The mechanical and chemical stability of the interfaces in bioactive materials: The substrate-bioactive surface layer and hydroxyapatite-bioactive surface layer interfaces.

Bioactive materials should maintain their properties during implantation and for long time in contact with physiological fluids and tissues. In the present research, five different bioactive materials (a bioactive glass and four different chemically treated bioactive titanium surfaces) have been studied and compared in terms of mechanical stability of the surface bioactive layer-substrate interface, their long term bioactivity, the type of hydroxyapatite matured and the stability of the hydroxyapatite-surface bioactive layer interface. Numerous physical and chemical analyses (such as Raman spectroscopy, macro and micro scratch tests, soaking in SBF, Field Emission Scanning Electron Microscopy equipped with Energy Dispersive Spectroscopy (SEM-EDS), zeta potential measurements and Fourier Transformed Infra-Red spectroscopy (FTIR) with chemical imaging) were used. Scratch measurements evidenced differences among the metallic surfaces concerning the mechanical stability of the surface bioactive layer-substrate interface. All the surfaces, despite of different kinetics of bioactivity, are covered by a bone like carbonate-hydroxyapatite with B-type substitution after 28 days of soaking in SBF. However, the stability of the apatite layer is not the same for all the materials: dissolution occurs at pH around 4 (close to inflammation condition) in a more pronounced way for the surfaces with faster bioactivity together with detachment of the surface bioactive layer. A protocol of characterization is here suggested to predict the implant-bone interface stability.

Bioactive materials: In vitro investigation of different mechanisms of hydroxyapatite precipitation.

Bioactive materials, able to induce hydroxyapatite precipitation in contact with body fluids, are of great interest for their bone bonding capacity. . The aim of this paper is to compare bioactive materials with different surface features to verify the mechanisms of action and the relationship with kinetics and type of precipitated hydroxyapatite over time. Four different surface treatments for Ti/Ti6Al4V alloy and a bioactive glass were selected and a different mechanism of bioactivity is supposed for each of them. Apart from the conventional techniques (FESEM, XPS and EDX), less common characterizations (zeta potential measurements on solid surfaces and FTIR chemical imaging) were applied. The results suggest that the OH groups on the surface have several effects: the total number of the OH groups mainly affects hydrophilicity of surfaces, while the isoelectric points, surface charge and ions attraction mainly depend on OH acidic/basic strength. Kinetics of hydroxyapatite precipitation is faster when it involves a mechanism of ion exchange while it is slower when it is due to electrostatic effects . The electrostatic effect cooperates with ion exchange and it speeds up kinetics of hydroxyapatite precipitation. Different bioactive surfaces are able to differently induce precipitation of type A and B of hydroxyapatite, as well as different degrees of crystallinity and carbonation. STATEMENT OF SIGNIFICANCE: The bone is made of a ceramic phase (a specific type of hydroxyapatite), a network of collagen fibers and the biological tissue. A strong bond of an orthopedic or dental implant with the bone is achieved by bioactive materials where precipitation and growth of hydroxyapatite occurs on the implant surface starting from the ions in the physiological fluids. Several bioactive materials are already known and used, but their mechanism of action is not completely known and the type of precipitated hydroxyapatite not fully investigated. In this work, bioactive titanium and bioglass surfaces are compared through conventional and innovative methodologies. Different mechanisms of bioactivity are identified, with different kinetics and the materials are able to induce precipitation of different types of hydroxyapatite, with different degree of crystallinity and carbonation.

Magnetoplasmonic nanoparticles for photothermal therapy.

In recent decades the applications of nanotechnology in the biomedical field have attracted a lot of attention. Magnetic and gold nanoparticles (MNPs and GNPs) are now of interest as selective tools for tumour treatment, due to their unique properties and biocompatibility. In this paper, superparamagnetic iron oxide nanoparticles (MNPs) decorated with gold nanoparticles (GNPs) have been prepared by means of an innovative synthesis process using tannic acid as the reducing agent. The as-obtained nanoplatforms were characterized in terms of size, morphology, structure, composition, magnetic response and plasmonic properties. The results revealed that hybrid nanoplatforms (magnetoplasmonic nanoparticles, MPNPs) composed of a magnetic core and an external GNP decoration, acting in synergy, have been developed. Biological tests were also performed on both healthy cells and cancer cells exposed to different nanoparticle concentrations, upon laser irradiation. GNPs grafted onto the surface of MNPs revealed the ability to convert the received light into thermal energy, which was selective in its detrimental effect on cancer cells.

Bioactivity, mechanical properties and drug delivery ability of bioactive glass-ceramic scaffolds coated with a natural-derived polymer.

In this work, hybrid melanin-coated bioactive glass-ceramic multifunctional scaffolds were developed and characterized in terms of mechanical strength, in vitro bioactivity in simulated body fluid (SBF) and ability to load ibuprofen. The coated scaffolds exhibited an accelerated bioactivity in comparison with the uncoated ones, being able of developing hydroxyapatite-like crystals after 7days soaking in simulated body fluid (SBF). Besides its positive influence on the scaffolds bioactivity, the melanin coating was able to enhance their mechanical properties, increasing the initial compressive strength by a factor of >2.5. Furthermore, ibuprofen was successfully loaded on this coating, allowing a controlled drug release of the anti-inflammatory agent.

Gastroretentive carbidopa/levodopa, DM-1992, for the treatment of advanced Parkinson's disease.

OBJECTIVES: This study was undertaken to compare efficacy, tolerability, and pharmacokinetics of DM-1992, an extended-release formulation of carbidopa/levodopa (CD/L-dopa) with immediate-release (IR) CD/L-dopa in patients with advanced Parkinson's disease. METHODS: This randomized, open-label, crossover study included a 3-d baseline and two 10-d treatment periods. Patients with daily OFF time of 2.5 h or more taking 400 mg or more L-dopa/d in four or more divided doses were titrated to stable regimens of DM-1992 2 times per day or CD/L-dopa IR 3 times to 8 times per day. Patients were allowed to take rescue CD/L-dopa as needed. Using home diaries, patients recorded OFF time and ON time with or without troublesome dyskinesia during baseline and treatment days 7 through 9. During 12-h clinic visits on day 10, plasma samples were collected for pharmacokinetics, and motor performance was assessed hourly. RESULTS: Thirty-four patients were enrolled; mean baseline L-dopa dosage was 968 mg/d. After titration, CD/L-dopa IR was dosed 4.8 times per day and DM-1992, 2 times per day. Rescue CD/L-dopa IR was given 1.3 times during the DM-1992 arm and 0.2 times during the CD/L-dopa IR arm. The reduction from baseline in % OFF time was greater for DM-1992 compared with CD/L-dopa IR (-5.52% vs. +1.33%; P = 0.0471). At steady-state, compared with CD/L-dopa IR, DM-1992 exhibited a smoother plasma L-dopa concentration profile mostly because of a significantly higher (day 10) predose L-dopa concentration, associated with enhanced motor performance. Although more patients taking DM-1992 had one or more adverse events (AEs) than CD/L-dopa IR patients (35% vs. 15%), no pattern to the AEs was seen, nor any resulting discontinuations. CONCLUSIONS: DM-1992 was associated with a reduction in %OFF time compared with CD/L-dopa IR despite a reduced dosing frequency. Although the open-label study design and the greater number of rescue doses during the DM-1992 arm call for caution in interpreting the results, the elevated predose plasma L-dopa concentration (12 h after DM-1992 administration) lends objective support to our findings, suggesting that phase 3 studies are warranted.

Pharmacokinetics, efficacy, and tolerability of a once-daily gastroretentive dosage form of gabapentin for the treatment of postherpetic neuralgia.

Neurontin®, an immediate-release (IR) formulation of gabapentin, was the first drug approved by the United States Food and Drug Administration for the treatment of postherpetic neuralgia (PHN). The effective dosing regimen of gabapentin IR (G-IR) for PHN is 1800 mg/day in three divided doses. In 2011, a gastroretentive (GR) formulation of gabapentin (G-GR, Gralise®) was approved for the treatment of PHN. The effective dosing regimen of G-GR is 1800 mg, once daily taken with the evening meal. Compared with G-IR, G-GR has an apparently better tolerability profile with a 1-2 weeks shorter titration period to reach the same therapeutically effective dose. The differences in the dosing frequency and tolerability between G-IR and GR are mainly because of the difference in formulations and thus pharmacokinetic properties. The GR formulation takes advantage of normal human gastrointestinal (GI) physiology and the unique pharmacokinetic properties of gabapentin. In this review, we compare the IR and GR formulations of gabapentin, overview the GI physiology and GR mechanism of G-GR, and describe the unique pharmacokinetic properties of gabapentin. The effect of GR formulation on efficacy and the incidence of adverse events that are commonly associated with G-IR treatment in PHN patients are also discussed.

The intestinal absorption mechanism of gabapentin makes it appropriate for gastroretentive delivery.

Gabapentin is approved for the treatment of postherpetic neuralgia (PHN) and epilepsy. The pharmacokinetic (PK) properties of gabapentin, including absorption, distribution, metabolism, and excretion (ADME), were investigated during the development of Neurontin®, an immediate-release (IR) formulation of gabapentin that is orally administered three-times daily. Recently, a gastroretentive (GR) once-daily formulation of gabapentin (Gralise®) has been developed and marketed for the treatment of PHN. This review focuses on the ADME properties of gabapentin and illustrates how GR delivery enhances its absorption compared with IR formulations and allows once-daily dosing with the evening meal for the treatment of PHN. It includes the following aspects: 1) the mechanism of gastroretention of gabapentin GR tablets, 2) in vitro dissolution profiles of the GR and IR formulations, 3) site of absorption of gabapentin in the human intestine, 4) studies of the mechanism of gabapentin absorption using intestinal tissue preparations, 5) human PK studies to examine the effects of dose and formulations on PK profiles and the bioavailability of gabapentin at therapeutically relevant doses, and 6) efficacy and safety of gastroretentive gabapentin in patients with PHN. The data reviewed support that GR delivery of gabapentin optimizes its absorption via a saturable uptake mechanism. The prolonged residence of the GR tablets in the stomach coupled with the gradual release of gabapentin attenuates saturation of the transporter, thus enhancing absorption and increasing bioavailability, especially at therapeutically relevant doses. The net result is a once-daily formulation of gabapentin that is well tolerated and efficacious for the treatment of PHN.

Effects of sterilization and storage on the properties of ALP-grafted biomaterials for prosthetic and bone tissue engineering applications.

Grafting of the biomaterial surfaces with biomolecules is nowadays a challenging research field for prosthetic and bone tissue engineering applications. On the other hand, very few research works investigate the effect of the sterilization processes on the properties of functionalized biomaterials. In this study, the effects of different sterilization techniques (e.g. gamma and electron beam irradiation, ethylene oxide) on the enzymatic activity of bioactive glasses and Ti6Al4V grafted with alkaline phosphatase (ALP) have been analyzed. Sterility maintenance and in vitro bioactivity of the sterilized surfaces have also been investigated. Finally the effect of packaging and storage conditions has been considered.

Clinical development of a once-daily gastroretentive formulation of gabapentin for treatment of postherpetic neuralgia: an overview.

INTRODUCTION: Gabapentin immediate-release formulations (G-IR) administered three times a day is an efficacious treatment for postherpetic neuralgia (PHN), but its potential benefits may not be fully realized due to tolerability issues as well as its pharmacokinetic (PK) properties such as its short half-life, and regional and saturable absorption in the proximal small intestine. The gastroretentive once-daily formulation of gabapentin (G-GR) allows for less frequent dosing while maintaining efficacy and may also reduce adverse events (AEs) associated with high plasma concentration of gabapentin occurring during the waking hours. G-GR slowly releases the drug from the tablet to the upper small intestine, where gabapentin is best absorbed, over approximately 10 h. AREA COVERED: This report reviews the development of the gastroretentive technology used in the once-daily formulation of gabapentin (G-GR), and describes the clinical development of G-GR from PK studies through the Phase III efficacy and safety studies, with comparisons made with G-IR. EXPERT OPINION: The technology takes advantage of the normal physiology of the stomach in the fed state to provide gastroretention, which in turn allows for gradual release of the active ingredient over several hours to the small intestine where gabapentin is best absorbed. The GR technology used in G-GR resulted in a decreased dosing frequency from three times per day for the IR product to once daily in the treatment of PHN, while maintaining the same efficacy with an apparent reduced incidence of AEs common to G-IR therapy.

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.

A gastroretentive gabapentin formulation for the treatment of painful diabetic peripheral neuropathy: efficacy and tolerability in a double-blind, randomized, controlled clinical trial.

AIMS: A randomized, double-blind, placebo-controlled study was conducted in 147 patients to determine the efficacy and safety of a gastroretentive formulation of gabapentin (G-GR) in treating painful diabetic peripheral neuropathy (DPN). METHODS: Diabetic patients with symmetrical painful symptoms in distal extremities for 1-5 years and a baseline average daily pain (ADP) score of ≥4 received G-GR 3000mg, as a single evening daily dose (G-GR-QD) or a divided dose (G-GR-DD, 1200mg AM/1800mg PM), or placebo for 4 weeks. G-GR was titrated from 300 to 3000mg/day over 2 weeks, followed by 2 additional weeks at 3000mg/day. Efficacy measures included changes from baseline to Week 4 in ADP score and average daily sleep interference score (SIS). RESULTS: A significantly larger decrease in ADP score was observed in the G-GR-QD dose group compared with placebo (-2.50 versus -1.30; p=0.002). A ≥50% reduction in ADP score was achieved in 34.8% of G-GR-QD recipients compared with 7.8% of placebo recipients (p=0.001). Similar results were observed for changes in SIS. The incidences of dizziness and somnolence, commonly associated with gabapentin, were low. CONCLUSIONS: Once-daily G-GR was effective and well tolerated for the treatment of pain due to DPN.

Pharmacokinetics and pharmacodynamics of gastroretentive delivery of levodopa/carbidopa in patients with Parkinson disease.

OBJECTIVE: To investigate, in patients with Parkinson disease, the pharmacokinetics and pharmacodynamics of levodopa/carbidopa delivered via 3 different extended-release (ER) tablet formulations. METHODS: This was a randomized, crossover study in patients with stable idiopathic Parkinson disease comparing a conventional ER tablet (C-ER) administered orally 3 times daily with 2 levodopa/carbidopa gastroretentive ER formulations administered orally twice daily, one with an immediate release (IR) component (IR/ER) and one without (ER). Blood samples were collected for pharmacokinetic (PK) analysis, and a finger-tapping test was performed to assess pharmacodynamics. Tolerability was evaluated by monitoring adverse events and measuring vital signs. PK modeling was performed to estimate steady-state levodopa concentrations. RESULTS: Fourteen patients completed the study. Compared with C-ER, both gastroretentive ER tablets significantly extended the first maximum time (6.0 vs 2.5 h; P < 0.025) and had smoother plasma concentration-time profiles while achieving a similar maximum plasma concentration and area under the curve. The IR/ER formulation exhibited a significantly longer duration of concentration above the presumed efficacious threshold of 300 ng/mL (21 vs 18 h; P = 0.0027) compared with C-ER. PK modeling predicts a steady-state levodopa peak/trough ratio of 4 for both IR/ER and ER formulations and a ratio of 21 for C-ER. Furthermore, superior response in the finger tapping test was observed for the IR/ER and ER formulations compared with the C-ER formulation. CONCLUSIONS: This study demonstrated that the gastroretentive ER formulations achieved more constant plasma levodopa concentrations and better pharmacodynamics with reduced dose frequency, potentially reducing the on-off phenomena that have been associated with fluctuations in plasma levodopa concentrations.

Pharmacokinetics of levodopa/carbidopa delivered from gastric-retentive extended-release formulations in patients with Parkinson's disease.

The investigators conducted a single-dose pharmacokinetic (PK) study of levodopa/carbidopa delivered from novel gastric-retentive extended-release (ER) tablets versus a comparator ER tablet (M-ER) in patients with Parkinson's disease. Two levodopa/carbidopa (200 mg/50 mg) gastric-retentive ER formulations (4 hours and 6 hours) and M-ER were administered orally with food. Blood samples were collected for up to 24 hours post dose to determine levodopa and carbidopa concentrations. Tolerability was assessed by monitoring adverse events and measuring vital signs. PK modeling was conducted to estimate the release characteristics for future gastric-retentive ER formulations to achieve a less fluctuating plasma concentration profiles. Compared with M-ER, both gastric-retentive ER formulations exhibited a longer time to reach a lower maximal plasma concentration for levodopa and carbidopa. The 4-hour formulation demonstrated a similar area under the concentration-time curve compared with M-ER, whereas the 6-hour formulation demonstrated a lower area under the concentration-time curve. All formulations were well tolerated. Modeling suggests that a gastric-retentive ER formulation with a longer release duration administered twice daily may achieve a less fluctuating levodopa concentration profile than M-ER administered 3 times daily. This study demonstrates that gastric-retentive ER dosage forms may reduce dose frequency while minimizing the plasma peak-to-trough fluctuation and consequently reduce motor fluctuation in patients with Parkinson's disease.

Surface modification of Ti-6Al-4 V alloy for biomineralization and specific biological response: part II, alkaline phosphatase grafting.

Titanium and its alloys are the most widespread materials for the realization of orthopaedic and dental implants due to their good mechanical properties and biocompatibility. Surface functionalization of biomaterials aimed to improve and quicken implant integration and tissue regeneration is an active research field. The opportunity to confer biological activity (ability to directly stimulate cells with proper biological signals) to the Ti6Al4 V alloy, previously modified to be bioactive from the inorganic point of view (apatite precipitation), was explored in this research work. The alkaline phosphatase (ALP) enzyme was grafted to metal surface via tresyl chloride activation, maintaining its activity. A synergistic effect between biological functionalization and inorganic bioactivity was observed.

Hierarchical nanoengineered surfaces for enhanced cytoadhesion and drug delivery.

Delivering therapeutics to mucosal tissues such as the nasal and gastrointestinal tracts is highly desirable due to ease of access and dense vasculature. However, the mucus layer effectively captures and removes most therapeutic macromolecules and devices. In previous work, we have shown that nanoengineered microparticles (NEMPs) adhere through the mucus layer, exhibiting up to 1000 times the pull-off force of an unmodified microsphere, and showing greater adhesion than some chemical targeting means. In this paper, we demonstrate that nanotopography improves device adhesion in vivo, increasing retention time up to ten-fold over unmodified devices. Moreover, we observe considerable adhesion in several cell lines using an in vitro shear flow model, indicating that this approach is promising for numerous tissues. We then demonstrate that nanowire-mediated adhesion is highly robust to variation in nanowire surface charge and cellular structure and function, and we characterize particle loading and elution. We present a form of cytoadhesion that utilizes the physical interaction of nanoengineered surfaces with subcellular structures to produce a robust and versatile cytoadhesive for drug delivery. These nanoscale adhesive mechanisms are also relevant to fields such as tissue engineering and wound healing because they likely affect stem cell differentiation, cell remodeling, migration, etc.

Surface modification of Ti-6Al-4V alloy for biomineralization and specific biological response: Part I, inorganic modification.

Titanium and its alloys represent the gold standard for orthopaedic and dental prosthetic devices, because of their good mechanical properties and biocompatibility. Recent research has been focused on surface treatments designed to promote their rapid osteointegration also in case of poor bone quality. A new surface treatment has been investigated in this research work, in order to improve tissue integration of titanium based implants. The surface treatment is able to induce a bioactive behaviour, without the introduction of a coating, and preserving mechanical properties of Ti6Al4V substrates (fatigue resistance). The application of the proposed technique results in a complex surface topography, characterized by the combination of a micro-roughness and a nanotexture, which can be coupled with the conventional macro-roughness induced by blasting. Modified metallic surfaces are rich in hydroxyls groups: this feature is extremely important for inorganic bioactivity (in vitro and in vivo apatite precipitation) and also for further functionalization procedures (grafting of biomolecules). Modified Ti6Al4V induced hydroxyapatite precipitation after 15 days soaking in simulated body fluid (SBF). The process was optimised in order to not induce cracks or damages on the surface. The surface oxide layer presents high scratch resistance.

Pharmacokinetics of gabapentin in a novel gastric-retentive extended-release formulation: comparison with an immediate-release formulation and effect of dose escalation and food.

The objectives of the 3 phase I studies described herein were (1) to compare the pharmacokinetics of gabapentin delivered from a novel gastric-retentive dosage form vs an immediate-release formulation, (2) to assess the dose proportionality of the gastric-retentive extended-release formulation, and (3) to determine the effect of food on the pharmacokinetics of gabapentin delivered from this formulation. The time to reach maximum plasma concentration (t(max)) was extended for gabapentin delivered from the gastric-retentive extended-release formulation compared with the immediate-release formulation. A dose-related increase in both the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) was observed as the gabapentin dose increased from 600 to 2400 mg. Fed status and increased fat content delayed t(max) and enhanced C(max) and AUC in proportion to the fat content. The pharmacokinetics of gabapentin delivered from this extended-release formulation allows a reduced dosing frequency while maintaining bioavailability and possibly diminishing the occurrence of adverse events attributable to a slower increase to the peak concentration compared with the immediate-release dosage form.

Gabapentin extended-release tablets for the treatment of patients with postherpetic neuralgia: a randomized, double-blind, placebo-controlled, multicentre study.

BACKGROUND: Postherpetic neuralgia (PHN) is a neuropathic pain syndrome that may develop subsequent to healing of herpes zoster rash. OBJECTIVES: This study aimed to determine the efficacy and safety of gabapentin extended-release (gabapentin ER) tablets for the treatment of patients with PHN and to determine whether optimal benefits might be achieved with once-daily (QD) or divided-dose (DD) administration. METHODS: This was a 10-week, randomized, double-blind, placebo-controlled, multicentre trial comparing gabapentin ER (total daily dose 1800 mg) either QD or as an asymmetrical DD with placebo in 407 patients with post-zoster pain for >or=3 months and a baseline average daily pain score (ADP)>or=4 on a 0-10 Likert numerical rating scale. The primary efficacy outcome was the ADP score mean change from baseline to week 10 using baseline observation carried forward (BOCF). Secondary efficacy outcomes included changes to week 10 in last observation carried forward (LOCF) ADP score, LOCF average daily sleep interference score, Short-Form McGill Pain Questionnaire score, Neuropathic Pain Scale score, and Brief Pain Inventory score. RESULTS: Of 407 randomized patients, 400 were included in the intent-to-treat population (gabapentin ER QD, n=134; gabapentin ER DD, n=135; placebo, n=131). Between-group differences in the least squares (LS) mean changes in BOCF ADP scores did not reach statistical significance (gabapentin ER QD -1.85 [p=0.110 vs placebo]; gabapentin ER DD -1.72 [p=0.255 vs placebo]; placebo -1.42). In the LOCF analysis, the LS mean ADP score for the gabapentin ER QD group, but not for the DD group, improved compared with placebo (gabapentin ER QD, -2.28; p=0.032 vs placebo). Improvements compared with placebo were also observed in the gabapentin ER QD group, but not for the DD group, for mean daily sleep interference scores (gabapentin ER QD, -2.49; placebo, -1.63; p<0.001). Most adverse events (AEs) were mild or moderate. Among gabapentin-treated patients, 12% and 11% withdrew due to AEs, most commonly for dizziness (2% and 3%), in the gabapentin ER QD and DD groups, respectively. Treatment-related AEs in the gabapentin ER-treated groups occurred in 31% of patients. The most common AEs in the gabapentin ER QD and DD groups included dizziness (10% and 15%), headache (4% and 7%), somnolence (3% and 7%) and peripheral oedema (5% and 5%), respectively. CONCLUSION: The primary efficacy endpoint for this study of gabapentin ER was not met, most likely due to the unexpectedly large placebo response. Outcomes on secondary endpoints suggest the potential efficacy of gabapentin ER QD. Gabapentin ER was well tolerated in this study. [Clinicaltrials.gov identifier NCT00335933].