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This trial aimed to identify the effects of providing pharmacogenomic (PGx) results and recommendations for patients with chronic pain treated in primary care practices compared to standard care. An open‐label, prospective, largely virtual, type‐2 hybrid effectiveness trial randomized participants to PGx or standard care arms. Adults with pain ≥ 3 months who were treated with tramadol, codeine, or hydrocodone enrolled. Alternative analgesics were recommended for CYP2D6 intermediate or poor metabolizers (IM/PMs). Prescribing decisions were at providers' discretion. The trial randomized 253 participants. A modified intent‐to‐treat primary analysis assessed change in pain intensity over 3 months among IM/PMs (PGx: 49; Standard care: 57). The PGx and standard care arms showed no difference in pain intensity change (−0.10 ± 0.63 vs. −0.21 ± 0.75 standard deviation; p = 0.74) or PGx‐aligned care (69% vs. 63%; standardized difference [SD] = 0.13). In IM/PMs, secondary analyses of pain intensity change suggested improvements with PGx‐aligned (n = 70; −0.21 ± 0.70) vs. unaligned care (n = 36; −0.06 ± 0.69) (SD = −0.22), with this difference increasing when examining IM/PMs with an analgesic change (aligned: n = 31, −0.28 ± 0.76; unaligned: n = 36, −0.06 ± 0.69; SD = −0.31). This approach to PGx implementation for chronic pain was not associated with different prescribing (i.e., similar proportions of PGx‐aligned care) or clinical outcomes. Secondary analyses suggest that prescribing aligned with PGx recommendations showed a small improvement in pain intensity. However, the proportion of patients with a clinically meaningful improvement (≥ 30%) in pain intensity was similar. Future efforts should identify effective implementation methods.

Abstract Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the oral abuse potential and pharmacokinetics (PK) of HYD intact, chewed, or milled to fine particles in comparison with hydrocodone solution or placebo. Design. Single-center, double-blind, randomized, five-period, five-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users. Methods. Forty subjects received orally administered treatments of hydrocodone 60 mg solution, HYD 60 mg intact, HYD 60 mg chewed, HYD 60 mg milled to fine particles, or placebo, separated by a five- to seven-day washout. Assessments over 36 hours postdose included subjective measures of drug liking and willingness to take drug again (assessed using visual analog scales [VAS]), pupillometry, PK, and safety measures. Results. Following oral administration, HYD intact, HYD chewed, and HYD fine particles led to significantly lower “at this moment” drug liking compared with hydrocodone solution. HYD intact and chewed were significantly different from hydrocodone solution on overall drug liking, take drug again, and good effects. Pupil constriction, as measured by pupillometry, occurred later with HYD intact and HYD chewed than with hydrocodone solution. Across treatments (hydrocodone solution, HYD fine particles, HYD chewed, and HYD intact, respectively), mean Cmax and rate of absorption (Cmax/Tmax) values decreased, respectively, and median Tmax values increased, respectively. Safety was consistent with the known effects of opioid agonists. Conclusion. HYD demonstrated reduced oral abuse potential compared with hydrocodone solution in healthy adult, nondependent, recreational opioid users.*

Abstract Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo. Design. Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. Methods. During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics. Results. Insufflation of both HYD coarse and fine particles led to lower “At this Moment” Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists. Conclusions. HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder.

Objective. To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design. Randomized, double-blind, placebo-controlled, crossover study. Setting and Patients. One study site in the United States; adult nondependent, recreational opioid users. Methods. After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was “at the moment” drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results. Mean maximum effect (Emax) for “at the moment” drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (Emax: 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective “at the moment” drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions. The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated.

Abstract Objective To assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF]). Design Single-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study. Setting One US site. Subjects Healthy, adult, nondependent, recreational opioid users. Methods Subjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on “at the moment” Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed. Results Mean maximum effect for “at the moment” Drug Liking was significantly (P < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled “at the moment” Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF. Conclusions The statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users.

A single-entity, once-daily, extended-release formulation of hydrocodone bitartrate (HYD) has been developed for the management of moderate to severe chronic pain. Hydrocodone undergoes cytochrome P-450 (CYP)-mediated metabolism involving the CYP3A4 and CYP2D6 isozymes. CYP3A4 yields norhydrocodone, a major inactive metabolite, whereas CYP2D6 yields hydromorphone, a minor active metabolite. This study examined the influence of the coadministration of paroxetine, a strong selective CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone (and hydromorphone) in healthy adults. In this randomized, double-blind, 2-period, 2-treatment crossover study, 24 healthy subjects received paroxetine 20 mg or placebo once daily for 12 days and an HYD 20-mg tablet on day 10 of each period. Hydrocodone mean Cmax and t½ and median Tmax values were similar with paroxetine or placebo coadministration (16.8 vs 15.9 ng/mL, 8.5 vs 8.4 hours, and 18.0 vs 18.0 hours, respectively), as were mean AUC0–t and AUC0–∞ values (342.9 vs 325.3 ng · h/mL and 346.3 vs 328.5 ng · h/mL). The 90% CIs of the geometric mean ratios of the hydrocodone AUC and Cmax values were fully within the predetermined range of 80% to 125%, suggesting that there was no effect of multiple doses of paroxetine on systemic exposure to hydrocodone. Mean hydromorphone AUC0–t and Cmax values were decreased with paroxetine versus placebo (0.64 vs 3.8 ng · h/mL and 0.06 vs 0.19 ng/mL), whereas Tmax values remained similar (18.0 vs 16.1 hours, respectively). The mean hydromorphone AUC0–∞ value could not be calculated. Both regimens were well tolerated; after HYD administration, the numbers of adverse events were similar between the 2 treatment regimens, and all adverse events were mild. In this study, the coadministration of single-dose HYD with paroxetine at steady state did not alter systemic exposure to hydrocodone, suggesting that HYD can be coadministered with CYP2D6 inhibitors at therapeutic doses, without dosage modification.

Abstract Objective Developing an acetaminophen-free, immediate-release hydrocodone product remains an unmet medical need; however, new opioid analgesics should not introduce new abuse risks. Benzhydrocodone is a prodrug of hydrocodone that must be metabolized into hydrocodone by enzymes in the intestinal tract to optimally deliver its pharmacologic effects. This study evaluated the intranasal pharmacokinetics and abuse potential of benzhydrocodone active pharmaceutical ingredient (API) compared with hydrocodone bitartrate (HB) API. Design Single-center, randomized, double-blind, crossover study. Setting Clinical research site. Subjects Healthy adult, nondependent, recreational opioid users. Methods Subjects (N = 51 Completers) were randomized to receive 13.34 mg of intranasal benzhydrocodone API and 15.0 mg of intranasal HB API (molar-equivalent doses of hydrocodone). Blood samples were taken, and Drug Liking scores (assessed on a bipolar visual analog scale) were obtained throughout each dosing interval. Nasal irritation and safety were assessed. Results Peak hydrocodone plasma concentration (Cmax) was 36.0% lower, and total hydrocodone exposures (AUClast and AUCinf) were 20.3% and 19.5% lower, respectively, for benzhydrocodone API compared with HB API (P < 0.0001). All partial AUC values were lower for benzhydrocodone API, with a ≥ 75% reduction in hydrocodone exposure at all time intervals up to one hour postdose (P < 0.0001). Median Tmax of hydrocodone following benzhydrocodone API was delayed by more than one hour compared with HB. Drug Liking score, as assessed by maximal liking (Emax), was significantly lower for benzhydrocodone API vs HB API (P = 0.004), with 45% of subjects showing a ≥ 30% reduction in Drug Liking Emax. Conclusion Reductions in hydrocodone exposure and associated decreases in Drug Liking relative to HB suggest that the prodrug benzhydrocodone may deter intranasal abuse.

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 purpose of this study was to evaluate the pharmacokinetics (PK) and 24-hour analgesic effectiveness of once-daily, single-entity, extended-release hydrocodone (HYD) with abuse-deterrent properties. Four studies were included. Three open-label PK studies had the following designs: single-dose, 5-treatment, 4-period, crossover, dose-proportionality study; HYD 120 mg for 5 days (steady-state study 1); 2-treatment, 2-period, multiple-dose crossover study assessing the relative bioavailability of HYD 30 mg and hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours (steady-state study 2). A long-term, open-label study assessed the safety and effectiveness of HYD 20 to 120 mg in patients during a 52-week maintenance period. Thirty-one, 25, and 22 healthy subjects completed the dose-proportionality study, steady-state study 1, and steady-state study 2, respectively, while 410 patients with moderate to severe chronic nonmalignant and non-neuropathic pain completed the long-term effectiveness study. Mean systemic exposure and peak plasma concentration were dose proportional after administration of single doses of HYD 20 to 120 mg. Pharmacokinetic profiles were comparable at day 1 and day 5 after administration of HYD 120 mg once daily. Once-daily HYD 30 mg was associated with lower-fluctuating plasma hydrocodone concentrations compared with immediate-release hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours. In the long-term study, pain control was consistent over the 24-hour dosing interval. Once-daily HYD exhibits linear, dose-proportional PK properties and is associated with a lower variability in plasma hydrocodone concentrations when compared with an immediate-release hydrocodone combination product. Notably, analgesia provided by HYD is sustained during the 24-hour dosing interval. ClinicalTrials.gov identifier: NCT01400139 (Study 4).

Background and objectives Food intake can alter the pharmacokinetics of certain medications, including changes in their oral bioavailability, which is of particular concern for extended-release (ER) opioids because of the high drug loads. Two randomized, open-label studies assessed the effect of food on the pharmacokinetics of single and multiple doses of hydrocodone ER formulated with CIMA ® Abuse-Deterrence Technology. Methods Healthy subjects in fed and fasted states received single 90-mg doses of hydrocodone ER (Studies 1 and 2) or multiple doses of hydrocodone ER (45 mg twice daily on days 2–3, 60 mg twice daily on days 4–5, 90 mg twice daily on days 6–10, and 90 mg once in the morning on day 11) (Study 2). Naltrexone was administered to minimize opioid-related adverse events. Pharmacokinetic parameters included maximum hydrocodone plasma concentration ( C max ) and area under the concentration-versus-time curve from time 0 to infinity (AUC 0–∞ ) in Study 1 (day 1) and for one dosing interval at steady state (AUC τ,ss ) in Study 2 (day 11). Before conducting the multiple-dose study, single-dose data were fitted with a population pharmacokinetic methodology. Results In total, 40 subjects were randomized to Study 1 and 43 subjects were randomized to Study 2. While overall exposure (AUC 0–∞ ) was relatively similar (least squares mean ratio [90% CI]: 1.11 [1.06–1.16]), results indicated that the single-dose C max was 40% higher under fed versus fasted conditions (least squares mean ratio [90% CI]: 1.40 [1.31–1.51]; Study 1). Modeling of single-dose data predicted that the effect of food would be much less at steady state [predicted fed:fasted C max at steady state ( C max,ss ) and AUC τ,ss ratios of 1.18 and 1.09, respectively]. The multiple-dose study results validated these predicted ratios and indicated that the steady-state 90% CIs were within 0.80–1.25 for the fed:fasted C max,ss (1.14 [1.07–1.21]) and AUC τ,ss (1.11 [1.04–1.17]) parameters, indicating that clinically meaningful food effects at steady state are not expected. Conclusion No evidence of an effect of food was found on the pharmacokinetics of hydrocodone ER after multiple days of twice-daily dosing.