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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.

Context: Multiple morning testosterone levels are needed to establish the presence of male hypogonadism and to justify its replacement therapy. Any influence on these levels by short-term opioid ingestion has not, however, been reported., Case Description: Serial testosterone levels are reported at 2-hour intervals once weekly for 22 weeks in a man after his ingestion of 0, 5, or 10 mg of hydrocodone., Conclusions: Five milligrams of hydrocodone did not significantly alter postingestion testosterone levels, but 10 mg ingestion lowered them at 2, 4, and 6 hours postingestion.

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.

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.

Objective: Evaluate levels of pain relief achieved in patients with chronic pain treated with hydrocodone-extended release (HC-ER) up to 48 weeks and show that these levels were associated with secondary functional and global outcomes., Design: Post hoc analyses were based on a previously reported study that started with an open-label conversion/titration phase for ≤ 6 weeks followed by an openlabel 48-week treatment phase., Setting: Private practice and institutional pain centers., Participants: Three hundred ninety-one opioid-experienced subjects with moderate to severe pain for ≥ 3 months., Interventions: Individualized doses (20-300 mg) of extended-release hydrocodone every 12 hours., Main Outcome: Almost 60 percent (232/391) of subjects achieved moderate or substantial levels of pain relief (≥ 30 percent reduction in pain score) during the study., Results: Subjects who achieved moderate or substantial pain relief demonstrated significant (p <0.001) improvements in Oswestry Disability Inventory (ODI), all pain interference outcomes, and Subject Global Assessment of Medication. Subjects with substantial pain relief had decreases in ODI, Hospital Anxiety and Depression Scale (HADS) anxiety, and HADS depression scores of -13.4 ± 14.92, -1.9 ± 3.37, and -1.7 ± 3.26, respectively. The five most commonly reported treatment-emergent adverse events were constipation (12.5 percent), back pain (11.1 percent), nausea (9.9 percent), vomiting (9.7 percent), and arthralgia (7.8 percent) and are consistent with opioid therapy., Conclusions: Moderate or substantial levels of pain relief were associated with the greatest functional improvements in patients treated with HC-ER. These results may help define success of opioid therapy and determine if it should be continued or an alternative treatment should be tried.

Objectives: To assess the single-dose and steady-state pharmacokinetics of a single-entity hydrocodone extended-release (ER) formulation in patients enrolled in two separate phase 2 clinical studies., Setting: Both studies were multicenter clinical studies., Subjects and Interventions: In study 1, 115 subjects with postsurgical pain (bunionectomy) received single doses of 10, 20, 30, or 40 mg hydrocodone-ER, 10 mg hydrocodone/325 mg acetaminophen immediate-release (IR), or placebo. In study 2, 37 subjects with osteoarthritic pain received doses of 10, 20, 30, or 40 mg of hydrocodone- ER twice-daily for 7 days. Venous blood samples were taken periodically up to 24 hours postdosing after the single dose (study 1) or after 7 days of dosing (study 2) and were assayed for concentrations of hydrocodone and its major metabolites., Main Outcome Measures: Standard pharmacokinetic parameters were estimated by noncompartmental analysis methods., Results: Following a single dose of hydrocodone-ER, Tmax was prolonged to approximately 6 hours at all dose levels of hydrocodone-ER compared with 2.9 hours for the IR formulation. All doses of hydrocodone-ER formulations provided prolonged and sustained release of hydrocodone throughout the 12-hour dosing interval with reduced peak-to-trough fluctuation at steady state compared with hydrocodone/acetaminophen-IR comparator. Both single-dose and steadystate mean Cmax and AUClast values showed reasonable dose-proportionality. Norhydrocodone and hydromorphone plasma concentrations were 32-38 percent and <2.1 percent, respectively, of hydrocodone concentrations in both studies., Conclusions: The sustained plasma concentrations of hydrocodone support twice-daily dosing with a 12-hour dosing interval.

Objective: To evaluate long-term safety of hydrocodone extended-release (ER) formulated with CIMA(®) Abuse-Deterrence Technology platform., Design: Phase 3, open-label study., Setting: Sixty-one US study centers., Patients: Patients with chronic pain newly enrolled or rolled over from a 12-week, placebo-controlled hydrocodone ER study; 330 patients enrolled, 329 patients received study drug, and 189 completed the study., Intervention: After titrating to an analgesic dose (15-90 mg every 12 hours), patients received ≤ 52 weeks of open-label treatment., Safety: adverse events (AEs), vital signs, laboratory values, electrocardiograms, and audiometry. Abuse potential: drug loss and diversion, Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), Addiction Behaviors Checklist (ABC), Current Opioid Misuse Measure (COMM) questionnaires, and Patient Global Assessment (PGA) of pain control., Results: Of 329 patients who received ≥ 1 hydrocodone ER dose, 284 (86 percent) reported ≥ 1 AE and 27 (8 percent) experienced ≥ 1 serious AE. Sixty-two (19 percent) patients withdrew because of AEs, and two AEs leading to death were reported. No serious AEs or AEs leading to death were considered treatment related by the investigator. There were no clinically meaningful trends in other safety assessments. SOAPP-R, ABC, and COMM scores demonstrated low risk of aberrant drug-related behavior. Good/excellent PGA responses were reported by 20 percent of patients at baseline and 75 percent at endpoint. The incidence of drug loss (11 percent) and diversion (2 percent) was low., Conclusions: Hydrocodone ER demonstrated acceptable safety when administered for ≤ 12 months in patients with chronic pain. Low occurrence of aberrant drugrelated behavior may support the abuse-deterrence properties of hydrocodone ER.

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/acetaminophen is not only the most commonly prescribed opioid in the United States but also the most common prescription medication written in America. Although original and early trials confirmed its ability to manage acute pain from surgery and musculoskeletal injury, it is perhaps more widely used today in the management of chronic pain. However, the opioid product was introduced for the management of moderate to moderately severe pain. Because it has been greatly abused as a prescription opioid medication, physicians need to be aware of the current knowledge regarding this analgesic drug. This review summarizes the current knowledge of the pharmacokinetics, pharmacodynamics, and metabolism of hydrocodone. Recent information regarding the possibility of hydrocodone as a prodrug for hydromorphone is discussed. The available clinical trials for the use of hydrocodone in the management of acute, chronic, and cancer pain are presented.

Objective: Prescription opioid analgesics play an important role in the management of moderate to severe pain. An unintended consequence of prescribing opioid analgesics is the abuse and diversion of these medications. The authors estimated abuse and diversion rates for tapentadol immediate release (IR) compared with oxycodone, hydrocodone, and tramadol during the first 24 months of tapentadol IR availability., Methods: The Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System measures rates of prescription opioid abuse and diversion throughout the United States. Quarterly data from the Poison Center, Drug Diversion, Opioid Treatment, and Survey of Key Informants' Patients (SKIP) programs were plotted to visually compare the rates of tapentadol IR abuse and diversion with those of other opioid analgesics from July 2009 through June 2011 using both cases per 100,000 population and per 1,000 unique recipients of dispensed drug (URDD) as denominators. Trends in abuse and diversion rates over time were determined using a linear regression model of rate versus time., Results: During the 24 months following its introduction, tapentadol IR had very low population-based rates of abuse and diversion that were similar to rates for tramadol and lower than rates for oxycodone and hydrocodone. Rates of tapentadol IR abuse and diversion based on URDD were variable by program due to changes in market share and had not stabilized as of June 2011., Conclusions: Rates of tapentadol IR abuse and diversion have been low during the first 24 months after its launch. Continued monitoring of trends in these data is warranted.

Background: Physicians treating patients for chronic pain have limited means of determining whether a person is taking their medications as prescribed and are not taking extra medication. Complicating patient treatment regimens is the fact that pain physicians' prescribing practices may come under scrutiny by the Drug Enforcement Agency and other licensing agencies. If questioned, doctors can be hard-pressed to substantiate that their particular practices meet the established standard of care. It would be helpful to establish that their patients adhere to medications when compared with other practices. Previous studies show that urinary excretion data transformed by mathematical models can produce a reliable range of expected values for pain medications and may be useful to help resolve the aforementioned issues., Purpose of the Study: To provide comparative urinary excretion information data on three commonly prescribed opioid medications (morphine, hydrocodone, and oxycodone)., Methods: This retrospective study involved quantitative analysis of300, 000 urine specimens for three test drugs using previously described methods. The results were analyzed as percent frequency distributions and logarithmic functions., Results: The authors established a creatinine-normalized range of urinary concentration values for each drug. Results for two practices were compared with the meta-findings, providing quantitative evidence of overall standard of care prescription practice by that physician., Conclusions: Expected urinary drug excretion values for morphine, hydrocodone, and oxycodone can potentially benefit pain physicians by showing that they are within the expected standard of care, helping to establish patient compliance, and identifying patients whose metabolism of these drugs may put them at risk.

Opioids are becoming more common in the treatment of chronic nonmalignant pain. With increased availability of opioids for chronic pain we may expect an increased misuse of these as analgesics as well. The authors describe the case report of a young woman with chronic back pain and intranasal abuse of prescribed hydrocodone/acetaminophen who was diagnosed after presenting for hypernasal speech and foreign body in the nose. This case report highlights the need for vigilance on the part of the physician for any aberrant drug-related behaviors. Any unusual symptoms or signs such as hypernasal speech, chronic nasal infection, or unexplained foreign body sensation in the nose should be thoroughly investigated.