Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys.

RATIONALE: Combinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects. OBJECTIVE: The present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A. METHODS: Adult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018 mg/kg/injection). Once trained, cocaine (0.018 mg/kg/injection) or oxycodone (0.0056 mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1-3.2 µg/kg/injection), nalfurafine (0.0032-0.1 µg/kg/injection), triazole 1.1 (3.2-100.0 µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components. RESULTS: Cocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed. CONCLUSIONS: These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse.

Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist.

Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on nalfurafine. In vitro, nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.

Complex Drug Delivery Systems: Controlling Transdermal Permeation Rates with Multiple Active Pharmaceutical Ingredients.

A transdermal drug delivery system (TDDS) is generally designed to deliver an active pharmaceutical ingredient (API) through the skin for systemic action. Permeation of an API through the skin is controlled by adjusting drug concentration, formulation composition, and patch design. A bilayer, drug-in-adhesive TDDS design may allow improved modulation of the drug release profile by facilitating varying layer thicknesses and drug spatial distribution across each layer. We hypothesized that the co-release of two fixed-dose APIs from a bilayer TDDS could be controlled by modifying spatial distribution and layer thickness while maintaining the same overall formulation composition. Franz cell diffusion studies demonstrated that three different bilayer patch designs, with different spatial distribution of drug and layer thicknesses, could modulate drug permeation and be compared with a reference single-layer monolith patch design. Compared with the monolith, decreased opioid antagonist permeation while maintaining fentanyl permeation could be achieved using a bilayer design. In addition, modulation of the drug spatial distribution and individual layer thicknesses, control of each drug's permeation could be independently achieved. Bilayer patch performance did not change over an 8-week period in accelerated stability storage conditions. In conclusion, modifying the patch design of a bilayer TDDS achieves an individualized permeation of each API while maintaining constant patch composition.

An in vitro approach for evaluating the oral abuse deterrence of solid oral extended-release opioids with properties intended to deter abuse via chewing.

The introduction of prescription opioids with abuse-deterrent (AD) properties to the marketplace has created a need for new testing methodologies to evaluate the performance of potentially abuse-deterrent opioid products. Drug abusers may attempt to chew solid oral extended-release (ER) opioids prior to ingestion to bypass the ER mechanism of the formulation to achieve euphoria. In the present study, a chewing apparatus was utilized to develop an in vitro chewing method for Hysingla ER tablets, a prescription opioid with labeling describing abuse deterrence via the oral route when chewed. Simulated chewing of Hysingla resulted in initially faster drug release during chewing while subsequent dissolution testing demonstrated that the masticated tablets still maintained ER properties. The degree of mastication and corresponding drug release were influenced by the compression gap and the resulting chewing forces. Simulated chewing followed by dissolution testing with different strengths of Hysingla indicated similar AD performance across strengths. By contrast, an opioid product with labeling that does not describe abuse-deterrent properties showed lower resistance to chewing resulting in higher drug release. The results of the present study suggest that the chewing methodology evaluated in this work may provide a useful in vitro tool for the comparative evaluation of AD properties.

Supply-Side Drug Policy in the Presence of Substitutes: Evidence from the Introduction of Abuse-Deterrent Opioids.

Overdose deaths from prescription opioid pain relievers nearly quadrupled between 1999 and 2010. We study the consequences of one of the largest supply disruptions to date to abusable opioids - the introduction of an abuse-deterrent version of OxyContin in 2010. Supply-side interventions which limit access to opioids may have the unintended consequence of increasing use of substitute drugs, including heroin. Exploiting cross-state variation in OxyContin exposure, we find that states with the highest initial rates of OxyContin misuse experienced the largest increases in heroin deaths. Our results imply that the recent heroin epidemic is largely due to the reformulation of OxyContin.

The Abuse Potential of Prescription Opioids in Humans-Closing in on the First Century of Research.

While opioids are very effective analgesics for treating acute pain, humans have struggled with opiate addiction for millenia. An opium abuse epidemic in the early 1900's led the US government to develop a systematic research infrastructure and scientific plan to produce new compounds with analgesic properties but without abuse liability. This review describes the techniques that were developed for testing in the human laboratory, including empirically derived outcome measures and required elements for human abuse potential assessment. The evaluation and characterization of semi-synthetic and synthetic opioids, including full mu opioid agonists, partial agonists and mixed agonist-antagonists, are described across several decades of research. Finally, the prescription opioid epidemic beginning in the 1990's in the US led to a resurgence in abuse potential evaluations, and the application of these methods to the study of novel abuse-deterrent formulations is discussed.

Oxycodone DETERx®: A Novel Abuse-Deterrent, Extended-Release Analgesic Option for the Treatment of Patients with Chronic Pain.

BACKGROUND: Extended-release (ER) opioid analgesics are commonly used to provide safe and effective pain relief to treat pain severe enough to require around-the-clock, long-term dosing. These ER opioid formulations usually contain more drug per dosage unit than immediate-release (IR) agents, and therefore bring with them challenges related to both opioid abuse and misuse, often through manipulation of the dosage form. Oxycodone DETERx® (Xtampza® ER, Collegium Pharmaceutical, Inc.) is a novel abuse-deterrent, ER formulation developed to deter common methods of manipulation. In addition to having abuse-deterrent properties, oxycodone DETERx was developed to provide alternative modes of administration for patients with chronic pain and difficulty swallowing. SCOPE: Using published articles, abstracts, and prescribing information, data supporting the use of oxycodone DETERx are reviewed. FINDINGS: Oxycodone DETERx was effective at reducing chronic pain in patients enrolled in a pivotal clinical trial, and had a tolerability profile expected of opioids. In addition to administration of the intact capsule, oxycodone DETERx can also be administered by sprinkling directly into the mouth from a dosing cup, onto soft foods, or through nasogastric or gastrostomy tubes, thus providing flexible dosing options for patients who have difficulty swallowing. In vitro studies demonstrated the reduced ability of oxycodone DETERx to be manipulated by common techniques used by abusers to defeat the ER characteristics or prepare the formulation for injection. Pharmacokinetic studies demonstrated that the ER characteristics of oxycodone DETERx are maintained if chewed or crushed. As a result, oxycodone DETERx is currently the only ER-formulated opioid without a boxed warning against crushing or chewing. Human abuse-potential studies conducted in a population of recreational opioid users demonstrated lower drug-liking scores for oxycodone DETERx administered intranasally and orally when compared with IR oxycodone. FUNDING: Collegium Pharmaceutical, Inc.

Recent advances in abuse-deterrent technologies for the delivery of opioids.

Over the past decade, the abuse of prescription opioid drugs has become a national health crisis in the United States. Pharmaceutical companies, the Food and Drug Administration, and other government agencies are confronting opioid abuse by developing and commercializing various abuse-deterrent drug delivery technologies. To deter opioid abuse, various strategies including physical barriers, chemical barriers, antagonists, aversive agents, and prodrugs have been investigated. A number of drug products with abuse-deterrent properties have been approved by the FDA over the last six years, while many products and technologies with progressively-improved abuse-deterrence properties are currently being evaluated. This article provides a comprehensive review of the material sciences principles that govern the formulation and processing of a wide range of abuse-deterrent products and technologies.

Safety concerns with long-term opioid use.

INTRODUCTION: The benefits of opioid therapy must be balanced by any adverse effects. In recent years, prescription opioids have been increasingly prescribed, but have also been associated with increased abuse, overdose and death. AREAS COVERED: This review will categorize the common risks of opioid administration. Recognized adverse effects of opioid therapy include constipation, tolerance, endocrinopathies, sleep disorders, cognitive effects, respiratory depression, overdose and addiction. Studies have shown that there is increased risk of overdose and death with higher daily opioid doses, particularly above a morphine equivalent oral daily dose of 100 milligrams. Extended-release/long acting (ER/LA) opioid formulations may be beneficial for the compliant patient, yet may expose a higher risk for abuse if used inappropriately since each tablet carries a larger dose of medication. EXPERT OPINION: Prospective, controlled one-year trials are needed to establish the efficacy and safety profile of chronic opioid therapy. In addition to the well known side effects of chronic opioid therapy, the influence and serious effect of opioids on sleep and central sleep apnea is only recently being investigated. The lowest possible daily opioid must be used to manage chronic pain, and all clinicians should be cautious in the use of daily morphine equivalent doses above 50-100 milligrams.

Abuse-deterrent formulations of prescription opioid analgesics in the management of chronic noncancer pain.

Misuse, abuse and diversion of prescription opioid analgesics represent a global public health concern. The development of abuse-deterrent formulations (ADFs) of prescription opioid analgesics is an important step toward reducing abuse and diversion of these medications, as well as potentially limiting medical consequences when misused or administered in error. ADFs aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or aversive. However, opioid ADFs may still be abused via the intended route of administration by increasing the dose and/or dosing frequency. The science of abuse deterrence and the regulatory landscape are still relatively new and evolving. This paper reviews the current status of opioid ADFs, with particular focus on different approaches that can be used to deter abuse, regulatory considerations and implications for clinical management.

Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations.

Prescription drug products abuse/misuse is epidemic in United States. Opioids drug forms major portion of prescription drug product abuse. Abuse deterrence formulation (ADF) is one of the many approaches taken by sponsors to tackle this problem. It involves formulating opioids into dosage forms that will be difficult to abuse/misuse. Current investigation focused on evaluating the abuse deterrent properties (ADP) of ADF manufactured by direct compression method. Effect of process and formulation variables on ADP was investigated by statistical design of experiment (fractional factorial design). Independent factors studied were molecular weight of polyethylene oxide (Polyox™), curing time, temperature and method, and antioxidant type. Sotalol hydrochloride was selected as a model drug. ADP investigated were hardness/crush resistance, syringeability and injectability, physical manipulation (reduction into powder) and drug extraction in water and alcohol. Hardness and syringeability are evaluated by newly developed quantitative procedure. Other properties were also investigated such as morphology, crystallinity, assay and dissolution. The hardness and drug extraction was significantly (p<0.05) affected by curing temperature. Formulations could be powdered in 3 min irrespective of their hardness. Syringeability and injectability were intrinsic properties of the polymer used in the formulation, and were not affected by the investigated factors. Crystallinity of the polymer and drug changed, and was dependent upon curing temperature and time. The dissolution and assay were independent of formulation and process parameters studied. In conclusion, the study indicated some advantages of ADF product compared to non-ADF prepared by direct compression. However, the ADF should not be viewed as abuse proof product rather as incrementally improved product.

A typology of people who tamper with pharmaceutical opioids: responses to introduction of a tamper-resistant formulation of controlled-release oxycodone.

PURPOSE: In April 2014, a tamper-resistant controlled-release oxycodone formulation was released in Australia. We aimed to determine whether there are latent classes of people who tamper with pharmaceutical opioids based on frequency of opioid and illicit drug use, the demographic and clinical profiles of these groups, and if there were changes in use and harms following the introduction. METHODS: A prospective cohort of 606 people who regularly tamper with pharmaceutical opioids was interviewed January to March 2014 (Wave 1) and May to August 2014 (Wave 2). Latent class analysis identified groups based on non-prescribed opioid, illicit drug and prescribed opioid substitution therapy (OST) use at Wave 1. Regression models examined whether group membership predicted use and harms at Wave 2. RESULTS: Four groups were identified: frequent OST group (39%), mixed OST/heroin group (7%), infrequent pharmaceutical opioid and heroin group (44%) and frequent oxycodone group (25%). Compared with the frequent OST group, the infrequent pharmaceutical opioid/heroin group was more likely to report non-everyday pain and risky alcohol use, and the frequent oxycodone group had higher odds of homelessness. At Wave 2, oxycodone use decreased across groups (odds ratios (OR) ≤ 0.18, p < 0.001, particularly for the frequent oxycodone group: OR ≤ 0.05, p < 0.001), with reductions in days of use (g ≥ 0.35, p < 0.050). Non-prescribed pharmaceutical opioid use, illicit drug use and harms remained stable or decreased. CONCLUSIONS: Despite heterogeneity among people who tamper with pharmaceutical opioids, the tamper-resistant formulation was followed by reductions in oxycodone tampering among high-frequency and low-frequency users. There was no evidence of increased use of other opioids or illicit drugs.

Methods and predictors of tampering with a tamper-resistant controlled-release oxycodone formulation.

BACKGROUND: In April 2014, a tamper-resistant controlled-release oxycodone formulation was introduced into the Australian market. This study aimed to identify the level and methods of tampering with reformulated oxycodone, demographic and clinical characteristics of those who reported tampering with reformulated oxycodone, and perceived attractiveness of original and reformulated oxycodone for misuse (via tampering). METHODS: A prospective cohort of 522 people who regularly tampered with pharmaceutical opioids and had tampered with the original oxycodone product in their lifetime completed two interviews before (January-March 2014: Wave 1) and after (May-August 2014: Wave 2) introduction of reformulated oxycodone. RESULTS: Four-fifths (81%) had tampered with the original oxycodone formulation in the month prior to Wave 1; use and attempted tampering with reformulated oxycodone amongst the sample was comparatively low at Wave 2 (29% and 19%, respectively). Reformulated oxycodone was primarily swallowed (15%), with low levels of recent successful injection (6%), chewing (2%), drinking/dissolving (1%), and smoking (<1%). Participants who tampered with original and reformulated oxycodone were socio-demographically and clinically similar to those who had only tampered with the original formulation, except the former were more likely to report prescribed oxycodone use and stealing pharmaceutical opioid, and less likely to report moderate/severe anxiety. There was significant diversity in the methods for tampering, with attempts predominantly prompted by self-experimentation (rather than informed by word-of-mouth or the internet). Participants rated reformulated oxycodone as more difficult to prepare and inject and less pleasant to use compared to the original formulation. CONCLUSION: Current findings suggest that the introduction of the tamper-resistant product has been successful at reducing, although not necessarily eliminating, tampering with the controlled-release oxycodone formulation, with lower attractiveness for misuse. Appropriate, effective treatment options must be available with increasing availability of abuse-deterrent products, given the reduction of oxycodone tampering and use amongst a group with high rates of pharmaceutical opioid dependence.

The introduction of a potentially abuse deterrent oxycodone formulation: Early findings from the Australian National Opioid Medications Abuse Deterrence (NOMAD) study.

BACKGROUND: There is increasing concern about tampering of pharmaceutical opioids. We describe early findings from an Australian study examining the potential impact of the April 2014 introduction of an abuse-deterrent sustained-release oxycodone formulation (Reformulated OxyContin(®)). METHODS: Data on pharmaceutical opioid sales; drug use by people who inject drugs regularly (PWID); client visits to the Sydney Medically Supervised Injecting Centre (MSIC); and last drug injected by clients of inner-Sydney needle-syringe programmes (NSPs) were obtained, 2009-2014. A cohort of n=606 people tampering with pharmaceutical opioids was formed pre-April 2014, and followed up May-August 2014. RESULTS: There were declines in pharmacy sales of 80mg OxyContin(®) post-introduction of the reformulated product, the dose most commonly diverted and injected by PWID. Reformulated OxyContin(®) was among the least commonly used and injected drugs among PWID. This was supported by Sydney NSP data. There was a dramatic reduction in MSIC visits for injection of OxyContin(®) post-introduction of the new formulation (from 62% of monthly visits pre-introduction to 5% of visits, August 2014). The NOMAD cohort confirmed a reduction in OxyContin(®) use/injection post-introduction. Reformulated OxyContin(®) was cheaper and less attractive for tampering than Original OxyContin(®). CONCLUSIONS: These data suggest that, in the short term, introduction of an abuse-deterrent formulation of OxyContin(®) in Australia was associated with a reduction in injection of OxyContin(®), with no clear switch to other drugs. Reformulated OxyContin(®), in this short follow-up, does not appear to be considered as attractive for tampering.

Abuse-deterrent formulations: part 1 - development of a formulation-based classification system.

INTRODUCTION: Strategies have been implemented to decrease the large proportion of individuals misusing abusable prescription medications. Abuse-deterrent formulations (ADFs) have been grown to incorporate many different technologies that still lack a systematic naming and organizational nomenclature. Without a proper classification system, it has been challenging to properly identify ADFs, study and determine common traits or characteristics and simplify communication within the field. AREAS COVERED: This article introduces a classification system for all ADF approaches and examines the physical, chemical and pharmacological characteristics of a formulation by placing them into primary, secondary and tertiary categories. Primary approaches block tampering done directly to the product. Secondary approaches work in vivo after the product is administered. Tertiary approaches use materials that discourage abuse but do not stop tampering. Part 2 of this article discusses proprietary technologies, patents and products utilizing primary approaches. EXPERT OPINION: Drug products using opioid antagonists and aversive agents have been seen over the past few decades to discourage primarily overuse and injection. However, innovation in formulation development has introduced products capable of deterring multiple forms of tampering and abuse. Often, this is accomplished using known excipients and manufacturing methods that are repurposed to prevent crushing, extraction and syringeability.

Evaluating the potential impact of a reformulated version of oxycodone upon tampering, non-adherence and diversion of opioids: the National Opioid Medications Abuse Deterrence (NOMAD) study protocol.

AIMS: A new oxycodone formulation (Reformulated OxyContin® was released in Australia, early 2014. It was developed as a tamper-resistant ('abuse-deterrent') formulation of the drug. We summarize methods used in the National Opioid Medication Abuse Deterrence (NOMAD) study, which will examine: (i) whether there is a reduction in extra-medical use (including via tampering) of OxyContin® following the introduction of Reformulated OxyContin®; (ii) potential changes in extra-medical use of non-abuse-deterrent forms of oxycodone, other pharmaceutical opioids and illicit drugs; (iii) whether methods of tampering with Reformulated OxyContin® become widespread over time; (iv) Reformulated OxyContin®'s attractiveness on the illicit market; and (v) sales, prescriptions and harms related to OxyContin® and other drugs. METHODS: There are three major components. First, analyses of existing routine data sources such as: pharmaceutical sales; prescribing data; data on drug overdose deaths; and survey data on drug use in the general population and among people who inject drugs; secondly, specific data on OxyContin® collected through the Illicit Drug Reporting System; and thirdly, a prospective cohort of n = 606 people who regularly misuse or tamper with pharmaceutical opioids was formed prior to the introduction of Reformulated OxyContin®, followed-up twice post-release to examine potential changes after Reformulated OxyContin®'s introduction. DISCUSSION: The study's strengths lie in varied data collections; interrupted time-series analysis; and prospective cohort. To our knowledge, this is one of the most comprehensive and transparently conducted studies conducted to date of the potential impact of an opioid medication upon use, tampering and diversion. Results have the potential to inform policymakers, clinicians, consumers and researchers alike.

Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-deterrent characteristics.

PURPOSE: Abuse and misuse of prescription opioids are serious public health problems. Abuse-deterrent formulations are an intervention to balance risk mitigation with appropriate patient access. This study evaluated the effects of physicochemical barriers to crushing and dissolving on safety outcomes associated with extended-release oxycodone (ERO) tablets (OxyContin) using a national surveillance system of poison centers. Other single-entity (SE) oxycodone tablets and heroin were used as comparators and to assess substitution effects. METHODS: The National Poison Data System covering all US poison centers was used to measure changes in exposures in the year before versus the 2 years after introduction of reformulated ERO (7/2009-6/2010 vs 9/2010-9/2012). Outcomes included abuse, therapeutic errors affecting patients, and accidental exposures. RESULTS: After ERO reformulation, abuse exposures decreased 36% for ERO, increased 20% for other SE oxycodone, and increased 42% for heroin. Therapeutic errors affecting patients decreased 20% for ERO and increased 19% for other SE oxycodone. Accidental exposures decreased 39% for ERO, increased 21% for heroin, and remained unchanged for other SE oxycodone. During the study period, other interventions to reduce opioid abuse occurred, for example, educational and prescription monitoring programs. However, these have shown small effects and do not explain a drop for ERO exposures but not for other opioids. CONCLUSIONS: After ERO reformulation, calls to poison centers involving abuse, therapeutic errors affecting patients, and accidental exposures decreased for ERO, but not for comparator opioids. Abuse-deterrent formulations of opioid analgesics can reduce abuse, but switching to other accessible non abuse-deterrent opioids might occur.