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PubMed2000

Intrathecally administered gabapentin inhibits formalin-evoked nociception and the expression of Fos-like immunoreactivity in the spinal cord of the rat.

In the present study, we investigated the effects of intrathecal gabapentin on nociceptive behaviors and the numbers of spinal Fos-like immunoreactive (Fos-LI) neurons evoked by injection of 0.25 to 2.5% formalin in the hindpaw of the rat. Pretreatment with gabapentin dose dependently decreased flinches and weighted pain scores in phase 2, but not phase 1, at each concentration of formalin. The highest dose of gabapentin (100 microgram) shifted the EC(50) values of formalin for both flinches and weighted pain scores to the right by 2.5-fold, suggesting that formalin was perceived to be significantly less noxious. Gabapentin also decreased phase 2 behaviors when administered after formalin but was only one third as potent. Unlike its inhibition of formalin-evoked nociceptive behaviors, the effect of gabapentin on the expression of Fos-like immunoreactivity in the spinal cord was highly dependent on the concentration of formalin. Intrathecal pretreatment with 100 microgram of gabapentin did not decrease the numbers of Fos-LI neurons evoked by 0.5% formalin, yet this dose decreased the numbers of Fos-LI neurons in laminae I-II and VII-X of rats that received 1.25% formalin and uniformly decreased by 50% the numbers of Fos-LI neurons in all laminae of rats that received 2.5% formalin. These latter findings suggest that gabapentin neither nonselectively decreases the excitability of spinal cord neurons nor uniformly inhibits the release of all neurotransmitters from primary afferent terminals. Rather, its effects may be preferential for those neurotransmitters released by higher, more noxious concentrations of formalin and for conditions in which there is a greater induction of central sensitization.

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PubMedDate not supplied

Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study.

OBJECTIVE: Gabapentin is an antiepileptic drug of new generation that increases brain GABA levels. We report the results of a three-month randomised double-blind placebo-controlled study on the effects of gabapentin in the prophylaxis of patients with migraine meeting the IHS criteria. PATIENTS AND METHODS: We treated 63 patients suffering from migraine with or without aura. Patients treated their attack at home using symptomatic drugs and clinical assessment was recorded on a diary. After a washout of 8 week from any other prophylactic treatment, all patients were treated with 1200 mg/day of gabapentin; this is our therapeutic plan: 400 mg/day from 1st to 3rd day, 800 mg/day from 4th to 6th day and 1200 mg/day from 7th day. RESULTS: No patients withdrew, gabapentin was well tolerated; adverse events (somnolence, dizziness, tremor, fatigue and ataxia) generally were transient and mild to moderate in severity and in 13 patients (27%) only occurred. At the end of treatment, in such case, we reported a significative reduction of frequency and intensity of migraine in 30 patients treated with gabapentin. DISCUSSION: Our observations indicate that gabapentin is well tolerated by patients and that reduces headache frequency and use of symptomatic drugs in both groups. Gabapentin shows to have an effective therapeutic action in the prophylactic treatment of migraine.

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PubMed2001

Gamma-aminobutyric acid type B receptors with specific heterodimer composition and postsynaptic actions in hippocampal neurons are targets of anticonvulsant gabapentin action.

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.

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PubMedDate not supplied

[Efficacy of gabapentin in a sample of bipolar patients].

INTRODUCTION: Field studies support the idea of gabapentin being helpful in the maintenance, and in the treatment of some symptoms in bipolar patients. Our study evaluates relapse rates previous and after gabapentin administration in severe bipolar patients. METHODOLOGY: Gapabentine was administered to all consecutive bipolar patients from a relapse prevention program who could not be given lithium, valproic acid or carbamacepin because of his current medical condition or his past history of secondary effects or lack of response to those treatments. Number and severity of relapses were evaluated before and after gabapentin administration. RESULTS: Seven patients were included in the study. Medium maintenance period with gabapentine was 9 months. In the gabapentin period, relapses per month increased from 0.18 in the previous three years to 0.29. This may be due because six patients interrupted abruptly previous treatment in less than 1 week. Relapses severity, evaluated by measuring length and number of hospitalisations, and number of interviews by month, was similar to the three previous years, and better than the period from the beginning of the condition. Clinical Global Impression evaluated gabapentin as similar to previous mood stabilizers in five patients and better in two. Irritability and dysphoria improved in all the patients. CONCLUSION: Although gabapentin may be helpful in some patients, a clinical essay that shows its efficacy as add-on treatment is need.

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PubMed2003

The pattern of gabapentin use in a tertiary palliative care unit.

BACKGROUND: Little is known about current practice in using the anticonvulsant gabapentin in the management of cancer-related neuropathic pain. OBJECTIVES: The main objective of this study was to describe the pattern of gabapentin use as an adjuvant analgesic for cancer-related neuropathic pain in patients admitted to a tertiary palliative care unit. METHODS: A retrospective medical chart review for 150 patients admitted to a tertiary palliative care unit over a period of 10 months. Abstracted data included patient characteristics, primary diagnoses, pain scores, and the type and dose of opioids and other adjuvants used. RESULTS: Of the 147 patients with a cancer diagnosis, 45 (31%) had neuropathic pain. Of those, 22 (49%) received gabapentin. The final daily dose of gabapentin ranged from 100 mg-3,000 mg (mean: 941 mg +/- 665 mg; median: 900 mg). Gabapentin was discontinued in 10 patients (46%). Suggested adverse effects included sedation (n = 4), dizziness (n = 1), and bitter taste (n = 1). The change in pain scores was not significantly different in those who continued on gabapentin compared to those who discontinued it. CONCLUSIONS: The retrospective nature of the study and the small sample size render solid conclusions difficult to make. However, gabapentin was discontinued in approximately half the patients who received it, and often when only modest doses were used. Similar studies from other centres may improve understanding of current practices and aid in designing future clinical trials on the subject.

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PubMed2004

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

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

Amines↗
PubMed2004

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

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

Amines↗
PubMedDate not supplied

The effect of gabapentin on antinociceptive action of analgesics.

The effect of gabapentin at a dose of 10 mg/kg (single administration) and at 3 mg/kg/day (administered for 10 days) on the analgesic action of morphine (10 mg/kg), metamizol (500 mg/kg) and indomethacin (10 mg/kg and 1.4 mg/kg) in mice was assessed on the basis of hot-plate and tail-flick tests. All the drugs were administered intraperitoneally (i.p.). Gabapentin was administered to mice 30 min before the administration of analgesics. The animals reactions to noxious stimuli were measured 60, 90 and 120 min after gabapentin administration. Gabapentin administered in a single dose, as well as in multiple ones, was found to cause antinociception, especially evident in the hot-plate test. The single dose of gabapentin enhances the analgesic effect of morphine in the hot-plate test, whereas in the tail-flick test it demonstrates an opposite effect. Gabapentin in a single dose does not affect significantly the effects of metamizol and indomethacin, whereas multiple doses decrease the action of these drugs. Gabapentin abolishes the tolerance of antinociceptive effect of morphine.

Amines↗
PubMed2005

Starting dose of gabapentin for patients with post-herpetic neuralgia--a dose-response study.

BACKGROUND: Gabapentin has been shown to provide pain relief for post-herpetic neuralgia at dosage of 1200 to 2400 mg/day. However, the initial dosing strategy has not been thoroughly investigated. The purpose of this study was to establish the initial dosing strategy in the treatment of the gabapentin-naive patients with post-herpetic neuralgia. METHODS: This clinical study was an open-label, randomized, time-sequence and controlled trial. Each gabapentin-naive subject was allocated to receive either 200 mg (100 mg, twice daily), 400 mg (100 mg, four times daily), or 600 mg (200 mg, three times daily) of gabapentin for three days. The analgesic effect and occurrence of dizziness, drowsiness, and fatigue were assessed at day 0 and day 3. RESULTS: A total of 61 subjects (32 male/29 female) were enrolled in this study. The intensity of pain was greatly improved in all three groups after three days of treatment (visual analog scale decreased from 6.5 +/- 1.6 to 4.5 +/- 2.1, P < 0.05). There was no statistically significant difference among subjects taking 200 mg, 400 mg, or 600 mg with respect to dizziness, drowsiness or fatigue. CONCLUSIONS: This study shows that elderly gabapentin-naive subjects no matter whether receiving 200, 400 or 600 mg/day of gabapentin benefited a moderate pain relief with minimal side effects at the first three days of treatment. Since starting with a minimal dose of 200 mg/day did not offer a better reduction of side effects, we suggest that 600 mg/day gabapentin could be a safe and effective starting dose for patients with post-herpetic neuralgia.

Adult↗
PubMed1986

Pharmacokinetics and metabolism of gabapentin in rat, dog and man.

This paper describes the pharmacokinetic studies of 1-(aminomethyl)-cyclohexane acetic acid (gabapentin, Gö 3450, CI-945) conducted with the 14C-labelled substance following intravenous and intragastric administration to rats and dogs and oral administration to humans. Gabapentin is well absorbed in rats, dogs and in humans, with maximum blood levels, reached within 1-3 h after peroral administration. Following i.v. administration to rats, similar blood and brain levels of gabapentin are observed after a short distribution phase, whereby concentrations in cerebrum and cerebellum are comparable. The highest concentrations are found in the pancreas and kidneys and the lowest values in adipose tissue. No binding of gabapentin to human plasma proteins or human serum albumin is observed. The distribution coefficient (octanol/buffer pH 7.4) is 7.5 X 10(-2). In man, no biotransformation of gabapentin is observed. In rats, biotransformation is only minor. In dogs, however, a remarkable formation of N-methyl-gabapentin is found. Elimination half-lives range between 2-3 h in rats, 3-4 h in dogs, and 5-6 h in man. Gabapentin is nearly exclusively eliminated via the kidneys. Renal elimination was up to 99.8% in rats and approx. 80% in man following oral administration. The blood level-time course after i.v. administration to rats can well be described by a three-compartment open model. Experiments in rats and dogs demonstrate that pharmacokinetics are not sex-dependent and are not changed after multiple dosage. Pharmacokinetics are shown to be linear in the range tested of 4 to 500 mg/kg i.v. in rats.

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PubMed1995

Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys.

Gabapentin, an analog of gamma-aminobutyric acid, exhibits anticonvulsant properties in both animal models and humans. Gabapentin pharmacokinetics was studied in laboratory animals using HPLC and radiometry. Oral bioavailability was 40% in monkeys administered 25 mg/kg, 79% in mice and rats receiving 50 mg/kg, and 80% in dogs administered 50 mg/kg. Binding to plasma proteins was < 3%. Maximum blood or plasma concentrations generally occurred within 2 hr of an oral dose. In rats and monkeys, increases in maximum plasma concentrations and/or areas under the curve were less than dose-proportional following oral administration, most likely because of saturable absorption. However, intravenous pharmacokinetics in rats were linear over the dosage range of 4-500 mg/kg. Mean intravenous elimination half-life was 1.7 hr in rats, 2.9 hr (14C only) in dogs, and 3.0 hr in monkeys. In rats and dogs, repeated administration did not alter gabapentin or 14C pharmacokinetics. Additionally, gabapentin did not induce hepatic cytochrome P450 monooxygenases in rats. There were no age- (rats only) or gender-associated changes in pharmacokinetic parameters. [14C]Gabapentin was extensively distributed to tissues. In the dog, gabapentin was metabolized to N-methylgabapentin (approximately 34% of dose); whereas metabolism in mouse, rat, and monkey was minimal (< 5%). The principal route of excretion was via urine. In summary, as an antiepileptic drug, gabapentin exhibited desirable pharmacokinetic properties, such as linear elimination kinetics, not highly bound to plasma proteins, not extensively metabolized, and not an inducer of hepatic cytochrome P450.

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PubMed2006

Smoked cocaine self-administration by humans is not reduced by large gabapentin maintenance doses.

Previously, we reported that gabapentin, a lambda-aminobutyric acid (GABA) agonist, significantly reduced "positive" subjective effects of cocaine without reducing cocaine self-administration. We speculated that the gabapentin doses used in that study were too low to detect subtle shifts in the reinforcing effects of cocaine. Thus, the present study examined the effects of larger gabapentin maintenance doses on cocaine-related effects, including self-administration. During this 48-day double-blind, crossover design study, the effects of gabapentin maintenance (0, 2400, 3200 mg/day) on response to cocaine (0, 12, 25, 50 mg) were investigated in six cocaine-dependent individuals not seeking treatment for their cocaine use. Active cocaine significantly increased choice to self-administer cocaine, subjective-effect ratings (e.g., "Good Drug Effect"), blood pressure, and heart rate. Gabapentin did not decrease cocaine self-administration, cardiovascular measures, or most subjective effects of cocaine. These data agree with findings from a clinical trial examining the effects of similar gabapentin doses on cocaine use by treatment-seeking cocaine-dependent individuals and suggest that gabapentin does not show promise as a treatment medication for cocaine dependence.

Adult↗
PubMed2000

Gabapentin monotherapy: new indication. Sometimes helpful.

(1) Gabapentin is now licensed for first-line or replacement monotherapy of partial epilepsy, in patients over 12 years of age. (2) The assessment file concurs with current recommendations of medicines agencies. (3) One comparative trial of first-line monotherapy showed a similar efficacy/adverse effects ratio of gabapentin and carbamazepine. Gabapentin has not been compared with valproate sodium. (4) In one trial, involving patients with refractory epilepsy, various doses of gabapentin were added to an ongoing inadequately effective treatment, which was then gradually stopped. Gabapentin monotherapy was considered satisfactory in a minority of patients. (5) The adverse effects of gabapentin are limited to neuropsychological disorders, namely dizzy spells, drowsiness, fatigue and headache. The risk of interactions is also limited. (6) The optimal dose regimen of gabapentin is not yet established.

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PubMed2002

Gabapentin: new indication. Little impact on partial epilepsy in children between 3 and 12.

(1) The standard treatment for partial epilepsy in children is carbamazepine. The efficacy of other antiepileptics has also been documented, either alone (phenobarbital, oxcarbazepine, valproate sodium, phenytoin), or in drug combinations (lamotrigine, topiramate). (2) A licence extension has been granted in France for gabapentin in partial epilepsy in children aged 3 to 12 years, in combination with other antiepileptics. (3) The clinical file contains no data from trials comparing gabapentin with other antiepileptics. (4) The main double-blind trial involved 247 children who were treated either with their usual treatment + gabapentin or usual treatment + placebo. Gabapentin was only moderately effective, and the overall number of responders did not differ significantly between the gabapentin and placebo groups. (5) In this trial the main adverse effects among the children on their usual treatment + gabapentin were behavioural disorders (hostility and mood swings). (6) In practice, the licensing of gabapentin for children with partial epilepsy aged between 3 and 12 years changes nothing in their practical management.

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PubMed2003

Update on gabapentin therapy of neuropathic pain.

OBJECTIVE: To provide current information regarding the efficacy and tolerability of the anticonvulsant gabapentin in the management of neuropathic pain. DATA SOURCES: A MEDLINE search was conducted to identify pertinent studies, case reports, letters, and reviews in the English language published from 1986 through October 2002. Additional references were obtained from the bibliographies of these articles. STUDY SELECTION: All studies evaluating any aspect of use of gabapentin as an analgesic. DATA SYNTHESIS: Numerous case reports and series (total N = 750) have suggested efficacy of gabapentin in daily doses of up to 3.6 g. Controlled trials in painful diabetic neuropathy, postherpetic neuralgia, and multiple sclerosis have confirmed the potential utility of this agent in a variety of neuropathic pain syndromes (total N = 511). Central nervous system side effects are of most concern with gabapentin. The absence of significant drug-drug interactions makes this agent a preferred treatment choice, as opposed to anticonvulsants such as carbamazepine or lamotrigine. CONCLUSION: In human pain models using patients with neuropathic pain, gabapentin has been found effective against both spontaneous and evoked pain, and these effects are independent of the pain source. Gabapentin, in doses ranging up to 3.6 g/day, has demonstrated efficacy in a variety of neuropathic pain states, including those refractory to agents such as the tricyclic antidepressants (TCA) and other anticonvulsants. A major question today is whether gabapentin should be considered as first-line therapy (i.e., even before a trial of a TCA or carbamazepine) or as second-line therapy for individuals unresponsive to or intolerant of TCAs and/or carbamazepine.

Journal Article↗
PubMed1999

A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor.

BACKGROUND: New medication is needed to treat essential tremor. Preliminary evidence suggests that gabapentin may be effective in the treatment of this disorder. OBJECTIVE: To study the effects of gabapentin in a comparative, double-blind, crossover, placebo-controlled trial of patients who have essential tremor. PATIENTS AND METHODS: 16 patients with essential tremor (6 with a new onset and 10 with a 2-week washout period of previous treatment with propranolol hydrochloride) received gabapentin (Neurontin), 400 mg 3 times daily; propranolol hydrochloride, 40 mg 3 times daily; and placebo for 15 days with a 1-week washout period between treatments. MAJOR OUTCOME MEASURES: Major outcome evaluations consisted of a Tremor Clinical Rating Scale, accelerometric recordings, and a self-reported disability scale obtained before drug intake on study days 1 and 15 of each treatment period. In addition, the initial (day 1) and superimposed (day 15) drug effects were studied before and 2, 4, 6, and 8 hours after drug intake. RESULTS: At day 15, both gabapentin and propranolol demonstrated significant and comparable efficacy in reducing tremor from baseline in all tremor measures. The initial drug effects evaluated through accelerometry revealed no significant changes with the use of a placebo, but gabapentin and propranolol use significantly reduced tremor power. CONCLUSION: Gabapentin may be useful for the treatment of essential tremor.

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PubMed1997

A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus.

We conducted a double-blind crossover trial comparing gabapentin (up to 900 mg/day) to baclofen (up to 30 mg/day) as therapy for acquired nystagmus in 21 patients. We measured visual acuity and the nystagmus before, and at the end of, 2 weeks on each medication. For a group of 15 patients with acquired pendular nystagmus (APN), visual acuity improved significantly with gabapentin, but not with baclofen. Gabapentin significantly reduced APN median eye speed in all three planes, but baclofen did so only in the vertical plane. In 10 patients with APN, the reduction of nystagmus with gabapentin was substantial and 8 of these elected to continue taking the drug. In 6 patients with downbeat or torsional downbeat nystagmus, changes in median slow-phase eye speed were less consistent with both drugs, either increasing or decreasing, and being dependent on viewing conditions. Only 1 patient showed consistent reduction of median eye speed, and this was achieved by either drug. Our findings suggest that gabapentin may be an effective treatment for many patients with APN and that occasional patients with downbeat nystagmus will respond to gabapentin or baclofen.

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PubMed2006

Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial.

Pruritus is defined as the second order of nociception, the first being pain; thus, there is a rationale to study gabapentin, a drug that increases the threshold to experience nociception. The aim of this double-blind, randomized, placebo-controlled trial was to study the effect of gabapentin on the perception of pruritus and its behavioral manifestation, scratching, in cholestasis. The participants were 16 women with chronic liver disease and chronic pruritus. Hourly scratching activity (HSA) was continuously recorded for up to 48 hours at baseline and on treatment for at least 4 weeks in an inpatient setting. The perception of pruritus was assessed by interviews and by a visual analog score (VAS) of pruritus recorded every hour while patients were awake. Patients were randomized to the study drug (gabapentin or placebo) at a starting dose of 300 mg orally per day in divided doses to a maximum of 2,400 mg or until relief from pruritus. Gabapentin was associated with an increase in mean HSA, in contrast to the placebo, which was associated with a decrease. The mean VAS decreased significantly among those taking the placebo and in some patients on gabapentin. In conclusion, gabapentin did not provide a significant therapeutic advantage over the placebo; in fact, it was associated with an increase in the perception of pruritus and in HSA in some patients.

Adult↗