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Background: Septorhinoplasty is one the most common class of procedures performed worldwide, and opioids are frequently prescribed for post-operative pain [1]., Objective: The objective of this study was to examine the rate of post-operative opioid prescription refills following septorhinoplasty., Methods: This study was a case-control study of patients who underwent septoplasty and other secondary concomitant procedures., Results: Of the 249 patients included in this study, the majority of patients (94.8%) were prescribed 12 tablets of hydrocodone-acetaminophen 5 mg - 325 mg and only 31 patients (13.3%) received refills. The presence of osteotomies and history of prior opioid use were associated with refills. Nasal valve repair type, open versus closed approach, and presence of autologous auricular cartilage graft harvest were not., Discussion: Our study highlights factors that surgeons should consider when prescribing opioids after septorhinoplasty. Twelve tablets of an opioid are likely sufficient for the majority of patients, but if osteotomies are performed or the patient has a history of prior opioid use, more may be indicated to avoid the need for refills. Additional narcotics are not necessary for an open approach or for patients in which auricular cartilage is needed., Competing Interests: Declaration of competing interest The authors of this study do not have any conflicts of interest to disclose. This study received no specific grant from any funding agency in the public, commercial, or non-profit sectors., (Published by Elsevier Inc.)

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Importance: Historically, opioid pain medications have been overprescribed following thyroid and parathyroid surgery. Many narcotic prescriptions are incompletely consumed, creating waste and opportunities for abuse., Objective: To determine whether limiting opioid prescriptions after outpatient thyroid and parathyroid surgery to patients who opt in to narcotic treatment reduces opioid consumption without increasing postoperative pain compared with usual care (routine narcotic prescriptions)., Design, Setting, and Participants: A randomized clinical trial of Postoperative Opt-In Narcotic Treatment (POINT) or routine narcotic prescription (control) was conducted at a single tertiary referral center from June 1 to December 30, 2020. A total of 180 adults undergoing ambulatory cervical endocrine surgery, excluding patients currently receiving opioids, were assessed for eligibility. POINT patients received perioperative pain management counseling and were prescribed opioids only on patient request. Patients reported pain scores (0-10) and medication use through 7 daily postoperative surveys. Logistic regression was used to determine factors associated with opioid consumption., Interventions: Patients in the POINT group were able to opt in or out of receiving prescriptions for opioid pain medication on discharge. Control patients received routine opioid prescriptions on discharge., Main Outcomes and Measures: Daily peak pain score through postoperative day 7 was the primary outcome. Noninferiority was defined as a difference less than 2 on an 11-point numeric rating scale from 0 to 10. Analysis was conducted on the evaluable population., Results: Of the 180 patients assessed for eligibility, the final study cohort comprised 102 patients: 48 randomized to POINT and 54 to control. Of these, 79 patients (77.5%) were women and median age was 52 (interquartile range, 43-62) years. A total of 550 opioid tablets were prescribed to the control group, and 230 tablets were prescribed to the POINT group, in which 23 patients (47.9%) opted in for an opioid prescription. None who opted out subsequently required rescue opioids. In the first postoperative week, 17 POINT patients (35.4% of survey responders in the POINT group) reported consuming opioids compared with 27 (50.0%) control patients (P = .16). Median peak outpatient pain scores were 6 (interquartile range, 4-8) in the control group vs 6 (interquartile range, 5-7) in the POINT group (P = .71). In multivariate analysis, patients with a history of narcotic use were 7.5 times more likely to opt in (95% CI, 1.61-50.11; P = .02) and 4.8 times more likely to consume opioids (95% CI, 1.04-1.52; P = .01). Higher body mass index (odds ratio, 1.11; 95% CI, 1.01-1.23; P = .03) and highest inpatient postoperative pain score (odds ratio, 1.24; 95% CI, 1.04-1.52; P = .02) were also associated with opioid consumption., Conclusions and Relevance: In this trial, an opt-in strategy for postoperative narcotics reduced opioid prescription without increasing pain after cervical endocrine surgery., Trial Registration: ClinicalTrials.gov Identifier: NCT04710069.

Opioid misuse is a public health crisis in the United States. The origin of this crisis is associated with a sharp increase in opioid analgesic prescribing. We used the urban scaling framework to analyze opioid prescribing patterns in US commuting zones (CZs), i.e., groups of counties based on commuting patterns. The urban scaling framework postulates that a set of scaling relations can be used to predict health outcomes and behaviors in cities. We used data from the Drug Enforcement Administration's Automated Reports and Consolidated Ordering System (ARCOS) to calculate counts of oxycodone/hydrocodone pills distributed to 607 CZs in the continental US from 2006 to 2014. We estimated the scaling coefficient of opioid pill counts by regressing log(pills) on log(population) using a piecewise linear spline with a single knot at 82,363. Our results show that CZs with populations below the knot scaled superlinearly (β = 1.36), i.e., larger CZs had disproportionally larger pill counts compared to smaller CZs. On the other hand, CZs with populations above the knot scaled sublinearly (β = 0.92), i.e., larger CZs had disproportionally smaller pill counts compared to smaller CZs. This dual scaling pattern was consistent across US census regions. For CZs with population below the knot, the superlinear scaling of pills is consistent with the explanation that an increased number of successful matches between prescribers and users will lead to higher prescribing rates. The non-linear scaling behavior observed could be the result of a combination of factors, including stronger health care systems and prescribing regulation in largely populated commuting zones, as well as high availability of other opioids such as heroin in these commuting zones. Future research should explore potential mechanisms for the non-linearity of prescription opioid pills., Competing Interests: The authors have declared that no competing interests exist.

Background: Opioids are commonly prescribed to treat moderate-to-severe pain. However, their use can trigger the development of opioid use disorder. A major problem in treating opioid use disorder remains the high rate of relapse., Aim: The purpose of this study was to determine whether there are differences among opioids in their ability to trigger relapse after pre-exposure during adolescence., Methods: On postnatal day 33, mice were examined for the acute locomotor response to saline, morphine, or hydrocodone (5 mg/kg). They were administered with the corresponding opioid or saline during postnatal days 34-38 (20 mg/kg) and 40-44 (40 mg/kg). On postnatal day 45, they were recorded for the development of locomotor sensitization (5 mg/kg). Starting on postnatal day 55, mice were examined for the acquisition (1, 5, 10, 20, and 40 mg/kg), extinction, and drug-induced reinstatement (1, 2.5, and 5 mg/kg) of conditioned place preference., Results: There were no significant differences in the acute locomotor response to morphine and hydrocodone. Morphine induced significantly stronger locomotor sensitization as compared to hydrocodone. Pre-exposure to morphine, but not hydrocodone, sensitized the acquisition of conditioned place preference. There were no significant differences in extinction rates. Mice pre-exposed to morphine reinstate conditioned place preference after priming with a 1 mg/kg dose. In contrast, higher priming doses were required for reinstatement in all other experimental groups., Conclusions: Adolescent mice administered with morphine develop greater sensitization to its effects and subsequently reinstate conditioned place preference more readily than mice administered with hydrocodone. This suggests higher risk for relapse after pre-exposure to morphine during adolescence as compared to hydrocodone.

Background: In 2014, the U.S. Drug Enforcement Agency reclassified hydrocodone from Schedule III to Schedule II of the Controlled Substances Act, resulting in new restrictions on refills. The authors hypothesized that hydrocodone rescheduling led to decreases in total opioid dispensing within 30 days of surgery and reduced new long-term opioid dispensing among surgical patients., Methods: The authors studied privately insured, opioid-naïve adults undergoing 10 general or orthopedic surgeries between 2011 and 2015. The authors conducted a differences-in-differences analysis that compared overall opioid dispensing before versus after the rescheduling rule for patients treated by surgeons who frequently prescribed hydrocodone before rescheduling (i.e., patients who were functionally exposed to rescheduling's impact) while adjusting for secular trends via a comparison group of patients treated by surgeons who rarely prescribed hydrocodone (i.e., unexposed patients). The primary outcome was any filled opioid prescription between 90 and 180 days after surgery; secondary outcomes included the 30-day refill rate and the amount of opioids dispensed initially and at 30 days postoperatively., Results: The sample included 65,136 patients. The percentage of patients filling a prescription beyond 90 days was similar after versus before rescheduling (absolute risk difference, -1.1%; 95% CI, -2.3% to 0.1%; P = 0.084). The authors estimated the rescheduling rule to be associated with a 45.4-mg oral morphine equivalent increase (difference-in-differences estimate; 95% CI, 34.2-56.7 mg; P < 0.001) in initial opioid dispensing, a 4.1% absolute decrease (95% CI, -5.5% to -2.7%; P < 0.001) in refills within 30 days, and a 37.7-mg oral morphine equivalent increase (95% CI, 20.6-54.8 mg; P = 0.008) in opioids dispensed within 30 days., Conclusions: Among patients treated by surgeons who frequently prescribed hydrocodone before the Drug Enforcement Agency 2014 hydrocodone rescheduling rule, rescheduling did not impact long-term opioid receipt, although it was associated with an increase in opioid dispensing within 30 days of surgery.

Introduction: Patient-reported pain scores and opioid use have not been quantified after outpatient adolescent anterior cruciate ligament reconstruction (ACLR)., Methods: Patients aged 12 to 18 years undergoing primary isolated ACLR, with or without meniscal treatment, were prospectively recruited. Patients actively taking opioids or with previous extended use of opioids were excluded. Two orthopaedic surgeons performed ACLR and determined the use of a hamstring or bone-patellar tendon-bone autograft. For postoperative pain management, patients were prescribed 40 tablets of hydrocodone/acetaminophen 5/325 mg. Patients were instructed to document daily pill consumption and side effects through a daily log for 6 weeks. Patients completed the American Pain Society Patient Outcome Questionnaire at the end of weeks 1 and 6., Results: One hundred three patients were enrolled, with age: 12.5 to 18.9 years (mean 16.2 y ± 1.3), weight: 41.3 to 113.6 kg (mean 72.4 kg ± 17.2), and body mass index: 17.8 to 40.1 (mean 25.9 ± 4.9). Sixty-nine patients received a hamstring autograft, and 34 received a bone-patellar tendon-bone autograft. Fifty-six received additional meniscal procedures. The median number of postoperative opioids taken by patients was 17 (range 0 to 40). No notable differences were found in total pill consumption with regard to age, weight, body mass index, sex, block type, autograft type, or meniscal treatment at 1 week post-op or 6 weeks post-op. No correlation was found between the self-reported "worst pain in the past 24 hours" at the end of the first postoperative week or after 6 weeks (r = 0.112, P = 0.26, and r = 0.093, P = 0.36). No correlation was found between the level of satisfaction with pain treatment and total number of pills taken during the first postoperative week or at the end of 6 weeks (r = -0.090, P = 0.37, and r = -0.172, P = 0.08)., Conclusion: Patients take most pain medication during the first postoperative week after adolescent ACLR, although patient and surgical variables had no notable influence on pill consumption., Level of Evidence: Level IV, case series.

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.)

Objectives: Deaths from prescription opioid overdoses have reached an epidemic level in the United States, particularly among persons with disabilities. The 2014 federal rescheduling regulation is associated with reduced opioid prescribing in the general US population; however, to date, no data have been published on this regulation's effect on persons with disabilities. We examined whether the 2014 hydrocodone rescheduling change was associated with reduced opioid prescribing among adult Medicare beneficiaries with disabilities., Methods: We identified 680 876 Medicare beneficiaries with disabilities aged 21-64 in 2013 and 657 687 in 2015 from a 20% national sample. We examined changes in the monthly opioid-prescribing rates from January 1, 2013, through December 31, 2015. We also compared opioid-prescribing rates in 2013 with rates in 2015., Results: In 2014, the percentage of Medicare beneficiaries with disabilities who received hydrocodone prescriptions decreased by 0.154% per month (95% confidence interval [CI], -0.186 to -0.121, P < .001). The percentage of Medicare beneficiaries with disabilities who received hydrocodone prescriptions decreased from 32.2% in 2013 to 27.7% in 2015, whereas rates of any opioid prescribing, prolonged prescribing (≥90-day supply), and high-dose prescribing (≥100 morphine milligram equivalents per day for >30 days) decreased only modestly, from 50.2% to 49.0%, from 27.4% to 26.5%, and from 7.5% to 7.0%, respectively., Conclusions: The 2014 federal rescheduling of hydrocodone was associated with only minor changes in overall and potentially high-risk opioid-prescribing rates. Neither state variation in long-term prescribing nor beneficiary characteristics explained the changes in persistently high opioid-prescribing rates among adults with disabilities after the 2014 regulation. Future studies should examine patient and provider characteristics underlying the persistent high-risk prescribing patterns in this population.

Introduction: Non-medical use and abuse of prescription opioids is a growing problem in both the civilian and military communities, with minimal technologies for detecting hydrocodone use. This study explored the proteomic changes that occur in the oral fluid and blood plasma following controlled hydrocodone administration in 20 subjects., Methods: The global proteomic profile was determined for samples taken at four time points per subject: pre-exposure and 4, 6, or 168 hours post-exposure. The oral fluid samples analyzed herein provided greater differentiation between baseline and response time points than was observed with blood plasma, at least partially due to significant person-to-person relative variability in the plasma proteome., Results: A total of 399 proteins were identified from oral fluid samples, and the abundance of 118 of those proteins was determined to be significantly different upon metabolism of hydrocodone (4 and 6 hour time points) as compared to baseline levels in the oral fluid (pre-dose and 168 hours)., Conclusions: We present an assessment of the oral fluid and plasma proteome following hydrocodone administration, which demonstrates the potential of oral fluid as a noninvasive sample that may reveal features of hydrocodone in opioid use, and with additional study, may be useful for other opioids and in settings of misuse.

Background: Hydrocodone and oxycodone are the Schedule II opioids most often prescribed in primary care. Notwithstanding the dangers of prescription opioid use, the likelihood of long-term use with either drug is presently unknown., Methods: Using a retrospective cohort design and data from a commerical healthcare claims repository, we compared the likelihood of long-term use of hydrocodone and oxycodone in primary care patients presenting with acute back pain. Treatment was categorized as long-term if the prescription dates spanned ≥90 days from initial prescription to the run-out date of the last prescription, and included ≥120 days' supply or ≥10 fills. Instrumental variable methods and probit regression were used to model the effect of drug choice on long-term use, estimate the average treatment effect, and correct for confounding by indication., Results: A total of 3,983 patients who were prescribed only hydrocodone or only oxycodone were followed for 270 days in 2016. Long-term opioid use was observed in 320 patients (8%). Controlling for potential confounders including morphine milligram equivalents and dosage, an estimated 12% (95 CI, 10%-14%) treated with hydrocodone transitioned to long-term use vs. 2% (95 CI, 1%-3%) on oxycodone. Among patients who received more than one prescription (n = 1,866), an estimated 23% (95 CI, 19%-26%) treated with hydrocodone transitioned to long-term use vs. 5% (95 CI, 3%-7%) on oxycodone. The difference between drugs was supported in sensitivity and subgroup analyses. Sample selection bias was not detected., Conclusions: Long-term use was substantially greater for patients treated with hydrocodone than oxycodone, despite equianalgesia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.

Introduction: A common belief is that some narcotic medications have a higher association with prolonged use. We assessed whether the initial opiate type prescribed to postoperative, opiate-naive orthopaedic trauma patients was associated with prolonged opioid use., Methods: We studied 17,961 adult, opiate-naive patients treated for a surgical musculoskeletal injury. Discharge prescription in morphine milligram equivalents (MMEs, a standardized dosing unit that allows for comparison across opioid types) was calculated. Opioid prescribing beyond 90 days after injury was defined as prolonged use., Results: Initial analysis demonstrated a higher likelihood of prolonged use for patients discharged on hydromorphone or morphine versus hydrocodone. However, when we adjusted for discharge MME, only opioid quantity was predictive of prolonged use (P < 0.001). In addition, discharge MME was associated with opioid type (P < 0.01)., Discussion: Persistent opiate use was associated with discharge opioid quantity, not the opioid type. These results highlight the importance of calculating equivalence doses when selecting opioid types and considering amount of narcotics prescribed., Level of Evidence: Level III.

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.

Due to rising misuse, the Drug Enforcement Administration (DEA) moved hydrocodone combination products (HCPs) from DEA Schedule III to DEA Schedule II in October 2014. Aside from increasing regulatory scrutiny, rescheduling may have increased the administrative burden surrounding HCP prescribing. This study explored how HCP rescheduling and associated administrative barriers may have affected physician treatment of acute (aNCP) and chronic (cNCP) noncancer pain. To this end, physician members of the Texas Medical Association completed a self-administered online questionnaire. Pharmacotherapy treatment plan was measured with two questions asking physicians whether they were more likely to recommend HCPs, acetaminophen/codeine (APAP/codeine), nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol, or other agents for the treatment of aNCP and cNCP. Two Likert-scaled items were used to assess administrative burden. In total, 1365 physicians responded (response rate = 15.39%). Physicians more frequently selected APAP/codeine (37%) for aNCP and tramadol (44%) for cNCP. A majority (78.8%) of physicians agreed that rescheduling led to modified prescribing, and those in agreement were significantly less likely than those who disagreed to prescribe HCPs for aNCP (24.2% vs. 56.4%; χ 2 = 68.6, P  < .001) and cNCP (16.9% vs. 37%; χ 2 = 36.1, P  < .001). Rescheduling and associated administrative burden are both associated with modified physician HCP prescribing in both aNCP and cNCP.

Introduction: Opioids are widely used after orthopaedic procedures. Nonmedical opioid use is a growing public health issue., Methods: An anonymous online survey was distributed by e-mail to the orthopaedic societies of all 50 states and several large private practices to assess practicing orthopaedic surgeons' opioid prescribing practices., Results: A total of 555 orthopaedic surgeons practicing in 37 states responded. The most commonly prescribed opioid for both teenagers and adults was hydrocodone/acetaminophen. Of note, 42.3% reported that a patient they have prescribed opioids for developed an opioid dependency, whereas 35.3% do not believe that opioid use is a problem in their practice. Of note, 30.3% reported prescribing refills, and factors significantly associated with increased prescribing of refills included a greater number of years in practice (P < 0.001) and practicing in a suburban rather than an urban or rural environment (P = 0.03)., Conclusion: Orthopaedic surgeons rarely prescribe any refills, tend to prescribe less opioids to teenagers than adults, and prescribe fairly uniformly for patients who are treated nonsurgically or undergo minor or arthroscopic surgery. They exhibit considerable variation in prescribing for fractures and major procedures.

Widely-prescribed prodrug opioids (e.g., hydrocodone) require conversion by liver enzyme CYP-2D6 to exert their analgesic effects. The most commonly prescribed antidepressant, selective serotonin reuptake inhibitors (SSRIs), inhibits CYP-2D6 activity and therefore may reduce the effectiveness of prodrug opioids. We used a machine learning approach to identify patients prescribed a combination of SSRIs and prodrug opioids postoperatively and to examine the effect of this combination on postoperative pain control. Using EHR data from an academic medical center, we identified patients receiving surgery over a 9-year period. We developed and validated natural language processing (NLP) algorithms to extract depression-related information (diagnosis, SSRI use, symptoms) from structured and unstructured data elements. The primary outcome was the difference between preoperative pain score and postoperative pain at discharge, 3-week and 8-week time points. We developed computational models to predict the increase or decrease in the postoperative pain across the 3 time points by using the patient's EHR data (e.g. medications, vitals, demographics) captured before surgery. We evaluate the generalizability of the model using 10-fold cross-validation method where the holdout test method is repeated 10 times and mean area-under-the-curve (AUC) is considered as evaluation metrics for the prediction performance. We identified 4,306 surgical patients with symptoms of depression. A total of 14.1% were prescribed both an SSRI and a prodrug opioid, 29.4% were prescribed an SSRI and a non-prodrug opioid, 18.6% were prescribed a prodrug opioid but were not on SSRIs, and 37.5% were prescribed a non-prodrug opioid but were not on SSRIs. Our NLP algorithm identified depression with a F1 score of 0.95 against manual annotation of 300 randomly sampled clinical notes. On average, patients receiving prodrug opioids had lower average pain scores (p<0.05), with the exception of the SSRI+ group at 3-weeks postoperative follow-up. However, SSRI+/Prodrug+ had significantly worse pain control at discharge, 3 and 8-week follow-up (p < .01) compared to SSRI+/Prodrug- patients, whereas there was no difference in pain control among the SSRI- patients by prodrug opioid (p>0.05). The machine learning algorithm accurately predicted the increase or decrease of the discharge, 3-week and 8-week follow-up pain scores when compared to the pre-operative pain score using 10-fold cross validation (mean area under the receiver operating characteristic curve 0.87, 0.81, and 0.69, respectively). Preoperative pain, surgery type, and opioid tolerance were the strongest predictors of postoperative pain control. We provide the first direct clinical evidence that the known ability of SSRIs to inhibit prodrug opioid effectiveness is associated with worse pain control among depressed patients. Current prescribing patterns indicate that prescribers may not account for this interaction when choosing an opioid. The study results imply that prescribers might instead choose direct acting opioids (e.g. oxycodone or morphine) in depressed patients on SSRIs., Competing Interests: The authors have declared that no competing interests exist.

Background: Managing postoperative pain is important for patients and surgeons. However, there is concern over opioid dependency. Cubital tunnel decompression is among the most common upper extremity surgeries. Our study aimed to analyze opioid use after cubital tunnel decompression to guide postoperative opioid prescribing., Methods: We prospectively collected opioid consumption for 16 consecutive months (February 2016 to June 2017) for cubital tunnel decompression patients. Data on demographics, insurance type, surgery performed, functional questionnaires (Quick Disabilities of the Arm, Shoulder and Hand [QuickDASH]), and electrodiagnostics (electromyography) were collected. Opioid consumption was reported at first postoperative visits., Results: One hundred patients consumed a mean of 50 morphine equivalent units (MEUs) (range, 0-300), or 7 oxycodone 5-mg pills, postoperatively. Cubital tunnel release (CuTR) patients consumed fewer than ulnar nerve transposition (UNT) patients (40.4 vs 62.5 MEUs or 5.4 vs 8.3 pills, P = .08). Patients undergoing submuscular UNT consumed more than CuTR (115.0 vs 40.4 MEUs or 15.3 vs 5.4 pills, p = 0.003) and more than subcutaneous UNT patients (37.8 MEU or 5.0 pills, p = 0.03). Medicare patients consumed less than privately insured (42.7 vs 54.1 MEUs, 5.7 vs 7.2 pills, P = .02) and less than workers' compensation patients (76.8 MEU or 10.2 pills, P = .04). Older patients consumed fewer than younger patients ( P = .03). Postoperative QuickDASH score was positively related to opioid intake ( P = .009)., Conclusions: Patients consumed 7 oxycodone 5-mg pills after cubital tunnel decompression. Younger, privately insured, and workers' compensation patients, and those with worse functional scores and those undergoing UNT (specifically the submuscular technique) consumed more opioids.

Background: In 2014, hydrocodone was moved from Schedule III to II, thus it could no longer be "called in" to a pharmacy. We analyzed current postoperative opioid prescribing patterns and the impact of the schedule change on the type and amount prescribed., Methods: Opioid prescriptions for common surgeries at 1 medical center from 2013 to 2016 were analyzed retrospectively. Milligram morphine equivalents prescribed before and after the schedule change were compared by t tests, and interrupted time series models and drug frequencies were compared by χ 2 and Fisher exact tests., Results: Data from 7,046 patients (7,361 prescriptions) after 29 different operations were analyzed. Milligram morphine equivalents prescribed for minor open procedures ranged from 211 to 342 milligram morphine equivalents, from 323 to 1297 for major open procedures, from 238 to 359 for basic laparoscopic procedures, and from 221 to 868 for complex laparoscopic procedures. Mean milligram morphine equivalents prescribed were not affected for most procedures, but over the entire population, milligram morphine equivalents prescribed began decreasing after the rule change. The percentage of hydrocodone prescriptions decreased after the rule change (from 33.8% down to 27.0%) and oxycodone and tramadol prescriptions increased., Conclusion: Before versus after the rule change, hydrocodone prescriptions decreased and oxycodone and tramadol prescriptions increased. Milligram morphine equivalents prescribed varied considerably across and within classes of procedures, but the schedule change did not affect mean milligram morphine equivalents prescribed for most procedures., (Published by Elsevier Inc.)

Background: Multimodal analgesic protocols are increasingly favored over traditional opioid regimens due to decreased adverse side effects and reduced opioid consumption. Concomitant use of selective cyclooxygenase (COX)-2 inhibitor celecoxib and anticonvulsant gabapentin have been proposed to adequately control acute postoperative pain., Objectives: To determine efficacy of postoperative pain control using nonopioid pain regimen vs traditional opioids for all aesthetic plastic surgery procedures., Methods: A retrospective chart review was performed on 462 consecutive outpatient plastic surgery procedures by a single surgeon between November 2015 and July 2017. Procedures in the historical control group (n = 275) received traditional postoperative narcotic, hydrocodone-acetaminophen. Patients in the more recent nonopioid study group (n = 187) received a pre-, peri-, and postoperative regimen of celecoxib and gabapentin., Results: Similar demographic characteristics between the control and study groups were observed: mean age, 39.7 vs 39.5 years; BMI, 24.6 vs 24.4 kg/m2; and ratio of female patients 92.7% vs 92.4%. A significant reduction in rescue analgesia (meperidine 44.6% vs 14.9%, P < 0.001) and antiemetic use (ondansetron 24.2% vs 16.3%, P < 0.05; promethazine 17.0% vs 4.7%, P < 0.001) in postanesthesia recovery unit (PACU) was noted in the nonopioid group compared to the control. The average stay in PACU also decreased in the study group (82 ± 39 min vs 70 ± 22 min, P < 0.001). Both groups reported low numbers of adverse events and need for additional pain prescriptions. These findings were reproducible in the breast subgroup., Conclusions: This nonopioid regimen is as effective as traditional opioid use for acute postoperative pain control and decreased recovery time for outpatient aesthetic plastic breast surgeries.

Objective In this study, we examined the relationship between alcohol mixed with energy drink use (AmED) and nonmedical prescription opioid use among 12th graders, using data from the 2015 Monitoring the Future Study. Methods Wilcoxon-Mann-Whitney and logistic regression analyses were used to determine differences in nonmedical prescription opioid use by students who used alcohol-only (AO) versus AmED and to identify covariates of nonmedical prescription opioid use. Results Greater frequency of AmED use was associated with greater frequency of nonmedical Oxycontin (r = 0.391, p < .001) and Vicodin (r = 0.379, p < .001) use with moderate effect sizes. Results revealed statistically significant differences in frequency of nonmedical Oxycontin (p < .001, Cohen's d = 0.29) and Vicodin (p < .001, Cohen's d = 0.30) use between AO and AmED use. Likelihood of nonmedical prescription opioid use increased by a factor of 2 for each time AmED was consumed in the past 12 months. Conclusion Our results highlight the need to improve understanding of the relationship between nonmedical prescription opioid, energy drink and AmED use. AmED use appears to be associated with increased nonmedical prescription opioid use.

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.

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

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

Background: The purpose of this study was to evaluate current surgical practice patterns, the factors that influence these patterns, and overall trends in the treatment of thumb carpometacarpal osteoarthritis., Methods: An online survey containing 14 questions was sent to all active members of the American Society for Surgery of the Hand. Information on demographics and treatments was collected. Results were anonymously uploaded to an online spreadsheet., Results: A total of 823 responses were recorded. Trapeziectomy with ligament reconstruction and tendon interposition (LRTI) using whole flexor carpi radialis was the most popular technique at 37.44%. In all, 26.38% of surgeons with fewer than 5 years of experience utilize trapeziectomy with suture suspension (bone anchor based or tendon based); 55.76% choose a particular procedure because of "Personal Clinical Experience" over "Current Evidence" and "Training." In addition, 24.17% of surgeons who have been practicing for longer than 5 years have changed procedures in the last 5 years. In the United States, 97.2% of hand surgeons prescribe either oxycodone or hydrocodone postoperatively compared with just 23.75% of international hand surgeons., Conclusions: The results show that trapeziectomy with LRTI remains the most popular treatment of choice. The use of trapeziectomy with suture suspension is on the rise, particularly in younger surgeons. International hand surgeons rely more on current evidence, utilize less postoperative therapy and opioid medications, and change procedures more often than US hand surgeons.

Objective: To determine the efficacy of oral extended-release hydrocodone compared with oral firocoxib for analgesia following tibial plateau leveling osteotomy surgery in dogs in a hospital setting., Study Design: Prospective, randomized, blinded, clinical trial., Animals: Thirty-six client-owned dogs weighing 25-43 kg with unilateral hindlimb lameness and cranial cruciate ligament rupture., Methods: Dogs were assigned to 1 of 2 groups (n = 18/group). Group 1 received hydrocodone 3 mg/kg orally every 24 hours, and group 2 received firocoxib 5 mg/kg orally every 24 hours. Both hydrocodone and firocoxib (according to group assignment) were provided as preemptive analgesia 10 hours before induction to anesthesia and then every 24 hours for the remainder of the study period The level of analgesia was compared between treatments on the basis of a modified Glasgow Composite Pain Score (mGCPS) in each dog, the number of dogs requiring rescue analgesia (hydromorphone 0.05 mg/kg subcutaneously), pressure platform stance data, and number of adverse events., Results: Nine of 18 dogs that received hydrocodone and 2/18 dogs that received firocoxib had an mGCPS ≥6 (P = .02). Two dogs had an mGCPS ≥6 three times, and 1 had an mGCPS ≥6 two times; all 3 of these dogs were in the hydrocodone group. Average postoperative peak pressure placed on the affected limb was lower in dogs that received hydrocodone (P = .01). Regurgitation and decreased appetite were more common in the dogs that received hydrocodone., Conclusion: Dogs that were treated with hydrocodone exhibited higher pain scores and lower limb function than dogs treated with firocoxib under the conditions of our study., Clinical Significance: Our results do not provide evidence to justify the administration of extended-release hydrocodone at 3 mg/kg orally every 24 hours rather than firocoxib at 5 mg/kg orally every 24 hours in dogs undergoing tibial plateau leveling osteotomy., (© 2018 The American College of Veterinary Surgeons.)

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.)

Objectives: Benzhydrocodone is a hydrocodone prodrug that has been combined with acetaminophen (APAP) in a novel immediate-release analgesic. This study evaluated the relative bioavailability, intranasal abuse potential, and safety of benzhydrocodone/APAP compared with commercially available hydrocodone bitartrate (HB)/APAP., Design: Single-center, randomized, double-blind, double-dummy, two-part study comprising a Dose Selection (Part A) phase and a Main Study (Part B) phase., Setting: Clinical research site., Subjects: Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse., Methods: Subjects (N = 42) in Part B received five in-clinic treatments consisting of intranasal and oral benzhydrocodone/APAP (13.34/650 mg), intranasal and oral hydrocodone/APAP (15/650 mg), and placebo, with four or more days of washout between treatments. Pharmacodynamic assessments included subjective effects of Drug Liking, Overall Drug Liking, and Take Drug Again (assessed on visual analog scale [VAS]), as well as nasal irritation. Pharmacokinetics and safety were also assessed., Results: Hydrocodone Cmax was 11% lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P = 0.0027). Early cumulative hydrocodone exposures for intranasal benzhydrocodone/APAP through 0.5, 1, and 2 hours were reduced by approximately 50%, 29%, and 15%, respectively (P ≤ 0.0024). Correspondingly, Drug Liking VAS values up to two hours postdose were significantly lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P ≤ 0.0079), although peak Drug Liking VAS (Emax) scores were not different (P = 0.2814). Adverse nasal effects were more frequent for intranasal benzhydrocodone/APAP vs intranasal HB/APAP., Conclusions: Reduced hydrocodone exposure and drug liking at early time intervals, coupled with adverse nasal effects, can be expected to provide a level of deterrence to the intranasal route of abuse for benzhydrocodone/APAP.

Purpose: Institutional prescribing trends of hydrocodone-containing products (HCPs) before and after the Drug Enforcement Administration's rescheduling of HCPs were evaluated., Methods: A retrospective evaluation was performed on 6 oral opioid analgesics on the hospital formulary that were prescribed to patients treated at Texas Children's Hospital and Pavilion for Women for the 6 months before and after the rescheduling of HCPs on October 6, 2014. Patients were eligible for inclusion if they were prescribed any of the following oral agents: HCPs (e.g., hydrocodone with acetaminophen), codeine-containing products (e.g., codeine, codeine with acetaminophen), morphine, hydromorphone, oxycodone-containing products (e.g., oxycodone, oxycodone with acetaminophen), and tramadol., Results: During the 12-month study period, a total of 38,928 inpatient orders and outpatient prescriptions were processed for the studied agents in both locations; the majority were orders for inpatients. An overall reduction in the total number of opioid prescriptions was observed after the rescheduling of HCPs. Substantial increases in the proportional use of codeine were observed in all 4 settings after HCP rescheduling. Data for each of the agents revealed a shift in prescribing patterns centered along the HCP rescheduling date of October 6, 2014, and revealed a decrease in HCP use across all areas with an accompanying increase in codeine-containing products, oxycodone-containing products, and tramadol., Conclusion: The rescheduling of HCPs resulted in a reduction in HCP prescriptions but was accompanied by increases in the use of codeine-containing products and tramadol in all settings., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

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

Importance: The choice of analgesic to treat acute pain in the emergency department (ED) lacks a clear evidence base. The combination of ibuprofen and acetaminophen (paracetamol) may represent a viable nonopioid alternative., Objectives: To compare the efficacy of 4 oral analgesics., Design, Settings, and Participants: Randomized clinical trial conducted at 2 urban EDs in the Bronx, New York, that included 416 patients aged 21 to 64 years with moderate to severe acute extremity pain enrolled from July 2015 to August 2016., Interventions: Participants (104 per each combination analgesic group) received 400 mg of ibuprofen and 1000 mg of acetaminophen; 5 mg of oxycodone and 325 mg of acetaminophen; 5 mg of hydrocodone and 300 mg of acetaminophen; or 30 mg of codeine and 300 mg of acetaminophen., Main Outcomes and Measures: The primary outcome was the between-group difference in decline in pain 2 hours after ingestion. Pain intensity was assessed using an 11-point numerical rating scale (NRS), in which 0 indicates no pain and 10 indicates the worst possible pain. The predefined minimum clinically important difference was 1.3 on the NRS. Analysis of variance was used to test the overall between-group difference at P = .05 and 99.2% CIs adjusted for multiple pairwise comparisons., Results: Of 416 patients randomized, 411 were analyzed (mean [SD] age, 37 [12] years; 199 [48%] women; 247 [60%] Latino). The baseline mean NRS pain score was 8.7 (SD, 1.3). At 2 hours, the mean NRS pain score decreased by 4.3 (95% CI, 3.6 to 4.9) in the ibuprofen and acetaminophen group; by 4.4 (95% CI, 3.7 to 5.0) in the oxycodone and acetaminophen group; by 3.5 (95% CI, 2.9 to 4.2) in the hydrocodone and acetaminophen group; and by 3.9 (95% CI, 3.2 to 4.5) in the codeine and acetaminophen group (P = .053). The largest difference in decline in the NRS pain score from baseline to 2 hours was between the oxycodone and acetaminophen group and the hydrocodone and acetaminophen group (0.9; 99.2% CI, -0.1 to 1.8), which was less than the minimum clinically important difference in NRS pain score of 1.3. Adverse events were not assessed., Conclusions and Relevance: For patients presenting to the ED with acute extremity pain, there were no statistically significant or clinically important differences in pain reduction at 2 hours among single-dose treatment with ibuprofen and acetaminophen or with 3 different opioid and acetaminophen combination analgesics. Further research to assess adverse events and other dosing may be warranted., Trial Registration: clinicaltrials.gov Identifier: NCT02455518.

Background: Pain is the most frequent complaint of burn-injured patients. Opioids are commonly used in the course of treatment. However, there is a lack of rodent studies that examine the differential effects of various opioids on burn pain., Objective: This study compared the ability of morphine, oxycodone, and hydrocodone to suppress the development of burn-induced mechanical allodynia and reduce pain sensitivity., Methods: Mice were examined for their baseline pain sensitivity thresholds using the von Frey Filaments test. Then, they were subjected to burn or sham injury and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 postburn., Results: In the sham animals, morphine produced significant opioid-induced hyperalgesia (OIH). Development of OIH was minimal for hydrocodone and was not observed for oxycodone. Secondary mechanical allodynia was observed beginning four days after the burn injury and intensified with time. All opioids produced comparable antinociceptive effects. Hydrocodone was effective in suppressing the development of burn-induced mechanical allodynia and fully treated the burn-induced increase in pain sensitivity. In contrast, morphine and oxycodone had only minimal effects on the development of burn-induced mechanical allodynia and only partially treated the burn-induced increase in pain sensitivity., Conclusions: This study demonstrated that hydrocodone is effective in suppressing the development of burn-induced mechanical allodynia, while both morphine and oxycodone had minimal effects. These findings underscore the need for additional studies on the differences among various opioids using clinically relevant pain models., (© 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

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.

The zebrafish (Danio rerio) has become an excellent tool to study mental health disorders, due to its physiological and genetic similarity to humans, ease of genetic manipulation, and feasibility of small molecule screening. Zebrafish have been shown to exhibit characteristics of addiction to drugs of abuse in non-contingent assays, including conditioned place preference, but contingent assays have been limited to a single assay for alcohol consumption. Using inexpensive electronic, mechanical, and optical components, we developed an automated opioid self-administration assay for zebrafish, enabling us to measure drug seeking and gain insight into the underlying biological pathways. Zebrafish trained in the assay for five days exhibited robust self-administration, which was dependent on the function of the μ-opioid receptor. In addition, a progressive ratio protocol was used to test conditioned animals for motivation. Furthermore, conditioned fish continued to seek the drug despite an adverse consequence and showed signs of stress and anxiety upon withdrawal of the drug. Finally, we validated our assay by confirming that self-administration in zebrafish is dependent on several of the same molecular pathways as in other animal models. Given the ease and throughput of this assay, it will enable identification of important biological pathways regulating drug seeking and could lead to the development of new therapeutic molecules to treat addiction., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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.)

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., (© 2016 American Academy of Pain Medicine.)

Burn victim patients are frequently prescribed opioids at doses that are significantly higher than standard analgesic dosing guidelines, and, even despite an escalation in opioid dosing, many continue to experience pain. Thus, the aim of this study was to determine the effect of burn injury on opioid antinociception. Mice were examined for their baseline pain sensitivity thresholds using the von Frey filaments test. Then, they were subjected to burn or sham injury to the dorsal surface of the hindpaw and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 following the burn injury. The antinociceptive effects of the various drugs were analyzed by computing the daily difference between pain sensitivity threshold scores (in g) before and after treatment. This study showed that burn injury decreases opioid antinociception potency. A marked reduction was observed in the antinociceptive effectiveness of all opioids, and for both doses, in the burn-injured versus the sham animals. These results suggest that burn trauma limits the ability of opioids to be effective in reducing pain.

Background: The U.S. Drug Enforcement Administration (DEA) rescheduled hydrocodone combination products (HCPs) in an attempt to mitigate the prescription opioid epidemic. Many in the medical and pharmacy community expressed concerns of unintended consequences as a result of rescheduling., Objectives: This study examined physicians' intentions to prescribe HCPs after rescheduling using the framework of the theory of reasoned action (TRA)., Methods: A cover letter containing a link to the online questionnaire was sent to physicians of the Texas Medical Association who were likely to prescribe opioids. The questionnaire assessed physicians' intentions to prescribe HCPs after rescheduling. Predictor variables included attitude toward rescheduling, subjective norm toward HCP prescribing, and past prescribing behavior of schedule II prescriptions. All variables were measured on a 7-point, Likert-type scale. Intention to prescribe as a dependent variable was regressed over TRA variables and respondent characteristics., Results: A total of 1176 usable responses were obtained, yielding a response rate of 13.3%. Mean (M) age was 53.07 ± 11 and most respondents were male (70%) and Caucasian (75%). Physicians held a moderately positive intention to prescribe HCPs (M = 4.36 ± 2.08), held a moderately negative attitude towards rescheduling, M = 4.68 ± 1.51 (reverse coded). Subjective norm was moderately low, M = 3.06 ± 1.78, and past prescribing behavior M = 2.43 ± 1.21. The linear regression analysis indicated that attitude (β = 0.10; P = 0.006), subjective norm (β = 0.35; P < 0.0001) and past prescribing behavior (β = 0.59; P < 0.0001) were significant predictors of intention to prescribe HCPs after rescheduling., Conclusions: TRA was shown to be a predictive model of physicians' intentions to prescribe HCPs after rescheduling. Overall, physicians held a moderately positive intention to prescribe HCPs. Past behavior concerning schedule II prescribing was found to be the most significant predictor of intention. Understanding the impact of federal rule changes on pain management care and patient satisfaction is necessary to determine whether this change has produced the intended consequences without harming patients in need of HCPs., (Published by Elsevier Inc.)

Background: In 2012, hydrocodone combination products (HCPs) were the most prescribed medications in the United States. Under the Controlled Substance Act of 1970, hydrocodone alone was classified as a Schedule II drug, while HCPs were classified as Schedule III, indicating a lower risk for abuse and misuse. However, according to a Drug Enforcement Agency analysis, the addition of nonopioids has not been shown to diminish abuse potential of hydrocodone. In response to concerns for drug abuse and overdose, the Drug Enforcement Agency rescheduled HCPs to Schedule II in October 2014, with the intent of limiting overprescribing and increasing awareness of their abuse potential. However, it is unknown whether this has affected the overall claims for HCPs in a Medicaid population., Objectives: To (a) compare the trend in HCP prescription claims with select non-HCP (opioid and nonopioid) analgesic claims before and after the HCP schedule change in the Massachusetts Medicaid fee-for-service/Primary Care Clinician plan population and (b) identify if there was a change in HCP new start member and claim characteristics before and after the HCP schedule change., Methods: This quasi-experimental, retrospective study used enrollment and pharmacy claims data to evaluate all members in the study population 1 year before and after the HCP schedule change. The number of claims for HCPs and select non-HCP analgesics was reported as the monthly rate per total population, and an interrupted time series analysis compared the change in the monthly rate of claims across groups. Members with 1 or more pharmacy claims for a new HCP prescription during a 5-month period before or after the HCP schedule change were analyzed to determine member demographics (age, gender, and number of claims) and claim characteristics (average daily dose, average quantity per claim, and days supply)., Results: The rate of HCP claims increased before and decreased after the HCP schedule change. Controlling for the trend during the period before the HCP schedule change, the rate of HCP claims per 1,000 members per month decreased at a greater rate than non-HCP analgesics in the period after the HCP schedule change (P < 0.001). The percentage of HCP claims for new start members decreased after the HCP schedule change (44.9% vs. 34.1% of all HCP claims pre- to post-schedule change; P < 0.001). In the group of new starts, there was not a significant difference in the average daily dose (26.3 mg vs. 26.4 mg; P = 0.69), while there was a decrease in average number of tablets dispensed per claim (from 37.1 to 20.3 tablets; P < 0.001) and an increase in the percentage of claims for a shorter days supply (from 57.7% to 81.6%; P < 0.001)., Conclusions: The findings of this study suggest that the HCP schedule change may have contributed to the decrease in claims for HCPs in a Medicaid population. After the HCP schedule change, there was a trend towards decreased HCP use among new starts., Disclosures: No outside funding supported this study. The authors have nothing to disclose. Study concept and design were contributed by all authors except for Arnold and Clements. Tran, Arnold, and Clements took the lead in data collection, along with Peristere, and data interpretation was performed by all the authors, except Arnold. The manuscript was written primarily by Tran, along with Lavitas, Stevens, and Greenwood, and revised by all the authors except Arnold and Peristere. A poster of this research project was presented at the Academy of Managed Care Pharmacy's 2016 Annual Meeting in San Francisco, California, April 2016.

Objectives: To compare rates of dental opioid prescribing between periods of full and partial integration of pharmacy services and periods of no integration., Methods: This observational study used a retrospective chart review of opioid prescriptions written by dental providers practicing in a free dental clinic for the medically underserved over a period of 74 months. Pharmacy services were fully integrated into the practice model for 48 of the 74 months under study. During this time frame, all dental opioid orders required review by the pharmacy department before prescribing. Outcomes related to prescribing rates and errors were compared between groups, which were defined by the level of integrated pharmacy services. Demographic and prescription-specific data (drug name, dose, quantity, directions, professional designation of individual entering order) and clinic appointment data were collected and analyzed with the use of descriptive and inferential statistics., Results: A total of 102 opioids were prescribed to 89 patients; hydrocodone-acetaminophen combination products were the most frequently used. Opioid prescribing rates were 5 times greater when pharmacy services were not integrated (P <0.001); and dentists were 81% less likely to prescribe opioids when pharmacy was fully integrated (odds ratio 0.19, 95% confidence interval 0.124-0.293; P <0.001). Frequency of hydrocodone use compared with other opioids did not decrease after the rescheduling of hydrocodone to a Schedule II controlled substance. The frequency of prescribing errors was not statistically different between groups, although there were numerically fewer errors with integrated pharmacy services., Conclusion: The literature reports that dentists are the third most frequent prescribers of opioids. The findings from this study suggest that collaboration between pharmacists and dentists has the potential to decrease opioid utilization in primary dental practice., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine (1) pharmacists' perceptions of how rescheduling of hydrocodone combination products (HCPs) from Drug Enforcement Agency (DEA) Schedule III to DEA Schedule II has influenced prescription volume and revenue, pharmacy workflow management, and patient outcomes; and (2) whether perceptions differed between pharmacists who support versus those who oppose HCP rescheduling., Design: A cross-sectional mail survey., Setting: Texas community pharmacies from October to December 2015., Participants: One thousand randomly selected, registered Texas community pharmacists drawn from the Texas State Board of Pharmacy registry., Main Outcome Measures: Pharmacists' perceptions, measured on a 5-point Likert scale of HCP rescheduling and its impact on prescription volume and revenue, workflow management, and patient outcomes. Measures were developed specifically for this study., Results: The response rate was 17% (n = 164). The majority of pharmacists (70.4%) supported HCP rescheduling. More than 80% of respondents perceived that the volume of 2 alternative pain medications-tramadol (DEA Schedule IV) and acetaminophen with codeine (DEA Schedule III) prescriptions dispensed-either "increased" or "significantly increased" (82.0% and 85.8%, respectively) following rescheduling. Overall, pharmacists who opposed rescheduling were significantly more likely to report negative perceptions regarding revenue (P = 0.0142), inventory management (P = 0.0024), and drug shortages (P = 0.0005) than those who supported rescheduling. However, pharmacists who supported rescheduling had more positive perceptions about electronic prescribing (P <0.0115), patient safety (P <0.001), drug abuse (P <0.0001), and legitimate use (P <0.0001)., Conclusion: Results showed that legislative efforts, such as rescheduling HCPs, influenced pharmacists' perceptions of practice and patient outcomes. Currently, little is known regarding the impact of HCP rescheduling on pharmacy practice. As new laws are passed to address the opioid epidemic in America, more research will be needed to determine whether legislation is an effective means for managing appropriate access to HCPs and other narcotic analgesics., (Copyright © 2017 American Pharmacists Association®. Published by 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.)

Objective: This article evaluates postoperative analgesia in pediatric palatoplasty patients using nonopioid oral medications., Design: This study was a retrospective chart review., Setting: The setting for this study was a tertiary-care children's hospital., Participants: Study participants were pediatric patients who underwent palatoplasty procedures performed by a single surgeon., Interventions: Interventions included nonopioid and opioid oral medications for postoperative analgesia., Main Outcome Measures: The adequacy of nonopioid versus opioid oral analgesia was assessed by (1) time to discontinue IV fluid, (2) total IV morphine doses for breakthrough pain, (3) daily IV morphine doses for breakthrough pain, (4) time to discharge from the hospital, and (5) perioperative weight change. Group comparisons of outcome measures were performed using a two one-sided test., Results: A total of 61 patients were identified who received three standard pain regimens: acetaminophen + ibuprofen (12), hydrocodone/acetaminophen (23), and hydrocodone/acetaminophen + ibuprofen (26). There was sufficient evidence to suggest equivalence in outcome measures for acetaminophen + ibuprofen versus hydrocodone/acetaminophen and hydrocodone/acetaminophen + ibuprofen for the following: time to discontinue IV fluid (P = .02, 90% confidence interval [CI] = -0.42 to 0.17; P = .007, 90% CI = -0.28 to 0.34), daily IV morphine doses (P = .023, 90% CI = -0.83 to 0.65; P = .032, 90% CI = -0.92 to 0.28), time to discharge from the hospital (P = .017, 90% CI = -0.40 to 0.27; P = .015, 90% CI = -0.24 to 0.39), and perioperative weight change (P = .002; 90% CI = -0.25 to 0.46; P < .0001; 90% CI = -0.34 to 0.18). There was no sufficient evidence to suggest equivalence for total IV morphine doses (P = .189, 90% CI = -1.51 to 1.78; P = .169, 90% CI = -1.51 to 0.88)., Conclusions: Oral acetaminophen and ibuprofen alone may provide similar analgesia to traditional regimens with reduced risks following pediatric palatoplasty.

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: 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., (© 2016 American Academy of Pain Medicine.)

Background: Use/misuse of the opioid combination hydrocodone-acetaminophen has been associated with permanent hearing loss. Although reports have been rare, this potential effect can have significant detrimental effect on patients' overall quality of life. To date, the ototoxic effect of hydrocodone alone has not been systematically investigated., Objective: In this report, we aimed to evaluate the potential ototoxicity of a novel, single-entity, once-daily, extended-release hydrocodone tablet (Hysingla® ER; HYD)., Study Design: Clinical study., Setting: Audiology clinics in US., Methods: Results from 1207 patients in two phase 3 clinical studies were evaluated: A placebo-controlled study with an enriched enrollment, randomized withdrawal design in patients with chronic low back pain, and an open-label, long-term, safety study in patients with chronic nonmalignant and non-neuropathic pain. Comprehensive audiologic assessments (comprising pure-tone air-conduction audiometry in the conventional [0.25-8 kHz] and ultra-high [10-16 kHz] frequencies, pure-tone bone-conduction audiometry, tympanometry, speech reception thresholds, and word recognition) were conducted at baseline and end-of-studies; air-conduction audiometry was conducted periodically during the studies. All audiologic assessments were performed in audiology clinics in the United States by licensed audiologists. The primary endpoint was changes from baseline in pure-tone air-conduction thresholds in the conventional frequencies during the studies. These trials are registered with ClinicalTrials.gov, identifiers NCT01400139 and NCT01452529., Results: During the studies, mean changes from baseline in air-conduction thresholds were clinically unremarkable. Bidirectional variability across all test frequencies was observed; 82% of patients did not experience significant threshold changes during the studies, 7% had potential hearing decrement, and 10% experienced hearing sensitivity improvement. No notable differences were observed between patients receiving HYD and placebo or between different HYD doses., Conclusion: No ototoxic signal was observed for single-entity hydrocodone tablets at the dosages and treatment durations investigated. Key words: Audiologic monitoring, clinical trials, hydrocodone, opioids, ototoxicity monitoring, sensorineural hearing loss.