Pregabalin and gabapentin in non-opioid poisoning deaths.

Post-mortem findings of gabapentinoids have often been connected to drug abuse and especially opioid use. We aimed to investigate whether gabapentinoids have been implicated in the cause of death without the presence of opioids. In a three-year study period from 2016 to 2018, a total of 907 Finnish post-mortem cases positive for pregabalin or gabapentin were found. In nearly half of the pregabalin cases and in a third of the gabapentin cases, the blood concentration was above the typical therapeutic range of the drug. Of the cases in which pregabalin was detected, in 35% the drug was implicated in a fatal poisoning with or without other drugs or alcohol. For gabapentin, the percentage was 22%. In most of the fatal gabapentinoid poisonings, opioids or other central nervous system depressants were additionally detected in relevant concentrations. There were eight non-opioid gabapentinoid poisonings, in which no relevant other drugs were detected. Many of these cases were unintentional poisonings with a relatively high gabapentinoid concentration in the blood. In all but one, the manner of death was accidental, or the intent was undetermined. This study confirmed the previous findings that gabapentinoids are mostly implicated in fatal poisoning together with opioids. Half of the non-opioid cases were related to drug abuse but in the other half the death was presumably caused by overuse of a prescribed drug or suicide. While the use of gabapentinoids is a well-known problem among people who use drugs, it is important to note other groups of users who may be at risk of overdose by gabapentinoids.

Green HPLC-DAD and HPTLC Methods for Quantitative Determination of Binary Mixture of Pregabalin and Amitriptyline Used for Neuropathic Pain Management.

First analytical methods were herein developed for determination of pregabalin (PGB) and amitriptyline (AMT) as an active binary mixture used for management of neuropathic pain whether in pure forms or in human biological fluids (plasma/urine). First method is green high-performance liquid chromatography-diode array detector (HPLC-DAD) after derivatization of PGB with ninhydrin (NIN) on a reversed-phase C18 column using a mobile phase consisting of ethanol:water (97:3%, v/v) pumped isocratically at 0.8 mL/min; AMT were scanned at 215 nm, whereas PGB-NIN was scanned at 580 nm. Second method is High-performance thin-layer chromatography (HPTLC), where PGB and AMT were separated on silica gel HPTLC F254 plates, using ethanol:ethyl acetate:acetone:ammonia solution (8:2:1:0.05, by volume) as a developing system. AMT peaks were scanned at 220 nm, whereas PGB peaks were visualized by spraying 3% (w/v) ethanolic NIN solution and scanning at 550 nm. Linear calibration curves were obtained for human plasma and urine spiked with PGB and AMT over the ranges of 5-100 µg/mL and 0.2-2.5 µg/band for PGB, and 1-100 µg/mL and 0.1-2.0 µg/band for AMT for HPLC-DAD and HPTLC methods, respectively. The suggested methods were validated according to Food and Drug Administration guidelines for bioanalytical methods validation and they can be applied for routine therapeutic drug monitoring for the concerned drugs.

Forensic application and evaluation of a commercially available pregabalin immunoassay test in serum on an Olympus AU480.

Misuse of pregabalin and its forensic relevance is steadily increasing. The aim of this study was to evaluate the usability of the commercially available ARKTM Pregabalin II Assay (ARK Diagnostics) for serum analysis of forensic samples. Overall, 156 samples were tested by both the immunoassay and a validated liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method. Sensitivity was 100%, and specificity was 98.7% (n = 79 positive cases confirmed by LC-MS/MS in a range of 380-37,000 ng/mL). A good correlation (R2  = 0.73) could also be shown between quantitative immunoassay and LC-MS/MS results. In conclusion, the assay shows excellent reliability for screening of forensic serum samples.

Ecologically evaluated and FDA-validated HPTLC method for assay of pregabalin and tramadol in human biological fluids.

The introduced research presents a novel in vivo quantitative method for assay of mixtures of pregabalin and tramadol as a common combinations approved for treatment of neuropathic pain. Green analytical chemistry is a recently emerging science concerned with control of the use of chemicals harmful to the environment in various analytical methods. Consequently, a green high-performance thin layer chromatography (HPTLC) method was achieved for determination of the mixture in human plasma and urine satisfying both analytical and environmental standards. The separation was achieved on HPTLC sheets using a separating mixture of ethanol-ethyl acetate-acetone-ammonia solution (8:2:1:0.05, by volume) as a mobile phase. The sheets were dried in air then scanned at two wavelengths. For tramadol, 220 nm was chosen; however, pregabalin is an unconjugated drug, so its determination was a challenge. Hence for pregabalin, the plates were sprayed with ethanolic solution of ninhydrin (3%, w/v), to obtain a conjugated complex, which could be assessed at 550 nm. Furthermore, the developed method fulfilled the US Food and Drug Administration validation guidelines, and proved to be useful in therapeutic drug monitoring of this combination. The Eco-scale assessment protocol was implemented to determine the greenness profile of the applied method.

Development of a Novel Controlled-Release Tablet of Pregabalin: Formulation Variation and Pharmacokinetics in Dogs and Humans.

BACKGROUND: Novel three-layered (TL) tablet systems were compared with both monolithic matrix (MM) formulations and a commercial immediate-release (IR) capsule to develop once-a-day (OAD) pregabalin tablets. METHODS: The physical properties of the TL tablets, including dissolution and swelling rates, were compared with those of the MM tablets and the pharmacokinetic parameters of the TL tablet were compared with those of an IR capsule in beagles and humans. RESULTS: Our results indicated that the same amount of a hydrophilic polymer in the formulations had similar dissolution profiles at 12 h, regardless of the tablet geometry. However, the degree of tablet swelling differed, with larger amounts of polymer in the tablets showing a greater degree of swelling. In addition, TL tablets swelled more rapidly compared with MM tablets. For the pharmacokinetic study of the TL tablet, the beagles demonstrated absorption results similar to those of an IR capsule, whereas the humans demonstrated low total absorption compared with an IR capsule. The time of the peak plasma concentration at 6 h in the fed state of humans coincided with the results of the study on beagles. CONCLUSION: The novel TL tablet system of pregabalin may prove to be helpful in developing improved formulations with better continuous drug absorption for OAD administration.

Validation of a High-throughput Screening and Quantification Method for the Determination of Gabapentinoids in Blood Using a Combination of LC-TOF-MS and LC-MS-MS.

Gabapentinoids such as gabapentin (GP) and pregabalin (PGL) have been used to treat a wide range of neurological and psychiatric disorders. In recent years, there has been an increasing awareness of GP and PGL misuse among individuals with a history of polysubstance use. Both GP and PGL are understood to potentiate the effects of opioids, with fatalities involving GP and PGL being reported with increasing frequency. An efficient procedure was developed to screen and quantitate GP and PGL in blood samples using a combination of liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) and liquid chromatography tandem mass spectrometry (LC-MS-MS). The developed LC-MS-MS method was linear from 0.5-50 mg/L, with a limit of detection (LOD) of 0.1 mg/L for GP and PGL. An LOD of 0.5 mg/L was determined for both analytes on the LC-TOF-MS screen. A total of 1,091 blood specimens were subjected to a protein crash with methanol, in the presence of deuterated internal standards, PGL-d6 and GP-d10, to minimize the effects of varying matrix conditions. Specimens tested included both post-mortem blood and preserved blood specimens collected for the purposes of investigating drug-impaired driving and suspected drug-facilitated crimes. Of the total of specimens tested, 101 (9.3%) screened positive using the developed LC-TOF-MS method for GP while only 13 (1.2%) blood specimens screened positive for PGL. All (100%) of the cases that screened positive for GP and PGL were confirmed positive by LC-MS-MS. Blood concentrations of GP and PGL ranged from <0.5 to 215 mg/L and from <0.5 to 32 mg/L, respectively. Of the blood specimens that had previously screened negative by LC-TOF-MS, 10% (N = 100) were randomly selected and tested by LC-MS-MS with 100% confirmed negative for GP and PGL. The developed methods provide a fast and reliable high-throughput screening and confirmation testing strategy for the detection of GP and PGL in blood specimens.

Pharmacokinetic and pharmacodynamic studies of pregabalin suppositories based on pharmacological research.

OBJECTIVES: As commercially available pregabalin preparations are limited to oral administration, it is impossible to use it as an adjuvant analgesic for neuropathic cancer-related pain in terminally ill cancer patients with oral feeding difficulties. The objective of this study was to develop a pregabalin suppository to be available at hospitals. METHODS: Pregabalin suppositories were prepared using bases comprising six different compositions of Witepsol H-15, Witepsol S-55, and Witepsol E-75. The suppository release test and stability test were performed in vitro. The pharmacokinetics and pharmacodynamics of the suppositories were assessed in rats. KEY FINDINGS: In the in vitro releasing test, the pregabalin suppositories with H-15, H-15 : S-55 = 1 : 1, H-15 : S-55 = 2 : 1, H-15 : S-55 = 1 : 2 released approximately 100% of the pregabalin within 180 min. Among these pregabalin suppositories, only the suppository with H-15 : S-55 = 2 : 1 demonstrated an equivalent AUC0-∞ with the oral administration group. Consistent with the results of the pharmacokinetic study, the pregabalin suppository with H-15 : S-55 = 2 : 1 exhibited antinociceptive effects. In addition, the pregabalin suppository with H-15 : S-55 = 2 : 1 was stable for 12 weeks when refrigerated with light shielding. CONCLUSIONS: The pregabalin suppositories prepared in this study may be applicable for pain control for terminally cancer ill patients with oral feeding difficulties.

Dose-proportional pharmacokinetic properties of GLA5PR GLARS-NF1 controlled-release pregabalin in healthy Korean volunteers: a randomized, open, single-dose, parallel study.

PURPOSE: The aim of this study was to evaluate the dose-proportional pharmacokinetic characteristics of pregabalin following the administration of GLA5PR GLARS-NF1 tablets (150, 300, 450, and 600 mg) in the fed state. SUBJECTS AND METHODS: An open-label, randomized, single-dose, parallel study was conducted in 40 eligible subjects who were randomly assigned to receive a single 150, 300, 450, or 600 mg dose of GLA5PR GLARS-NF1. Serial blood samples were collected before and after dosing for 36 hours, and plasma concentrations were determined using liquid chromatography-tandem mass spectrometry. Safety profiles were evaluated throughout the study (trial registration number: NCT02327000). RESULTS: Thirty-seven subjects completed the studies. The area under the plasma concentration-time curve up to the last measurable concentration of pregabalin exhibited dose proportionality following administration of GLA5PR GLARS-NF1 tablets from 150 to 600 mg while its maximum plasma concentration showed dose proportionality at a dose range of 150-450 mg. The safety evaluations showed no clinically significant finding after administration of GLA5PR GLARS-NF1 tablets (150, 300, 450, and 600 mg) in the fed state. CONCLUSIONS: The dose-proportional properties of GLA5PR GLARS-NF1 150-450 mg tablets were determined.

An Improved LC-ESI-MS/MS Method to Quantify Pregabalin in Human Plasma and Dry Plasma Spot for Therapeutic Monitoring and Pharmacokinetic Applications.

BACKGROUND: Therapeutic drug monitoring (TDM) of antiepileptic drugs provides a valid clinical tool in optimization of overall therapy. However, TDM is challenging because of the high biological sample (plasma/blood) storage/shipment costs and the limited availability of laboratories providing TDM services. Sampling in the form of dry plasma spot (DPS) or dry blood spot is a suitable alternative to overcome these issues. METHODS: An improved, simple, rapid, and stability-indicating method for quantification of pregabalin (PGB) in human plasma and DPS has been developed and validated. Analyses were performed on liquid chromatography-tandem mass spectrometer under positive ionization mode of electrospray interface. PGB-d4 was used as internal standard, and the chromatographic separations were performed on Poroshell 120 EC-C18 column using an isocratic mobile phase flow rate of 1 mL/min. Stability of PGB in DPS was evaluated under simulated real-time conditions. Extraction procedures from plasma and DPS samples were compared using statistical tests. The method was validated considering the Food and Drug Administration method validation guideline. RESULTS: The method was linear over the concentration range of 20-16,000 ng/mL and 100-10,000 ng/mL in plasma and DPS, respectively. DPS samples were found stable for only 1 week on storage at room temperature and for at least 4 weeks at freezing temperature (-20 ± 5°C). Method was applied for quantification of PGB in over 600 samples of a clinical study. Statistical analyses revealed that 2 extraction procedures in plasma and DPS samples showed statistically insignificant difference and can be used interchangeably without any bias. CONCLUSIONS: Proposed method involves simple and rapid steps of sample processing that do not require a precolumn or postcolumn derivatization procedure. The method is suitable for routine pharmacokinetic analysis and therapeutic monitoring of PGB.

Saliva versus Plasma Therapeutic Drug Monitoring of Pregabalin in Jordanian Patients.

The objective is using saliva instead of plasma for pregabalin therapeutic drug monitoring (TDM) since saliva reflects the free non-protein bound drug concentration, simple and noninvasive sampling, cheaper and does not require the expertise of drawing blood. Forty four patients participated in this study, two samples of saliva and another two of blood were taken from each patient; first sample of both saliva and blood is the trough sample and was taken just before the first dose of the day and second sample is the peak sample and was taken 1 h after taking the first dose of the day. Descriptive statistics and t-testing after log transformation were done using Excel, p-value=0.05 was adopted for significant difference. Optimized effective intestinal permeability of pregabalin was estimated by PK-Sim program version 7. This study for the first time revealed that pregabalin is excreted in saliva and classified as class 1 based on Salivary Excretion Classification System (SECS). A good correlation of 0.71-0.83 between Cmin and Cmax of plasma and saliva pregabalin was observed respectively which indicate that saliva sampling is a good alternative matrix for pregabalin TDM. C/D-ratios were calculated to demonstrate pharmacokinetic variability of Pregabalin; the results showed that C/D-ratio was higher in women, elderly and in those patients who had Scr.≥0.9 mg/dl. Proposed pregabalin therapeutic ranges are 0.7 to 1.84 µg/ml in plasma and 0.055 to 0.145 µg/ml in saliva, for neuropathic pain, diabetic neuropathy and disc prolapse patients.

Stacking-cyclodextrin-microchip electrokinetic chromatographic determination of gabapentinoid drugs in pharmaceutical and biological matrices.

A facile, rapid, and highly sensitive microchip-based electrokinetic chromatographic method was developed for the simultaneous analysis of two gabapentinoid drugs, gabapentin (GPN) and pregabalin (PGN). Both drugs were first reacted with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) via nucleophilic substitution reactions to yield highly fluorescent products with λex/em 470/540nm. Analyses of both fluorescently labeled compounds were achieved within 200s in a poly(methyl methacrylate) (PMMA) microchip with a 30mm separation channel. Optimum separation was achieved using a borate buffer (pH 9.0) solution containing methylcellulose and ß-cyclodextrin (ß-CD) as buffer additives. Methylcellulose acted as a dynamic coating to prevent adsorption of the studied compounds on the inner surfaces of the microchannels, while ß-CD acted as a pseudo-stationary phase to improve the separation efficiency between the labeled drugs with high resolution (Rs>7). The fluorescence intensities of the labeled drugs were measured using a light emitting diode-induced fluorescence detector at 540nm after excitation at 470nm. The sensitivity of the method was enhanced 14- and 17-fold for PGN and GPN, respectively by field-amplified stacking relative to traditional pinched injection so that it could quantify 10ngmL-1 for both analytes, with a detection limit lower than 3ngmL-1. The developed method was efficiently applied to analyze PGN and GPN in their pharmaceutical dosage forms and in biological fluids. The extraction recoveries of the studied drugs from plasma and urine samples were more than 89% with%RSD values lower than 6.2.

The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin, and their Combination in Painful Polyneuropathy.

OBJECTIVE: The aim of this study was to explore the serum concentration-effect relation for first-line drugs in neuropathic pain and to determine if efficacy could be increased. METHODS: Data from a randomized, placebo-controlled, cross-over trial on imipramine, pregabalin, and their combination in painful polyneuropathy were used. Treatment periods were of 4 weeks' duration, outcome was the weekly median of daily pain rated by a 0 to 10 numeric scale, and drug concentrations were determined by high-performance liquid chromatography. RESULTS: In 47 patients, pain was reduced -1.0 (95% confidence interval [CI], -1.5 to -0.6) by imipramine, -0.4 (95% CI, -0.9 to 0.1) by pregabalin, and -1.6 (95% CI, -2.1 to -1.1) by combination therapy. On monotherapy, there was no difference between responders and nonresponders with respect to concentrations of imipramine (mean, 161 vs. 229 nmol/L, P=0.129) and pregabalin (mean, 9.8 vs. 11.7 µmol/L, P=0.178). There was no correlation between drug concentration and pain reduction for imipramine (r=0.17, P=0.247), whereas there was a marginally, positive correlation for pregabalin (r=0.28, P=0.057). There was no interaction between treatment and concentration classes (imipramine < or ≥100 nmol/L, pregabalin < or ≥10 µmol/L) either for monotherapy or for combination therapy (P=0.161 to 0.797). Isobolographic presentations of reponders with imipramine and pregabalin concentrations during combination therapy did not indicate synergistic interaction. DISCUSSION: There were no important relations between drug concentrations and efficacy, or indication of synergistic interaction between the drugs. It was not concluded that treatment can be improved by measurement of drug concentration of pregabalin.

Validated Method for the Screening and Quantification of Baclofen, Gabapentin and Pregabalin in Human Post-Mortem Whole Blood Using Protein Precipitation and Liquid Chromatography-Tandem Mass Spectrometry.

There has been a rapid increase in the number of prescriptions for baclofen (BLF), gabapentin (GBP) and pregabalin (PGL) in the UK since their introduction to therapy. Recent studies across the European Union and USA have shown the illicit abuse potential of these drugs and deaths have been observed. A simple, reliable and fully validated method was developed for the screening and quantification of BLF, GBP and PGL in human post-mortem (PM) blood. The analytes and their deuterated analogs as internal standard were extracted from blood using a single addition acetonitrile protein precipitation reaction followed by analysis using liquid chromatography-tandem mass spectrometry (LC-MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous confirmation and quantification. The assay was linear from 0.05 to 1.00 µg/mL for BLF and 0.5 to 50.0 µg/mL for GBP and PGL, respectively with r2 > 0.999 (n = 9) for all analytes. Intra-day and inter-day imprecisions (n = 80) were calculated using one-way ANOVA; no significant difference (P > 0.99) was observed for all analytes over 8 non-consecutive days. The average recovery for all analytes was >98.9%. The limits of detection and quantification were both 0.05 µg/mL for BLF, and 0.5 µg/mL for GBP and PGL. The method was highly selective with no interference from endogenous compounds or from 54 drugs commonly encountered in PM toxicology. To prove method applicability, 17 PM blood samples submitted for analysis were successfully analyzed. The concentration range observed in PM blood for BLF was 0.08-102.00 µg/mL (median = 0.25 µg/mL), for GBP 1.0-134.0 µg/mL (median = 49.0 µg/mL) and 2.0-540.0 µg/mL (median = 42.0 µg/mL) for PGL.

Bioequivalence of two formulations of pregabalin 150-mg capsules under fasting conditions in healthy male subjects
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BACKGROUND: Pregabalin binds to the α2δ auxiliary subunit of voltage-gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems and modulate calcium-dependent neurotransmitter release. Pregabalin is indicated for the treatment of peripheral and central neuropathic pain, partial seizures with or without secondary generalization, and treatment of generalized anxiety disorder (GAD). OBJECTIVE: The purpose of this study was to assess the bioequivalence of two different formulations of pregabalin 150-mg capsules in healthy Korean male subjects under fasting conditions. METHODS: This bioequivalence study was based on an open-label, single-dose, randomized, 2-period, 2-sequence crossover design with a washout period of 7 days. Blood samples for pharmacokinetic (PK) evaluation were collected up to 24 hours postdose. Plasma concentrations of pregabalin were determined using a validated LC-MS/MS method. PK parameters were determined using noncompartmental analysis. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of log-transformed Cmax and AUClast values met the bioequivalence criteria specified by Korean regulatory guidelines (90% CI 0.8 - 1.25). RESULTS: The extent of exposure in terms of AUClast amounted to 26,018.3 - 3,580.8 µg×h/L for the test formulation and 25,680.2 ± 3,083.6 µg×h/L for the reference formulation. Cmax reached values of 4,782.7 ± 1,124.2 µg/L and 4,654.0 ± 911.4 µg/L for the test product and reference product, respectively. The geometric mean ratio and 90% CIs of the test product to the reference product were 1.0132 (0.9862 - 1.0351) for AUClast and 1.0153 (0.9351 - 1.1044) for Cmax, which were well within the range necessary to establish bioequivalence (90% CI 0.8 - 1.25). CONCLUSIONS: The bioequivalence between test and reference formulations under fasting conditions was confirmed both in terms of the rate and extent of absorption.
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Determining the Toxicological Significance of Pregabalin in Fatalities.

Pregabalin has become more widely prescribed and abused in recent years but is still not always included in laboratory analysis. An LC-MS-MS method has been developed and applied to measure pregabalin in 93 postmortem cases, including drug-related deaths, alternative causes of death, and fatalities where pregabalin was likely to have contributed to death. Other drugs or alcohol was detected, and the most common drug types (in decreasing frequency) were antidepressants, opioids, benzodiazepines, opiates, alcohol, antipsychotics, cocaine, cardiac drugs, amphetamines, cannabis, anticonvulsants, and antihistamines. New psychoactive substances (methoxphenidine and synthetic cannabinoids) were only found in two cases. The results provide further data to assist in evaluating the significance of postmortem pregabalin concentrations and a toxicologically significant concentration of 25 mg/L is proposed. Pregabalin, especially with concomitant use of other CNS depressant drugs, presents a significant toxicological risk and existing laboratory protocols should be reviewed for their suitability to detect pregabalin.

Comparison of oral absorption models for pregabalin: usefulness of transit compartment model.

Pregabalin is an anticonvulsant used for the treatment of neuropathic pain and partial seizure in adults. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the absorption characteristics of pregabalin given fasted or after meals. Data from five healthy subject PK studies (n=88) of single- or multiple-dose pregabalin (150 mg) were used. Pregabalin was administered twice daily, without meals or 30 min after a meal (regular or high-fat diet) in the morning and 30 min or 4 h after a meal (regular diet) in the evening. Serial plasma samples were collected up to 24 h after the last dose for PK analysis. Because the peak concentrations were not properly modeled by a conventional first-order absorption model, Erlang frequency distribution, Weibull-type absorption, and transit compartment models were tested on a two-compartment linear PK model using a nonlinear mixed-effects method (NONMEM; version 7.3). The transit compartment model best described the absorption characteristics of pregabalin regardless of meal status. We conclude that the absorption model should be carefully chosen based on the principle of model development and validation and not by following a conventional first-order absorption model for its popularity and simplicity, especially when the PK dataset includes densely sampled absorption-phase data.

Gabapentin, Pregabalin and Vigabatrin Quantification in Human Serum by GC-MS After Hexyl Chloroformate Derivatization.

A simple, sensitive and robust method for simultaneous determination of antiepileptic drugs (gabapentin, pregabalin and vigabatrin) in human serum using GC-MS was developed and validated for clinical toxicology purposes. This method employs an emerging class of derivatization agents - alkyl chloroformates allowing the efficient and rapid derivatization of both the amino and carboxylic groups of the tested antiepileptic drugs within seconds. The derivatization protocol was optimized using the Design of Experiment statistical methodology, and the entire sample preparation requires less than 5 min. Linear calibration curves were obtained in the concentration range from 0.5 to 50.0 mg/L, with adequate accuracy (97.9-109.3%) and precision (<12.1%). The method was successfully applied to quantification of selected γ-aminobutyric acid analogs in the serum of patients in both therapeutic and toxic concentration ranges.

A Validated Fluorometric Method for the Rapid Determination of Pregabalin in Human Plasma Applied to Patients With Pain.

BACKGROUND: Pregabalin has been used for the treatment of pain. A clinically accepted method applied to patients with pain has not been published for the determination of pregabalin in human plasma. This study developed a fluorometric ultrahigh-performance liquid chromatography (UHPLC) method to measure pregabalin concentration in patients with pain. METHODS: After plasma pretreatment involving protein precipitation, pregabalin and gabapentin as an internal standard were derivatized with 4-fluoro-7-nitrobenzofurazan (NBD-F) under the following reaction conditions: 1 minute, pH 10, and 60°C. The UHPLC separation was performed using a 2.3-µm particle size octadecylsilyl column. The fluorescence detector was set at excitation and emission wavelengths of 470 and 530 nm, respectively. The predose blood samples were collected from 40 patients with pain who have been treated with 75 mg of pregabalin twice daily. RESULTS: The chromatographic run time was 1.25 minutes. No interfering peaks were observed in the blank plasma at the retention times of NBD derivatives. The calibration curve of pregabalin was linear at a range of 0.05-10 mcg/mL (r > 0.999). The lower limit of quantification was 0.05 mcg/mL. The intra-assay accuracy and precision were 98.3%-99.8% and within 4.3%, respectively. The inter-assay accuracy and precision were 103.2%-107.1% and within 4.1%, respectively. The predose plasma concentration of pregabalin in patients with pain ranged from 0.14 to 8.5 mcg/mL. CONCLUSIONS: This study provides a validated fluorometric UHPLC method with fast analytical performance for the determination of pregabalin in human plasma. The present method could be applied to patients with pain and be used for the clinical research or therapeutic drug monitoring of pregabalin.

Pregabalin concentrations in post-mortem blood-A two year study.

Pregabalin (PRG) is indicated for the treatment of neuropathic pain, epilepsy and generalised anxiety disorder. Limited data exists on reference blood concentrations for this drug and levels above which death can be attributed to PRG toxicity. Furthermore, there is increasing evidence that the drug is subject to abuse. This study reviews the post-mortem blood concentrations of PRG analysed in the authors' laboratory between 2012 and 2014 in order to try and assign the likely therapeutic and fatal ranges. PRG was detected in 70 post-mortem blood samples of which 33% were at concentrations considered to be in excess of the reference range (above 17mg/L). PRG concentrations ranged from 0.05mg/L to 226mg/L (median 8.0mg/L) in the group as a whole and in one case a PRG concentration of 76mg/L was determined to be the likely cause of death as no other drugs of significance were involved. The results from this study are consistent with the scientific literature with respect to a high frequency of multidrug use, particularly with opioids/opiates which can increase the probability of a fatal outcome.

Effect of preoperative pregabalin on post-caesarean delivery analgesia: a dose-response study.

INTRODUCTION: We hypothesised that preoperative administration of a single-dose of pregabalin would be associated with lower morphine consumption after uncomplicated caesarean delivery. METHODS: After Institutional Ethics Committee approval, 135 parturients scheduled for elective caesarean delivery under spinal anaesthesia were randomly allocated to receive either placebo, or oral pregabalin 150mg or 300mg, one hour before induction of anaesthesia. Maternal cumulative morphine requirement at 24h, pain scores, sedation scores, nausea and vomiting, pruritus, pregabalin-related adverse effects, Apgar scores, Neurologic and Adaptive Capacity scores and umbilical cord acid-base status were recorded. RESULTS: Compared with placebo or pregabalin 150mg, the use of a preoperative dose of pregabalin 300mg resulted in significantly lower cumulative morphine consumption at 24h (mean dose: placebo 12.9mg [95% CI 11.6 to 14.2]; pregabalin 150mg 11.9mg; [95% CI 10.7 to 13.1]; pregabalin 300mg 6mg [95% CI 5.4 to 7.3]; P<0.001). Pregabalin 300mg resulted in lower pain scores at 4h and 6h after delivery (P<0.001), and fewer instances of nausea, vomiting and pruritus (P<0.009). Dizziness and abnormal vision were observed most frequently in the pregabalin 300mg group (P<0.05 and P<0.009, respectively). The three groups were similar in terms of maternal sedation, Apgar scores, Neurologic and Adaptive Capacity scores and umbilical cord acid-base status. Three babies in the pregabalin 300mg group (6.7%) experienced short-term poor latching-on for breastfeeding. CONCLUSION: In our study, preoperative administration of pregabalin 300mg reduced postoperative morphine consumption and early postoperative pain in parturients undergoing elective caesarean delivery, although maternal side effects were more common.