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Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population. Each cohort consisted exclusively of person-time exposed to both an SMR and one of the three most dispensed opioids-hydrocodone, oxycodone, and tramadol. Opioid users were further divided into three cohorts based on the initiation order of SMRs and opioids-synchronically triggered, opioid-triggered, and SMR-triggered. Within each cohort, we used Cox proportional hazard models to compare the injury rates for different SMRs compared to methocarbamol, adjusting for covariates. We identified 349,543, 139,458, and 218,967 concurrent users of SMRs with hydrocodone, oxycodone, and tramadol, respectively. In the oxycodone-SMR-triggered cohort, the adjusted hazard ratios (HRs) were 1.86 (95% CI, 1.23-2.82) for carisoprodol and 1.73 (1.09-2.73) for tizanidine. In the tramadol-synchronically triggered cohort, the adjusted HRs were 0.69 (0.49-0.97) for metaxalone and 0.62 (0.42-0.90) for tizanidine. In the tramadol-SMR-triggered cohort, the adjusted HRs were 1.51 (1.01-2.26) for baclofen and 1.48 (1.03-2.11) for cyclobenzaprine. All other HRs were statistically nonsignificant. In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: With addiction rates and opioid deaths increasing, health care providers are obligated to help stem the opioid crisis. As limited studies examine the comparative effectiveness of fixed-dose combination nonopioid analgesia to opioid-containing analgesia, a comparative effectiveness study was planned and refined by conducting a pilot study., Methods: The Opioid Analgesic Reduction Study (OARS) pilot, a stratified, randomized, multisite, double-blind clinical trial, was designed to test technology and procedures to be used in the full OARS trial. Participants engaged in the full protocol, enabling the collection of OARS outcome data. Eligible participants reporting to 1 of 5 sites for partial or full bony impacted mandibular third molar extraction were stratified by biologic sex and randomized to 1 of 2 treatment groups, OPIOID or NONOPIOID. OPIOID participants were provided 20 doses of hydrocodone 5 mg/acetaminophen 300 mg. NONOPIOID participants were provided 20 doses of ibuprofen 400 mg/acetaminophen 500 mg. OARS outcomes data, including pain experience, adverse effects, sleep quality, pain interference, overall satisfaction, and remaining opioid tablets available for diversion, were collected via surveys, electronic medication bottles, eDiary, and activity/sleep monitor., Results: Fifty-three participants were randomized with 50 completing the OARS pilot protocol. Across all outcome pain domains, in all but 1 time period, NONOPIOID was better in managing pain than OPIOID ( P < 0.05 level). Other outcomes suggest less pain interference, less adverse events, better sleep quality, better overall satisfaction, and fewer opioid-containing tablets available for diversion., Discussion: Results suggest patients requiring impacted mandibular third molar extraction would benefit from fixed-dose combination nonopioid analgesia., Knowledge Transfer Statement: Study results suggest fixed-dose nonopioid combination ibuprofen 400 mg/acetaminophen 500 mg is superior to opioid-containing analgesic (hydrocodone 5 mg/acetaminophen 500 mg). This knowledge should inform surgeons and patients in the selection of postsurgical analgesia., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The Na V 1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of Na V 1.8, on control of acute pain is being studied., Methods: After establishing the selectivity of VX-548 for Na V 1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo., Results: A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548., Conclusions: As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.)., (Copyright © 2023 Massachusetts Medical Society.)

Aim: Serotonin syndrome (SS) is a life-threatening syndrome that occurs with the use of serotonergic drugs, most commonly due to two or more agents. Cerebral palsy is associated with mood disorders, and more commonly pain, with a prevalence of up to 50-80%. Case presentation: A 58-year-old female with cerebral palsy, metastatic malignancy and mood disorder who presented to the emergency department with acute-on-chronic pain, and signs of SS. She was initiated on iv. dilaudid, titrated off oral medications and scheduled for a left-sided sacroiliac joint injection. Results: It was suspected that due to additional doses of hydrocodone and cyclobenzaprine, she developed moderate-SS. Conclusion: Physicians need to be cognizant of comorbidities and uncommon pain medications that can predispose patients to SS.

Objective: To explore the impact on opioid prescribing patterns and trends after implementing a prescription drug monitoring program (PDMP) in Pennsylvania from 2016 to 2020., Design: A cross-sectional data analysis using deidentified data from Pennsylvania's PDMP delivered by the Pennsylvania Department of Health was undertaken., Setting: Data were collected from the entire state of Pennsylvania, and statistics were run at Rothman Orthopedic Institute Foundation for Opioid Research & Education., Interventions: Evaluating the effect on opioid prescriptions after introduction of the PDMP., Main Outcome Measure: In 2016, nearly 2 million opioid prescriptions were given to patients across the state. However, by the end of the study period in 2020, there was a 38 percent decrease in opioid prescriptions written., Results: Beginning with Q3 2016, each subsequent quarter saw fewer opioids prescribed, decreasing on average by 3.4 ± 1.7 percent through Q1 2020. Specifically, over 700,000 fewer prescriptions were in the first quarter of 2020 compared to the third quarter in 2016. The opioids that were most frequently prescribed were oxycodone, hydrocodone, and morphine., Conclusion: While fewer prescriptions were being prescribed overall, the breakdown of drug type being prescribed remained similar in 2020 compared to 2016. Fentanyl and hydrocodone saw the largest decrease between 2016 and 2020.

Objective: This study sought to: (1) construct and validate a composite potential opioid misuse score; and (2) compare potential opioid misuse among individuals prescribed long-term therapy on tramadol, short-acting hydrocodone or short-acting oxycodone., Methods: A retrospective cohort study was conducted using Arkansas All-Payer Claims Database (APCD; 2013-2018) linked to Arkansas Prescription Drug Monitoring Program (PDMP; 2014-2017) and state death certificate data (2013-2018). The study subjects were ambulatory, cancer-free adults with incident long-term therapy on tramadol, short-acting hydrocodone or short-acting oxycodone. The number of opioid prescribers/pharmacies, cash payment for opioid prescriptions, overlapping prescribers/pharmacies and a composite misuse score (derived from opioid prescribers/pharmacies and cash payment) were assessed in two 180 day windows as potential measures of misuse. The composite score was developed based on associations observed with opioid overdose and opioid-related injuries., Results: A total of 17,816 (tramadol), 23,660 (hydrocodone) and 4799 (oxycodone) persons were included. The composite score had modest discrimination for overdose ( c -index = 0.65). In the first 180 day period, the average composite misuse scores were 1.28 (tramadol), 1.93 (hydrocodone) and 2.18 (oxycodone). Compared to long-term hydrocodone, long-term tramadol had lower misuse (IRR [95% CI]: 0.75 [0.73-0.76]), and long-term oxycodone had higher misuse (1.09 [1.07-1.11]) in adjusted analyses. Qualitatively similar associations were observed for nearly all individual component measures of misuse., Conclusion: A composite measure of potential opioid misuse had modest levels of discrimination in detecting overdose. In comparison to long-term hydrocodone therapy, long-term oxycodone had higher and tramadol had lower risk of potential opioid misuse.

Background: Kratom (Mitragyna speciosa), an evergreen tree native to Southeast Asia, contains alkaloids that cause both stimulant and opioid-like effects. In the United States, its use continues to grow. Kratom products, however, are unregulated and nonstandardized, and reports of adulteration have been described previously., Case Report: A 21-year-old African-American woman with a history of occasional headaches and self-treatment with internet-purchased kratom presented to the emergency department with the chief symptoms of nausea, vomiting, and left flank pain. Laboratory tests showed a markedly elevated serum creatinine of 4.25 mg/dL (reference range 0.6-1.2 mg/dL) and proteinuria. A computed tomography scan of the abdomen and pelvis was unrevealing. A standard urine screen for drugs of abuse was positive for opiates. A confirmatory testing revealed the presence of hydrocodone and morphine in the urine. Hydrocodone, morphine, and mitragynine were identified in a sample of kratom leaves provided by the patient. The patient's renal function improved with supportive care and normalized 1 month post discharge after kratom discontinuation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Despite widespread use, relatively little is known about kratom's adverse effects, particularly regarding its potential to cause renal insufficiency. This case illustrates the vital importance of recognizing that adulteration of unregulated products is certainly a possibility and clinicians may continue to see a rise in adverse effects, given kratom's increasing popularity., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: To quantify the prevalence of opioid drug dependence and abuse in United States between 2017 and 2018 and identify which opioid molecules are associated with a higher level of dependence and abuse., Design: National Survey on Drug Use and Health (NSDUH) data for 2017 and 2018 have been extracted. The variables related to painkillers were studied, the most important ones were selected, and several variable crosses were made. After the data were extracted, they were analyzed using Microsoft Excel and PivotTables, calculating the relative prevalence and percentages of patients with abuse and dependence., Results: In total, 1.4 million people had dependence on pain relievers (PRs) in 2018. The last PR used was mostly hydrocodone (33 percent) and oxycodone (24 percent). The main reasons for using a PR without a doctor's prescription were relieving pain (48 percent), feel good (16 percent), and relax or relieve tension (15 percent). Among patients who used a PR with a medical prescription, 1.5 million used it more frequently than prescribed, 1.2 million used it longer than prescribed, and 1.9 million used it in higher amounts than prescribed., Conclusions: Abuse and dependence to PRs is lower than expected with over 1.4 million people in the United States having dependence in 2018 (0.6 percent point prevalence). Most cases of dependence are associated with misuse or abuse of prescriptions without medical supervision or the use of medications without a prescription of their own. Oxycodone and hydrocodone are the molecules most associated with dependence, misuse, abuse, and use without prescription. The age of onset of oxycodone misuse is very early (14 years old). Fentanyl does not seem relevant in any of the variables studied.

Background: Hydrocodone and oxycodone are prescribed commonly to treat pain. However, differences in risk of opioid-related adverse outcomes after an initial prescription are unknown. This study aims to determine the risk of opioid-related adverse events, defined as either chronic use or opioid overdose, following a first prescription of hydrocodone or oxycodone to opioid naïve patients., Methods: A retrospective analysis of multiple linked public health datasets in the state of Oregon. Adult patients ages 18 and older who a) received an initial prescription for oxycodone or hydrocodone between 2015-2017 and b) had no opioid prescriptions or opioid-related hospitalizations or emergency department visits in the year preceding the prescription were followed through the end of 2018. First-year chronic opioid use was defined as ≥6 opioid prescriptions (including index) and average ≤30 days uncovered between prescriptions. Fatal or non-fatal opioid overdose was indicated from insurance claims, hospital discharge data or vital records., Results: After index prescription, 2.8% (n = 14,458) of individuals developed chronic use and 0.3% (n = 1,480) experienced overdose. After adjustment for patient and index prescription characteristics, patients receiving oxycodone had lower odds of developing chronic use relative to patients receiving hydrocodone (adjusted odds ratio = 0.95, 95% confidence interval (CI) 0.91-1.00) but a higher risk of overdose (adjusted hazard ratio (aHR) = 1.65, 95% CI 1.45-1.87). Oxycodone monotherapy appears to greatly increase the hazard of opioid overdose (aHR 2.18, 95% CI 1.86-2.57) compared with hydrocodone with acetaminophen. Oxycodone combined with acetaminophen also shows a significant increase (aHR 1.26, 95% CI 1.06-1.50), but not to the same extent., Conclusions: Among previously opioid-naïve patients, the risk of developing chronic use was slightly higher with hydrocodone, whereas the risk of overdose was higher after oxycodone, in combination with acetaminophen or monotherapy. With a goal of reducing overdose-related deaths, hydrocodone may be the favorable agent., Competing Interests: The authors have declared that no competing interests exist.

Objectives. To present data for opioid misuse among US reservation-based American Indian (AI) adolescents and to compare these data with national rates from Monitoring the Future (MTF). Methods. Data were from a national sample of 33 schools participating in a substance use epidemiological survey of reservation-based AI adolescents during 2018 and 2019. Participants were 8th-, 10th-, and 12th-grade AI students (n = 1592). Measures included 12-month and 30-day use of OxyContin, Vicodin, heroin, and narcotics. We computed prevalence and compared it with MTF national prevalence. Results. Across grades, AI youths demonstrated significantly greater past 12-month and 30-day opioid use relative to a national sample. Significant absolute differences in 12-month and 30-day prevalence levels ranged from 1.6% (8th-grade heroin) to 4.7% (12th-grade narcotics) and from 1.6% (12th-grade narcotics) to 1.8% (12th-grade heroin), respectively. Conclusions. Opioid misuse prevalence levels were significantly greater for reservation-based AI adolescents relative to national prevalence levels. Public Health Implications. Findings suggest that implementation of evidence-based efforts, adapted or developed to be culturally appropriate, should be significantly increased in tribal communities, along with policies to address the unique social, economic, and health issues they face.

Background: Initial opioid exposure for most individuals with substance use disorder comes from the healthcare system, and overprescription of opioids in ambulatory operations is common. This report describes an academic medical center's experience implementing opioid-free thyroid and parathyroid operations., Materials and Methods: This is a retrospective chart review of patients undergoing a thyroid or parathyroid operation before and after implementation of an opioid-free analgesia protocol. The primary endpoint was new postoperative opioid prescription. Secondary endpoints included prescription characteristics and predictors of new opioid prescription., Results: A total of 515 patients were enrolled in the study: 240 in the control or "pre-intervention" cohort (May through October 2017) and 275 in the intervention or "post" cohort (May through October 2018). Patients in the intervention cohort were significantly less likely to receive an opioid prescription (12.0% versus 59.6%, P < 0.001). When opioids were prescribed, they were used for shorter durations and at lower doses in the intervention cohort. Among the patients prescribed opioids in the intervention cohort (N = 33), the only significant predictor of postoperative opioid use was preoperative opioid use (P = 0.001)., Conclusions: Opioids may not be required after thyroidectomy and parathyroidectomy, especially for opioid-naïve patients. Future research should examine patient satisfaction with opioid-sparing analgesia., (Published by Elsevier Inc.)

Background: Between 2016 and 2017, the national mortality rate involving opioids continued its escalation; opioid deaths rose from 42,249 to 47,600, bringing the public health crisis to a new height. Considering that 69% of adults in the United States use online social media sites, a resource that builds a more complete understanding of prescription drug misuse and abuse could supplement traditional surveillance instruments. The Food and Drug Administration has identified 5 key risks and consequences of opioid drugs-misuse, abuse, addiction, overdose, and death. Identifying posts that discuss these key risks could lead to novel information that is not typically captured by traditional surveillance systems., Objective: The goal of this study was to describe the trends of online posts (frequency over time) involving abuse, misuse, addiction, overdose, and death in the United States and to describe the types of websites that host these discussions. Internet posts that mentioned fentanyl, hydrocodone, oxycodone, or oxymorphone were examined., Methods: Posts that did not refer to personal experiences were removed, after which 3.1 million posts remained. A stratified sample of 61,000 was selected. Unstructured data were classified into 5 key risks by manually coding for key outcomes of misuse, abuse, addiction, overdose, and death. Sampling probabilities of the coded posts were used to estimate the total post volume for each key risk., Results: Addiction and misuse were the two most commonly discussed key risks for hydrocodone, oxycodone, and oxymorphone. For fentanyl, overdose and death were the most discussed key risks. Fentanyl had the highest estimated number of misuse-, overdose-, and death-related mentions (41,808, 42,659, and 94,169, respectively). Oxycodone had the highest estimated number of abuse- and addiction-related mentions (3548 and 12,679, respectively). The estimated volume of online posts for fentanyl increased by more than 10-fold in late 2017 and 2018. The odds of discussing fentanyl overdose (odds ratios [OR] 4.32, 95% CI 2.43-7.66) and death (OR 5.05, 95% CI 3.10-8.21) were higher for social media, while the odds of discussing fentanyl abuse (OR 0.10, 95% CI 0.04-0.22) and addiction (OR 0.24, 95% CI 0.15-0.38) were higher for blogs and forums., Conclusions: Of the 5 FDA-defined key risks, fentanyl overdose and death has dominated discussion in recent years, while discussion of oxycodone, hydrocodone, and oxymorphone has decreased. As drug-related deaths continue to increase, an understanding of the motivations, circumstances, and consequences of drug abuse would assist in developing policy responses. Furthermore, content was notably different based on media origin, and studies that exclusively use either social media sites (such as Twitter) or blogs and forums could miss important content. This study sets out sustainable, ongoing methodology for surveilling internet postings regarding these drugs., (©Joshua C Black, Zachary R Margolin, Richard A Olson, Richard C Dart. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 29.06.2020.)

We examined the results of 1.3 million drug tests performed on patients being monitored for compliance with pain medications and substance abuse rehabilitation to determine if the 2016 CDC prescribing guidelines had any impact on opiate benzodiazepine use. We observed that the combination of the opiate drugs morphine, oxycodone, and hydrocodone with the benzodiazepine metabolites oxazepam, alphahydroxyalprazolam, and 7-aminoclonazepam showed many patients were on a combination of these drugs. This ranged from approximately 9 to 16%. There was considerable variability between opiate drug pairs, but there was a general trend to fewer patients on the combination of opiate-benzodiazepine over the 2016 to 2019 time frame., (© 2020 by the Association of Clinical Scientists, Inc.)

Background: There is increasing need to avoid excess opioid prescribing after surgery. We prospectively assessed overprescription in our hospital system and used these data to design a quality improvement intervention to reduce overprescription., Materials and Methods: Beginning in January 2017, an e-mail-based survey to assess the quantity of opioids used postoperatively as well as patient-reported pain control was sent to all surgical patients in a 23-hospital system. In January 2018, as a quality improvement initiative, guidelines were given to surgeons based on patient consumption data. Prescription and consumption were then tracked prospectively. Wilcoxon signed-rank, analysis of variance, and Cuzick trend tests were used to assess for overprescription and changes over time in opioid prescribing and consumption., Results: We included 2239 patients in our cohort. The amount prescribed (median [IQR]: 30 [24-45] versus 18 [12-30], P < 0.001) and consumed (median [IQR]: 12 [7-20] versus 8 [3-15], P < 0.001) each decreased between the first and last quarter studied. Academic hospitals prescribed fewer opioids than nonacademic hospitals (median [IQR]: 24[15-40] versus median [IQR]: 30 [20-45], P < 0.001). There was no difference in the quantity of opioids consumed between patients treated at academic and nonacademic facilities (median [IQR]: 10[3-19] versus 10.5 [4-20], P = 0.08). Patients consumed a median of 42% of the opioids prescribed, and there was no significant trend in the percent consumed over time (P = 0.8)., Conclusions: Patients used far fewer opioids than prescribed after common adult general surgery procedures. When surgeons were provided with patient consumption data, the number of opioids prescribed decreased significantly., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: 'Braun' is an illegal injectable dihydrocodeinone-enriched drug mixture of semi-synthetic opioids. It is prepared by palladium-catalysed hydrogenation from codeine-containing tablets., Objective: We aimed to characterize the dermatologic consequences of long-term abuse of 'Braun'., Methods: Skin biopsies of two long-term 'Braun' abusers were evaluated histopathologically, immunohistochemically and ultrastructurally. Palladium skin content was assessed by X-ray fluorescence (XRF) spectrometry., Results: Both patients showed generalized diffuse dark blue-grey hyperpigmentation of the skin. In both, an abnormal population of cells containing intracytoplasmic brownish granular material was identified in the papillary dermis by light microscopy. Electron microscopy revealed a dense and minimally structured material that predominantly accumulated in macrophages, fibroblasts and vascular endothelial cells. XRF analysis confirmed elevated levels of palladium in the patient's skin in comparison to healthy controls., Conclusion: Long-term abuse of palladium-contaminated dihydrocodeinone ('Braun') results in excessive accumulation of granular material in various dermal cell types and causes generalized diffuse skin hyperpigmentation., (© 2019 European Academy of Dermatology and Venereology.)

The prescription drug epidemic in the United States has gained attention in recent years. Vicodin, along with its generic version, is the country's mostly widely prescribed pain reliever, and it contains a narcotic component that can lead to physical and chemical dependency. The majority of Vicodin abusers were first introduced via prescription, unlike other drugs which are often experienced for the first time due to experimentation. Most abusers report obtaining their supply from a prescription, either their own or someone else's. Although the problem with prescription drug abuse is well known, there is no standard method of addressing the problem. To better understand how to do this, we develop and analyze a mathematical model of Vicodin use and abuse, considering only those patients who were initially prescribed the drug. Through global sensitivity analysis, we show that focusing efforts on abuse prevention rather than treatment has greater success at reducing the population of Vicodin abusers. Our results demonstrate that relying solely on rehabilitation and other treatment programs is not enough to combat the prescription drug problem in the United States. We anticipate that implementing preventative measures in both prescribers and patients will reduce the number of Vicodin abusers., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: Data regarding opioid effects on esophageal function are limited. We previously demonstrated an association between chronic opioid use and esophageal motor dysfunction characterized by esophagogastric junction outflow obstruction, distal esophageal spasm, achalasia type III, and possibly Jackhammer esophagus. Our aim was to characterize the influence of different opioids and doses on esophageal dysfunction., Methods: Retrospective review of 225 patients prescribed oxycodone, hydrocodone, or tramadol for >3 months, who completed high-resolution manometry from 2012 to 2017. Demographic and manometric data were extracted from a prospectively maintained motility database. Frequency of opioid-induced esophageal dysfunction (OIED, defined as distal esophageal spasm, esophagogastric junction outflow obstruction, achalasia type III, or Jackhammer esophagus on high-resolution manometry, was compared among different opioids. The total 24-hour opioid doses for oxycodone, hydrocodone, and tramadol were converted to a morphine equivalent for dose effect analysis., Results: OIED was present in 24% (55 of 225) of opioid users. OIED was significantly more prevalent with oxycodone or hydrocodone use compared with tramadol (31% vs 28% vs 12%, P = 0.0162), and for oxycodone alone vs oxycodone with acetaminophen (43% vs 21%, P = 0.0482). There was no difference in OIED for patients taking hydrocodone alone vs hydrocodone with acetaminophen. Patients with OIED were taking a higher median 24-hour opioid dose than those without OIED (45 vs 30 mg, P = 0.058)., Discussion: OIED is more prevalent in patients taking oxycodone or hydrocodone compared with tramadol. There is greater likelihood of OIED developing with higher doses. Reducing the opioid dose or changing to tramadol may reduce OIED in opioid users.

Objective: To describe the prescription of hydrocodone-containing products (HCPs) and codeine-containing products (CCPs) by patient and provider race and ethnicity at two pediatric emergency departments (EDs) before and after the US Drug Enforcement Administration (DEA) rescheduling of HCPs in 2014., Design and Setting: The authors performed a secondary analysis of data describing the prescription of HCPs and CCPs for 6 months before and after the DEA rescheduling of HCPs in two academic, urban pediatric EDs., Patients, Participants: The authors included all children for whom race and ethnicity data were available and who were prescribed HCPs or CCPs at the time of discharge from the ED during a 12-month period (n = 1,246). The authors sent a three-question survey soliciting name, race, and ethnicity to all providers who prescribed an HCP or a CCP during the study period., Main Outcome Measures: Chi-square comparisons were made between the number of HCP and CCP prescriptions for primary ED diagnosis and patient ethnicity or race. The number of HCP and CCP prescriptions before and after the DEA rescheduling were compared to patient and provider race and ethnicity using the Breslow-Day test for homogeneity., Results: There were no significant differences in the number of HCP and CCP prescriptions between the pre- and post-DEA rescheduling periods across all racial and ethnic groups. When comparing the number of HCP and CCP prescriptions to patient race, Caucasian patients (84.4 percent) were prescribed more HCPs and CCPs than African Americans (15.6 percent) for abdominal pain (p value = 0.02). Non-Hispanic providers prescribed CCPs more often (n = 38, 55.2 percent) than Hispanic providers (n = 0, 0.0 percent) after DEA rescheduling (Breslow-Day p value = 0.01). Providers of all races wrote similar numbers of HCP and CCP prescriptions before and after the DEA rescheduling (Breslow-Day p value = 0.99)., Conclusions: Pediatric patients of all races and ethnicities received fewer HCP prescriptions after the 2014 DEA rescheduling of HCPs. However, Caucasian patients were prescribed HCPs and CCPs for abdominal pain more frequently than African American patients. There were no significant differences in the number of prescriptions of HCPs and CCPs by provider race.

Objective: To qualitatively assess prescribers) perceptions regarding the consequences associated with hydrocodone rescheduling among geriatric patients being discharged from inpatient settings., Design: This was a cross-sectional study., Setting: Two focus groups were conducted by a trained facilitator in a metropolitan academic medical center in January 2016., Participants: Prescribers who manage noncancer pain for geriatric patients were recruited. Focus groups were recorded, transcribed, and then analyzed using ATLAS.ti Qualitative Data Analysis software. Codes were derived from six primary research questions and results were summarized into key themes regarding the impact of rescheduling., Main Outcome Measures: Prescribers) perceptions regarding hydrocodone rescheduling., Results: Prescribers mentioned that they review the prescription monitoring program (PMP) more often before prescribing opioids after rescheduling. They expressed concern regarding the required special serialized prescription forms needed to issue schedule II prescriptions. This led to substituting hydrocodone with potentially less effective pain medications, the inability to issue refills on hydrocodone prescriptions, and an ethical concern over prescribing hydrocodone to patients not under their direct care. Additionally, rescheduling has affected the coordination of care upon discharge, as patients moving to long-term care or skilled nursing facilities may not have adequate pain management when transferred., Conclusions: The majority of physicians felt rescheduling negatively impacted both practical and ethical aspects of patient care related to pain management after discharge. Rescheduling has changed physicians) hydrocodone prescribing patterns, leading to more caution when prescribing hydrocodone and greater use of the PMP. Future studies should assess geriatric patients) satisfaction and quality of life regarding pain management since hydrocodone was rescheduled.

Objective: The objective of this study was to examine the rescheduling of hydrocodone-combination products (HCPs) and associated changes in prescriber patterns in an urban county healthcare system in Texas., Methods: Pharmacy data were obtained electronically for tramadol, hydrocodone-acetaminophen, and acetaminophen-codeine from 180 days before and after the schedule change on October 6, 2014. x 2 and t tests were used to calculate the significance of changes between the medications over the studied time., Results: Hydrocodone-acetaminophen saw a decline in dispense events and pills dispensed of 80.2 and 67.9 percent, respectively, in the immediate 30-day period following the scheduling change with a total decrease of 80.8 and 67.5 percent, respectively, in the 180-day period. Acetaminophen-codeine dispense events and total pills dispensed increased by 302.3 and 288.9 percent, respectively, in the immediate 30-day period while 180-day results experienced an increase of 215.1 and 209.8 percent, respectively. There were no major changes with tramadol. Additionally, an increase of 69.5 percent in pills per dispense event of hydroco-done-acetaminophen was noted in the 180-day period following the schedule change., Conclusion: The scheduling change of HCPs is associated with an immediate decrease in hydrocodone-acetaminophen use at our institution while a simultaneous rise in acetaminophen-codeine products was observed.

Purpose: To examine differences in opioid prescribing by patient characteristics and variation in hydrocodone combination product (HCP) prescribing attributed to states, before and after the 2014 Drug Enforcement Administration's reclassification of HCP from schedule III to the more restrictive schedule II., Methods: We used 2013 to 2015 data for 9 202 958 patients aged 18 to 64 from a large nationally representative commercial health insurance program to assess the temporal trends in the monthly rate of opioid prescribing., Results: HCP prescribing decreased by 26% from June 2013 to June 2015; the rate of prescriptions for any opioid decreased by 11%. Prescribing of non-hydrocodone schedule III opioids increased slightly while prescribing of non-hydrocodone schedule II opioids and tramadol was stable. Absolute decreases in HCP prescribing rates were larger in patients being treated for cancer (-2.26% vs -0.7% for non-cancer patients, P < 0.0001) and in those with high comorbidities (-2.13% vs -0.55% for those with no comorbidity, P < 0.0001). Differences in the absolute and relative changes in HCP prescribing rates among states were large; for example, a relative decrease of 46.7% in Texas and a 12.7% increase in South Dakota. The variation in HCP prescribing attributable to the state of residence increased from 6.6% in 2013 to 8.7% in 2015., Conclusions: The 2014 federal policy was associated with a decrease in rates of HCP and total opioid prescribing. The large decrease in the rates of HCP prescribing for patients with actively treated cancer may represent an unintended consequence., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objective: Distracted and drug-influenced driving presents a major risk for traffic safety morbidity and mortality. As part of an ongoing research program, we examined the effects of a commonly prescribed combination of medications for pain relief: alprazolam, a benzodiazepine, and a hydrocodone preparation, a combination opiate and acetaminophen, on a simulated driving protocol., Methods: Utilizing a within-subjects design, we recruited 8 healthy experienced drivers without major physical and psychological histories. Using a double-blind, placebo-controlled crossover design, we administered placebo, alprazolam alone, hydrocodone/acetaminophen, and the combination of the 2 drugs in a standardized simulated driving protocol. Measures of lateral and longitudinal control were collected and the data were reduced and statically analyzed., Results: The study observed clear detrimental effects of alprazolam on driving measures of lateral control and longitudinal control. Driving appeared to more aberrant at higher speeds and in rural scenarios. There were no statistical differences between hydrocodone and placebo. A measure of sedation showed that subjects rated alprazolam as more sedating than both hydrocodone and placebo., Conclusions: The findings suggest that impairing effects of this commonly prescribed combination of pharmacologic agents impact simulated driving performance. Negative changes in driving performance included measures of lateral and longitudinal control, although the deleterious effects on lateral control measures such as standard deviation of lane position (SDLP) were larger and more robust. Although the number of subjects was small, thus making it more difficult to draw conclusions on the narcotic effects, these results suggest that in this combination of central nervous system (CNS)-active drugs the benzodiazepine alprazolam accounted for the majority of impairing drug effects. The effect sizes associated with the hydrocodone preparation ranged from very small to medium. These results have potential implications for prescribing physicians and dispensing pharmacists, traffic safety experts, law enforcement officers, and patients themselves.

Objective: To examine abuse prevalence for OxyContin and comparator opioids over a 6-year period prior to and following market entry of reformulated OxyContin and assess consistency in abuse across treatment settings and geographic regions., Design: An observational study examining longitudinal changes using cross-sectional data from treatment centers for substance use disorder., Setting: A total of 874 facilities in 39 states in the United States within the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO®) surveillance system., Participants: Adults (72,060) assessed for drug problems using the Addiction Severity Index-Multimedia Version (ASI-MV®) from January 2009 through December 2015 who abused prescription opioids., Main Outcome Measure(s): Percent change in past 30-day abuse., Results: OxyContin had significantly lower abuse 5 years after reformulation compared to levels for original OxyContin. Consistency of magnitude in OxyContin abuse reductions across geographic regions, ranging from 41 to 52 percent with differences in abuse reductions in treatment setting categories occurred. Changes in geographic region and treatment settings across study years did not bias the estimate of lower OxyContin abuse through confounding., Conclusion: In the postmarket setting, limitations and methodologic challenges in abuse measurement exist and it is difficult to isolate singular impacts of any one intervention given the complexity of prescription opioid abuse. Expectations for a reasonable threshold of abuse for any one ADF product or ADF opioids as a class are still uncertain and undefined. A significant decline in abuse prevalence of reformulated OxyContin was observed 5 years after its reformulation among this treatment sample of individuals assessed for substance use disorder that was lower historically for the original formulation of this product.

Aim: Long-term safety and effectiveness of a once-daily, single-entity, extended-release formulation of hydrocodone bitartrate (HYD) for the treatment of moderate to severe noncancer and nonneuropathic pain among patients with and without concurrent depression/anxiety at baseline., Materials & Methods: Post hoc analysis., Results: HYD demonstrated a safety profile consistent with μ-opioid agonists: Serious adverse events in 12% patients with depression/anxiety including four deaths; 6% without depression/anxiety including one death. All pain scores declined by ≥2 points and mean daily HYD dose remained stable in both subgroups., Conclusion: More serious adverse events occurred among patients with comorbid depression/anxiety at baseline than among those without. HYD provided stable and effective analgesia for 52 weeks among chronic pain patients with and without comorbid depression/anxiety at baseline.

Objective: Hot-melt extrusion (HME) technology has been used for manufacturing extended-release abuse-deterrent formulations (ADFs) of opioid-type analgesics with improved tamper-resistant properties. Our objective was to describe application of this technology to immediate-release (IR) ADFs., Design: For development of a sample IR ADF (hydrocodone 10 mg/acetaminophen 325 mg) based on HME, feasibility studies were performed using different excipients. The formulation selected for further development was evaluated via in vitro test battery. Moreover, in vivo performance of IR ADF technologies was investigated in an open-label, randomized, cross-over, phase 1, relative oral bioavailability study with another opioid (model compound)., Setting: Single-center bioavailability trial., Participants: Twenty-four healthy white male subjects., Interventions: ADF IR formulation of an opioid and marketed IR formulation., Main Outcome Measure(s): For feasibility and in vitro studies, dissolution profiles, syringeability, particle size distribution after physical manipulation, and extractability were evaluated. For the phase 1 study, pharmacokinetic parameters were evaluated and compared for ADF IR and a marketed IR formulation., Results: After manipulation, the majority of particles from the ADF IR formulation were >500µm and, thus, not considered suitable for intranasal abuse, while the majority of particles for the reference marketed IR formulation were <500µm. The ADF IR formulation was resistant to syringing and preparation for potential intravenous injection. In healthy subjects, pharmacokinetics of an ADF and marketed IR formulation of an opioid were nearly identical., Conclusions: Application of HME to IR formulations led to development of products with improved mechanical resistance to manipulation for intranasal or intravenous preparation, but similar bioavailability.

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., (© 2017 The Authors. Pharmacoepidemiology & Drug Safety published by John Wiley & Sons Ltd.)

Background: Opioids are an effective, and often necessary, treatment of postoperative pain after total knee arthroplasty (TKA). However, it is often difficult to know how much medication patients will need after discharge. The purpose of this study was to determine if patients discharged with greater quantities of opioids after TKA are more likely to request refills., Methods: This is a retrospective review of 105 primary TKAs performed with at least 1 year of follow-up. Exclusion criteria included bilateral TKA, preoperative opioid use, or reoperation within the first 3 months. Data collected included opioid refills, Knee Society Score, and total and daily morphine equivalent dose (MED) prescribed., Results: Patients were most commonly discharged on oxycodone (90%), hydromorphone (5%), and hydrocodone/acetaminophen (1%). The average total prescribed MED was 1405 ± 616 mg (range, 273-3250 mg). Patients requiring refills did not differ in the total prescribed MED (1521 ± 624 vs 1349 ± 609 mg; P = .1), daily prescribed MED (153 ± 10 vs 155 ± 7 mg; P = .8), or preoperative Knee Society Score (63 ± 16 vs 60 ± 13; P = .3). Average follow-up time was 2.4 ± 0.5 years., Conclusion: The quantity of opioids prescribed after TKA varied widely, ranging from a total MED of 273-3250 mg. The refill rate did not differ between large prescriptions (≥1400 mg) and smaller prescriptions. Excessive opioid prescriptions should be avoided as they did not decrease the number of refills and pose the risk of divergence and subsequent abuse., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: This post hoc analysis examined the effectiveness and safety of hydrocodone bitartrate (HYD) in patients with moderate-to-severe chronic pain who were previously taking extended-release morphine (morphine ER) for pain management., Study Design: The primary analysis was an open-label, 12-month study., Setting: The study was conducted in 88 sites in the United States., Methods: The study was approved by an institutional review board. Eligible patients were enrolled and titrated to a once-daily dose of HYD 20, 40, 60, 80, or 120 mg for a 45-day period. The subgroup of patients in this report was using morphine ER prior to study entry. After achieving a stable HYD daily dose, patients entered a 12-month maintenance period during which additional dose adjustment could be made and nonopioid or short-acting opioid medications could be received. Average pain over the last 24 hours was recorded daily (on a scale of 0 to 10) Patients completed the Brief Pain Inventory (BPI) short form, which assessed pain severity and the interference of pain in daily life, every 4 weeks during the maintenance period. Safety was assessed routinely., Results: Of the 26 patients who switched from morphine ER to HYD, 19 entered the maintenance period. At study entry, mean "average pain over the last 24 hours" was scored as 5.21. This was reduced to 3.90 by the time patients entered the maintenance phase; this level of pain control was maintained over the 12-month period, with 16 patients requiring no further HYD dose adjustment. BPI scores decreased for both pain severity and pain interference during the maintenance period. HYD was well tolerated., Conclusions: The results of this subgroup analysis suggest that rotation from morphine ER to once-daily HYD in patients with moderate-to-severe chronic pain maintains or improves pain relief and does not increase safety concerns., (© 2016 The authors. Pain Practice published by Wiley Periodicals, Inc. on behalf of World Institute of 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., (© 2016 World Institute of Pain.)

Objective: The objective was to examine the effect of hydrocodone-containing product (HCP) rescheduling on the proportion of prescriptions for HCPs given to patients discharged from the emergency department (ED)., Methods: Electronic queries of ED records were used to identify patients aged 15 years and older discharged with a pain-related prescription in the 12 months before and after HCP rescheduling. Prescriptions were classified as HCPs; other Schedule II medications (eg, oxycodone products); other Schedule III medications (eg, codeine products); and non-Schedule II/III products (eg, nonsteroidal anti-inflammatory drugs). We compared the proportions of patients receiving each type of prescription before and after rescheduling using χ 2 analysis and used logistic regression to explore the relationship between prescription type and time period while controlling for age, sex, race, and ethnicity., Results: Before rescheduling, 58.1% (95% confidence interval [CI], 57.4-58.7) of patients receiving a pain-related prescription received an HCP; after rescheduling, 13.2% (95% CI, 12.7-13.7) received an HCP (P < .001). Concurrently, other Schedule III prescriptions increased (pre: 11.7% [CI, 11.3-12.2] vs post: 44.9% [CI, 44.2-45.6], P < .001)), as did non-Schedule II/III prescriptions (pre: 51.8% [CI, 51.2-52.5] vs post: 59.3% [CI, 58.6-60.0], P < .001). When controlling for demographic characteristics, patients remained less likely to receive an HCP after rescheduling (adjusted odds ratio [AOR], 0.11; CI, 0.10-0.11) and more likely to receive other Schedule III (AOR, 6.1; CI, 5.8-6.5) and non-Schedule II/III (AOR, 1.4; CI, 1.3-1.4) products., Conclusion: Rescheduling HCPs from Schedule III to Schedule II led to a substantial decrease in HCP prescriptions in our ED and an increase in prescriptions for other Schedule III and non-Schedule II/III products., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Several data gathered in the last decade indicate an increase of abuse of prescription opioid drugs oxycodone (OXY) and hydrocodone (HYDRO) in women. However, to date there are no conclusive evidences investigating the gender-dependent abuse liability of prescription opioids. This study aims to supply a specific focus on women's data through a selective summary of the literature analyzing gender differences in the pharmacokinetic and pharmacodynamic dimension of OXY and HYDRO. Findings from this study suggest that the majority of OXY and HYDRO pharmacokinetic and pharmacodynamic effects do not differ according to gender, though confirming a significant difference in the incidence of adverse effects as demonstrated by the increased gastrointestinal adverse reactions in female subjects. Although the majority of recent clinical studies include an equal number of female and male subjects, the main outcome parameters do not relate specifically to gender differences. Due to the gender influence in activity of CYP3A4 and its crucial role in metabolism of both OXY than HYDRO, we suggest that assessing pharmacokinetic and pharmacodynamic interactions in clinical studies may be useful to clarify the effect of the higher CYP3A4 activity in female in relation to CYP2D6 genotype. Overall, considering the paucity of data regarding gender differences in European Union, this work highlights that impact of new abuse deterrent formulations should be assessed with a special focus on data concerning female subjects., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Hydrocodone-containing products were recently rescheduled from Drug Enforcement Agency (DEA) schedule III to schedule II due to concerns of abuse and misuse. These changes went into effect on October 6, 2014., Objective: This quality improvement project involved a retrospective analysis to determine the effect of the DEA schedule change on prescribing habits of hydrocodone-containing products as well as the remaining schedule III and IV opioids, codeine (schedule III) and tramadol (schedule IV)., Methods: The authors performed a medication use evaluation at our academic level 1 trauma hospital system on outpatient use of hydrocodone-containing products, tramadol, and codeine-containing products for 6 months before and 6 months after the change to schedule II using our electronic record and pharmacy system., Results: A total of 88,428 prescription orders were analyzed. Comparison of prescriptions before and after the DEA schedule changes showed hydrocodone prescriptions reduced from an average of 225.97 per day to 1.20 per day. In addition, tramadol increased from 60.04 per day to 91.85 per day and codeine from 6.81 per day to 98.94 per day., Conclusions: Our data show a very substantial decrease in utilization of hydrocodone-containing products and concomitant increase in the utilization of tramadol and codeine products at our hospital after the DEA schedule change.

Purpose: Longer duration of prescription opioid use is associated with risk of major depression after controlling for daily morphine equivalent dose and pain. It is not known if risk of depression varies as a function of the type of opioid prescribed., Methods: A retrospective cohort design was used to model onset of new depression diagnosis among 11 462 Veterans Health Administration (VA) patients who were prescribed only codeine, only hydrocodone or only oxycodone for >30 days. Patients were free of prevalent opioid use and depression at baseline (2000-2001). Follow-up was 2002-2012. Propensity scores and weighting were used to balance covariates across opioid type. Cox-proportional hazard models were computed, using weighted data and additional adjustment for morphine equivalent dose (MED), duration of use, and pain after opioid initiation, to estimate the risk of new depression diagnosis among patients prescribed only codeine, only oxycodone vs. those prescribed only hydrocodone., Results: After controlling for confounding, we observed that patients prescribed codeine, compared to hydrocodone, were significantly more likely to have a new depression diagnosis (HR = 1.27; 95%CI: 1.12-1.43). Oxycodone was significantly associated with onset of new depression diagnosis when exposure was modeled as total days exposed in post-hoc analysis, but not when exposure was duration of incident period of use., Conclusions: Although codeine is a less potent opioid, after controlling for MED, chronic use of this agent is associated with nearly a 30% greater risk of depression compared to hydrocodone. Additional research is needed to determine the mechanisms for this association. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Objective: To evaluate long-term safety, maintenance of analgesia, and aberrant drug-related behaviors of hydrocodone extended release (ER) formulated with CIMA® Abuse-Deterrence Technology., Design: Phase 3, multicenter, open-label extension., Setting: Fifty-six US centers., Patients: Adults with chronic low back pain completing a 12-week placebocontrolled study of abuse-deterrent hydrocodone ER were eligible. One hundred eighty-two patients enrolled and received ≥1 dose of study drug, 170 entered openlabel treatment, and 136 completed the study., Interventions: Patients receiving hydrocodone ER in the 12-week, placebo-controlled study continued their previous dose unless adjustment was needed; those previously receiving placebo (n=78) underwent dose titration/adjustment to an analgesic dose (15-90 mg every 12 hours). Patients received 22 weeks of open-label treatment., Safety: adverse events (AEs). Maintenance of analgesia: worst pain intensity (WPI) and average pain intensity (API) at each study visit. Aberrant drug behavior: study drug loss and diversion., Results: AEs were reported for 65/182 (36 percent) patients during dose titration/ adjustment and 88/170 (52 percent) during open-label treatment. No treatmentrelated serious AEs were reported. There were no clinically meaningful trends in other safety assessments, including physical examinations and pure tone audiometry. One patient receiving hydrocodone ER 30 mg twice daily experienced a severe AE of neurosensory deafness that was considered treatment related. Mean WPI and API remained steady throughout open-label treatment. Six (3 percent) patients reported medication loss, and 5 (3 percent) reported diversion., Conclusions: Abuse-deterrent hydrocodone ER was generally well tolerated in patients with chronic low back pain, maintained efficacy, and was associated with low rates of loss and diversion.

Two open-label, single-dose, parallel-group studies assessed effects of renal and hepatic impairment on the pharmacokinetics of a hydrocodone extended-release (ER) formulation developed with the CIMA Abuse-Deterrence Technology platform. Forty-eight subjects with normal renal function or varying degrees of renal impairment received hydrocodone ER 45 mg (study 1); 16 subjects with normal hepatic function or moderate hepatic impairment received hydrocodone ER 15 mg (study 2). Blood samples were obtained predose and through 144 hours postdose. Mean maximum observed plasma hydrocodone concentration (Cmax ) in subjects with normal renal function, mild, moderate, and severe impairment, and end-stage renal disease was 28.6, 33.4, 42.4, 36.5, and 31.6 ng/mL, and mean area under the plasma hydrocodone concentration-versus-time curve from time 0 to infinity (AUC0-∞ ) was 565, 660, 973, 983, and 638 ng·h/mL, respectively. Incidence of adverse events was 57%, 38%, 44%, 33%, and 56%, respectively. Mean Cmax with normal hepatic function and moderate impairment was 10.1 and 13.0 ng/mL, and mean AUC0-∞ was 155 and 269 ng·h/mL, respectively. Incidence of adverse events was 38% in both groups. Altered systemic exposure in renally or hepatically impaired populations (up to ∼70% higher) should be considered when titrating to an effective dose of hydrocodone ER., (© 2016, The American College of Clinical Pharmacology.)

Objective: To characterize emergency department (ED) patients' knowledge and beliefs about the addictive potential of opioids., Design: Mixed methods analysis of data from a randomized controlled trial., Setting: Urban academic ED (>88,000 visits)., Subjects: One hundred and seventy four discharged ED patients prescribed hydrocodone-acetaminophen for acute pain., Methods: The study analyzed data collected from a randomized controlled trial investigating patients' knowledge of opioids. ED patients discharged with hydrocodone-acetaminophen completed an audio-recorded phone interview 4–7 days later. This analysis focuses on responses about addiction. Responses were categorized using content analysis; thematic analysis identified broad themes common across different categories., Results: Participants' mean age was 45.5 years (SD, 14.8), 58.6% female, 50.6% white, and the majority had an orthopedic diagnosis (24.1% back pain, 52.3% other injuries). Responses were categorized first based on whether the patient believed that opioids could be addictive (categorized as: yes, 58.7%; no, 19.5%; depends, 17.2%; or do not know, 4.6%), and second based on whether or not the patient discussed his/her own experience with the medication (categorized as: personalized, 35.6%; or not personalized, 64.4%). Cohen's Kappa was 0.84 for all categories. Three themes emerged in the thematic analysis: theme 1) patients expect to “feel” addicted if they are addicted, theme 2) patients fear addiction, and theme 3) side effects affected patient views of addiction., Conclusion: In this sample, patients had misconceptions about opioid addiction. Some patients did not know opioids could be addictive, others underestimated their personal risk of addiction, and others overtly feared addiction and, therefore, risked inadequate pain management. Despite limited data, we recommend providers discuss opioid addiction with their patients., (Published by Oxford University Press on behalf of the American Academy of Pain Medicine. 2016. This work is written by US Government employees and is in the public domain in the US.)

Background: Biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) 7.5/325-mg tablets are formulated with gastroretentive ER drug delivery technology that has been associated with clinically meaningful food effects in other approved products. Two phase 1 studies evaluated potential effects of food on single-dose pharmacokinetics of IR/ER HB/APAP tablets., Methods: These were single-center, open-label, randomized, single-dose, 3-period crossover studies in healthy volunteers (aged 18-55 years). IR/ER HB/APAP was administered as a single 2-tablet dose (study 1) or 3-tablet dose (study 2) under fed (high- and low-fat) and fasted conditions. Area under the plasma concentration-time curve from 0 h to time t (AUC0-t) and from time 0 extrapolated to infinity (AUC0-inf) and maximum observed plasma concentration (Cmax) of hydrocodone and APAP under fed versus fasted conditions were compared using analysis of variance. A 90% confidence interval of the geometric least squares mean ratio fully contained within 80 to 125 % indicated no treatment difference. Safety and tolerability were assessed., Results: Forty of 48 participants in study 1 and 21 of 30 in study 2 completed all treatments. In both studies, under fed (high- or low-fat meal) versus fasted conditions, 90% CIs for AUC0-t and AUC0-inf for both hydrocodone and APAP were entirely contained within the bioequivalent range (80-125%), indicating that high- and low-fat meals did not affect the extent of exposure. In both studies, a high-fat meal did not affect the Cmax for hydrocodone. Hydrocodone Cmax was not affected by a low-fat meal in study 1 but increased by approximately 19% in study 2. A high-fat meal decreased APAP Cmax by approximately 20 % (study 1) and 13 % (study 2); a low-fat meal decreased APAP Cmax by 22% (study 1) and 21% (study 2). Approximately 50% of participants in both studies reported ≥1 treatment-emergent adverse event (TEAE), with no notable difference based on food intake. There were no serious or severe AEs. The most common TEAEs were nausea, vomiting, and dizziness., Conclusions: Pharmacokinetic and safety findings were similar regardless of food intake. TEAEs were consistent with those reported with low-dose combination opioids. IR/ER HB/APAP can be administered without regard to food., Trial Registration: ClinicalTrials.gov NCT02561650 and NCT02561741 .

Objective: To evaluate efficacy and safety of hydrocodone bitartrate extended release (ER) tablets developed with CIMA(®) Abuse-Deterrence Technology (ADT) versus placebo in alleviating moderate-to-severe pain in patients with chronic low back pain., Design: Phase 3, randomized, double-blind study consisting of a screening period (7-14 days), open-label titration period (≤ 6 weeks), and double-blind treatment period (≤ 12 weeks)., Setting: Seventy-eight US centers., Main Outcome Measures: Changes from baseline at week 12 in weekly average of daily worst pain intensity (WPI; primary efficacy measure), weekly average pain intensity (API; secondary efficacy measure), adverse events (AEs), and study drug loss and diversion., Results: Patients (N = 625) who entered open-label dose titration and identified the analgesic hydrocodone ER dose (30-90 mg every 12 h) providing optimal pain relief with minimal AEs were randomized to hydrocodone ER (n = 191) or placebo (n = 180) for double-blind treatment at the identified dose; 297 patients completed the study. Least squares means [SE] changes from baseline were significantly greater (worsening pain; 11-point scale) with placebo than hydrocodone ER in weekly average of daily WPI (0.74 [0.15] vs 0.11 [0.14]; p < 0.001) and weekly API (0.55 [0.14] vs -0.03 [0.12]; p < 0.001). The most common AEs with hydrocodone ER were constipation (14 percent) and nausea (10 percent). Study drug loss (≤ 4 percent) and diversion (≤ 2 percent) rates were low., Conclusions: Hydrocodone ER formulated with ADT was significantly more effective than placebo in alleviating chronic low back pain and demonstrated a safety profile consistent with that of opioids, with a low occurrence of study drug loss and diversion.

Objectives: The objective was to test the hypothesis that oxycodone/acetaminophen provides superior analgesia to hydrocodone/acetaminophen for the treatment of acute extremity pain following emergency department (ED) discharge., Methods: This was a prospective, randomized, double-blind clinical trial of nonelderly adult ED patients with acute musculoskeletal extremity pain, randomly allocated at discharge to receive oxycodone/acetaminophen (5 mg/325 mg) or hydrocodone/acetaminophen (5 mg/325 mg). The primary outcome was the between-group difference in improvement in numerical rating scale (NRS) pain scores over a 2-hour period following the most recent ingestion of study drug, obtained during telephone contact 24 hours after ED discharge. Secondary outcomes included proportionate decrease in pain, comparative side-effect profiles, and patient satisfaction., Results: A total of 240 patients were enrolled. The final sample consisted of 220 patients, 107 randomly allocated to oxycodone/acetaminophen and 113 to hydrocodone/acetaminophen. At 24 hours after ED discharge, the mean NRS pain scores prior to the most recent dose of outpatient pain medication were 7.8 and 7.9 in the oxycodone/acetaminophen and hydrocodone/acetaminophen groups, respectively. The mean decreases in pain scores over 2 hours were 4.4 NRS units in the oxycodone/acetaminophen group versus 4.0 NRS units in the hydrocodone/acetaminophen group, for a difference of 0.4 NRS units (95% confidence interval = -0.2 to 1.1 NRS units). Satisfaction with the analgesics was similar., Conclusions: This study design could not detect a clinically or statistically significant difference in analgesic efficacy between oxycodone/acetaminophen (5 mg/325 mg) and hydrocodone/acetaminophen (5 mg/325 mg) for treatment of acute musculoskeletal extremity pain in adults following ED discharge. Both opioids reduced pain scores by approximately 50%., (© 2015 by the Society for Academic Emergency Medicine.)

The past decade has witnessed an alarming increase in the number of deaths due to prescription opioids that has paralleled the rise in the number of opioid prescriptions dispensed. Prescription drug monitoring programs, abuse-deterrent formulations and proper disposal of opioids have been promoted to help combat the opioid epidemic. We discuss changes that dentists, the third most frequent prescribers of opioids, can implement to help reduce the risk of prescription opioid abuse in their communities.

Opioids have become a mainstay of treatment for pain in the United States, with over 250 million prescription issued in 2012 alone. The increased prescribing of these medications has also contributed to the unintended consequence of a widening prevalence of abuse and misuse, and therefore safety has become a top agenda item for both government and health care providers alike. The move toward new abuse-deterrent formulation technologies, enhanced regulatory requirements from the Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA), and developments in national/state policies have worked together to target a goal of promoting safer clinician prescribing, pharmacy dispensing and patient use of opioids. Hydrocodone in particular, as the most widely prescribed opioid product, has recently been subject to a myriad of changes, both through the federal rescheduling of hydrocodone-combination products (HCPs) to Schedule II, as well as the introduction of two new extended-release formulations to the USA market. These efforts represent a first step toward tackling the opioid harms epidemic, although continuing follow-up through research and policy implementation is needed to see any measureable impact on safety in the future., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To characterize the long-term safety and effectiveness of Hysingla™ ER, single-entity, once-daily, extended-release hydrocodone bitartrate tablets formulated with abuse-deterrent properties (HYD), offering a new treatment option for appropriate patients with chronic pain., Design: An open-label study with a dose-titration period (up to 45 days) and a maintenance period (12 months)., Patients, Participants: A total of 922 patients with chronic nonmalignant and non-neuropathic moderate to severe pain received open-label HYD tablets 20-120 mg; 728 of these achieved a stabilized dose of HYD at the end of dose-titration and entered the maintenance period., Results: The safety profile was similar to that of other oral opioid analgesics, without new or unexpected safety concerns. The most frequent treatment-emergent adverse events (AEs; ≥ 5 percent) were those commonly associated with the use of systemic µ-opioid analgesics, including nausea, constipation, vomiting, fatigue, dizziness, somnolence, and headache. There were 77 (8 percent) patients with a total of 109 nonfatal treatment-emergent serious AEs. Few patients discontinued due to lack of therapeutic effect overall (6 percent), especially during the 12-month maintenance period (4 percent). Pain relief, sleep, functional health, and activities of daily living all improved at the end of the dose-titration period with HYD. These improvements were maintained through the 12-month maintenance period with stable HYD doses and without increase in concomitant supplemental analgesic medications., Conclusions: This long-term study demonstrated the safety and long-term maintenance of analgesic effect of HYD without continued need for dose increase.

Hydrocodone bitartrate is the most commonly used drug for acute and chronic pain in the U.S. with over 135 million prescriptions in 2012. The U.S. is the primary consumer of hydrocodone, using 99% of the global supply for 4.4% of the global population. With its easy availability and abuse patterns, hydrocodone has been touted as a primary driver of opioid-related abuse and misuse. There are no clinical efficacy studies of hydrocodone in short-acting form in combination with acetaminophen or ibuprofen in chronic pain. Hydrocodone has been approved with two long-term formulations since 2014. The FDA has rescheduled hydrocodone from Schedule III to Schedule II which went into effect on October 6, 2014, along with a limit on added acetaminophen of 325 mg for each dose of hydrocodone. This review examines the evolution of hydrocodone into a common and yet controversial drug in the U.S. with its pharmacokinetics, pharmacodynamics, safety and efficacy., (Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.)

Purpose: This study aimed to assess the tolerability of the extended use (≤35 days) of MNK-155, a biphasic (immediate-release/extended-release) hydrocodone bitartrate/N-acetyl-p-aminophenol (acetaminophen) (IR/ER HB/APAP) 7.5/325-mg fixed-dose combination analgesic agent, in patients with chronic noncancer pain (CNCP) caused by osteoarthritis or chronic low back pain. IR/ER HB/APAP tablets deliver 25% of the HB dose and 50% of the APAP dose by IR and the remainder by ER over a 12-hour dosing interval. Although IR/ER HB/APAP is being developed for the management of moderate to severe acute pain, this model of CNCP was used for assessing tolerability over a term longer than would be possible in a model of acute pain., Methods: This Phase III, multicenter, open-label study enrolled patients with moderate to severe OA (knee or hip) pain despite the use of nonopioid or opioid analgesic agents, or with moderate to severe CLBP present for several hours per day for ≥3 months. Patients received a 3-tablet initial dose of IR/ER HB/APAP (total dose, 22.5/975 mg) on day 1, followed by 2 tablets of IR/ER HB/APAP (total dose, 15/650 mg) q12h for up to 35 days. Tolerability, the primary end point, was assessed using time to treatment discontinuation, the prevalence of treatment-emergent adverse events (TEAEs), vital sign measurements, pulse oximetry, clinical laboratory tests, and compliance. Secondary outcomes included the modified Brief Pain Inventory-Short Form, the Western Ontario and McMaster Universities Arthritis Index, and The Roland-Morris Low Back Pain and Disability Questionnaire., Findings: Of the 153 patients enrolled (95 women [62.1%]; mean age, 53.9 [14.5] years; OA, n = 73; CLBP, n = 80), 37 (24.2%) discontinued the study early (mean time to discontinuation, 21.3 days). Thirteen patients (8.5%) discontinued because of TEAEs. A total of 88 patients (57.5%) reported ≥1 TEAE, 65 (42.5%) of whom experienced AEs considered by the investigator as treatment related. The most frequent TEAEs were nausea (16.3%), somnolence (14.4%), and constipation (11.1%). Eight severe TEAEs were experienced by 6 (3.9%) patients and included single occurrences of nausea, fatigue, nasopharyngitis, elevated liver enzymes, headache, nightmare, and ejaculation delay. No serious treatment-related AEs were reported. Clinically significant changes in laboratory values were reported in 13 patients, 6 of whom had abnormal liver function test results that did not meet Hy's law criteria for acute liver failure. Most laboratory abnormalities were mild and transient. Measures of pain intensity, function, and quality of life improved from baseline but in an open-label study these changes cannot be attributed to treatment., Implications: The safety profile of IR/ER HB/APAP during extended use was consistent with those of other low-dose opioid/APAP combination products. IR/ER HB/APAP is intended for acute pain; its efficacy for relief of CNCP would require further evaluation in an active- or placebo-controlled study. ClinicalTrials.gov Identifier: NCT01722864., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Background: A fixed-dose combination biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) tablet is being developed for the management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate., Methods: This Phase III, randomized, double-blind, placebo-controlled, parallel-group study evaluated the analgesic efficacy and safety of IR/ER HB/APAP (n = 201) versus placebo (n = 202) over a period of 48 hours in patients with acute moderate to severe pain following unilateral bunionectomy. Patients received three tablets of placebo or IR/ER HB/APAP as an initial dose (hour 0) followed by two tablets every 12 hours for a total daily dose of 37.5/1625 mg HB/APAP on day 1 and 30/1300 mg HB/APAP thereafter. The primary efficacy outcome was the summed pain intensity difference (SPID) over the first 48 hours (SPID48) after the first dose., Results: SPID48 was significantly greater with IR/ER HB/APAP versus placebo (p < 0.001). SPID dosing interval analyses demonstrated consistent, superior pain relief with IR/ER HB/APAP for each dosing interval (all p < 0.001). Mean PID was greater with IR/ER HB/APAP versus placebo beginning 30 minutes after the first dose (p < 0.05), and IR/ER HB/APAP demonstrated faster median time to the onset of perceptible, meaningful, and confirmed pain relief (all p < 0.001). Mean total pain relief scores also indicated greater pain relief with IR/ER HB/APAP versus placebo throughout the 48-hour period (p = 0.012) for all comparisons. A greater proportion of IR/ER HB/APAP versus placebo patients was either "very satisfied" or "satisfied" with their pain relief (69.3% vs 49.4%; p < 0.001). Nausea was the most common treatment-emergent adverse event (TEAE; IR/ER HB/APAP, 25%; placebo, 7.9%). All TEAEs in IR/ER HB/APAP-treated patients were mild or moderate in severity., Conclusion: IR/ER HB/APAP provided rapid, significant, and consistent analgesic efficacy over a period of 48 hours in an established model of acute pain and was tolerated with a safety profile similar to other low-dose opioids.

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., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Lortab® Elixir, a proprietary combination product containing hydrocodone and acetaminophen, is approved in the US for the treatment of moderate to moderately severe pain in children. Despite this approval, pediatric pharmacokinetic data using this product have not been previously published. Using a single-dose open-label study approach, we evaluated the pharmacokinetics, tolerability, and safety of this product in 17 healthy children 6-17 years of age. Results showed that the body weight-normalized oral clearance (L/h/kg) of hydrocodone and acetaminophen were 42% and 27% higher, respectively when compared to data from healthy adults. This suggests that a higher mg/kg dose would be required in children to achieve exposures similar to adults. We found adjustment of hydrocodone and acetaminophen dose by body surface area to be more optimal than body weight-based dose adjustments for achieving similar systemic exposure in children and adults. However, body weight-based hydrocodone and acetaminophen dosing regimens provided close approximation of adult exposures in pediatric patients with approximately 22% to 24% lower hydrocodone and acetaminophen dose/BW-normalized AUC in pediatric patients compared to adults. Finally, the adverse event profile in our pediatric cohort was consistent with that expected of opioid-naive subjects receiving opioid-combination therapy., (© 2014, The American College of Clinical Pharmacology.)

Objectives: This multicenter, randomized, double-blind, placebo-controlled study with an enriched enrollment, randomized withdrawal design was conducted to evaluate the analgesic efficacy and safety of single-entity, once-daily hydrocodone 20 to 120 mg tablets (HYD) in opioid-naive and opioid-experienced patients with uncontrolled moderate to severe chronic low back pain (CLBP)., Research Design and Methods: The primary endpoint was week 12 pain intensity scores (11-point scale, 0 = no pain) using a mixed effect model with repeated measures incorporating a pattern mixture model framework. Responder analysis was a secondary endpoint. Safety was assessed., Results: Out of 905 patients who were treated with HYD during the open-label titration period, 588 (65%) were randomized to continue to receive HYD (n = 296, 20 - 120 mg taken once daily, average daily dose 57 mg) or a matching placebo (n = 292). HYD demonstrated superior pain reduction (p = 0.0016); this result was supported by sensitivity analyses using different approaches to handling missing data. Proportions of patients achieving ≥ 30 and ≥ 50% improvement in pain from screening to week 12 also favored HYD (p = 0.0033 and 0.0225, respectively). HYD was generally well tolerated., Conclusions: HYD was shown to be an efficacious treatment for CLBP in this study. There were no new or unexpected safety concerns detected.

Background: The abuse potential of prescription opioids is well established. This study compared positive, subjective drug effects of single, equal doses of biphasic immediate release (IR)/extended release (ER) hydrocodone bitartrate (HB)/acetaminophen (acetyl-p-aminophenol [APAP]) 7.5/325 mg tablets versus IR HB/APAP 7.5/325-mg tablets and placebo., Methods: Healthy adult recreational users of prescription opioids entered this randomized, double-blind, double-dummy, active- and placebo-controlled, seven-way crossover study. Participants received single, total doses of IR/ER HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), IR HB/APAP 22.5/975 mg (intact; three active tablets) and 45/1950 mg (intact and crushed [encapsulated]; six active tablets), and placebo. Peak subjective effects (E(max)); time to peak effects (TE(max)); and area under the drug-effect curves for drug liking, high, and good drug effects were measured using visual analog scales. Median values with 95% confidence interval (CI) were compared using analysis of variance., Results: Among completers (n = 52), IR/ER HB/APAP produced delayed and lower peak effects compared to equal doses of IR HB/APAP. Comparing intact tablets, the drug liking E(max) (median [95% CI]) was significantly lower for IR/ER HB/APAP 45/1950 mg (78.0 [73.0, 81.0]) than an equal dose of IR HB/APAP (89.5 [85.0, 93.0]; difference, -8.5 [-12.0, -6.0]; P < 0.001). Similar results were observed for intact IR/ER HB/APAP and IR HB/APAP 22.5/975 mg. Crushing IR/ER HB/APAP 45/1950 mg delayed these effects compared with an equal dose of crushed IR HB/APAP and intact IR/ER HB/APAP., Conclusion: IR/ER HB/APAP resulted in lower subjective positive drug effects than an equal dose of IR HB/APAP. Crushing IR/ER HB/APAP also delayed the onset of subjective effects compared with intact IR/ER HB/APAP. These findings suggest that biphasic IR/ER HB/APAP has lower abuse potential than IR HB/APAP in single equal doses., Registration: This Phase I clinical trial conducted in the USA was not registered.