The impact of more restrictive hydrocodone rescheduling on unintentional pediatric opioid exposures.

PURPOSE: To evaluate the impact of rescheduling hydrocodone combination products (HCPs) from schedule III of the Controlled Substances Act to the more restrictive schedule II on unintentional pediatric exposures (≤5 years old). METHODS: Using U.S. data on outpatient retail pharmacy dispensing, emergency department (ED) visits, and poison center (PC) exposure cases, we assessed trends in prescriptions dispensed and unintentional pediatric exposure cases involving hydrocodone (rescheduled from III to II) compared to oxycodone (schedule II) and codeine (schedule III for combination products) using descriptive and interrupted time-series (ITS) analyses during the 16 quarters before and after the October 2014 rescheduling of HCPs. RESULTS: Dispensing of hydrocodone products was declining before rescheduling but declined more steeply post-rescheduling. In ITS analyses, both hydrocodone and oxycodone had significant slope decreases in PC case rates in the post versus pre-period that was larger for hydrocodone, while codeine had a small but significant slope increase in PC case rates. An estimated 4202 ED visits for pediatric hydrocodone exposures occurred in the pre-period and 2090 visits occurred in the post-period, a significant decrease of 50.3%. Oxycodone exposures showed no significant decrease. CONCLUSIONS: Pediatric hydrocodone unintentional exposure ED visits and PC cases decreased after HCP rescheduling more than would be expected had the pre-rescheduling trend continued; the acceleration in the decrease in hydrocodone PC cases was partially offset by a slowing in the decrease in codeine-involved cases. The trend changes were likely due to multiple factors, including changes in dispensing that followed the rescheduling. Unintentional pediatric medication exposures and poisonings remain a public health concern requiring ongoing, multifaceted mitigation efforts.

Opioid therapy trajectories of patients with chronic non-cancer pain over 1 year of follow-up after initiation of short-acting opioid formulations.

OBJECTIVE: This study compared opioid utilization trajectories of persons initiating tramadol, short-acting hydrocodone, or short-acting oxycodone, and it characterized opioid dose trajectories and type of opioid in persistent opioid therapy subsamples. METHODS: A retrospective cohort study of adults with chronic non-cancer pain who were initiating opioid therapy was conducted with the IQVIA PharMetrics® Plus for Academics data (2008-2018). Continuous enrollment was required for 6 months before ("baseline") and 12 months after ("follow-up") the first opioid prescription ("index date"). Opioid therapy measures were assessed every 7 days over follow-up. Group-based trajectory modeling (GBTM) was used to identify trajectories for any opioid and total morphine milligram equivalent measures, and longitudinal latent class analysis was used for opioid therapy type. RESULTS: A total of 40 276 tramadol, 141 023 hydrocodone, and 45 221 oxycodone initiators were included. GBTM on any opioid therapy identified 3 latent trajectories: early discontinuers (tramadol 39.0%, hydrocodone 54.1%, oxycodone 61.4%), late discontinuers (tramadol 37.9%, hydrocodone 39.4%, oxycodone 33.3%), and persistent therapy (tramadol 6.7%, hydrocodone 6.5%, oxycodone 5.3%). An additional fourth trajectory, intermittent therapy (tramadol 16.4%), was identified for tramadol initiators. Of those on persistent therapy, 2687 individuals were on persistent therapy with tramadol, 9169 with hydrocodone, and 2377 with oxycodone. GBTM on opioid dose resulted in 6 similar trajectory groups in each persistent therapy group. Longitudinal latent class analysis on opioid therapy type identified 6 latent classes for tramadol and oxycodone and 7 classes for hydrocodone. CONCLUSION: Opioid therapy patterns meaningfully differed by the initial opioid prescribed, notably the presence of intermittent therapy among tramadol initiators and higher morphine milligram equivalents and prescribing of long-acting opioids among oxycodone initiators.

Neuropsychiatric Effects Associated with Opioid-Based Management for Palliative Care Patients.

PURPOSE OF REVIEW: The abundance of opioids administered in the palliative care setting that was once considered a standard of care is at present necessitating that providers evaluate patients for unintentional and deleterious symptomology related to aberrant opioid use and addiction. Polypharmacy with opioids is dynamic in affecting patients neurologically, and increased amounts of prescriptions have had inimical effects, not only for the individual, but also for their families and healthcare providers. The purpose of this review is to widen the perspective of opioid consequences and bring awareness to the numerous neuropsychiatric effects associated with the most commonly prescribed opioids for patients receiving palliative care. RECENT FINDINGS: Numerous clinical and research studies have found evidence in support for increased incidence of opioid usage and abuse as well as undesirable neurological outcomes. The most common and concerning effects of opioid usage in this setting are delirium and problematic drug-related behavioral changes such as deceitful behavior towards family and physicians, anger outbursts, overtaking of medications, and early prescription refill requests. Other neuropsychiatric effects detailed by recent studies include drug-seeking behavior, tolerance, dependence, addictive disorder, anxiety, substance use disorder, emotional distress, continuation of opioids to avoid opioid withdrawal syndrome, depression, and suicidal ideation. Opioid usage has detrimental and confounding effects that have been overlooked for many years by palliative care providers and patients receiving palliative care. It is necessary, even lifesaving, to be cognizant of potential neuropsychiatric effects that opioids can have on an individual, especially for those under palliative care. By having an increased understanding and awareness of potential opioid neuropsychiatric effects, patient quality of life can be improved, healthcare system costs can be decreased, and patient outcomes can be met and exceeded.

Comparative safety of tramadol and other opioids following total hip and knee arthroplasty.

BACKGROUND: Tramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex pharmacology and may be no safer than full opioid agonists. We compared the safety of tramadol, oxycodone, and hydrocodone among opioid-naïve older adults following elective THA/TKA. METHODS: This retrospective cohort included Medicare Fee-for-Service beneficiaries ≥ 65 years with elective THA/TKA between January 1, 2010 and September 30, 2015, 12 months of continuous Parts A and B enrollment, 6 months of continuous Part D enrollment, and no opioid use in the 6 months prior to THA/TKA. Participants initiated single-opioid therapy with tramadol, oxycodone, or hydrocodone within 7 days of discharge from THA/TKA hospitalization, regardless of concurrently administered nonopioid analgesics. Outcomes of interest included all-cause hospitalizations or emergency department visits (serious adverse events (SAEs)) and a composite of 10 surgical- and opioid-related SAEs within 90-days of THA/TKA. The intention-to-treat (ITT) and per-protocol (PP) hazard ratios (HRs) for tramadol versus other opioids were estimated using inverse-probability-of-treatment-weighted pooled logistic regression models. RESULTS: The study population included 2,697 tramadol, 11,407 oxycodone, and 14,665 hydrocodone initiators. Compared to oxycodone, tramadol increased the rate of all-cause SAEs in ITT analyses only (ITT HR 1.19, 95%CLs, 1.02, 1.41; PP HR 1.05, 95%CLs, 0.86, 1.29). Rates of composite SAEs were not significant across comparisons. Compared to hydrocodone, tramadol increased the rate of all-cause SAEs in the ITT and PP analyses (ITT HR 1.40, 95%CLs, 1.10, 1.76; PP HR 1.34, 95%CLs, 1.03, 1.75), but rates of composite SAEs were not significant across comparisons. CONCLUSIONS: Postoperative tramadol was associated with increased rates of all-cause SAEs, but not composite SAEs, compared to oxycodone and hydrocodone. Tramadol does not appear to have a superior safety profile and should not be preferentially prescribed to opioid-naïve older adults following THA/TKA.

Effects of Selective and Mixed-Action Kappa and Delta Opioid Receptor Agonists on Pain-Related Behavioral Depression in Mice.

We recently developed a series of nalfurafine analogs (TK10, TK33, and TK35) that may serve as non-addictive candidate analgesics. These compounds are mixed-action agonists at the kappa and delta opioid receptors (KOR and DOR, respectively) and produce antinociception in a mouse warm-water tail-immersion test while failing to produce typical mu opioid receptor (MOR)-mediated side effects. The warm-water tail-immersion test is an assay of pain-stimulated behavior vulnerable to false-positive analgesic-like effects by drugs that produce motor impairment. Accordingly, this study evaluated TK10, TK33, and TK35 in a recently validated assay of pain-related behavioral depression in mice that are less vulnerable to false-positive effects. For comparison, we also evaluated the effects of the MOR agonist/analgesic hydrocodone (positive control), the neurokinin 1 receptor (NK1R) antagonist aprepitant (negative control), nalfurafine as a selective KOR agonist, SNC80 as a selective DOR agonist, and a nalfurafine/SNC80 mixture. Intraperitoneal injection of dilute lactic acid (IP lactic acid) served as a noxious stimulus to depress vertical and horizontal locomotor activity in male and female ICR mice. IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine/SNC80 mixture, or the KOR/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR/DOR agonists as candidate analgesics.

The impact of hydrocodone rescheduling on utilization, abuse, misuse, and overdose deaths.

PURPOSE: To evaluate the impact of increased federal restrictions on hydrocodone combination product (HCP) utilization, misuse, abuse, and overdose death. METHODS: We assessed utilization, misuse, abuse, and overdose death trends involving hydrocodone versus select opioid analgesics (OAs) and heroin using descriptive and interrupted time-series (ITS) analyses during the nine quarters before and after the October 2014 rescheduling of HCPs from a less restrictive (CIII) to more restrictive (CII) category. RESULTS: Hydrocodone dispensing declined >30% over the study period, and declines accelerated after rescheduling. ITS analyses showed that immediately postrescheduling, quarterly hydrocodone dispensing decreased by 177M dosage units while codeine, oxycodone, and morphine dispensing increased by 49M, 62M, and 4M dosage units, respectively. Postrescheduling, hydrocodone-involved misuse/abuse poison center (PC) case rates had a statistically significant immediate drop but a deceleration of preperiod declines. There were small level increases in codeine-involved PC misuse/abuse and overdose death rates immediately after HCP's rescheduling, but these were smaller than level decreases in rates for hydrocodone. Heroin-involved PC case rates and overdose death rates increased across the study period, with exponential increases in PC case rates beginning 2015. CONCLUSIONS: HCP rescheduling was associated with accelerated declines in hydrocodone dispensing, only partially offset by smaller increases in codeine, oxycodone, and morphine dispensing. The net impact on hydrocodone and other OA-involved misuse/abuse and fatal overdose was unclear. We did not detect an immediate impact on heroin abuse or overdose death rates; however, the dynamic nature of the crisis and data limitations present challenges to causal inference.

Changes in Hydrocodone Misuse Exposures Reported to U.S. Poison Centers Following Rescheduling in 2014.

BACKGROUND: In 2014, the Drug Enforcement Administration rescheduled hydrocodone combination products to Schedule II to reduce nonmedical use and diversion. METHODS: The impact of rescheduling was assessed using quarterly data from 2011 through 2019 from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System Poison Center Program and IQVIATM Longitudinal Prescription Data. Trends and immediate changes in prescriptions dispensed and misuse exposures before and after rescheduling involving hydrocodone, oxycodone, and other Schedule II opioid analgesics were calculated using segmented regression. RESULTS: Hydrocodone prescriptions were stable pre-rescheduling, decreased by 2.7% (95% CI: -3.6%, -1.8%, p < 0.0001) per quarter post-rescheduling. Misuse exposures involving hydrocodone were decreasing by 3.2% (95% CI: -3.9%, -2.4%, p < 0.0001) per quarter pre-rescheduling and decreased by 4.9% (95% CI: -5.5%, -4.2%, p < 0.0001) post-rescheduling. Immediate decreases in hydrocodone prescriptions and misuse exposure rates in 2014Q4 compared to 2014Q3 were significant and different from oxycodone or other Schedule II opioids. Schedule II opioid analgesics prescriptions in aggregate were stable prior to rescheduling, decreased by 10.8% (95%CI: -14.0%, -7.6%, p < 0.0001) immediately after the rescheduling, and decreased by 2.3% per quarter (95% CI: -3.1%, -1.5%, p < 0.0001) subsequently. Misuse exposures involving these opioids were decreasing by 3.3% (95% CI: -4.1%, -2.5%, p < 0.0001) prior to rescheduling then by 2.8%, (95% CI: -3.4%, -2.2%, p < 0.0001) after rescheduling. The immediate change in misuse was not significant. CONCLUSIONS: Rescheduling corresponded with changes in hydrocodone prescribing and misuse not offset by increases in other Schedule II opioid analgesics. Misuse exposures for hydrocodone and comparators were decreasing prior to rescheduling with little change post-intervention.

Opioid Prescribing Trends in Women Following Mastectomy or Breast-Conserving Surgery Before and After the 2014 Federal Reclassification of Hydrocodone.

BACKGROUND: Given concerns about suboptimal pain management for actively treated cancer patients following the 2014 federal reclassification of hydrocodone, we examined changes in patterns of opioid prescribing among surgical breast cancer patients. MATERIALS AND METHODS: Data from a large nationally representative commercial health insurance program from 2009 to 2017 were used to identify women aged 18 years and older who were diagnosed with carcinoma in-situ or malignant breast cancer and received breast-conserving surgery or mastectomy from 2010 to 2016. Generalized linear mixed models were used to estimate the adjusted odds ratio (aOR) for receipt of ≥1-day, >30-day, or ≥ 90-day supply of opioids in the 12 months following surgery adjusting for demographics, cancer treatment-related characteristics, and preoperative opioid use. RESULTS: A total of 60,080 patients were included in the study. Surgically treated breast cancer patients in 2015 (aOR = 0.90, 0.84-0.97) and 2016 (aOR = 0.80, 0.74-0.86) were less likely to receive ≥1-day supply of opioid prescriptions when compared with patients in 2013. Patients who had surgery in 2015 (aOR = 0.89, 0.81-0.98) and 2016 (aOR = 0.80, 0.73-0.87) were also less likely to receive >30-day supply of prescription opioids in the 12 months following surgery. However, only surgical breast cancer patients in 2016 were less likely to receive ≥90-day supply (aOR = 0.86, 0.76-0.98). CONCLUSION: Surgically treated breast cancer patients are less likely to receive short- and long-term opioid prescriptions following the implementation of hydrocodone rescheduling. Further studies on the potential impact of federal policy on cancer patient pain management are needed. IMPLICATIONS FOR PRACTICE: Clinicians and researchers with diverse perspectives should be included as stakeholders during policy development for restricting opioid prescriptions. Stakeholders can identify potential unintended consequences early and help identify methods to mitigate concerns, specifically as it relates to policy that influences how providers manage pain for actively treated cancer patients. This work shows how federal policy may have led to declines in opioid prescribing for breast cancer patients who underwent mastectomy or breast-conserving surgery.

Nonopioid versus opioid analgesia after hospital discharge following cesarean delivery: a randomized equivalence trial.

OBJECTIVE: To determine whether pain score after cesarean delivery is equivalent among women receiving outpatient nonopioid vs opioid analgesics. STUDY DESIGN: In this trial 170 women with cesarean delivery were randomized to outpatient ibuprofen plus acetaminophen (nonopioid, n=85) or ibuprofen plus hydrocodone-acetaminophen (opioid, n=85). Primary outcome was pain score on a visual analog scale at 2-4 weeks postpartum, which was obtained from 149 (88%) women. Treatments were considered equivalent if the difference between the mean pain scores of each group and its 95% confidence interval were between -10 and 10 mm. A zero-inflated negative binomial model was used to estimate the difference between group means. RESULTS: Treatments were not equivalent; mean pain score was lower (better) in the nonopioid group (12.3±19.5 vs 15.9±20.4 mm, adjusted mean difference, 4.8; 95% CI, -2.1 to 11.9 mm). CONCLUSION: Pain score 2-4 weeks after cesarean delivery was lower in women receiving nonopioid analgesics.

Effects of Rescheduling Hydrocodone on Opioid Prescribing in Ohio.

BACKGROUND: We quantified opioid prescribing after the 2014 rescheduling of hydrocodone from schedule III to II in the United States using a state-wide prescription database and studied trends three years before and after the policy change, focusing on certain specialties. METHODS: We used Ohio's state prescription drug monitoring program database, which includes all filled schedule II and III prescriptions regardless of payer or pharmacy, to conduct an interrupted time series analysis of the nine most prescribed opioids: hydrocodone, oxycodone, tramadol, codeine, and others. We analyzed hydrocodone prescribing trends for the physician specialties of internal medicine, anesthesiology, and emergency medicine. We evaluated trends 37 months before and after the rescheduling change. RESULTS: Rescheduling was associated with a hydrocodone level change of -26,358 (95% confidence interval [CI] = -36,700 to -16,016) prescriptions (-5.8%) and an additional decrease in prescriptions of -1,568 (95% CI = -2,296 to -839) per month (-0.8%). Codeine prescribing temporarily increased, at a level change of 6,304 (95% CI = 3,003 to 9,606) prescriptions (18.5%), indicating a substitution effect. Hydrocodone prescriptions by specialty were associated with a level change of -805 (95% CI = -1,280 to -330) prescriptions (-8.5%) for anesthesiologists and a level change of -14,619 (95% CI = -23,710 to -5,528) prescriptions (-10.2%) for internists. There was no effect on prescriptions by emergency physicians. CONCLUSIONS: The 2014 federal rescheduling of hydrocodone was associated with declines in hydrocodone prescriptions in Ohio beyond what had already been occurring, and hydrocodone may have been briefly substituted with codeine. These results indicate that rescheduling did have a lasting effect but affected prescribing specialties variably.

Sex differences in the response to opioids for pain relief: A systematic review and meta-analysis.

There are conflicting results about sex differences in the response to opioids for pain control and the role of potential influencing factors of these differences has not been investigated. We meta-analyzed differences and similarities between men and women in opioid response for pain control and investigated the potential influence of baseline pain intensity, age, body weight, and other factors in these findings. PubMed, Scopus, and Cochrane CENTRAL were searched through January 15, 2019, for clinical studies in which opioids were administered for pain control. We included clinical studies in which (a) opioids were used to treat acute or chronic pain, (b) the response to opioids was broken down for men and women, and (c) the response to opioids was reported as (i) difference between baseline and final Visual Analog Scale of Pain Intensity (VASPI) score 30 min after opioid administration (Delta-VASPI at 30'), or daily dose of opioids (ii) self-administered by patients (patient-controlled analgesia PCA), or (iii) administered by physicians. Risk of bias was evaluated using ROBINS-I and the overall quality of evidence for primary outcomes was evaluated using the GRADE system. Globally, we included 40 comparisons (6794 patients). Regarding acute pain, we found moderate quality of evidence that women and men do not differ in their response to opioids 30 min after their administration [Delta-VASPI at 30': mean difference, MD = 0.42 (-0.07; 0.91)]. We also found moderate quality of evidence that women self-administer lower daily amounts of opioids [daily PCA: standardized mean difference, SMD = -0.30 (-0.41; -0.18)]. Regarding chronic pain, we found low quality of evidence that women receive lower daily doses for non-cancer pain [MD = -36.42 (-57.86; -14.99)]. By contrast, we found very low quality of evidence that women and men do not differ in the daily dose of opioids for cancer pain [MD = -16.09 (-40.13; 7.94)]. Age, comorbid mental disorders, type of administration, type of opioids, type of patients, and body weight significantly modified these results. In conclusion, the results of the present meta-analysis suggest that men and women may differ in the response to opioids for pain relief, but these differences as well as similarities are significantly influenced by factors like age and comorbid mental disorders. However, the role of these factors is not usually evaluated in the prescription of opioids for pain control. There is an urgent need to conduct clinical trials on the use of opioid medications for pain, in which information about all possible influencing factors are provided and broken down for men and women.

Implementation fidelity of patient-centered prescription label to promote opioid safe use.

PURPOSE: Patient-centered labels may improve safe medication use, but implementation challenges limit use. We assessed implementation of a patient-centered "PRN" (as needed) label entitled "Take-Wait-Stop" (TWS) with three deconstructed steps replacing traditional wording. METHODS: As part of a larger investigation, patients received TWS prescriptions (eg, Take: 1 pill if you have pain; Wait: at least 4 h before taking again; Stop: do not take more than 6 pills in 24 h). Prescriptions labels recorded at follow-up were classified into three categories: (1) one-step wording (Take 1 pill every 4 h [without daily limits]), (2) two-step wording (Take 1 pill every 4 h; do not exceed 6 pills/day), and (3) three-step wording. There were three subtypes of three-step wording: (3a) three-step, not TWS (three deconstructed steps, not necessarily TWS wording), (3b) TWS format, employing three steps with leading verbs, but "with additions or replacements" (eg, replaced "do not take" with "do not exceed"), and (3c) verbatim TWS. RESULTS: Two hundred eleven participants completed follow-up. Mean age was 44.3 years (SD 14.3); 44% were male. One-step bottles represented 12% (n = 25) of the sample, whereas 26% (n = 55) had two-step wording. The majority (44%, n = 93) had three-deconstructed steps, not TWS (3a); 16% (n = 34) retained TWS structure, but not verbatim (3b). Only 2% (n = 4) displayed verbatim TWS wording (3c). All category three labels (utilizing deconstructed instructions) were considered adequate implementation (62%). CONCLUSIONS: Exact intervention adherence was not achieved in the majority of cases, limiting impact. Nonetheless, community pharmacies were responsive to new instructions, but higher implementation reliability requires additional supports.

Prevention of Opioid-Induced Nausea and Vomiting During Treatment of Moderate to Severe Acute Pain: A Randomized Placebo-Controlled Trial Comparing CL-108 (Hydrocodone 7.5 mg/Acetaminophen 325 mg/Rapid-Release, Low-Dose Promethazine 12.5 mg) with Conventional Hydrocodone 7.5 mg/Acetaminophen 325 mg.

OBJECTIVES: To evaluate the prevention of opioid-induced nausea and vomiting (OINV) and the relief of moderate to severe acute pain by CL-108, a novel drug combining a low-dose antiemetic (rapid-release promethazine 12.5 mg) with hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) was used. METHODS: This was a multicenter, randomized, double-blind, placebo- and active-controlled multidose study. After surgical extraction of two or more impacted third molar teeth (including at least one mandibular impaction), 466 patients with moderate to severe pain (measured on a categorical pain intensity scale [PI-CAT]) were randomized to CL-108, HC/APAP, or placebo. Over the next 24 hours, patients used the PI-CAT to assess pain at regular intervals whereas nausea, vomiting, and other opioid-related side effects were also assessed prospectively. Study medications were taken every four to six hours as needed; supplemental rescue analgesic and antiemetic medications were permitted. Co-primary end points were the incidence of OINV and the time-weighted sum of pain intensity differences over 24 hours (SPID24). RESULTS: Relative to HC/APAP treatment alone, CL-108 treatment reduced OINV by 64% (P < 0.001). Treatment with CL-108 significantly reduced pain intensity compared with placebo (SPID24 = 16.2 vs 3.5, P < 0.001). There were no unexpected or serious adverse events. CONCLUSIONS: CL-108 is a safe and effective combination analgesic/antiemetic for the prevention of OINV during treatment of moderate to severe acute pain.

Patterns of abuse and routes of administration for immediate-release hydrocodone combination products.

PURPOSE: Prescriptions for hydrocodone immediate-release (IR) combination products have recently decreased, yet they represent the majority of opioid prescriptions dispensed and are commonly abused analgesics among both adults and adolescents. Little data exist to understand the contribution of IR products to the problem of prescription opioid abuse. This study aimed to better understand abuse patterns for hydrocodone IR combination products among adult and adolescent substance abusers. METHODS: This cross-sectional study examines abuse prevalence (including abuse adjusted for prescription volume and morphine milligram equivalents) and abuse characteristics for hydrocodone IR combination products and other prescription opioids among separate samples of adults and adolescents assessed for substance abuse problems or entering treatment from January 2012 through June 2015. RESULTS: Results indicate higher abuse for hydrocodone IR combination products than other opioid categories per 100 assessments but lower per prescriptions dispensed. Hydrocodone IR combination products had similar abuse prevalence to all extended-release and long-acting opioids when considering abuse measured per morphine milligram equivalents dispensed. An upward trend in hydrocodone IR combination product abuse was observed among adult substance abusers comparing the period prior to and after Drug Enforcement Administration rescheduling of these products in October 2014. Most individuals reported oral abuse of hydrocodone IR combination products, but snorting, reported by 23% of hydrocodone IR combination product abusers, also appears to be a route of abuse that may have public health relevance. CONCLUSIONS: Given their high prescription volume, hydrocodone IR combination products, even at a relatively low prevalence of abuse, may contribute substantially to the overall problem of prescription opioid abuse. Additional public health interventions, including development of abuse-deterrent formulations for these types of opioid products may aid in reducing their abuse.

Oral Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users.

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 C max and rate of absorption (C max /T max ) values decreased, respectively, and median T max 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.

Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

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 (E max ) 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 (E max : 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.

Pharmacokinetics of guaifenesin, pseudoephedrine and hydrocodone in a combination oral liquid formulation, administered as single and multiple doses in healthy Chinese volunteers, and comparison with data for individual compounds formulated as Antuss®.

1. A new oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone is effective in improving the symptoms of common cold. The pharmacokinetic properties of the individual components were evaluated in a randomized, open-label, four-period study in 12 healthy Chinese volunteers following single and multiple doses. The data were compared with data for the individual ingredients in Antuss®. 2. In the single-dose period, exposure levels (AUC and Cmax) for guaifenesin, pseudoephedrine and hydrocodone increased directly as the dose of the oral liquid formulation increased from 5 to 15 mL. Only minor amounts of guaifenesin and hydrocodone were excreted in urine (∼0.10% and 4.66%, respectively). Pseudoephedrine was mainly excreted unchanged, with 44.95% of the dose excreted in urine within 24 h. After multiple dosing, there was no obvious accumulation of any drug, as assessed by AUC. When considering Cmax, there was a trend toward accumulation of hydrocodone and pseudoephedrine. The pharmacokinetic profiles of guaifenesin and pseudoephedrine in the oral liquid formulation were similar to those in the branded preparation, Antuss®. 3. The newly developed oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone was safe and well tolerated and might provide a reliable alternative to the branded formulation for patients with common colds.

Decreased Opioid Prescribing in a Pediatric Emergency Department After the Rescheduling of Hydrocodone.

BACKGROUND: The Drug Enforcement Administration (DEA) changed hydrocodone-containing products (HCPs) from Schedule III to II status on October 6, 2014, making codeine-containing products (CCPs) the only non-Schedule II oral opioid agents. OBJECTIVES: We sought to describe prescribing patterns of oral opioid agents in the pediatric emergency department before and after the 2014 DEA rescheduling of HCPs. METHODS: We performed a cross-sectional study evaluating prescribing patterns in the pediatric emergency department at an urban, academic, quaternary care children's hospital system for 6 months before and 6 months after the DEA rescheduling of HCPs. Differences in patient demographics, provider type, and diagnoses were assessed during the two time periods using Pearson's chi-squared test. The Breslow-Day statistic was used to assess differences in prescribing patterns by provider type. RESULTS: There were 1256 prescriptions for HCPs and CCPs in our pediatric emergency department during the study period, and only 36 prescriptions for alternate oral opioid medications. Prescriptions of all opioid pain medications decreased by 55% after rescheduling. The odds of prescribing HCPs were reduced by 60% after the DEA rescheduling (odds ratio 0.40 [95% confidence interval {CI} 0.30-0.54]; p < 0.001). There was no difference between monthly ordering frequencies for CCPs before or after the DEA rescheduling (p = 0.75). CONCLUSIONS: The period after rescheduling of HCPs was associated with a lower odds of HCP prescriptions in our emergency department without an increase in the prescription of CCPs.

Long-term effectiveness and safety of once-daily, single-entity, extended-release hydrocodone in patients of ≥75 years of age with moderate to severe nonmalignant and nonneuropathic pain.

In elderly (≥75 years) individuals, age-associated physiologic changes and a higher prevalence of comorbidities, polypharmacy, and increased susceptibility to medication-induced side effects complicate pain management. Hysingla® ER (HYD) is a once-daily, single-entity, extended-release hydrocodone formulation approved for the treatment of chronic pain that is insufficiently controlled by alternative treatments. In this post-hoc analysis of a previously reported study, the effectiveness and safety of HYD for the treatment of moderate-to-severe chronic pain among the elderly (≥75 years) for a 52-week duration was investigated. HYD dose administered during the maintenance period-remained relatively stable and provided clinically meaningful decreases in mean "pain over the last 24 h" and pain interference scores. Patients achieved pain control without additional non-study opioid use at the end of the study. Adverse events were typical of opioids. In summary, HYD provided clinically meaningful reduction of pain scores in elderly patients that were maintained over a 52-week period.

Evaluation of Quality of Life, Functioning, Disability, and Work/School Productivity Following Treatment with an Extended-Release Hydrocodone Tablet Formulated with Abuse-Deterrence Technology: A 12-month Open-label Study in Patients with Chronic Pain.

BACKGROUND: This phase 3 study evaluated quality of life, functioning, and productivity after treatment with extended-release (ER) hydrocodone formulated with CIMA® Abuse-Deterrence Technology platform. METHODS: Patients with chronic pain were rolled over from a 12-week placebo-controlled hydrocodone ER study or were newly enrolled. Hydrocodone ER doses were titrated (15 to 90 mg every 12 hours) to an analgesic dose, and patients received up to 52 weeks of open-label treatment. Assessments included Clinician Assessment of Patient Function (CAPF), Patient Assessment of Function (PAF), Brief Pain Inventory-Short Form (BPI-SF), 36-item Short-Form Health Survey (SF-36), Sheehan Disability Scale (SDS), and World Health Organization Health and Work Performance Questionnaire-Short Form (HPQ-SF). RESULTS: Of 330 enrolled patients, 291 composed the full analysis population. By week 4, ≥ 50% of patients showed improvement from baseline in all 5 CAPF domains (general activities, walking, work/daily living, relationships, and enjoyment of life) and 6 of 7 PAF domains (work attendance, work performance, walking, exercise, socializing, and enjoying life). Mean decreases from baseline of 2 to 3 points were noted for BPI-SF pain interference questions from week 4 through endpoint. Mean improvements from baseline to endpoint in SF-36 subscales ranged from 3.3 to 22.3, and SDS scores improved from moderate (4.8 to 5.1) to mild (2.5 to 2.8) disruptions in work/school, social life, and family life. At endpoint, mean HPQ-SF absolute absenteeism scores decreased from 13.6 to 10.0 hours lost/month and absolute presenteeism scores improved from 67.0 to 77.1. CONCLUSIONS: Patients receiving hydrocodone ER showed early numeric improvements in functioning that continued throughout this 12-month study.