Innovative Abuse-Deterrent Opioid Medications

• Lipp Life Sciences LLC

Introduction

Pain affects more patients in the United States than diabetes, heart disease and cancer combined. Chronic pain in particular impacts over 100 million Americans.^1,2 The burden of pain is high, both for the individual patient and society, and the combined annual cost of health care and decreased work productivity due to pain is $635 billion in the United States.³ There is a significant number of interventions to treat pain available, including medicines based on entities from the classes of nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, and opioids for example. Patients managing moderate to severe chronic pain often benefit from the use of opioid-based medications. However, these medications are subject to abuse, and overdose deaths involving opioid analgesics rose to 16,651 in 2010 in the United States.⁴ Ways to create safer opioid analgesics comprise the use of abusedeterrent formulations (ADFs), pro-drugs, and new molecular entities as described in more detail in FDA’s recently published guidance “Abuse-Deterrent Opioids – Evaluation and Labeling”.⁵

The current article discusses various innovative ways to create ADFs, including: physical/chemical barrier, agonist/antagonist combination, aversion (addition of substances which create an unpleasant effect if the dosage form is manipulated) as well as drug delivery system approaches and pro-drugs for opioids.

Multifaceted Approach to Opioid Abuse Reduction

It is deemed to be likely that various factors have contributed to the current issues related to abuse of opioids, including among others the significant increases in prescriptions written for opioids and greater social acceptability for using medications for different purposes.⁶ Looking at global data reveals that the US is the biggest market for the opioids hydrocodone (almost 100% of the global market) and oxycodone (81% of the global market).⁶

Furthermore, recent data suggests that abusers of prescription opioids may shift to heroin use, as it becomes more difficult to obtain or misuse newer opioid pain medications, thus adding to the complexity of the opioid abuse issue.⁶ In order to tackle opioid abuse, a multifaceted approach needs to be taken. In 2001, the National Institute on Drug Abuse (NIDA) started a three-pronged approach to reduce opioid abuse and its impact, comprising

• enhancing the understanding of pain and its management,
• preventing overdose deaths, and
• effectively treating opioid addiction.⁶

Given the complexity of the task at hand, it is clear that innovation in the area of abuse-deterrent formulations, delivery systems, pro-drugs, and new chemical entities alone will not be able to solve the issue in full. However, the aforementioned innovations play a vital role and can contribute to reaching the overall aim of reducing the abuse of prescription medicines.

Abuse is defined as the intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desirable psychological or physiological effect.⁷ Abuse of opioids may lead to euphoria (the socalled “high”) and the abuser’s desired “reward” in particular if opioids reach the μ-opioid receptors in the brain rapidly (rapid rise) and at high concentrations after intake of the substance. In contrast to that, in the course of the intended use of opioid medications, the opioid receptors in the brain (and peripheral ones) will be occupied at lower levels and in a less rapid fashion. While this is adequate for pain relief, it typically does not lead to euphoria.

Based on the above mentioned PK/PD-relationship (rapid rise to high central receptor occupation triggering euphoria), abuse of prescription drugs often involves manipulation or tampering with the original drug, for example destroying the retarding principle of an extended release (ER) oral dosage form before oral ingestion and/or the use of other routes of application. These routes include i.v. application, pulmonary application (smoking), and nasal application (snorting).

Figure 1 is a schematic representation of the impact of different ways of manipulation of an oral ER formulation on the resulting pharmacokinetic (PK) profile and pharmacodynamic effect (PD) in comparison to its intended use.

 Figure 1. Effect of dosage form manipulation on the PK and PD of opioids

As can been seen from Figure 1, the intended use of an oral ER formulation of an opioid results, after disintegration of the dose form in the GI tract and dissolution of the opioid, is the uptake into systemic circulation and an extended plasma plateau with a relatively low C_max and a relatively high t_max. Provided high permeability of the blood brain barrier of the given opioid, a protracted occupation of both central and peripheral opioid receptors will result in the desired analgesic effect. If, on the other hand, the dose form was manipulated, e.g. by grinding/destruction of its extended release technology, for example snorting of the resulting powder can lead to a more rapid absorption with significantly higher C_max- and significantly shorter t_max-values, thus triggering euphoria. In this case the abuse quotient AQ of an opioid (defined as: AQ = C_max/t_max) is significantly increased.³

It is obvious, that immediate release (IR) dosage forms can be manipulated and abused as well. Previously, it was believed that ER dosage forms had a lower abuse potential when compared to IR dosage forms, due to their inherently lower C_max and higher t_max values. In many abuse settings, however, standard ER forms are preferred over IR forms due to their higher overall opioid doses, as long as manipulation of the dose form will allow for the intended rapid up-take of the opioid.

Given the numerous ways of manipulating prescription drugs it becomes clear, that it is not feasible to design and develop opioid medicines which fully prevent abuse. Abuse-deterrence, therefore, is the goal. At a conceptual level, abuse-deterrence can be achieved by any technology or combination of technologies which limits the maximum occupation level of central opioid receptors by agonists and delays the rate of said receptor occupation.

Evaluation of Abuse-Deterrent Products

The concept devised in the FDA guidance “Abuse-Deterrent Opioids”⁵, describes three categories of tests to evaluate the abuse-deterrent potential of opioid drugs in the pre-registration setting (see Figure 2).

 Figure 2. Three categories of pre-registration studies for abuse-deterrence

During pre-registration stages, Category 1 evaluations comprise laboratory-based in vitro manipulation and extraction studies on abuse-deterrent formulations (like the abuse-deterrent extended release formulation (AD ER) in Figure 2). These in vitro studies help to assess the ease or relative difficulty of defeating the abuse-deterrent technology applied in the ADF. They will assess a variety of ways a drug might be manipulated, including increasing the release rate of the opioid from an ER product, preparation for different routes of administration, for example by grinding, extraction with solvents, and/or separation of antagonists from agonists in combination formulations. Where possible, these tests should be run in comparison to an already approved product without ADF technology, in order to allow for better judgement relative to the degree of abuse-deterrence provided by the novel formulation. Results from Category 1 studies will often inform design of Category 2 & 3 studies.

Category 2 studies are being used to evaluate the pharmacokinetics (PK) of the manipulated ADF with that of the intact ADF and further comparators, particularly looking at C_max and t_max and thus allowing for the calculation of the aforementioned Abuse Quotient. These PK studies may be performed in healthy volunteers while the antagonist naltrexone is used to block the PD effects of the opioid agonist.

Category 3 comprises clinical abuse studies which are generally conducted in a recreational opioid user population. Study design (preferably randomized, double-blind, placebo-controlled crossover with positive control) should allow for a comparison of the abuse-deterrent product with the positive control (for example a conventional ER formulation, without abuse-deterrent technology) taking into consideration routes of administration, dose selection and manipulation mode/sample preparation. Study outcomes will be measured using Visual Analogue Scales (VAS) for drug liking, among other means.

The results of these studies will be used to determine specific labeling of the market product, as provided in the package insert.

Subsequently, Category 4 studies, i.e. postmarket studies, may be conducted. Category 4 comprises both formal studies and supportive information. A formal Category 4 study should be a hypothesis-driven, population-based, observational evaluation which must be tailored to the specifics of the drug to be evaluated. Typically Category 4 studies capture one or more outcomes such as reduction in misuse, abuse, addiction, overdose, and death. At least one study should include a high risk population (for example known drug abusers). Supportive information can be used as well, which may focus on behavioral and clinical aspects of abuse (-deterrence).

Labeling of Abuse-Deterrent Medicines

Depending on the data generated in Category 1, 2 & 3 studies, FDA may grant specific label language relative to abuse-deterrence for the product investigated. The currently proposed labeling language examples describe which types of studies were performed (manipulation / PK / clinical) and that corresponding data demonstrates certain product properties which are expected to deter abuse. The proposed labeling examples also contain statements that abuse still is possible, in light of the fact that full prevention of abuse does not seem to be feasible.

Once the FDA grants specific abuse-deterrent labeling for a new product approval of generic versions without proof of abusedeterrence will not be granted.

Design and Development of Innovative Abuse-Deterrent Medications

From a technical perspective design and development of abusedeterrent medications can be achieved by a variety of means, including those mentioned in the FDA Guidance “Abuse-deterrent opioids” cited above:

• physical/chemical barriers, preventing chewing, crushing, cutting, grating or grinding; addition of gelling agents to make opioid extraction more difficult
• agonist/antagonist combinations, where the addition of an (potentially sequestered) opioid antagonist may reduce the euphoria
• aversion, where substances can be added to create an unpleasant effect during abuse (e.g. irritation of mucosa during snorting)
• delivery system, designed to offer resistance to abuse, including depot injectables, implants, etc.
• new molecular entities & prodrugs, designed to exhibit lower and/or slower penetration into the CNS
• combination, of the aforementioned levers, and
• novel approaches, not captured so far.

Abuse-Deterrent Products and Technologies Under Development and In the Market Place

Various abuse-deterrent technologies have been utilized to develop new medications and Table 1 provides a high level overview over several developmental and marketed products.

Table 1. Innovative opioid medications based on abuse deterrent technology

Looking at the example of OxyContin^® in more depth, the physical barrier/crush resistant technology utilized for abuse deterrence is based in part on the use of the polymer polyethylene oxide in the formulation.¹⁸ Several formulation patents are listed in the FDA’s Orange Book¹⁹ relative to OxyContin^®, including among others US 7,776,314 B2 describing the use of at least one viscosityincreasing agent to protect formulations from parenteral abuse²⁰ and US 8,114,383 B2 describing an abuse-proofed, thermoformed dosage form containing at least one synthetic or natural polymer with a breaking strength of at least 500 N.²¹ The product has been studied extensively, including: testing of bioequivalence to the previously marketed product (without abuse-deterrent technology), physical manipulation studies, clinical abuse studies, and pharmacoepidemiologic studies.^3,12,22Figure 3 shows the results of a cross-over study comparing the drug liking for finely crushed OxyContin^® (test) with that of powdered oxycodone HCl (control).

 Figure 3. Reduction in drug liking for finely crushed OxyContin^® vs. powdered oxycodone HCl (data from prescribing information¹⁸)

It is important to note, that the clinical safety and efficacy of any abusedeterrent medication in the treatment of pain must be comparable to the product without abuse-deterrent technology, and may be evaluated in certain cases via bioequivalence testing.

From a formulation design perspective, development of a next generation formulation with integrated abuse-deterrent features on the basis of an already existing product with proven safety and efficacy might restrict the available formulation space to a certain degree. While de-novo design of an abuse-deterrent medication will likely open a larger formulation space, it will also necessitate an additional investment in clinical development.

Conclusion

Innovation in the area of abuse-deterrent opioids has been achieved via various technologies and particularly in the domain of abuse deterrent formulations. While progress to date is encouraging, significantly more progress needs to be made to further deter abuse and thus contribute to reducing opioid related overdose deaths in the US. Today’s and future innovations in this important field need to be complemented by progress in adjacent areas, like enhancing the understanding of pain and its management and effectively treating opioid addiction to fight the problem at hand in an integrated and effective manner.

References

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Author biography

Ralph Lipp, PhD, President and CEO of Lipp Life Sciences LLC, advises clients on various aspects of innovation-based value creation and generates new product opportunities by addressing unmet medical need with patient-centered innovation. He also serves as the founding Advisory Board Member of the Catalent Applied Drug Delivery Institute. Before founding Lipp Life Sciences LLC, Ralph served as Vice President Pharmaceutical Sciences R&D at Eli Lilly and Company and Head Pharmaceutical Development at Schering AG. Ralph holds a degree in Pharmacy from Johannes Gutenberg University in Mainz, Germany, and obtained a Ph.D. in Medicinal Chemistry as well as a Habilitation for Pharmaceutical Technology from Free University Berlin, Germany. His scientific contributions comprise over 130 publications, including more than 20 patents, covering 5 marketed medicines.