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Gabapentin potentiates the antiseizure activity of certain anticonvulsants in DBA/2 mice.

Gabapentin (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in Dilute Brown Agouti DBA2J (DBA/2) mice in a dose-dependent manner. Gabapentin at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The potentiation induced by gabapentin was greatest for diazepam, phenobarbital and valproate, less for felbamate and phenytoin and least for carbamazepine and lamotrigine. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment of the above drugs + gabapentin was more favourable than that of the same drugs + saline. Since gabapentin did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that gabapentin can modify the clearance from the brain of the anticonvulsant drugs studied can not be excluded. In addition, gabapentin did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, gabapentin showed an additive effect when administered in combination with certain classical anticonvulsants, most notably diazepam, phenobarbital, felbamate, phenytoin and valproate.

Acetates↗

An open label study of gabapentin in the treatment of acute mania.

Recent anecdotal single case reports have suggested that the new antiepileptic drug gabapentin might be effective in the treatment of manic episodes and in the prophylaxis of bipolar disorder. In the present open trial, 14 patients with acute mania were treated for up to 21 days with gabapentin in a dose range from 1200 to 4800 mg/day. Six patients were treated with gabapentin as add-on medication and 8 patients were treated with a high dose of gabapentin alone. Gabapentin was both efficacious and safe when applied in combination with other drugs such as lithium and valproic acid. All patients in the add-on group and 4/8 patients on gabapentin monotherapy finished the 21 day protocol. Analysis of the scores of the Bech-Rafaelsen Mania Assessment Scale (BRMAS) of these patients showed that the mean BRMAS score declined from 37.7 to 7.8 on day 21 in the add-on group and from 27.8 to 9.0 in 4/8 patients finishing 21 days in the monotherapy group. It is suggested that gabapentin monotherapy might be useful in selected patients to treat modest but not severe manic states. In addition, gabapentin in conjunction with other effective mood stabilisers seems to be safe and efficacious in the treatment of severe mania.

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Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial.

OBJECTIVE: To evaluate whether treatment with the anticonvulsant gabapentin may be effective in reducing hot flash frequency and severity. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in 59 postmenopausal women with seven or more hot flashes per day examining the effects of gabapentin 900 mg per day on hot flash frequency after 12 weeks of treatment. Subsequently, study patients were enrolled in a 5-week, open-label treatment phase, during which patients could increase the dose of gabapentin to 2,700 mg per day, if needed. RESULTS: After 12 weeks of double-blind treatment, intention-to-treat analysis showed that gabapentin 900 mg per day was associated with a 45% reduction in hot flash frequency and a 54% reduction in hot flash composite score (frequency and severity combined into one score) from baseline, compared with 29% (P =.02) and 31% (P =.01) reductions, respectively, for placebo. Four patients (13%) in the gabapentin group and one (3%) in the placebo group withdrew from the double-blind study because of adverse events. Fifteen patients (50.0%) in the gabapentin group reported at least one adverse event, compared with eight patients (27.6%) in the placebo group. Higher, open-label gabapentin dosing was associated with 54% and 67% reductions in hot flash frequency and composite score from baseline, respectively. CONCLUSION: Gabapentin is effective in reducing hot flash frequency and severity in postmenopausal women.

Acetates↗

Evidence for the use of gabapentin in the treatment of diabetic peripheral neuropathy.

BACKGROUND: One of the most common peripheral nerve complications of diabetes is painful diabetic peripheral neuropathy (DPN). Although tricyclic antidepressants (TCAs) have traditionally been used to relieve the pain of this condition, gabapentin's reported efficacy in various neuropathic pain states and its favorable side-effect profile compared with other available agents have led to interest in the use of this agent for the treatment of DPN. OBJECTIVES: This paper reviews the current clinical literature on the effectiveness and tolerability of gabapentin in the treatment of DPN. It also considers whether the evidence favors gabapentin's use as an alternative or first-line agent. METHODS: A search of the English- and French-language literature for the years 1990 through 2000 was performed using MEDLINE, Current Contents/Clinical Medicine, and International Pharmaceutical Abstracts, plus the reference lists of the articles identified through this search. The search terms used were gabapentin, anticonvulsant, diabetic peripheral neuropathy, and neuropathy. Included studies were limited to trials in human subjects. RESULTS: The literature search identified several case reports and case series, as well as 3 small placebo-controlled studies (2 complete, 1 brief report) and 1 comparative trial against the TCA amitriptyline. The designs and dosing regimens differed between studies. CONCLUSIONS: Many clinicians consider gabapentin an alternative treatment option in patients with DPN who are unable to tolerate traditional agents or in whom traditional agents are contraindicated. To date, gabapentin has been well tolerated, superior to placebo, and equivalent to amitriptyline in small clinical trials of short duration. Although overall efficacy and safety profiles appear to be favorable, larger long-term studies are needed to determine the place of gabapentin in relation to other treatment options. There is currently insufficient evidence from controlled trials to support the use of gabapentin as first-line therapy for DPN.

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Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial.

A double-blind, randomised, placebo-controlled 8-week study was conducted to evaluate the efficacy and safety of gabapentin in the treatment of neuropathic pain, using doses up to 2400 mg/day. The study used a novel design that was symptom- rather than syndrome-based; an approach that aimed to reflect the realities of clinical practice. Participants had a wide range of neuropathic pain syndromes, with at least two of the following symptoms: allodynia, burning pain, shooting pain, or hyperalgesia. Patients were randomised to gabapentin (n=153) or placebo (n=152). Gabapentin was given in three divided doses, initially titrated to 900 mg/day over 3 days, followed by two further increases, to a maximum of 2400 mg/day if required by the end of week 5. The primary outcome measure was changed in average daily pain diary score (baseline versus final week). Over the 8 week study, this score decreased (i.e. improved) by 1.5 (21%) in gabapentin treated patients and by 1.0 (14%) in placebo treated patients (P=0.048, rank-based analysis of covariance). Significant differences were shown in favour of gabapentin (P<0.05) for the Clinician and Patient Global Impression of Change, and some domains of the Short Form-McGill Pain Questionnaire. Improvements were also shown in patient-reported outcomes in quality of life, as seen by significant differences in favour of gabapentin in several domains of the Short-Form-36 Health Survey. Gabapentin was well tolerated and the majority of patients completed the study (79 versus 73% for placebo). The most common adverse events were mild to moderate dizziness and somnolence, most of which were transient and occurred during the titration phase. This study shows that gabapentin reduces pain and improves some quality-of-life measures in patients with a wide range of neuropathic pain syndromes.

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Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study.

The objective of this study was to compare the efficacy and tolerability of gabapentin and amitriptyline monotherapy in painful diabetic neuropathy. This was a 12-week, open-label, prospective, randomized trial. Twenty-five type-II diabetic patients with pain attributed to diabetic neuropathy and a minimum score of 2 on a pain intensity scale ranging from 0 (no pain) to 4 (excruciating pain) were randomized to receive either gabapentin, titrated from 1,200 mg/day to a maximum of 2,400 mg/day, or amitriptyline, titrated from 30 mg/day to a maximum of 90 mg/day. Both drugs were titrated over a 4-week period and maintained at the maximum tolerated dose for 8 weeks. The main outcome measures were weekly pain intensity and paresthesia intensity, measured on two categorical scales. Thirteen patients received gabapentin and 12 received amitriptyline. All 25 patients completed the trial. Gabapentin produced greater pain reductions than amitriptyline (mean final scores were 1.9 vs. 1.3 points below baseline scores; P = 0.026). Decreases in paresthesia scores also were in favor of gabapentin (1.8 vs. 0.9 points; P = 0. 004). Adverse events were more frequent in the amitriptyline group than in the gabapentin group: they were reported by 11/12 (92%) and 4/13 (31%) of patients, respectively (P = 0.003). Side effects were the main limiting factor preventing dose escalation. Gabapentin produced greater improvements than amitriptyline in pain and paresthesia associated with diabetic neuropathy. Additionally, gabapentin was better tolerated than amitriptyline. Further controlled trials are needed to confirm these preliminary results.

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Effect of oral gabapentin on postoperative epidural analgesia.

BACKGROUND: Gabapentin has been used successfully as a non-opioid analgesic adjuvant for postoperative pain management. We hypothesized that gabapentin might be a useful adjuvant for postoperative analgesia provided with patient-controlled epidural analgesia (PCEA). METHODS: Forty patients undergoing lower extremity surgery procedures were randomly assigned to receive (i) placebo capsules (control) or (ii) gabapentin (1.2 g day(-1)) before and for 2 days after surgery. Anaesthetic technique was standardized. Postoperative assessments included verbal rating scale scoring for pain and sedation, PCEA usage, quality of recovery assessment, times of GI function recovery, and patient satisfaction scoring for pain management. RESULTS: Pain scores at 1, 4, 8, 12, and 16 h (P<0.001), PCEA bolus requirements (n) at 24 [21 (3), 14 (2)], 48 [15 (4), 10 (3)] and 72 [8 (5), 2 (3)] (P<0.05) and paracetamol (mg) consumption [700 (523), 350 (400)]; P<0.05), were significantly lower in the gabapentin-treated patients than in the control group. Patient satisfaction with postoperative pain management at 24 h was better in gabapentin-treated patients [85.5 (7.5), 66.5 (15)]; P<0.001). Gabapentin-treated patients had less motor block when compared with control group. Times of return of bowel function, hospitalization, and resumption of dietary intake were similar in the groups. However, the incidence of dizziness was higher in the gabapentin group (35% vs 5%; P<0.05). CONCLUSIONS: Oral gabapentin (1.2 g day(-1)) as an adjunct to epidural analgesia decreased pain and analgesic consumption. Despite an increased incidence of dizziness it also increased patient satisfaction.

Acetaminophen↗

Gabapentin-induced mitogenic activity in rat pancreatic acinar cells.

Gabapentin induces pancreatic acinar cell tumors in rats through unknown, yet apparently nongenotoxic mechanisms. The primary objective of this study was to determine whether gabapentin acts as a tumor promoter by stimulating acinar cell proliferation in rat pancreas. To this end, indices of pancreatic growth, including increased pancreatic weight, stimulation of acinar cell proliferation, and/or enhanced expression of immediate-early oncogenes were monitored in rats given gabapentin in the diet at 2 g/kg/day for up to 12 months. Rats fed raw soy flour (RSF), a known inducer of pancreatic acinar cell tumors through cholecystokinin-mediated mitogenic stimulation, were used throughout as positive controls. In addition, recent data suggests that gabapentin binds to the alpha(2)delta subunit of a voltage-gated, L-type calcium channel. Because signaling pathways for proliferative processes in pancreatic acinar cells involve intracellular calcium mobilization, the effects of gabapentin on intracellular calcium mobilization ([Ca(2+)](i)) and (3)H-thymidine incorporation were investigated in pancreatic acinar cells isolated from normal rat pancreas and in the AR42J rat pancreatic tumor cell line. As indicated by BrdU labeling indices, acinar cell proliferation increased 3-fold by Day 3 of RSF treatment and remained slightly greater than controls throughout the experiment. Pancreatic weights of RSF-fed rats were 32 to 56% greater than controls throughout the experiment. In contrast, gabapentin had no effect on pancreatic weight or acinar cell labeling index, and therefore had no apparent effect on pancreatic growth. In isolated pancreatic acinar cells, however, gabapentin induced mobilization of intracellular calcium and caused a slight increase in (3)H-thymidine incorporation. The data suggest that gabapentin may possess low level mitogenic activity, which is not easily detectable in in vivo assays.

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The analgesic effect of gabapentin and mexiletine after breast surgery for cancer.

UNLABELLED: We investigated the analgesic efficacy of mexiletine and gabapentin on acute and chronic pain associated with cancer breast surgery in 75 patients. They were randomized to receive, in a double-blinded manner, mexiletine 600 mg/d, gabapentin 1200 mg/d, or placebo for 10 days. Anesthesia was standardized, and all patients had access to routine postoperative analgesics on demand. The visual analog scale score assessed pain at rest and after movement. Three months later, all patients were interviewed to identify intensity of chronic pain and analgesic requirements. Mexiletine and gabapentin reduced codeine consumed from the second to tenth day by 50% (P = 0.029; P = 0.018 and P = 0.035 for mexiletine versus control and gabapentin versus control comparisons, respectively). Total paracetamol consumption was also reduced during the same time (P = 0.0085; P = 0.007 and P = 0.011 for the mexiletine and gabapentin groups when compared with the control, respectively). Pain at rest and after movement was reduced by both drugs on the third postoperative day. Pain after movement also was reduced by gabapentin between the second and fifth postoperative day. Three months later, the incidence of chronic pain, its intensity, and need for analgesics were not affected by either treatment. However, burning pain was more frequent in the control group (P = 0.033). IMPLICATIONS: Patients undergoing breast surgery for cancer may develop chronic pain. We evaluated the effect of mexiletine and gabapentin on the acute and chronic pain after breast surgery for cancer. Both drugs reduced the postoperative analgesic requirements, and particularly, gabapentin reduced pain after movement. The overall incidence of chronic pain was unaffected except for burning pain.

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Synergistic effect between intrathecal non-NMDA antagonist and gabapentin on allodynia induced by spinal nerve ligation in rats.

BACKGROUND: Glutamate and non-N-methyl-D-aspartate (NMDA) receptors have been implicated in the development of neuroplasticity in the spinal cord in neuropathic pain. The spinal cord has been identified as one of the sites of the analgesic action of gabapentin. In the current study, the authors determined the antiallodynic effect of intrathecal 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in a rat model of neuropathic pain. Also tested was a hypothesis that intrathecal injection of CNQX and gabapentin produces a synergistic effect on allodynia in neuropathic rats. METHODS: Allodynia was produced in rats by ligation of the left L5 and L6 spinal nerves. Allodynia was determined by application of von Frey filaments to the left hind paw. Through an implanted intrathecal catheter, 10-100 microg gabapentin or 0.5-8 microg CNQX disodium (a water-soluble formulation of CNQX) was injected in conscious rats. Isobolographic analysis was performed comparing the interaction of intrathecal gabapentin and CNQX using the ED50 dose ratio of 15:1. RESULTS: Intrathecal treatment with gabapentin or CNQX produced a dose-dependent increase in the withdrawal threshold to mechanical stimulation. The ED50 for gabapentin and CNQX was 45.9+/-4.65 and 3.4+/-0.22 microg, respectively. Intrathecal injection of a combination of CNQX and gabapentin produced a strong synergistic antiallodynic effect in neuropathic rats. CONCLUSIONS: This study shows that intrathecal administration of CNQX exhibits an antiallodynic effect in this rat model of neuropathic pain. Furthermore, CNQX and gabapentin, when combined intrathecally, produce a potent synergistic antiallodynic effect on neuropathic pain in spinal nerve-ligated rats.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

A combination of gabapentin and morphine mediates enhanced inhibitory effects on dorsal horn neuronal responses in a rat model of neuropathy.

BACKGROUND: Peripheral nerve damage can result in severe, long-lasting pain accompanied by sensory deficits. This neuropathic pain remains a clinical problem, and effective morphine analgesia is often limited by intolerable side effects. The antiepileptic gabapentin has recently emerged as an alternative chronic pain treatment. Improved management of the diverse symptoms and mechanisms of neuropathic pain may arise from combination therapy, based on multiple pharmacologic targets and low drug doses. METHODS: The authors used the Kim and Chung rodent model of neuropathy to induce mechanical and cold allodynia in the ipsilateral hind paw. In vivo electrophysiologic techniques were subsequently used to record evoked dorsal horn neuronal responses in which the effects of systemic morphine and gabapentin were investigated, both individually and in combination. RESULTS: Morphine (1 and 4 mg/kg) inhibited neuronal responses of control rats but not after neuropathy. Gabapentin (10 and 20 mg/kg) inhibited neuronal responses in nerve injured rats and to a lesser extent in sham rats but not in naive rats. In the presence of gabapentin (ineffective low dose of 10 mg/kg), morphine (1 and 3 mg/kg) mediated significant inhibitory effects in all experimental groups, with the greatest inhibitions observed in spinal nerve-ligated and sham-operated rats. After neuropathy, inhibitions mediated by morphine were significantly increased in the presence of gabapentin compared with morphine alone. CONCLUSIONS: After spinal nerve ligation, the inhibitory effects of systemic morphine on evoked dorsal horn neuronal responses are reduced compared with control, whereas the effectiveness of systemic gabapentin is enhanced. In combination with low-dose gabapentin, significant improvement in the effectiveness of morphine is observed, which demonstrates a clinical potential for the use of morphine and gabapentin combinational treatment for neuropathic pain.

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Intrathecal gabapentin enhances the analgesic effects of subtherapeutic dose morphine in a rat experimental pancreatitis model.

BACKGROUND: Morphine sulfate has long been used for analgesia, but clinical applications can be limited by side effects, tolerance, and potential for addiction at therapeutic doses. An agent that produces therapeutic analgesia when coadministered with low-dose morphine could have important clinical uses. The anticonvulsant agent gabapentin has been identified as having antihyperalgesic properties acting on the alpha2delta1 subunit of N-type voltage-activated calcium channels on dorsal root ganglia neurons. In this study, intrathecal gabapentin, which by itself is ineffective when administered spinally, was combined with low-dose morphine and tested in an acute bradykinin-induced pancreatitis model in rats. METHODS: An intrathecal catheter was surgically inserted into the subarachnoid space of male Sprague-Dawley rats. A laparotomy was performed for ligation and cannulation of the bile-pancreatic duct. Rats were pretreated intrathecally with artificial cerebrospinal fluid, gabapentin, morphine, or combined gabapentin and morphine 30 min before bradykinin injection into the bile-pancreatic duct. Spontaneous behavioral activity (cage crossing, rearing, and hind limb extension) was monitored before drug injection (baseline) and after bradykinin injection into the bile-pancreatic duct to assess visceral pain. RESULTS: Spinal pretreatment with up to 300 microg gabapentin alone was not effective in reducing hind limb extension in this model, but did restore some cage crossing and rearing behaviors. Spinal treatment with low-dose morphine reduced hind limb extension only. Spinal pretreatment with combined gabapentin and subtherapeutic doses of morphine sulfate resulted in restoration of all spontaneous behaviors to surgical baseline levels including elimination of hind limb extension. CONCLUSION: Combined spinal administration of gabapentin and low doses of morphine significantly reduces pain-related behaviors in this acute rat pancreatitis model, whereas these agents were ineffective when used alone in this dose range. These data suggest that the alpha2delta1 subunit of the N-type voltage-activated Ca2+ channels is involved in transmission of this visceral pain, likely through effects on primary afferent endings in the spinal cord. Thus, gabapentin may be an effective adjuvant to initial low dose spinal opioid therapy for clinical management of visceral pain.

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Evaluation of the optimal preemptive dose of gabapentin for postoperative pain relief after lumbar diskectomy: a randomized, double-blind, placebo-controlled study.

We evaluated the optimal preemptive dose of gabapentin for postoperative pain relief after single-level lumbar diskectomy and its effect on fentanyl consumption during the initial 24 hours in a randomized, double-blinded, placebo-controlled study in 100 patients with American Society of Anesthesiologists physical status I and II. Patients were divided into five groups to receive placebo or gabapentin 300, 600, 900, or 1200 mg 2 hours before surgery. After surgery, patients were transferred to the postanesthesia care unit (PACU). A blinded anesthesiologist recorded the pain scores at time points of 6, 12, 18, and 24 hours in the PACU on a Visual Analog Scale (VAS; 0-10 cm) at rest. Patients received patient-controlled analgesia (fentanyl 1.0 mug/kg on each demand with lockout interval of 10 minutes); total fentanyl consumption during initial 24 hours was recorded. Data were entered into the statistical software package SPSS 9.0 for analysis (one-way analysis of variance and Student-Newman-Keuls test). Patients who received gabapentin 300 mg had significantly lower VAS score at all time points. They consumed less fentanyl (patients who received placebo processed 1217.5 +/- 182.0 versus 987.5 +/- 129.6 mug; P < 0.05). Patients who received gabapentin 600, 900, and 1200 mg had lower VAS scores at all time points than patients who received gabapentin 300 mg (P < 0.05). Increasing the dose of gabapentin from 600 to 1200 mg did not decrease the VAS score, nor did the increasing dose of gabapentin significantly decrease fentanyl consumption (702.5, 635, and 626.5 microg). Thus, gabapentin 600 mg is the optimal dose for postoperative pain relief following lumbar diskectomy.

Adult↗

Gabapentin effect on neuropathic pain compared among patients with spinal cord injury and different durations of symptoms.

STUDY DESIGN: This study evaluated the effect of gabapentin on neuropathic pain in patients with spinal cord injury. OBJECTIVE: To compare the effect of gabapentin on neuropathic pain refractory to conventional analgesics in patients with spinal cord injury and different durations of symptoms. SUMMARY OF BACKGROUND DATA: Neuropathic pain in patients with spinal cord injury severely compromises their quality of life. Gabapentin is a new antiepileptic drug that may additionally have a role in the treatment of neuropathic pain. So far, there has been little prospective research investigating the effect of gabapentin on neuropathic pain in patients after spinal cord injury or comparing gabapentin-treated patients with varying durations of symptoms after spinal cord injury. METHODS: The study included 31 patients who had experienced neuropathic pain associated with spinal cord injury or cauda equina syndrome. These subjects were divided into two groups. Group 1 (n = 13) was composed of patients whose duration of pain was less than 6 months, and Group 2 (n = 18) comprised patients whose symptoms of neuropathic pain had lasted more than 6 months. Although these patients had been treated with conventional analgesics such as antidepressants, anticonvulsants, membrane stabilizer, and neuroleptics, they reported that their condition did not improve after a medication trial of at least 2 weeks duration. In this study, conventional analgesics were continued at a therapeutic level, and gabapentin was administrated for an 18-day titration period followed by a 5-week maintenance period at a dosage of 1800 mg/day or the maximum tolerable dosage. The efficacy of gabapentin administration was gauged by a pain score and a sleep interference score using a 100-mm visual analogue scale (VAS) every 2 weeks. The scores of the two groups were compared every 2 weeks over the course of the 8-week study. RESULTS: The mean pain score and the mean sleep interference score for Group 1 decreased more than that of Group 2 during the interval between 2 to 8 weeks (P < 0.05). The mean pain score for Group 1 decreased from 7.3 +/- 0.5 initially to 3 +/- 0.6 after 8 weeks of treatment, whereas the corresponding score for Group 2 decreased from 7.6 +/- 0.4 to 5.1 +/- 0.6 ( < 0.05). The mean sleep interference score for Group 1 decreased from 5.7 +/- 0.9 initially to 1.8 +/- 0.8 after 8 weeks of treatment, whereas the corresponding score for Group 2 decreased from 5.9 +/- 0.8 to 4.2 +/- 0.7 (P < 0.05). As compared with the onset of this study, a decrease in pain score of 2 or more was reported at the completion of this study for 11 patients (100%) in Group 1 and 10 (71%) of 14 patients in Group 2. A decrease of 2 or more in sleep interference scores was reported for 8 (89%) of 9 patients with sleep interference in Group 1 and for 8 (62%) of 13 patients with sleep interference in Group 2. Some adverse effects such as somnolence were noted, but they were mild or moderate in intensity. CONCLUSIONS: Gabapentin may be effective in decreasing neuropathic pain refractory to conventional analgesics in some patients with spinal cord injury whose duration of symptoms is less than 6 months, although those with duration of symptoms longer than 6 months showed a significant decrease as well. The drug is unlikely to cause serious adverse effects that limit its use in patients with spinal cord injury.

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Gabapentin does not reduce smoked cocaine self-administration: employment of a novel self-administration procedure.

Previously, we reported that gabapentin, a nonselective gamma-aminobutyric acid agonist, reduced 'positive' subjective effects of cocaine without reducing cocaine self-administration. We speculated that the self-administration procedure used in that study was not sensitive to subtle shifts in the reinforcing effects of cocaine. Thus, this study examined the effects of gabapentin maintenance on cocaine self-administration using a purchase-cocaine choice procedure. During this 48-day inpatient/outpatient study, nontreatment-seeking cocaine abusers (n = 12) were maintained on gabapentin (0, 600, 1200 mg/day); four doses of cocaine (0, 12, 25, 50 mg) were each tested twice under each gabapentin condition. All cocaine testing was conducted while participants were inpatients. Before the start of each session, participants were provided with 25 dollars (five 5 dollar bills, one for each choice opportunity) and smoked the 'sample' cocaine dose once. Subsequently, participants were given five opportunities to purchase the sampled dose of cocaine (at 5 dollars per dose) or to keep 5 dollars for that choice trial. Choice to self-administer cocaine increased significantly with escalating cocaine doses; gabapentin maintenance did not alter choice to self-administer cocaine. These results concur with findings from our previous investigations of gabapentin and with those from a clinical trial examining the effects of larger gabapentin doses on cocaine use by treatment-seeking cocaine-dependent individuals. Together, the data indicate that gabapentin does not show promise as a treatment medication for cocaine dependence.

Adult↗

Effects of gabapentin on postoperative morphine consumption and pain after abdominal hysterectomy: a randomized, double-blind trial.

BACKGROUND: Preliminary clinical studies have suggested that gabapentin may produce analgesia and reduce the need for opioids in postoperative patients. The aim of the present study was to investigate the opioid-sparing and analgesic effects of gabapentin administered during the first 24 h after abdominal hysterectomy. METHODS: In a randomized, double-blind study, 80 patients received oral gabapentin 1200 mg or placebo 1 h before surgery, followed by oral gabapentin 600 mg or placebo 8, 16 and 24 h after the initial dose. Patients received patient-controlled analgesia with morphine at doses of 2.5 mg with a lock-out time of 10 min for 24 h postoperatively. Pain was assessed on a visual analogue scale (VAS) at rest and during mobilization, nausea, somnolence and dizziness on a four-point verbal scale, and vomiting as present/not present at 2, 4, 22 and 24 h postoperatively. RESULTS: Thirty-nine patients in the gabapentin group, and 32 patients in the placebo group completed the study. Gabapentin reduced total morphine consumption from median 63 (interquartile range 53-88) mg to 43 (28-60) mg (P < 0.001). We observed a significant inverse association between plasma levels of gabapentin at 2 h postoperatively, and morphine usage from 0 to 2 h, and from 0 to 4 h postoperatively (R2 = 0.30, P = 0.003 and R2 = 0.24 P = 0.008, respectively). No significant differences in pain at rest or during mobilization, or in side-effects, were observed between groups. CONCLUSION: Gabapentin in a total dose of 3000 mg, administered before and during the first 24 h after abdominal hysterectomy, reduced morphine consumption with 32%, without significant effects on pain scores. No significant differences in side-effects were observed between study-groups.

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Pharmacokinetics of gabapentin in paediatric patients with uncontrolled seizures.

PURPOSE: The pharmacokinetics of gabapentin in paediatric patients with uncontrolled seizures was studied. METHODS: Thirteen paediatric patients (mean age: 9.4 years) with uncontrolled partial seizures were included. Patients received gabapentin orally until doses were individualized to 9.6-39.8 mg/kg/day. Blood samples were obtained just prior to the dose and over 8 h after gabapentin was administered in the fasting state. The plasma concentration of gabapentin was measured by a high-performance liquid chromatography assay. Pharmacokinetic parameters for gabapentin were determined by non-compartment methods using multivariate regression analysis. RESULTS: Data from nine patients were suitable for pharmacokinetic analysis. The C(max) from 0.9 to 5.8 microg/mL (mean: 2.6 +/- 1.7 microg/mL) and T(max) from 0.5 to 2.0 h (mean: 1.6 +/- 1.0 h). The apparent clearance (Cl/F) ranged from 0.12 to 1.12 L/h/kg (mean: 0.50 +/- 0.29 L/h/kg), and the elimination half-life from 3.2 to 12.2 h (mean: 5.5 +/- 0.8 h). Five patients experienced moderate (n = 4) to severe (n = 1) aggressive behaviour and another gained weight on gabapentin. CONCLUSIONS: Our data suggests that gabapentin pharmacokinetics can vary substantially among paediatric patients. Gabapentin was well tolerated in patients with uncontrolled partial seizures up to 6 months of therapy.

Adolescent↗

The effect of combined administration of ethanol and gabapentin on rabbit electroencephalographic activity.

The central effect of ethanol is mainly connected with the effect on GABAergic, glutamatergic, serotonergic and opioid transmission. The mechanism of gabapentin effect suggests that it may alleviate the rewarding effect of ethanol, which may be used in the treatment of addiction. We decided to examine the interaction of ethanol with gabapentin by a pharmaco-electroencephalographic (EEG) method. The influence of gabapentin on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was tested. Gabapentin was administered at a single dose (25 and 100 mg/kg orally) or repeatedly twice a day at a total dose of 25 mg/kg for 14 days. Ethanol was injected at a dose of 0.8 g/kg 60 min. after gabapentin treatment. Ethanol caused an increase in the slow frequencies (0.5-4 Hz) in the recording, as well as a marked decrease of the fastest frequencies (13-30 and 30-45 Hz). Gabapentin lead to changes in rabbit EEG recording suggesting an depressant effect on the CNS (increase of slow and decrease of fast frequencies). The effects were less pronounced after repeated doses, which may indicate adaptative changes in the receptors. Gabapentin administered both in a single dose and for 7 days markedly enhanced the effect of ethanol on EEG recordings in rabbits. Repeated doses of gabapentin decrease the sensitivity of the hippocampus to the effect of ethanol.

Amines↗