Gabapentin

Gabapentin is structurally similar to GABA and is reported in various research studies to increase GABA concentrations within the brain. Gabapentin is also noted to bind to a novel site on voltage-sensitive Ca2+ channels. Additionally, Gabapentin is reported to demonstrate inhibition of dopamine release from caudate nucleus, prevent neuronal cell death, and is antinociceptive.

Gabapentin Does Not Appear to Improve Postoperative Pain and Sleep Patterns in Patients Who Concomitantly Receive Regional Anesthesia for Lower Extremity Orthopedic Surgery: A Randomized Control Trial.[Pubmed:28348503]

Pain Res Manag. 2017;2017:2310382.

In recent years, Gabapentin has gained popularity as an adjuvant therapy for the treatment of postoperative pain. Numerous studies have shown a decrease in pain score, even with immediate postoperative activity, which is significant for early post-op ambulation and regaining functionality sooner. However, studies have been in conclusive in patients undergoing lower extremity orthopedic surgery. For this reason, we hoped to study the effect of Gabapentin on postoperative pain in patients undergoing total knee arthroplasty, total hip arthroplasty, or a hip fracture repair. This was done in the setting of ensuring adequate postoperative analgesia with regional blocks and opioid PCA, as is protocol at our institution. Given the sedative effects of Gabapentin and the potential for improving postoperative sleep patterns, we also studied the drug's effect on this aspect of our patient's postoperative course. We utilized the Pittsburg Sleep Quality Index and Visual Analog Scale for pain to obtain a more objective standardized score amongst our study population. Our results indicate that Gabapentin does not offer any additional relief in pain or improve sleep habits in patients who have received either a femoral or lumbar plexus block for lower extremity orthopedic surgery. This trial is registered with NCT01546857.

The Effect of Gabapentin on Delayed Discharge from the Postanesthesia Care Unit: A Retrospective Analysis.[Pubmed:28371158]

Pain Pract. 2018 Jan;18(1):18-22.

BACKGROUND: Enhanced recovery after surgery programs has incorporated Gabapentin as part of a multimodal analgesia protocol. The preemptive use of Gabapentin was found to be beneficial due to its opioid-sparing effect. However, excessive sedation and delayed discharge from postanesthesia recovery units are of concern. The aim of this study was to investigate whether preoperative Gabapentin increased the length of stay in the recovery unit. METHODS: This retrospective cross-sectional study was carried out over a period of 2 months in the postanesthesia care unit (PACU) of a tertiary care hospital in Canada. Two hundred and twenty-eight consecutive patients who underwent elective surgical procedures and who required a longer than 2-hour stay in the PACU were included. Prolonged stays caused by respiratory inadequacy, hemodynamic instability, nausea, vomiting, pain, and loss of consciousness were recorded. The data were collected from patients' charts and nursing flow sheets. RESULTS: All patients were grouped into those who received 300 mg Gabapentin (n = 108), 600 mg Gabapentin (n = 41), and no Gabapentin (n = 139). No significant difference was observed between the groups in terms of opioid consumption, respiratory inadequacy, nausea, vomiting, and hemodynamic parameters. Gabapentin administration groups had significantly lower postoperative pain scores (P < 0.001). Decreased level of consciousness occurred significantly more often in a dose-dependent fashion in the Gabapentin groups and led to a longer stay in the PACU (P < 0.001). CONCLUSION: In the setting of enhanced recovery after surgery, Gabapentin did reduce pain scores, but at the cost of delayed discharge from the recovery room. Future studies are needed to evaluate the efficacy of Gabapentin in this setting.

Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis.[Pubmed:28348186]

BMJ Open. 2017 Mar 27;7(3):e013433.

INTRODUCTION: Gabapentin has been extensively prescribed off-label for psychiatric indications, with little established evidence of efficacy. Gabapentin and pregabalin, a very similar drug with the same mechanism of action, bind to a subunit of voltage-dependent calcium channels which are implicated in the aetiopathogenesis of bipolar disorder, anxiety and insomnia. This systematic review and meta-analysis aims to collect and critically appraise all the available evidence about the efficacy and tolerability of Gabapentin and pregabalin in the treatment of bipolar disorder, insomnia and anxiety. METHODS AND ANALYSIS: We will include all randomised controlled trials (RCTs) reported as double-blind and comparing Gabapentin or pregabalin with placebo or any other active pharmacological treatment (any preparation, dose, frequency, route of delivery or setting) in patients with bipolar disorder, anxiety or insomnia. For consideration of adverse effects (tolerability), single-blind or open-label RCTs and non-randomised evidence will also be summarised. The main outcomes will be efficacy (measured as dichotomous and continuous outcome) and acceptability (proportion of patients who dropped out of the allocated treatment). Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least 2 independent reviewers. We will conduct a random-effects meta-analysis to synthesise all evidence for each outcome. Heterogeneity between studies will be investigated by the I(2) statistic. Data from included studies will be entered into a funnel plot for investigation of small-study effects. No subgroup analysis will be undertaken, but we will carry out sensitivity analyses about combination treatment, psychiatric comorbidity, use of rescue medications and fixed versus random-effects model. ETHICS AND DISSEMINATION: This review does not require ethical approval. This protocol has been registered on PROSPERO (CRD42016041802). The results of the systematic review will be disseminated via publication in a peer-reviewed journal.

Inhibition of neuronal Ca(2+) influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices.[Pubmed:10864898]

Br J Pharmacol. 2000 Jun;130(4):900-6.

Cytosolic calcium ion concentrations ([Ca(2+)](i)) were measured in rat neocortical synaptosomes using fura-2, and depolarization of synaptosomal membranes was induced by K(+) (30 mM). The release of the endogenous excitatory amino acids glutamate and aspartate was evoked by K(+) (50 mM) and determined by HPLC. The release of [(3)H]-noradrenaline from rat neocortical synaptosomes or slices was evoked by K(+) (15 and 25 mM) and measured by liquid scintillation counting. Gabapentin produced a concentration-dependent inhibition of the K(+)-induced [Ca(2+)](i) increase in synaptosomes (IC(50)=14 microM; maximal inhibition by 36%). The inhibitory effect of Gabapentin was abolished in the presence of the P/Q-type Ca(2+) channel blocker omega-agatoxin IVA, but not by the N-type Ca(2+) channel antagonist omega-conotoxin GVIA. Gabapentin (100 microM) decreased the K(+)-evoked release of endogenous aspartate and glutamate in neocortical slices by 16 and 18%, respectively. Gabapentin reduced the K(+)-evoked [(3)H]-noradrenaline release in neocortical slices (IC(50)=48 microM; maximal inhibition of 46%) but not from synaptosomes. In the presence of the AMPA receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2, 3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide (NBQX), Gabapentin did not reduce [(3)H]-noradrenaline release. Gabapentin did, however, cause inhibition in the presence of the NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849). Gabapentin is concluded to reduce the depolarization-induced [Ca(2+)](i) increase in excitatory amino acid nerve terminals by inhibiting P/Q-type Ca(2+) channels; this decreased Ca(2+) influx subsequently attenuates K(+)-evoked excitatory amino acid release. The latter effect leads to a reduced activation of AMPA receptors which contribute to K(+)-evoked noradrenaline release from noradrenergic varicosities, resulting in an indirect inhibition of noradrenaline release.

A microdialysis study on the mechanism of action of gabapentin.[Pubmed:10856447]

Eur J Pharmacol. 2000 Jun 9;398(1):53-7.

To gain insight into the mechanism of action of the anti-epileptic, Gabapentin, the effects of Gabapentin on the in vivo extracellular gamma-aminobutyric acid (GABA) levels in the rat substantia nigra reticulata were studied using microdialysis. In order to investigate possible interference with different GABA-ergic compartments in the substantia nigra reticulata, we studied the effects of Gabapentin under basal, K(+)-, nipecotic acid- and glutamate-stimulated conditions. Intraperitoneally (i.p.) administered Gabapentin, at a dose of 100 mg/kg, did not significantly affect extracellular GABA levels under any condition. Thus, our data do not support the involvement of nigral GABA release in the mechanism of action of the anti-epileptic Gabapentin.

A summary of mechanistic hypotheses of gabapentin pharmacology.[Pubmed:9551785]

Epilepsy Res. 1998 Feb;29(3):233-49.

Although the cellular mechanisms of pharmacological actions of Gabapentin (Neurontin) remain incompletely described, several hypotheses have been proposed. It is possible that different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies with [14C]Gabapentin suggest that Gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology of Gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysiology results suggest that Gabapentin may modulate certain types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that Gabapentin inhibits voltage-activated Na+ channels, but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t).

Mechanisms of action of new antiepileptic drugs: rational design and serendipitous findings.[Pubmed:7886818]

Trends Pharmacol Sci. 1994 Dec;15(12):456-63.

After years without any major breakthroughs in the treatment of epilepsy disorders, a new wave of antiepileptic drugs have become available to clinicians. Felbamate, Gabapentin, lamotrigine and vigabatrin are among the most promising of this new generation of drugs and, when used as add-on therapy, provide some improvement in a significant number of patients suffering from previously refractory epilepsy whilst exhibiting a lower risk of unwanted side-effects than traditional antiepileptic drugs. In this article, Neil Upton reviews the recent discoveries that suggest these four new agents exert their antiepileptic properties by acting through diverse and often novel mechanisms, some of which are by design, and some of which are by chance. Also highlighted are examples of the most innovative mechanistic approaches currently being adopted to produce the next generation of antiepileptic drugs.