{'fraction_non_alphanumeric': 0.019010043041606885, 'fraction_numerical': 0.017176789414952973, 'mean_word_length': 5.399642948227493, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Patterns of abuse and routes of administration for immediate‐release hydrocodone combination products

Abstract 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.


| INTRODUCTION
Abuse of prescription opioid medications is a significant and pervasive public health problem in the United States affecting the adult and adolescent populations. Of the 21.5 million Americans 12 years or older with a substance use disorder in 2014, 1.9 million involved prescription pain relievers. 1 Further, in 2014, 467 000 adolescents were current nonmedical users of pain relievers, with 168 000 reporting a past year prescription pain reliever use disorder. 1 While the problem is multifaceted, one contributing aspect is overprescribing of these medications and the resulting availability for these products to be diverted for purposes of misuse and abuse. Over a 10-year period from 2000 to 2010, prescriptions of opioid analgesics increased by 104%, with prescribing rates among adolescents and young adults nearly doubling during this time. 2 While opioid prescribing stabilized from 2010 to 2012, 3 and more recently prescriptions for hydrocodone immediate-release (IR) combination products have decreased from approximately 125 to 90 million from 2011 through 2015, these products alone still represent the largest category of opioid prescriptions dispensed nationwide (approximately 37%). 4,5 Hydrocodone is also one of the more commonly abused opioid medications among adults. [6][7][8] Further, hydrocodone IR combination products have also been reported as one of the most common drugs involved in prescription overdose deaths. 9 Recently published data from US poison control centers indicate that for intentional exposures among adolescents specifically, hydrocodone is the most frequently reported misused or abused drug. 10 Several interventions and nationally based efforts have been implemented to lessen the burden of prescription opioid abuse. Strategies to address the prescription opioid abuse epidemic include controls and monitoring of appropriate prescribing practices through implementation of state-wide prescription monitoring programs 11,12 increased efforts to improve prescriber education related to safe opioid prescribing 13 and more recently, efforts to expand access to and funding for medication-assisted substance abuse treatment services. 14 The US Food and Drug Administration (FDA) has also taken specific steps to improve the safe use of prescription opioids by implementing a class-wide risk evaluation and mitigation strategy for extendedrelease (ER) and long-acting (LA) opioid products. In addition, black box safety warnings for both ER and IR pain medications were issued to highlight the risks of misuse, abuse, overdose, and death due to these products. 15 The FDA also encouraged pharmaceutical companies to develop new drug technologies and abuse-deterrent formulations (ADFs) that address opioid abuse.
In October 2014, the Drug Enforcement Administration (DEA) rescheduled hydrocodone IR combination products from a schedule 3 controlled substance to schedule 2 resulting in certain restrictions in prescribing and dispensing of these opioid medications. 16 While the rescheduling is expected to result in lower abuse and diversion of these products, it is important to understand and characterize their associated patterns of abuse to be able to examine the impact of this change and potential future changes in the opioid landscape. Moreover, hydrocodone IR combination products still remain the most widely prescribed and available opioid products. In addition, although lifetime abuse of IR opioids is at least as prevalent as abuse of ER opioids, nearly all currently marketed opioids with FDA-approved abuse-deterrent product labels are ER products. To further understand abuse of hydrocodone IR combination products, we examined their pattern of abuse among 2 high-risk populations of adults and adolescents assessed for substance abuse treatment problems relative to other opioid compounds including IR and ER products as well as ADF and non-ADF opioid formulations currently on the market.

| Sample description
This study was a cross-sectional design that examined data from adults (ages 18 and older) and adolescents (primarily ages 13 to 18) assessed for substance-abuse problems using 2 data sources from NAVIPPRO®, a public health surveillance system for monitoring patterns and trends in substance abuse including prescription medication use and abuse. 17 We examined prevalence of past 30-day abuse of hydrocodone IR combination products in comparison to other prescription opioids among separate samples of adults who completed an ASI-MV® (Addiction Severity Index -Multimedia Version) assessment and adolescents who completed a CHAT® (Comprehensive Health Assessment for Teens) assessment. Data were examined across a 3.5-year period from January 1, 2012, through June 30, 2015, with a specific focus on the 18-month period before and after the change in scheduling of hydrocodone IR combination products from schedules 3 to 2 (ie, January 2014 through June 2015).
Both the ASI-MV and CHAT assessments are structured, self-administered, computerized interviews that measure the severity of a range of problem areas associated with drug and alcohol abuse and are used for clinical assessment and treatment planning on admission to drug and

KEY POINTS
• While the number of prescriptions for hydrocodone IR combination products has recently decreased, these products still represent the majority of opioid prescriptions dispensed in the United States and are commonly abused by both adults and adolescents.
Lifetime abuse of immediate-release opioids is at least as prevalent as abuse of extended-release opioid products, but little data exist to understand their contribution to the problem.
• Postmarket surveillance data were used to examine patterns in abuse prevalence and ROA for hydrocodone IR combination products among 2 highrisk populations of adults and adolescents assessed for substance abuse treatment.
• Abuse prevalence was higher for hydrocodone IR combination products than other opioid categories but was lower than other opioid categories per prescriptions dispensed. Hydrocodone IR combination products had similar abuse prevalence to all ER/LA opioids when considering abuse measured per MME dispensed. alcohol treatment. [18][19][20] Data were drawn from 831 facilities located within the United States that participate by contributing data to the ASI-MV network and 180 facilities that contribute data on adolescents.

| Measures/data analysis
Abuse and specific route of administration (ROA) for hydrocodone IR combination products and 6 other prescription opioid categories including oxycodone IR combination products, oxycodone IR singleentity products, all other IR opioid products, all ER/LA opioids, all ADF ER/LA opioids (product with approved ADF label or formulated to deter abuse without ADF label), and all non-ADF ER/LA opioids were captured via self-report during either the ASI-MV or CHAT assessment. Products included in the opioid groups examined are provided in Table 1. Abuse was defined as use of a prescription opioid product at least once within the past 30 days prior to assessment not prescribed to you or used in a way not intended for pain relief.
Route of administration pattern was measured as the frequency and percent of individuals reporting a specific route of abuse among individuals who reported overall past 30-day abuse of the individual opioid categories reviewed (ie, proportion of abuse via oral route, snorting, or injection). Characteristics (eg, abuse severity and illicit drug use) of abusers of hydrocodone IR combination products were also examined.
Abuse prevalence was calculated first as the proportion of any past 30-day abuse for a particular opioid category among the study sample (the number of past 30-day abuse cases per 100 assessments where the denominator is equal to the total number of either adult or adolescent assessments). Two additional measures of abuse prevalence were calculated to account for differences in prescription volume across the opioid categories examined including (1) the number of cases of past 30-day abuse for a particular opioid category per 100 000 prescriptions dispensed and (2) the number of cases of past 30-day abuse for a particular opioid compound per 10 000 000 morphine milligram equivalents (MME) dispensed.
Abuse estimates presented as per 10 000 000 MME dispensed were derived using the total weight in milligrams dispensed for each opioid category multiplied by the morphine equivalence factor for each opioid compound. 21 Weights for individual products were summed across all of the available product dosage strengths and across all products included in a specific opioid category. Prescription data for these analyses were obtained from IMS Health using the IDW (Integrated Data Warehouse) pain market prescription database. These data provide national level projected prescription tracking captured at the pharmacy level within the United States and include cash, Medicaid, and third-party transactions.
To examine changes in abuse prevalence and the possible impact of rescheduling of hydrocodone IR combination products in October 2014, an analysis of temporal trend in abuse was conducted using general estimating equation regression models to determine the probabilities of abuse prevalence over time for 2 denominators: (1) abuse per 100 assessments and (2) abuse per 10 000 000 MME. The models estimated period-specific slopes in the rate of abuse for a given opioid category per quarter in the period before and after rescheduling of hydrocodone IR combination products. Models were parameterized where the fixed effects included a categorical indicator variable for period, a time covariate (measured in calendar quarter units), and the interaction of both fixed effects. A log-binomial model was used to estimate changes in linear trends in abuse per 100 assessments across each of the 4 years examined. A log-Poisson model was used to estimate changes in linear trends in abuse per 10 000 000 MME dispensed. The number of assessments and prescription volume, defined as MME, were treated as offsets in the models. 22 Analyses for trend were performed for the adult sample only. Trend analyses were not feasible among the adolescent sample due to small sample size across the period examined.

| Sample demographics
The adult sample consisted of 226 357 assessments from 831 sites in 45 states within the United States during January 2012 through June 2015. Demographically, the adult sample was primarily individuals of younger age (59% between 18 to 34 years) and male (64%).
The majority of adults in the sample were Caucasian race (62.1%) ( Table 2). Overall, 60% of the adult sample were prompted to enter substance abuse treatment via the criminal justice system and nearly 33% reported a chronic pain problem. Approximately 23% reported that they had abused a prescription opioid within the past 30 days. In general, adult prescription opioid abusers within the sample had a similar demographic profile to the total sample with the exception that a lower percentage was prompted to enter treatment by the criminal justice system (36%) and a higher percentage reported a problem with pain (approximately 50%

| Abuse prevalence of hydrocodone IR combination products
Across the 3.5-year period examined, prevalence of abuse of hydrocodone IR combination products within the adult sample was highest (9.6 per 100 assessments) compared to all other opioid categories examined (range = 3.0 per 100 assessments for all other IR opioids to 8.0 per 100 assessments for oxycodone IR combination products).
For adults, abuse prevalence for hydrocodone IR combination products was nearly twice that of all non-ADF ER/LA opioids (5.2 per 100    Figures 3A,B). However, when considering the dosage and potency of the total prescriptions dispensed (MME dispensed) across the 6 opioid categories, abuse prevalence for hydrocodone IR combination products was comparable to ER/LA opioids (among adults 1.16 per 10 000 000 MME dispensed and 1.01 per 10 000 000 MME dispensed, respectively) ( Figures 4A,B).

| Trend in abuse of hydrocodone IR combination products
Consistent with abuse patterns observed over the total 3.5-year period assessed, hydrocodone IR combination products also had the highest past 30-day abuse prevalence of the opioid categories examined during each quarter prior to and following hydrocodone rescheduling ( Figure 5) To further evaluate the patterns of abuse described above as well as

| Route of administration
A variety of ROAs was endorsed by both adults and adolescents who reported past 30-day abuse of hydrocodone IR combination products.

| History and severity of hydrocodone IR combination product abusers
An additional question of interest for this analysis was to examine characteristics of individuals who report abuse of hydrocodone IR combination products as it relates to their substance abuse profile or history as reported among adults entering or assessed for treatment. other prescription opioid products shows that among abusers of hydrocodone products, approximately 44% report only abusing hydrocodone and no other prescription opioid. Nearly 80% of those who report using only hydrocodone IR combination products also report abusing at least 1 illicit substance in the past 30 days including 8% reporting past 30-day heroin abuse. Calculated drug-problem severity scores for these individuals also indicate that a large number of abusers of hydrocodone IR combination products have substance abuse problems considered significant or extreme ( Figure S3). Because of a small sample size within subgroups of hydrocodone abusers, data regarding drug problem severity among adolescents were too limited to provide meaningful analysis.

| DISCUSSION
Results of this study indicate that across the period of January 2012 through June 2015, past 30-day abuse prevalence of hydrocodone IR combination products by both adults and adolescents assessed for substance abuse treatment was higher than any other opioid category reviewed. This pattern was similar when reviewed quarterly across the 6 quarter period (Q1 2014 to Q2 2015) where the level of past 30-day abuse of each of the opioid categories relative to each other remained the same. Our study also found large differences in the relative ranking of abuse prevalence for hydrocodone IR combination products when measured using the denominator of total prescriptions dispensed versus total MME. Abuse prevalence per total prescriptions dispensed was lower for hydrocodone IR combination products than other opioids examined, a result of the large prescription volume for hydrocodone IR combination products that far exceeds that of the other opioid categories. However, in total MME dispensed, abuse of hydrocodone IR combination products showed prevalence estimates similar to the level observed for all ER/LA opioids combined. Use of these two denominators was intended to provide different perspectives of abuse prevalence by adjusting for the amount of abusable (or "at-risk") product in 2 ways: total prescriptions-by definition, simply adjusts for the number of prescriptions dispensed for a particular opioid product, MME also considers the dosage, number of tablets dispensed, and potency of each opioid, and thus removes some of the distortion in prescription-level prevalence estimates that do not account for these product-specific differences.
A statistically significant upward trend in the slope and prevalence of abuse of hydrocodone IR combination products per 100 assessments and per 10 000 000 MME was observed when comparing the 3 quarters prior to and after rescheduling of these products in October There are notable differences in reported ROAs among prescription opioid analgesic formulations. The preferred ROA most likely reflects the level of attractiveness an abuser perceives for a certain drug, which is itself determined by a myriad of pharmacological, behavioral, and social factors. 24,25 Furthermore, individual abusers often report using several different routes of abuse. 26,27  There are several strengths and limitations to be considered when interpreting the analyses presented. We attempted to provide a broader public health perspective for understanding the potential burden of abuse of hydrocodone IR combination products relative to other prescription opioids by evaluating abuse prevalence using several denominators. Although the relative abuse level and ranking of hydrocodone IR combination products varied when different denominators were used, there is no single agreed upon denominator for which to measure abuse across the various subpopulations of abusers of prescription opioids. 28 Each calculation of abuse prevalence presented here provides a certain vantage point from which to assess abuse, and each of these measures has its own merits and drawbacks when viewed in isolation. For example, studies have indicated a relationship exists between the level of abuse of a drug and the amount of exposure or availability of a drug in the community. 26,[29][30][31][32][33][34] In the current analysis, abuse prevalence of hydrocodone IR combination products and comparison opioid categories were adjusted for prescribed availability of the products as a proxy for estimating exposure (ie, amount of product potentially available for abuse in the community). In this context, exposure or availability was measured in 2 ways: either per total prescriptions or per total MME dispensed for each product. These values represent abuse based on the total potentially abusable (at-risk) prescriptions circulating in a specified period (ie, cases per 100 000 prescriptions dispensed) or on the dosage and potency level of the opioid evaluated (ie, cases per 10 million MME dispensed). However, given that the number of prescriptions dispensed for hydrocodone IR combination products is much larger than for all other prescription opioids, reliance solely on use of total prescriptions as a denominator in the abuse prevalence estimates may underestimate the true burden of abuse of these products. Prescriptions for hydrocodone IR combination products are typically of shorter duration than the other opioid categories, and these variations across opioid products are not accounted for when using prescription-level use as a denominator in abuse estimates. Furthermore, although a relationship between prescription volume and abuse has been observed, use of total prescriptions as a denominator assumes a linear or proportional relationship between abuse and a product's prescription volume.
A recent analysis of abuse and prescription volume for different opioids suggests that it is possible that there is a point in prescription volume at which the abuse of a product does not proportionally increase with increasing prescriptions. 35  Because both the ASI-MV and CHAT are convenience samples, meaning that the data are not collected as a random sample but provided from sites that participate in these surveillance networks by administering the assessment in their clinical settings, they are limited in geographic scope. For example, the ASI-MV has better representation in the West and South and a majority of data within the CHAT are from sites located in Missouri. Despite this, a strength of the present study includes the large and diverse sample that allows examination of abuse patterns among a sensitive population at high risk of prescription opioid abuse and likely with a high prevalence of tampering with these medications for abuse purposes. Although data from both the adult and adolescent study samples rely on self-report, they are validated clinical instruments [36][37][38][39] that collect data as part of a clinical assessment rather than for pure research purposes. These data may therefore be more accurate as compared to self-report of substance use patterns in general population surveys since data collection occurs as part of patient treatment. Additionally, the data from the ASI-MV and CHAT constitute a uniform and systematic method of data collection over time and across sites with detailed questions that differentiate product-specific abuse and ROA in near real-time. This data collection procedure has been shown to be sensitive to detecting rapid changes in abuse patterns particularly in detecting more recent shifts in prescription opioid abuse after introduction ADFs to the market. 31,40 In summary, examination of abuse of hydrocodone IR combination products in 2 high-risk populations (adults/adolescents assessed for substance abuse treatment) indicated that abuse of these products impacts a large number of prescription opioid abusers and occurs at a level of severity that represents considerable or extreme abuse behavior. Although proportionally most individuals report oral abuse of hydrocodone IR combination products, snorting also appears to be an ROA for these products that has public health relevance. Of particular public health relevance is the high percentage of snorting of hydrocodone IR combination products observed among adolescents in substance abuse treatment. Since no one standard denominator exists for which to assess prevalence or incidence of abuse of prescription opioid products across the various segments of abuser populations, evaluating abuse burden of hydrocodone should include examination of abuse not only adjusted for drug exposure (prescriptions dispensed) and amount of active pharmaceutical ingredient available but also absolute prevalence of abuse. The combined data can provide a better understanding of the magnitude of abuse of these products, which can in turn inform strategies to reduce their risk of abuse. Our findings suggest that frequently prescribed opioids, such as hydrocodone IR combination products, even at a relatively low prevalence of abuse, may contribute substantially to the overall problem of prescription opioid abuse. While new abuse-deterrent opioid products have been introduced to the market over the past few years, as of this writing almost all currently marketed ADF opioid products are ER or LA formulations with recent approval of an ADF version of IR single-entity oxycodone in April 2017. There is no hydrocodone IR combination product formulated with abuse-deterrent technology yet on the market. The findings of this study underscore the potential benefit that not only development of ADFs for IR opioids may have towards mitigating the public health burden of prescription opioid abuse but also the value of additional public health interventions for these types of opioid products.

ETHICS STATEMENT
These surveillance data from the ASI-MV were reviewed by the New England Institutional Review Board and determined as exempt from human subject research as they are a limited dataset in which subjects cannot be identified.