Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT® ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSIONS: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

Decrease in Long-Chain Acylcarnitine Tissue Content Determines the Duration of and Correlates with the Cardioprotective Effect of Methyl-GBB.

Ischaemia in the heart is accompanied by the accumulation of long-chain acylcarnitines (LCACs) which is one of the multiple factors that contribute to the ischaemia-reperfusion damage development. Long-term pre-treatment that decreases carnitine and LCAC contents also reduces ischaemia-reperfusion (IR) damage; however, the duration of the post-treatment effects is not known. The aim of the study was to assess the post-treatment effects of the carnitine transport (OCTN2) inhibitor, methyl-GBB, on LCAC content and the duration of its cardioprotective effect. Male Wistar rats received methyl-GBB (5 mg/kg for 28 days), and the anti-infarction effects on Langendorff-perfused hearts and the acylcarnitine profile in cardiac tissues were measured up to 28 days following the end of the treatment. Methyl-GBB pre-treatment for 28 days decreased LCAC heart tissue content by 87%, and the infarct size was decreased by 57%. Fourteen days post-treatment, the LCAC content was still decreased by 69%, and the infarct size was decreased by 32% compared to Control. A significant Pearson correlation (r = 0.48, p = 0.026) was found between infarct size and LCAC tissue content in the methyl-GBB-treated rat hearts. The addition of 2 mM carnitine to isolated heart perfusate significantly diminished the methyl-GBB-induced decrease in LCACs and infarct size. In conclusion, the anti-infarction effect of methyl-GBB continues for at least 2 weeks post-treatment. No less than a 70% decrease in LCAC content is required to protect ischaemic heart tissues, and the decrease in LCAC levels defines the duration of the post-treatment cardioprotective effect of the OCTN2 inhibitor, methyl-GBB.

Involvement of l-type amino acid transporter 1 in the transport of gabapentin into human placental choriocarcinoma cells.

Gabapentin (GBP) is a widely used antiepileptic drug, with potential for use in the treatment of epilepsy in pregnant women. Although studies have examined GBP transport mechanisms across the blood-brain barrier, kidney, and intestine, the mechanism in the placenta has not been fully elucidated. We previously reported that GBP accumulates at high concentrations in human placental choriocarcinoma BeWo cells. The purpose of this study was to examine the transport mechanism of GBP in placental choriocarcinoma cells (BeWo and JEG-3), and to identify the carrier involved. High concentrations of intracellular GBP accumulations were also found in JEG-3 cells. A kinetic analysis showed that a single carrier system was involved in the uptake of GBP. Furthermore, substrates for l-type amino acid transporter (LAT) and siRNAs targeted to LAT1 significantly decreased GBP uptake. Our observations from this study suggest that LAT1 is the main contributor to GBP transport in placental choriocarcinoma cells.

Pharmacokinetics of Compounded Intravenous and Oral Gabapentin in Hispaniolan Amazon Parrots ( Amazona ventralis ).

Neuropathic pain is a manifestation of chronic pain that arises with damage to the somatosensory system. Pharmacologic treatment recommendations for alleviation of neuropathic pain are often multimodal, and the few reports communicating treatment of suspected neuropathic pain in avian patients describe the use of gabapentin as part of the therapeutic regimen. To determine the pharmacokinetics of gabapentin in Hispaniolan Amazon parrots ( Amazona ventralis ), compounded gabapentin suspensions were administered at 30 mg/kg IV to 2 birds, 10 mg/kg PO to 3 birds, and 30 mg/kg PO to 3 birds. Blood samples were collected immediately before and at 9 different time points after drug administration. Plasma samples were analyzed for gabapentin concentration, and pharmacokinetic parameters were calculated with both a nonlinear mixed-effect approach and a noncompartmental analysis. The best compartmental, oral model was used to simulate the concentration-time profiles resulting from different dosing scenarios. Mild sedation was observed in both study birds after intravenous injection. Computer simulation of different dosing scenarios with the mean parameter estimates showed that 15 mg/kg every 8 hours would be a starting point for oral dosing in Hispaniolan Amazon parrots based on effective plasma concentrations reported for human patients; however, additional studies need to be performed to establish a therapeutic dose.

P2X7 receptor activation downmodulates Na(+)-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes.

Sodium-dependent high-affinity amino-acid transporters play crucial roles in terminating synaptic transmission in the central nervous system (CNS). However, there is lack of information about the mechanisms underlying the regulation of amino-acid transport by fast-acting neuromodulators, like ATP. Here, we investigated whether activation of the ATP-sensitive P2X7 receptor modulates Na(+)-dependent high-affinity γ-aminobutyric acid (GABA) and glutamate uptake into nerve terminals (synaptosomes) of the rat cerebral cortex. Radiolabeled neurotransmitter accumulation was evaluated by liquid scintillation spectrometry. The cell-permeant sodium-selective fluorescent indicator, SBFI-AM, was used to estimate Na(+) influx across plasma membrane. 2'(3')-O-(4-benzoylbenzoyl)ATP (BzATP, 3-300 µM), a prototypic P2X7 receptor agonist, concentration-dependently decreased [(3)H]GABA (14%) and [(14)C]glutamate (24%) uptake; BzATP decreased transport maximum velocity (Vmax) without affecting the Michaelis constant (Km) values. The selective P2X7 receptor antagonist, A-438079 (3 µM), prevented inhibition of [(3)H]GABA and [(14)C]glutamate uptake by BzATP (100 µM). The inhibitory effect of BzATP coincided with its ability to increase intracellular Na(+) and was mimicked by Na(+) ionophores, like gramicidin and monensin. Increases in intracellular Na(+) (with veratridine or ouabain) or substitution of extracellular Na(+) by N-methyl-D-glucamine (NMDG)(+) all decreased [(3)H]GABA and [(14)C]glutamate uptake and attenuated BzATP effects. Uptake inhibition by BzATP (100 µM) was also attenuated by calmidazolium, which selectively inhibits Na(+) currents through the P2X7 receptor pore. In conclusion, disruption of the Na(+) gradient by P2X7 receptor activation downmodulates high-affinity GABA and glutamate uptake into rat cortical synaptosomes. Interference with amino-acid transport efficacy may constitute a novel target for therapeutic management of cortical excitability.

Dosing time-dependent changes in the analgesic effect of pregabalin on diabetic neuropathy in mice.

Patients with diabetes often develop peripheral nerve complications, including numbness and pain in the extremities. Diabetes-induced peripheral neuropathic pain is characterized by hypersensitivity to innocuous stimuli, known as tactile allodynia. Pregabalin (PGN) is currently used to treat diabetes-induced peripheral neuropathy and alleviates allodynia. In the present study, we demonstrated that the antiallodynic effect of PGN on diabetic mice was modulated by circadian changes in its intestinal absorption. A single intraperitoneal administration of 200 mg/kg streptozotocin (STZ) to mice induced type I diabetic pathologic changes that were accompanied by tactile allodynia. The intensity of tactile allodynia in STZ-induced diabetic mice was alleviated by the oral administration of PGN; however, the antiallodynic effect varied according to its dosing time. The analgesic effect of PGN was enhanced by its administration at the times of day when its intestinal absorption was accelerated. Organic cation transporter novel type 1 (Octn1) mediated the uptake of PGN into intestinal epithelial cells. The expression of Octn1 in the small intestine of STZ-induced diabetic mice oscillated in a circadian time-dependent manner. This oscillation in Octn1 appeared to cause the time of day-dependent changes in the intestinal absorption of PGN. Similar dosing time dependencies of the antiallodynic effect of PGN and oscillation in Octn1 expression were also detected in type II diabetic db/db mice. These results suggested that the dosing time-dependent differences in the analgesic effect of PGN were attributable to circadian oscillations in the intestinal expression of Octn1 and also that optimizing its dosing schedule may assist in achieving rational pharmacotherapy for diabetes-induced peripheral neuropathic pain.

Gabapentin in acute postoperative pain management.

Gabapentin (1-aminomethyl-cyclohexaneacetic acid) is an amino acid that has the structure of the neurotransmitter γ -aminobutyric acid (GABA). It is a novel drug used for the treatment of postoperative pain with antihyperalgesic properties and a unique mechanism of action. Gabapentin and the related, more potent compound pregabalin have been shown to be beneficial in the treatment of neuropathic pain as well as postoperative pain following spinal surgery and hysterectomy. This study reviews five aspects of gabapentin: (1) chemical and structural characteristics; (2) pharmacokinetics and pharmacodynamics; (3) application in acute pain management; (4) adverse effects; and (5) drug safety. Overall, gabapentin has been reported to be a safe and efficacious drug for the treatment of postoperative pain.

A back translation of pregabalin and carbamazepine against evoked and non-evoked endpoints in the rat spared nerve injury model of neuropathic pain.

The purpose of the present study was twofold. First to characterize endpoints distinct to the reflexive responses to sensory stimuli typically used in neuropathic pain models. A second aim was to evaluate two clinically approved drugs carbamazepine (Tegretol) and pregabalin (Lyrica) against these endpoints with the purpose to backtranslate from the clinical to preclinical setting. The selected neuropathic pain model was the spared nerve injury (SNI) model and the endpoints were burrowing and measures of paw posture in Sprague Dawley rats. As previously described, SNI surgery produced a robust heightened sensitivity to tactile and thermal (cold) stimuli. SNI surgery also produced robust decreases in burrowing and affected multiple measures of paw position. There was no correlation between magnitude of change in burrowing and sensory allodynia within SNI operated rats. Pregabalin (10-30 mg/kg IP) produced a reliable reversal of both tactile and cold allodynia and also the burrowing deficit, with minimal effect on neurological function evaluated using rotorod, beam walking and open field activity. Pregabalin did not affect any measure of paw position. Pharmacokinetic studies conducted in satellite animals identified plasma levels of pregabalin at the 10 mg/kg IP dose to be equivalent to clinically efficacious levels recorded in neuropathic patients (3-6 µg/ml). In contrast carbamazepine (10-60 mg/kg IP) had only a very modest effect against a reflexive (tactile) measure, and no effect against the burrowing deficit. Carbamazepine also affected various measures of neurological function, complicating interpretation of the reflexive measure. Measurement of burrowing appears to detect a behavioural deficit associated with the SNI model, that may be attenuated by pregabalin but not carbamazepine. Overall the present findings support an advantage of pregabalin over carbamazepine in terms of both efficacy and tolerability which is consistent with clinical experience. The inclusion of additional endpoints beyond traditional reflexive behaviours further supports the value of rodent neuropathic pain models, such as the SNI, as behavioural assays to detect new chemical entities to treat this pain condition.

Steady-state pharmacokinetics of gabapentin after administration of a novel gastroretentive extended-release formulation in postmenopausal women with vasomotor symptoms.

BACKGROUND AND OBJECTIVE: Approximately 75% of postmenopausal women experience vasomotor symptoms (hot flashes). Currently, hormone replacement therapy is the only approved treatment for hot flashes. However, its use has been associated with an increased risk of invasive breast cancer, coronary heart disease, stroke and venous thromboembolic disease. Gabapentin has also been demonstrated to be efficacious in the treatment of vasomotor symptoms in postmenopausal women when administered three times a day. A gastroretentive extended-release formulation of gabapentin (gabapentin-ER) has recently been demonstrated to be efficacious in the treatment of postmenopausal hot flashes. The objective of this paper is to report the steady-state pharmacokinetics and safety of gabapentin with different dosing regimens of gabapentin-ER in postmenopausal women with hot flashes. METHODS: This was a multicentre, randomized, double-blind, dose-escalating, placebo-controlled, parallel group study in 124 postmenopausal women experiencing ≥7 moderate to severe hot flashes per day. The study consisted of two 5-week treatment periods, with each one preceded by a 1-week titration to the assigned dose. Groups A, B and C received gabapentin-ER 600 mg evening (pm), 600 mg morning (am)/600 mg pm and 1200 mg pm in the first period, and then 600 mg am/1200 mg pm, 600 mg am/1800 mg pm and 1200 mg am/1800 mg pm in the second period, respectively. The tablets were taken after a non-specified meal. Pharmacokinetic sampling was conducted over a 24-hour period at the end of each study period. Plasma samples were analysed by a validated liquid chromatography tandem mass spectrometry method. Non-compartmental pharmacokinetic analysis was performed on the concentration-time data to determine area under the plasma concentration versus time curve from time zero to 24 hours (AUC(24)). Maximum (C(max)), minimum (C(min)) and average (C(avg)) drug concentration and time to reach C(max) (t(max)) were determined by inspection of the data. Tolerability was evaluated by physical examination, clinical laboratory measurements and adverse events monitoring. RESULTS: Gabapentin exposure at steady state, as measured by AUC(24), increased with doses from 600 mg/day to 3000 mg/day, although there was a slight decrease in gabapentin's relative bioavailability with increasing dose compared with the 600 mg dose. The relative bioavailability compared with the 600 mg dose was 86-88% for the 1200 mg/day doses, 75% for the 1800 mg/day dose, 84% for the 2400 mg/day dose, and 73% for the 3000 mg/day dose. C(max) generally increased with increasing dose as did C(min) and C(avg) for the various treatments in a manner that was consistent with the dosing regimen. The values of t(max) were not different between the various doses, with the median t(max) values relative to the most recent dose ranging from 6 to 8 hours for all dose levels. Gabapentin-ER was generally well tolerated at all doses studied. The most common AEs were headache, dizziness and somnolence, with most being mild in intensity. Seven patients withdrew from the study due to AEs. CONCLUSION: The pharmacokinetic profile of gabapentin-ER may allow for once- or twice-daily dosing while maintaining bioavailability and thus efficacy. Gabapentin-ER was well tolerated. CLINICAL TRIAL REGISTRATION: Registered as ClinicalTrials.gov Identifier: NCT00511953.

[Pregabalin--a drug with abuse potential?]. / Pregabalin--ein Arzneistoff mit Missbrauchspotential?

A case of pregabalin misuse associated with delusional ideas in a drug addict is reported. Pregabalin has been approved as an adjunct therapy for epilepsy, but also for neuropathic pain and generalized anxiety disorders and is widely used today. It has also been used in clinical trials to study its potential utility as a treatment for tobacco, alcohol and benzodiazepine addiction. Web sites, case reports and an epidemiological study (Swedish National Register of Adverse Drug Reactions) suggest that the drug may be abused, especially by substance-dependent individuals. Pregabalin was analyzed by LC/MS/MS following precipitation of serum proteins. Vigabatrin was used as internal standard. The concentration of 25 pg pregabalin/mL serum determined in the present case is the second highest value published so far after misuse of the substance. Due to paradoxical agitation, anxiety attacks and abnormal thinking, the man was exculpated. Further studies are required to assess the actual abuse potential of pregabalin.

Gabapentin enacarbil for treatment of restless legs syndrome in adults.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, precautions, dosing recommendations, and patient counseling for gabapentin enacarbil for the treatment of restless legs syndrome (RLS) in adults. DATA SOURCES: A literature search was conducted using the terms gabapentin enacarbil, XP13512/GSK1838262, and restless legs syndrome. MEDLINE, Books@Ovid, Journals@Ovid Full Text, BIOSIS Previews, and EMED databases were the primary search sites (2004-October 2011). All English-based articles and abstracts obtained from the literature searches were reviewed. Additional information was obtained from references cited in the articles. STUDY SELECTION AND DATA EXTRACTION: All gabapentin enacarbil information related to RLS was considered. Study selection included human trials evaluating safety and efficacy of gabapentin enacarbil for the treatment of RLS. DATA SYNTHESIS: Gabapentin enacarbil is a prodrug of gabapentin that is Food and Drug Administration (FDA) approved for the treatment of moderate-to-severe primary RLS in adults. In placebo-controlled trials, gabapentin enacarbil demonstrated efficacy in reducing the symptoms of RLS. Most clinical trials assessed gabapentin enacarbil at dosages greater than the FDA-approved 600-mg dosage. For the approved dose of 600 mg, the most commonly reported adverse effects are somnolence and dizziness. CONCLUSIONS: Clinical trials have evaluated gabapentin enacarbil for safety and efficacy in treating moderate-to-severe RLS symptoms for up to 64 weeks. It offers a pharmacokinetic advantage over gabapentin by having improved absorption and a longer duration of action, but clinically significant differences are yet to be determined. Potential disadvantages of gabapentin enacarbil include cost, concerns of suicide risk and pancreatic cancer, and a lack of data for the FDA-approved 600-mg dosage. Overall, gabapentin enacarbil is a viable therapeutic option for adults with moderate-to-severe RLS for whom more conventional therapies have failed.

Population pharmacokinetics of pregabalin in healthy subjects and patients with post-herpetic neuralgia or diabetic peripheral neuropathy.

AIM: Pregabalin, a chemical analogue of the mammalian neurotransmitter γ-aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters. METHODS: This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy (n= 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM. RESULTS: A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CL(cr) ). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy. CONCLUSION: The developed model identified CL(cr) and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug.

Can a single dose of 300 mg of pregabalin reach acute antihyperalgesic levels in the central nervous system?

BACKGROUND AND OBJECTIVES: Central spinal cord sensitization can occur during surgery and may lead to persistent pain after surgery. Pregabalin has been shown to decrease central sensitization in experimental pain paradigms, and so the same antihyperalgesic effect of pregabalin may occur during and immediately after surgery. Our study investigated whether a single 300-mg dose of pregabalin in patients has sufficient central nervous system bioavailability to be useful under acute conditions where brain or spinal cord excitability may lead to long-term disease, such as chronic pain. METHODS: Nine patients undergoing primary total knee replacement received pregabalin 300 mg orally, 1 hr before surgery. An intrathecal catheter was inserted for anesthesia, postoperative analgesic drug administration, and cerebrospinal fluid (CSF) sampling. Blood and CSF were then simultaneously sampled at 2, 4, 6, 8, and 24 hrs after oral pregabalin administration. Pregabalin concentration in plasma and CSF was measured using a validated high-pressure liquid chromatography assay. RESULTS: By 2 hrs after pregabalin administration, the CSF pregabalin concentration is high enough (0.115 µg/mL) to have anticonvulsant activity, and by 6 hrs after pregabalin administration, the CSF pregabalin level is high enough (0.359 µg/mL) to reduce central nervous system hypersensitivity. The median time to peak pregabalin concentration in CSF was at 8 hrs. The pregabalin CSF/plasma based on area under the curve (AUC[0-24 hrs]) was 0.098 ± 0.016, and for AUC[0-∞], the ratio was 0.176 ± 0.064. CONCLUSIONS: Sufficient central nervous system drug concentrations are reached after oral administration of pregabalin, suggesting that postoperative pain hypersensitivity can be reduced. Decreasing this acute brain or spinal cord excitability may prevent chronic pain from developing after surgery.

Can gabapentin help reduce postoperative pain in arthroscopic rotator cuff repair? A prospective, randomized, double-blind study.

PURPOSE: The aim of the study was to determine the effect of low-dose gabapentin on postoperative pain management in patients undergoing arthroscopic rotator cuff repair. METHODS: This randomized, double-blinded, placebo-controlled study included 46 patients. The patients were divided into 2 groups according to the drug administered 2 hours before surgery, either 300 mg of gabapentin or placebo. The primary outcome measure was the visual analog scale (VAS) score at 2, 6, 12, and 24 hours postoperatively. The secondary outcome measures were fentanyl consumption and side effects during the first 2 hours in the postanesthesia care unit and then at 6 and 24 hours postoperatively. The patients were evaluated for side effects including nausea, vomiting, respiratory depression, dizziness, drowsiness, voiding difficulty, and pruritus. RESULTS: The VAS scores at 2, 6, and 12 hours postoperatively were significantly lower in the gabapentin group than in the placebo group (P = .023, P = .019, and P = .022, respectively). The consumption of fentanyl, over a period of 24 hours, was not different in the comparisons between the groups (P = .686). The incidence of side effects was similar in the 2 groups. CONCLUSIONS: A single dose of 300 mg of gabapentin reduced the VAS score during the first 24 hours postoperatively in patients undergoing shoulder arthroscopic rotator cuff repair, without significant side effects when compared with placebo. However, the fentanyl consumption did not differ between the gabapentin and placebo groups. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Simulations of the nonlinear dose dependence for substrates of influx and efflux transporters in the human intestine.

The purpose of this study was to develop simulation and modeling methods for the evaluation of pharmacokinetics when intestinal influx and efflux transporters are involved in gastrointestinal absorption. The advanced compartmental absorption and transit (ACAT) model as part of the computer program GastroPlus was used to simulate the absorption and pharmacokinetics of valacyclovir, gabapentin, and talinolol. Each of these drugs is a substrate for an influx or efflux transporter and all show nonlinear dose dependence within the normal therapeutic range. These simulations incorporated the experimentally derived gastrointestinal distributions of transporter expression levels for oligopeptide transporters PepT1 and HPT1 (valacyclovir); System L-amino acid transporter LAT2 and organic cation transporter OCTN1 (gabapentin); and organic anion transporter (OATP1A2) and P-glycoprotein (talinolol). By assuming a uniform distribution of oligopeptide transporter and by application of the in vitro K(m) value for valacyclovir, the simulations accurately reproduced the experimental nonlinear dose dependence. For gabapentin, LAT2 distribution produced simulation results that were much more accurate than OCTN1 distributions. For talinolol, an influx transporter distribution for OATP1A2 and the efflux transporter P-glycoprotein distributed with increasing expression in the distal small intestine produced the best results. The physiological characteristics of the small and large intestines used in the ACAT model were able to accurately account for the positional and temporal changes in concentration and carrier-mediated transport of the three drugs included in this study. The ACAT model reproduced the nonlinear dose dependence for each of these drugs.

Rash associated with pregabalin use.

OBJECTIVE: To report a case of extensive rash induced by orally administered pregabalin in a patient with neuropathic pain. CASE SUMMARY: A 35-year-old white female with a diffuse, erythematous, maculopapular rash localized to her back and extremities presented to the preoperative holding area for planned exploratory nerve surgery. Prior to presentation, she had been receiving oral pregabalin 50 mg 3 times a day for approximately 2 weeks to treat her neuropathy. Prior to pregabalin therapy, the patient indicated that she had taken gabapentin for approximately 3 weeks for the pain, but had discontinued it due to adverse effects and perceived lack of efficacy. Pregabalin was discontinued and diphenhydramine and methylprednisolone were given to treat the rash. The rash almost completely resolved one week after pregabalin was discontinued. DISCUSSION: Pregabalin-induced rash was rarely reported in Phase 3 trials, and a clinical description of such events has not been published. Pregabalin exhibits pharmacokinetics different from those of most other antiepileptic agents. Presently, there are no clear mechanisms known for rash associated with pregabalin. The Naranjo probability scale indicates a probable relationship between the development of rash and use of pregabalin by our patient. CONCLUSIONS: There are currently no other available reports of the development of a rash coinciding with the use of pregabalin. As both Food and Drug Administration-approved and off-label use of this drug increases, further consideration of risk factors associated with the development of rash is needed.

Pregabalin: a review of its use in fibromyalgia.

Oral pregabalin, a calcium channel alpha(2)delta-subunit ligand with analgesic, anxiolytic and antiepileptic activity, has shown efficacy in the treatment of fibromyalgia. It has a multidimensional effect in the treatment of this complex condition, and is associated with rapid and clinically significant improvements in several outcome measures relating to core symptoms of the syndrome, including pain and sleep, in patients with long-standing fibromyalgia. Pregabalin treatment is also associated with improvements in the overall health status of these patients. The beneficial effects of pregabalin are durable in patients with an initial response to the drug. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients. Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia.

Gabapentin and breastfeeding: a case report.

The aim of this study was to describe the milk-plasma ratio and relative infant dose of gabapentin in a breastfeeding mother and to determine the well-being of her exposed infant. The mother-infant pair was studied over a 24-hour dose interval at steady state. Gabapentin concentrations were quantified by high-performance liquid chromatography. Infant exposure was calculated as concentration in milk multiplied by an estimated milk production of 0.15 L/kg/d and normalized to the weight-adjusted maternal dose. The milk-plasma ratio was 0.86; the relative infant dose was 2.34%. The absolute infant dose was approximately 3% of the children's dose for gabapentin, and the infant plasma level of 0.4 mg/L was approximately 6% of the maternal plasma drug concentration. No adverse effects attributable to gabapentin were noted in the infant. In combination with a previously published report, these limited data support the prescription of gabapentin to a breastfeeding mother after a careful individual risk-benefit analysis.

Expression of functional CB1 cannabinoid receptors in retinoic acid-differentiated P19 embryonal carcinoma cells.

Although primary neuronal cell cultures, usually obtained from embryonic or early postnatal rodents, have been used in vitro to study the neural cannabinoid signalling system, development of cell lines with neural properties exhibiting native expression of cannabinoid receptors is desirable. This study was undertaken to investigate the expression of CB1 and CB2 cannabinoid receptors in neurons that develop from retinoic acid (RA)-primed mouse P19 embryonal carcinoma cells. Both undifferentiated P19 cells and RA-treated P19 neurons were positive, by using reverse transcription-polymerase chain reaction (RT-PCR), for CB1 (but not CB2) mRNA. Neuronal differentiation increased the CB1 mRNA expression, and Western blotting with a CB1 receptor antibody showed a strong immunoreactive band at approximately 62 kDa in membranes from P19-derived neurons. The cannabinoid receptor agonists CP 55,940 and HU-210 produced concentration-dependent inhibition of forskolin-induced (3 microM) cyclic AMP production in the P19-derived neurons (29% at 1 microM CP 55,940 and 34% at 1 microM HU-210), which could be blocked by the CB1-selective receptor antagonist AM251, but not by the CB2-selective antagonist AM630. Furthermore, glutamate (100 microM) induced a sustained increase in [Ca2+]i in P19-derived neurons that could be concentration-dependently blocked by the cannabinoid receptor agonists WIN 55,212-2. Thus, the protocol used provides an in vitro model system expressing CB1 cannabinoid receptors at the level of mRNA, protein, and AM251-sensitive agonist-induced inhibition of intracellular cyclic AMP accumulation, which may be useful to investigate the developmental regulation, expression and function of neuronal cannabinoid receptors.