) dose-dependently blocked both types of allodynia. However, the corresponding R-enantiomer (10-100 mg/kg, p.o.) of pregabalin, was found to be inactive. The intrathecal administration of gabapentin dose-dependently (1-100 microg/animal) blocked both static and dynamic allodynia. In contrast, administration of similar doses of gabapentin into the hind paw failed to block these responses. It is suggested that in this model of neuropathic pain dynamic allodynia is mediated by A beta-fibres and the static type involves small diameter nociceptive fibres. These data suggest that gabapentin and pregabalin possess a superior antiallodynic profile than morphine and amitriptyline, and may represent a novel class of therapeutic agents for the treatment of neuropathic pain.

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PubMed1999

Gabapentin as an adjuvant to opioid analgesia for neuropathic cancer pain.

Gabapentin was administered as an "add on" therapy to 22 patients with neuropathic cancer pain only partially responsive to opioid therapy. Global pain, burning pain, shooting pain episodes, and allodynia were assessed separately. Gabapentin was given for at least a week and efficacy was assessed after 7 to 14 days of therapy. Global pain score decreased from a mean (+/- SD) of 6.4 (+/- 1.5) to 3.2 (+/- 1.3) (95% confidence interval of the baseline minus final score differences [95% CI] = 1.0-2.4). Burning pain intensity decreased from a mean (+/- SD) of 5.1 (+/- 3.6) to 2.0 (+/- 2.3) (95% CI = 1.5-3.8), and episodes of shooting pain decreased in frequency from 7.2 (+/- 3.7) to 2.2 (+/- 2.2) daily episodes (95% CI = 1.8-4.3). Allodynia was found in 9 patients and disappeared in 7 during gabapentin administration. Twenty patients judged the new drug efficacious in relieving their symptoms. The potential role of gabapentin as an adjuvant to opioid analgesia in cancer pain is discussed.

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PubMed2001

Population pharmacokinetics of gabapentin in infants and children.

PURPOSE: To characterize gabapentin pharmacokinetics in infants and children using a population approach and to identify important demographic and/or physiologic determinants of gabapentin disposition. METHODS: Gabapentin was administered in single doses of 10 mg/kg (N=48 healthy subjects, age 1 month-12 years) or in multiple doses of 10-65 mg/kg per day (N=205 patients with epilepsy, age 2 months-13 years) at 08:00, 14:00, and 20:00. Serial concentration-time data from the healthy subjects were combined with sparse data obtained in patients and were modeled using NONMEM. RESULTS: Gabapentin oral clearance (l/h) was directly related to creatinine clearance (ml/min) with a slope of 0.116. The slope of the relationship was 36% greater in blacks than in subjects of other races. When oral clearance was normalized for body weight, young children (<5 years) had higher and more variable values than older children. Volume of distribution was related to body weight and appeared to differ between subjects and patients. Intersubject variability was approximately 30% for oral clearance and volume of distribution and was larger for the absorption rate constant and lag time. Residual variability, a measure of intrasubject variability and measurement error, was smaller in subjects than in patients. CONCLUSIONS: On a weight basis, 33% larger doses would be required in younger children (<5 years) to achieve the same exposure as older children.

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PubMed1999

Gabapentin modifies extracellular opioid peptide content in amygdala: a microdialysis study.

Opioid peptide release was monitored in the amygdala and hippocampus of freely moving rats following a single oral administration of gabapentin using microdialysis. Extracellular opioid peptide levels were elevated above basal levels in the amygdala within the first 60 (54%) and 90 min (68%) after gabapentin administration. Levels returned to basal conditions 120 min following the treatment. No significant changes were detected in the hippocampus. The majority of immunoreactive material recovered from the amygdala following gabapentin administration was identified as Leu-enkephalin and Met-enkephalin by high performance liquid chromatography (HPLC) analysis. It is proposed that the enhanced opioid peptide release in the amygdala induced by gabapentin might be involved with the antiepileptic effects as well as with some adverse events produced by this drug.

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PubMed1999

Cognitive abilities and adjustment with gabapentin: results of a multisite study.

The cognitive and quality of life effects of gabapentin are not yet well explored. While preliminary work in the area has provided positive findings, a large double-blinded study has been needed to explore this area more thoroughly. From 24 sites in North America, 201 adults were studied who had uncontrolled complex partial seizures with or without secondary generalization. Attempts were made to convert each patient from one or two marketed antiepileptic drugs (AEDs) taken in baseline to gabapentin monotherapy (600, 1200, or 2400 mg/day). Tests of cognitive abilities and adjustment were administered at the end of the 8-week baseline period and at the end of the 26-week double-blind treatment period. Analyses of baseline to treatment period changes were conducted for each dose group in comparison with a reference group of placebo-treated patients from another study. In the area of cognitive functioning, no changes in any of the gabapentin groups were found in comparison with the reference group. In the area of adjustment and mood, however, improvement with gabapentin administration was noted on several variables pertaining to emotional and interpersonal adjustment. These results are consistent with findings from previous studies.

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