Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended-Release Tablets.

Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ2 and Pearson r2 values were calculated for PD (maximum effect [Emax ] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration-time curve [AUC], maximum drug concentration [Cmax ], time to Cmax [Tmax ], and abuse quotient [PK AQ; Cmax /Tmax ]) for all treatments. In the oral study, correlations were strongest between Emax of "at the moment" Drug Liking and PK parameters (Cmax [ρ2  = 0.4446], PK AQ [ρ2  = 0.5179], Tmax [ρ2  = 0.5093], and early systemic exposure [ρ2  = 0.4782]). For Overall Drug Liking and Take Drug Again VAS, ρ2 values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent.

Time Scaling for In Vitro-In Vivo Correlation: the Inverse Release Function (IRF) Approach.

In vitro-in vivo correlations (IVIVC) are methods used to create a link between biopharmaceutical properties such as dissolution and physiological response such as plasma concentration. Level A IVIVC defines 1:1 relationship between the percent absorbed in vivo and the percent dissolved in vitro. A successful level A IVIVC provides the capacity to predict in vivo behavior based only on in vitro data with application in formulation development and support of biowaivers recognized by regulatory agencies across the world. Level A regression may be complicated due to differences in time scales as well as the lack of coincident times of similar release in vitro and in vivo leading to approximate time-to-time links and subsequent loss of information. Here, a novel method to establish Levy's plot and to provide time scaling for improved IVIVC predictive capacity is presented. The method is mathematically closed and is an inverse release function (IRF) characterizing the single (or more) phases of dissolution/absorption. It uses the complete set of information available from all time points both in vitro and in vivo. An extended-release formulation development situation is presented with three increasing release rate test products compared in a trial versus a reference product. First, the standard level A regression was made. Prediction errors for internal validation were higher than 10% for Cmax. The IRF method was applied to obtain the in vitro times of percentage dissolved equivalent to percentage absorbed. The prediction errors from the IRF level A correlation were nearly negligible.

Fast quantitation of opioid isomers in human plasma by differential mobility spectrometry/mass spectrometry via SPME/open-port probe sampling interface.

Mass spectrometry (MS) based quantitative approaches typically require a thorough sample clean-up and a decent chromatographic step in order to achieve needed figures of merit. However, in most cases, such processes are not optimal for urgent assessments and high-throughput determinations. The direct coupling of solid phase microextraction (SPME) to MS has shown great potential to shorten the total sample analysis time of complex matrices, as well as to diminish potential matrix effects and instrument contamination. In this study, we demonstrate the use of the open-port probe (OPP) as a direct and robust sampling interface to couple biocompatible-SPME (Bio-SPME) fibres to MS for the rapid quantitation of opioid isomers (i.e. codeine and hydrocodone) in human plasma. In place of chromatography, a differential mobility spectrometry (DMS) device was implemented to provide the essential selectivity required to quantify these constitutional isomers. Taking advantage of the simplified sample preparation process based on Bio-SPME and the fast separation with DMS-MS coupling via OPP, a high-throughput assay (10-15 s per sample) with limits of detection in the sub-ng/mL range was developed. Succinctly, we demonstrated that by tuning adequate ion mobility separation conditions, SPME-OPP-MS can be employed to quantify non-resolved compounds or those otherwise hindered by co-extracted isobaric interferences without further need of coupling to other separation platforms.

An Advance in Prescription Opioid Vaccines: Overdose Mortality Reduction and Extraordinary Alteration of Drug Half-Life.

Prescription opioids (POs) such as oxycodone and hydrocodone are highly effective medications for pain management, yet they also present a substantial risk for abuse and addiction. The consumption of POs has been escalating worldwide, resulting in tens of thousands of deaths due to overdose each year. Pharmacokinetic strategies based upon vaccination present an attractive avenue to suppress PO abuse. Herein, the preparation of two active PO vaccines is described that were found to elicit high-affinity antiopioid antibodies through a structurally congruent drug-hapten design. Administration of these vaccines resulted in a significant blockade of opioid analgesic activity, along with an unprecedented increase in drug serum half-life and protection against lethal overdose.

Assessment of Alcohol-Induced Dose Dumping with a Hydrocodone Bitartrate Extended-Release Tablet Formulated with CIMA(®) Abuse Deterrence Technology.

BACKGROUND: Greater drug content requirements for extended-release (ER) opioids necessitate greater protection against dose dumping. Hydrocodone ER employs the CIMA(®) Abuse-Deterrence Technology platform, which provides resistance against rapid release of the active moiety when the tablet is manipulated or taken with alcohol. OBJECTIVE: Assess effects of alcohol on hydrocodone ER pharmacokinetics. STUDY DESIGN: Open-label, crossover (January 25-April 30, 2010). SETTING: Single center. PARTICIPANTS: Forty healthy adults. INTERVENTION: Subjects received all four treatments in a randomized manner (separated by a minimum 5-day washout): hydrocodone ER 15 mg with 240 mL water and 240 mL orange juice containing 4, 20, and 40% alcohol in a fasted state. Naltrexone was administered to minimize opioid-related adverse events. MAIN OUTCOME MEASURE: Effect of alcohol on pharmacokinetics of hydrocodone ER assessed by comparing systemic exposure [maximum plasma drug concentration (Cmax) and area under the plasma drug concentration-versus-time curve from time 0 to infinity (AUC0-∞)] after administration with alcohol or with water. RESULTS: Geometric means ratios of hydrocodone ER with 4, 20, and 40% alcohol relative to water were 1.05, 1.09, and 1.14, respectively, for Cmax and 1.07, 1.13, and 1.17, respectively, for AUC0-∞. All 90% confidence intervals for these geometric means ratios fell within the limits of 0.8 and 1.25. Increasing alcohol concentrations did not notably affect systemic exposure but were associated with increased adverse events. CONCLUSIONS: Hydrocodone ER tablets were resistant to dose dumping when administered with alcohol in healthy subjects based on similar systemic exposures observed across all treatments.

Prescription Opioids. IV: Disposition of Hydrocodone in Oral Fluid and Blood Following Single-Dose Administration.

The Substance Abuse and Mental Health Services Administration (SAMHSA) is currently evaluating hydrocodone (HC) for inclusion in the Mandatory Guidelines for Federal Workplace Drug Testing Programs. This study evaluated the time course of HC, norhydrocodone (NHC), dihydrocodeine (DHC) and hydromorphone (HM) in paired oral fluid and whole blood specimens by liquid chromatography-tandem mass spectrometry (limit of quantitation = 1 ng/mL of oral fluid, 5 ng/mL of blood) over a 52-h period. A single dose of HC bitartrate, 20 mg, was administered to 12 subjects. Analyte prevalence was as follows: oral fluid, HC > NHC > DHC; and blood, HC > NHC. HM was not detected in any specimen. HC was frequently detected within 15 min in oral fluid and 30 min in blood. Mean oral fluid to blood (OF : BL) ratios and correlations were 3.2 for HC (r = 0.73) and 0.7 for NHC (r = 0.42). The period of detection for oral fluid exceeded blood at all evaluated thresholds. At a 1-ng/mL threshold for oral fluid, mean detection time was 30 h for HC and 18 h for NHC and DHC. This description of HC and metabolite disposition in oral fluid following single-dose administration provides valuable interpretive guidance of HC test results.

Dose proportionality of a hydrocodone extended-release tablet formulated with abuse-deterrence technology.

BACKGROUND AND OBJECTIVE: This open-label, crossover study evaluated the dose proportionality of a hydrocodone extended-release (ER) tablet employing the CIMA(®) Abuse-Deterrence Technology platform. METHODS: Healthy volunteers were randomized to receive single doses of hydrocodone ER 15, 30, 45, 60, and 90 mg separated by a minimum 14-day washout. Subjects received naltrexone to minimize opioid-related adverse events (AEs). Blood samples were collected for 72 h after each hydrocodone administration. Pharmacokinetic measures included maximum observed plasma hydrocodone concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUC∞). Dose proportionality was concluded if the confidence interval (CI) of the slope of the regression line for C max and AUC∞ versus dose fell within 0.875-1.125. RESULTS: In total, 60 subjects were evaluable for pharmacokinetics. The mean C max was 12.6, 20.7, 30.3, 41.2, and 62.5 ng/mL and the mean AUC∞ was 199, 382, 592, 766, and 1189 ng.h/mL for hydrocodone ER 15, 30, 45, 60, and 90 mg, respectively. C max and AUC∞ increased linearly with increasing dose. The 90 % CIs of the slope of the regression line for C max (0.880-0.922) and AUC∞ (0.984-1.026) indicated systemic exposure to hydrocodone increased in a dose-proportional manner. In these naltrexone-blocked subjects, no increased incidence of AEs was apparent with increasing dose. CONCLUSION: Hydrocodone exposure increased in a dose-proportional manner after administration of hydrocodone ER 15-90 mg tablets in healthy, naltrexone-blocked subjects.

Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing.

OBJECTIVES: (1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety. SETTING: In silico clinical trial simulation. PARTICIPANTS: Healthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg). MAIN OUTCOME MEASURES: CYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC. RESULTS: PMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC's apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM's therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects. CONCLUSIONS: Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.

Pharmacokinetics of hydrocodone extended-release tablets formulated with different levels of coating to achieve abuse deterrence compared with a hydrocodone immediate-release/acetaminophen tablet in healthy subjects.

BACKGROUND AND OBJECTIVE: A hydrocodone extended-release (ER) formulation employing the CIMA(®) Abuse-Deterrence Technology platform was developed to provide resistance against rapid release of hydrocodone when tablets are comminuted or taken with alcohol. This study evaluated the pharmacokinetics of three hydrocodone ER tablet prototypes with varying levels of polymer coating to identify the prototype expected to have the greatest abuse deterrence potential based on pharmacokinetic characteristics that maintain systemic exposure to hydrocodone comparable to that of a commercially available hydrocodone immediate-release (IR) product. METHODS: In this four-period crossover study, healthy subjects aged 18-45 years were randomized to receive a single intact, oral 45-mg tablet of one of three hydrocodone ER prototypes (low-, intermediate-, or high-level coating) or an intact, oral tablet of hydrocodone IR/acetaminophen (APAP) 10/325 mg every 6 h until four tablets were administered, with each of the four treatments administered once over the four study periods. Dosing periods were separated by a minimum 5-day washout. Naltrexone 50 mg was administered to block opioid receptors. Blood samples for pharmacokinetic assessments were collected predose and through 72 h postdose. Parameters assessed included maximum observed plasma hydrocodone concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve from time 0 to infinity (AUC(0-∞)). RESULTS: Mean C(max) values were 49.2, 32.6, and 28.4 ng/mL for the low-, intermediate-, and high-level coating hydrocodone ER tablet prototypes, respectively, and 37.3 ng/mL for the hydrocodone IR/APAP tablet; respective median t(max) values were 5.9, 8.0, 8.0, and 1.0 h. Total systemic exposure to hydrocodone (AUC(0-∞)) was comparable between hydrocodone ER tablet prototypes (640, 600, and 578 ng·h/mL, respectively) and hydrocodone IR/APAP (581 ng·h/mL). No serious adverse events or deaths were reported. The most common adverse events included headache (26%) and nausea (18%). CONCLUSION: All three hydrocodone ER tablet prototypes (low-, intermediate-, and high-level polymer coating) demonstrated ER pharmacokinetic characteristics. The hydrocodone ER tablet prototype with the high-level coating was selected for development because of its comparable exposure to the hydrocodone IR/APAP formulation and potentially increased ability to resist rapid drug release upon product tampering because of a higher polymer coating level. All study medications were well tolerated in healthy naltrexone-blocked volunteers.

Single- and multiple-dose pharmacokinetics of a hydrocodone bitartrate extended-release tablet formulated with abuse-deterrence technology in healthy, naltrexone-blocked volunteers.

PURPOSE: A hydrocodone extended-release (ER) formulation was developed to provide sustained pain relief with twice-daily dosing. Developed using the CIMA abuse-deterrence technology platform (CIMA Labs Inc, Brooklyn Park, Minnesota), this formulation also provides resistance against rapid release of hydrocodone when tablets are comminuted and resistance against dose dumping when tablets are taken with alcohol. Two open-label studies evaluated hydrocodone ER pharmacokinetics (PK) after single- and multiple-dose administration in healthy, naltrexone-blocked subjects. METHODS: In the single-dose period of both studies, healthy subjects aged 18 to 45 years of age received hydrocodone ER (study 1, 45 mg; study 2, 90 mg). In the multiple-dose period of study 1, subjects received one 45-mg hydrocodone ER tablet twice daily from the morning of day 1 through the morning of day 6. In the multiple-dose period of study 2, subjects received hydrocodone ER twice daily, titrated to 90 mg over 10 days (days 1 and 2, 45 mg; days 3 and 4, 60 mg; days 5-10, 90 mg). All subjects received naltrexone to block opioid receptors. Blood samples were collected pre-dose and through 72 hours post-dose in the single-dose period and after the final dose in the multiple-dose period. PK measures included maximum observed plasma drug concentration (C(max)), area under the plasma drug concentration by time curve from time 0 to the time of the last measurable drug concentration (AUC(0-t)), time to C(max) (T(max)), observed accumulation ratio (R(obs)), and steady-state plasma concentration (C(ss)). Safety and tolerability were assessed. FINDINGS: The PK analyses included 36 subjects from study 1 and 33 from study 2. Plasma hydrocodone PK parameters after single- and multiple-dose administration of hydrocodone ER 45 mg (study 1) were dose-normalized to 90 mg and pooled with data from study 2. As expected, C(max) was higher (125.4 vs 57.2 ng/mL), AUC(0-t) was higher (2561 vs 1095 ng·h/mL), and T(max) occurred earlier (5.0 vs 8.0 hours) with multiple-dose administration. Mean R(obs) after multiple-dose administration of hydrocodone ER was also slightly higher than predicted from single-dose data (2.8 vs 2.4). C(ss) were achieved within 5 days of twice-daily administration of both doses. Mean fluctuation with hydrocodone ER 45 or 90 mg was 36.4% and 33.9%, respectively, and mean swing was 46.9% and 43.5%, respectively. The incidence of adverse events was similar in the single-dose (33%) and multiple-dose (29%) periods in study 1 and slightly higher in the multiple-dose (76%) than in the single-dose (53%) period in study 2. IMPLICATIONS: The PK profile of hydrocodone ER was qualitatively similar after single- and multiple-dose administration. The steady-state profile demonstrated sustained exposure with limited swing and fluctuation. Single and multiple doses of hydrocodone ER (45 and 90 mg) were generally well tolerated in healthy subjects receiving naltrexone; however, exposure to naltrexone may have confounded the interpretation of safety findings.

Multi-drug and metabolite quantification in postmortem blood by liquid chromatography-high-resolution mass spectrometry: comparison with nominal mass technology.

High-resolution mass spectrometry (HRMS) is being applied in postmortem drug screening as an alternative to nominal mass spectrometry, and additional evaluation in quantitative casework is needed. We report quantitative analysis of benzoylecgonine, citalopram, cocaethylene, cocaine, codeine, dextromethorphan, dihydrocodeine, diphenhydramine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone and oxymorphone in postmortem blood by ultra-performance liquid chromatography (UPLC)-MS(E)/time-of-flight (TOF). The method employs analyte-matched deuterated internal standardization and MS(E) acquisition of precursor and product ions at low (6 eV) and ramped (10-40 eV) collision energies, respectively. Quantification was performed using precursor ion data obtained with a mass extraction window of ± 5 ppm. Fragment and residual precursor ion acquisitions at ramped collision energies were evaluated as additional analyte identifiers. Extraction recovery of >60% and matrix effect of <20% were determined for all analytes and internal standards. Defined limits of detection (10 ng/mL) and quantification (25 ng/mL) were validated along with a linearity analytical range of 25-3,000 ng/mL (R(2) > 0.99) for all analytes. Parallel UPLC-MS(E)/TOF and UPLC-MS/MS analysis showed comparable precision and bias along with concordance of 253 positive (y = 1.002x + 1.523; R(2) = 0.993) and 2,269 negative analyte findings in 159 postmortem cases. Analytical performance and correlation studies demonstrate accurate quantification by UPLC-MS(E)/TOF and extended application of HRMS in postmortem casework.

Hydrocodone in postoperative personalized pain management: pro-drug or drug?

BACKGROUND: Genetic variations in enzymes that produce active metabolites from pro-drugs are well known. Such variability could account for some of the clinically observed differences in analgesia and side effects seen in postoperative patients. Using genotyping and quantitation of serum concentrations of hydrocodone and its metabolites, we sought to demonstrate the clinical effects of the metabolites of hydrocodone on pain relief. The objective of the current study was to determine whether CYP2D6 genotype and serum hydromorphone levels account for some of the variability in pain relief seen with hydrocodone in a cohort of women post-Cesarean section. METHODS: In 156 post-Cesarean section patients who received hydrocodone, we assessed serum opioid concentrations and CYP2D6 genotypes. Blood samples were collected at that time for genotyping and determination of concentrations of hydrocodone and metabolites by LC-MS/MS. Multivariate analysis was used to determine the relationship between CYP2D6 genotypes, pain relief, side effects, and serum concentrations of hydrocodone and hydromorphone. RESULTS: The CYP2D6 genotyping results indicated that 60% of subjects were extensive, 30% intermediate, 3% poor, and 7% ultra-rapid metabolizers. In the poor metabolizers, the mean plasma hydromorphone concentration was 8-fold lower when compared to that of ultra-rapid metabolizers. Hydromorphone, and not hydrocodone concentrations correlated with pain relief. CONCLUSIONS: This study shows that hydromorphone is generated at substantially different rates, dependent on CYP2D6 genotype. Pain relief correlated with plasma concentrations of hydromorphone, and not with hydrocodone. This suggests that pain relief will vary with CYP2D6 genotype. Inability to metabolize hydrocodone to hydromorphone as seen in the poor metabolizers should alert the clinician to consider alternative medications for managing pain postoperatively.

Population pharmacokinetic analysis for hydrocodone following the administration of hydrocodone bitartrate extended-release capsules.

BACKGROUND AND OBJECTIVE: Hydrocodone is a semi-synthetic narcotic analgesic and antitussive. Although hydrocodone products have been on the market for over 50 years, relatively little is known about its pharmacokinetics. Additionally, there are no published reports of population pharmacokinetic analyses for hydrocodone. Furthermore, current labeling of hydrocodone-containing products provides little guidance in terms of the impact of patient descriptors on the pharmacokinetics of hydrocodone. The objectives of this analysis were to develop a population pharmacokinetic model that characterizes the pharmacokinetics of hydrocodone following single and multiple oral doses of hydrocodone extended-release capsules (hydrocodone bitartrate ER capsules) in healthy subjects and patients, to examine the impact of patient descriptors on pharmacokinetic parameters and to assess the dose-proportionality of hydrocodone pharmacokinetic. METHODS: A total of 4,714 plasma hydrocodone concentrations from 220 subjects were available for this analysis. The data were extracted from seven studies (five phase 1 and two phase 2 studies). A two-compartment open mamillary model with linear elimination and a complex absorption model was used to fit the data, using NONMEM(®) version 7.1.2 software. The absorption model involved two sequential first-order absorption processes with the delay in the first process accomplished by means of multiple transit compartments. Covariate analysis was performed using standard forward selection followed by backward elimination processes. Model evaluation was performed using a prediction-corrected visual predictive check (pcVPC). RESULTS: The population estimates of apparent oral central volume of distribution and apparent oral linear clearance were 714 L and 64.4 L/h, respectively. The first absorption process was rapid. Creatinine clearance and body surface area (BSA) were statistically significant predictors of the apparent oral clearance and apparent oral volume of distribution. The pcVPC indicated that the model provided a robust and unbiased fit to the data. CONCLUSIONS: A linear model for hydrocodone elimination provided an adequate fit to the observed data over the entire dose range, which supports that hydrocodone bitartrate ER capsules exhibit dose-proportional pharmacokinetics. The formulation of hydrocodone bitartrate ER capsules results in absorption profiles that are variable across and within subjects. Despite the variability in absorption profiles, a relatively simple model provided an adequate fit to the data. Creatinine clearance and BSA were statistically significant predictors of the apparent oral clearance and apparent oral volume of distribution. Absorption characteristics of hydrocodone bitartrate ER capsules should still allow effective plasma concentrations of hydrocodone to be reached quickly and for effective concentrations to be maintained for a long period.

The role of hydromorphone and OPRM1 in postoperative pain relief with hydrocodone.

BACKGROUND: Postoperative pain management remains a challenge for clinicians due to unpredictable patient responses to opioid therapy. Some of this variability may result from single nucleotide polymorphisms (SNPs) of the human opioid mu-1 receptor (OPRM1) that modify receptor binding or signal transduction. The OPRM1 variant with the highest frequency is the A118G SNP. However, previous studies have produced inconsistent results regarding the clinical effects of A118G on opioid response. We hypothesized that measurement of serum opioid concentrations, in addition to determining total opioid consumption, may provide a more precise method of assessing the effects of A118G on analgesic response. The current study evaluated the relationship of analgesia, side effects, total hydrocodone consumption, quantitative serum hydrocodone and hydromorphone concentrations, and A118G SNP in postoperative patients following Cesarean section. METHODS: 158 women scheduled for Cesarean section were enrolled prospectively in the study. The patients had bupivacaine spinal anesthesia for surgery and received intrathcal morphine with the spinal anesthetic or parenteral morphine for the first 24 hours after surgery. Thereafter, patients received hydrocodone/acetaminophen for postoperative pain control. On postoperative day 3, venous blood samples were obtained for OPRM1 A118G genotyping and serum opioid concentrations. RESULTS: 131 (82.9%) of the subjects were homozygous for the 118A allele of OPRM1 (AA) and 27 (17.1%) carried the G allele (AG/GG). By regression analysis, pain relief was significantly associated with total hydrocodone dose in the AA group (P = 0.01), but not in the AG/GG group (P = 0.554). In contrast, there was no association between pain relief and serum hydrocodone concentration in either group. However, pain relief was significantly associated with serum hydromorphone concentration (a metabolite of hydrocodone) in the AA group (P = 0.004), but not in the AG/GG group (P = 0.724). Conversely, side effects were significantly higher (P < 0.04) in the AG/GG group (mean = 6.4) than in the AA group (mean = 4.4), regardless of adjustment for BMI, pain level, or total dose of hydrocodone. CONCLUSION: This study found a correlation between pain relief and total hydrocodone dose in patients homozygous for the 118A allele (AA) of the OPRM1 gene, but not in patients with the 118G allele (AG/GG). However, pain relief in 118A patients did not correlate with serum hydrocodone concentrations, but rather with serum hydromorphone levels, the active metabolite of hydrocodone. This suggests that pain relief with hydrocodone may be due primarily to hydromorphone. Although pain relief did not correlate with opioid dose in AG/GG patients, they had a higher incidence of opioid side effects. The correlations identified in this study may reflect the fact that serum opioid concentrations were measured directly, avoiding the inherent imprecision associated with relying solely on total opioid consumption as a determinant of opioid effectiveness. Thus, measurement of serum opioid concentrations is recommended when assessing the role of OPRM1 variants in pain relief. This study supports pharmacogenetic analysis of OPRM1 in conjunction with serum opioid concentrations when evaluating patient responses to opioid therapy.

Quantitative method for analysis of hydrocodone, hydromorphone and norhydrocodone in human plasma by liquid chromatography-tandem mass spectrometry.

A selective, sensitive and accurate high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the quantitation of hydrocodone, hydromorphone and norhydrocodone in human plasma was developed. The internal standard stock solution comprised of hydrocodone-d6, hydromorphone-d6 and norhydrocodone-d3 was added to 0.5 mL plasma samples. Samples were extracted using a copolymeric sorbent (mixed mode) solid phase extraction (SPE) column. Chromatographic separation was carried out using a reversed-phase C18 analytical column with a gradient mobile phase consisting of solvent A=5% acetonitrile with 0.1% formic acid and solvent B=100% acetonitrile. MS analysis was performed using positive electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. Linearity was established over the range 1-100 ng/mL with correlation coefficients ≥0.998 for all three analytes. The coefficient of variation (CV) of intra-day samples was ≤5.6% at 10 ng/mL. The precision of inter-day (6 days) samples resulted in CVs ≤8.1% at concentrations tested at 2.5, 10 and 25 ng/mL for all three analytes. The lower limit of quantification (LOQ) was 1.0 ng/mL with signal-to-noise (S/N) ratio >10, the limit of detection (LOD) was 0.25 ng/mL with S/N ratio >3 for the drug and its metabolites. Dilution effects, extraction recovery, stability, interference, carryover and ion suppression were also evaluated. This method was successfully applied to human subject plasma samples in support of a hydrocodone pharmacokinetic study.

Update on hydrocodone metabolites in rats and dogs aided with a semi-automatic software for metabolite identification Mass-MetaSite.

1. There has been a lack of in vivo metabolite profiling update of hydrocodone since the original report on species differences was published in 1978. As such, the mechanism for its analgesic activity in different species has been ambiguous. To address safety concern from regulatory agencies, hydrocodone metabolite profiles in rats and dogs are updated herein aided by a newly developed software, Mass-MetaSite. 2. Samples collected from rats and dogs dosed orally with hydrocodone were analyzed with reversed phase liquid chromatography coupled with LTQ-Orbitrap. The exact mass measurement data collected with data-dependent acquisition methodology were analyzed both traditionally, using Xcalibur Qual Browser and MetWorks, and by Mass-MetaSite. 3. Profiling of hydrocodone metabolites in rat and dog plasma reflected previously reported species differences in circulating metabolites. While hydrocodone mainly underwent O-demethylation and ketone reduction in rats forming hydromorphone and reduced hydromorphone, which were then subsequently cleared via glucuronide conjugation, hydrocodone in dogs was cleared predominantly by N-demethylation and N-oxidation. 4. Given the success ratio of metabolite detection offered by Mass-MetaSite, the software will be able to aid chemists in early identification of drug metabolites from complex biomatrices.

Pharmacokinetics of hydrocodone and hydromorphone after oral hydrocodone in healthy Greyhound dogs.

The purpose of this study was to determine the pharmacokinetics of hydrocodone and its active metabolite hydromorphone in six healthy Greyhound dogs. Hydrocodone bitartrate was administered at a targeted dose of 0.5 mg/kg PO. Plasma concentrations of hydrocodone and hydromorphone were determined by liquid chromatography triple quadrupole mass spectrometry. The mean hydrocodone CMAX was 11.73 ng/mL at 0.74 h with a terminal half-life of 1.60 h. The mean hydromorphone CMAX was 5.2 ng/mL at 1.37 h with a terminal half-life of 3.07 h. Mean plasma hydromorphone concentrations exceeded 2 ng/mL from 0.5 to 8 h after hydrocodone administration. Further studies assessing the antinociceptive effects of oral hydrocodone are needed.

Quantitation of opioids in whole blood by electron impact-gas chromatography-mass spectrometry.

Opioids are frequently encountered in Forensic Toxicology casework. A PubMed literature search was conducted to find a method using electron impact-gas chromatography-mass spectrometry to examine whole blood specimens. A previously published method was identified, and an updated version was provided by the State of North Carolina Office of the Chief Medical Examiner. This procedure was used as a starting point for development and validation of a refined procedure to be used in the Palm Beach County Sheriff's Office Forensic Toxicology laboratory for routine analysis of antemortem forensic toxicology case samples. Materials and instrumentation common to most forensic toxicology laboratories were utilized while obtaining detection limits from 1 to 10 ng/mL and quantitation limits of 2.5 to 10 ng/mL using 1 mL of whole blood. Target compounds were chosen based on applicability to the method as well as availability and common use in the United States and include dihydrocodeine, codeine, morphine, hydrocodone, 6-monoacetylmorphine, hydromorphone, oxycodone, and oxymorphone. Each analyte demonstrated two zero-order linear ranges (r(2) > 0.990) over the concentrations evaluated (from 2.5 to 500 ng/mL). The coefficient of variation of replicate analyses was less than 12%. Quantitative accuracy was within ± 27% at 2.5 ng/mL, ± 11% at 10 ng/mL, and ± 8% at 50 ng/mL. The validated method provides a more sensitive procedure for the quantitation of common opioids in blood using standard laboratory equipment and a small amount of sample.

What is the lethal concentration of hydrocodone?: a comparison of postmortem hydrocodone concentrations in lethal and incidental intoxications.

Hydrocodone is a semisynthetic opioid medication that is widely used as an analgesic and antitussive. Since 2004 it has been the most commonly prescribed drug in the United States and is often misused as a drug of abuse. Hydrocodone is frequently encountered in the postmortem setting, both as a cause of death and incidentally. Unfortunately, information regarding the concentrations of hydrocodone found with chronic high-dose use is lacking, and interpretation of postmortem concentrations can be difficult. A retrospective review of postmortem and "Driving under the Influence" (DUI) cases in Bexar County Texas in which hydrocodone was present was conducted. The cases were included in the study if they fit the criteria of belonging to 1 of 3 categories: the hydrocodone either caused or was the main contributor to death; the hydrocodone was incidental and definitively did not cause or contribute to death; and the DUI cases. The average hydrocodone concentration in the cases where the hydrocodone caused death was 0.47 mg/L (median, 0.38 mg/L). The average hydrocodone concentration in cases where it was incidental to death was 0.15 mg/L (median, 0.08 mg/L). The average hydrocodone concentration in the DUI cases was 0.09 mg/L (median, 0.08 mg/L). Analysis showed the possibility of postmortem redistribution as well as significant overlap of the concentrations noted in the different groups. Given that no definitive lethal concentration could be delineated, it is recommended that each hydrocodone case encountered be assessed individually to include a thorough medical record review to accurately interpret hydrocodone concentrations. It has also been shown that concentrations as high as 0.3 mg/L peripherally and 1.4 mg/L centrally can be present and not result in death. In addition, further research into hydrocodone concentrations with chronic use and hydrocodone metabolism is necessary.

Quantitation of opioids in blood and urine using gas chromatography-mass spectrometry (GC-MS).

The opioid and 6-acetylmorphine assays utilize gas chromatography-mass spectrometry (GC-MS) for the analysis of morphine, codeine, hydromorphone, hydrocodone, and 6-acetylmorphine in blood and urine. The specimens are fortified with deuterated internal standard and a five-point calibration curve is constructed. Specimens are extracted by mixed-mode solid phase extraction. The morphine, codeine, hydromorphone, hydrocodone, and 6-acetylmorphine extracts are derivatized with N-methyl-bis(trifluoroacetamide) (MBTFA) producing trifluoroacetyl derivatives. The final extracts are then analyzed using selected ion monitoring GC-MS.