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FOR those who actually want to read something related and pertinent to the topic at hand:

Are Abuse-Deterrent Opioid Products A Double-Edged Sword?

https://www.practicalpainmanagement.com/treatments/pharmacological/opioids/are-abuse-deterrent-opioid-products-double-edged-sword

A review and analysis of formulations and efficacy of medications designed to lessen access to active ingredients while maintaining analgesic effects for chronic pain patients with appropriate need.
The United States Department of Health and Human Services states that the United States is in the midst of an “opioid epidemic,” referring to the dramatic increase in abuse, misuse, and diversion of prescription opioid medications in the past decade.1 Between 2004 and 2011, emergency department visits involving prescription opioid abuse increased by 153%.2

On an average day in the United States, 3,900 people will initiate “nonmedical use” of a prescription opioid, which is defined as taking a prescription drug, whether prescribed or otherwise, in a manner for which it was not prescribed.1,3 In 2015, nearly 22,000 deaths—approximately 62 deaths each day—involved medical or nonmedical use of natural, semi-synthetic, and synthetic prescription opioid analgesics.4 This surpasses the annual number of deaths due to major diseases such as lymphomas or skin cancer.5

Solving the opioid epidemic is complex because of the multifactorial underlying causes. Complicating this issue is the need to maintain access to opioids for patients with chronic pain conditions for which prescription opioid analgesics are the only effective treatment.6 Any attempts to mitigate opioid abuse must not have the unintended consequence of eliminating a viable treatment option for patients using opioid medications appropriately and experiencing meaningful clinical improvement.

National Effort to Curb Abuse
In 2011, the Office of National Drug Control Policy (ONDCP) issued a multifaceted national strategy to curb drug abuse that called on pharmaceutical firms and regulatory health agencies to collaborate in developing abuse-deterrent formulations (ADFs) of opioid medications.7,8 Abuse-deterrent medications use unique formulation strategies and technologies that make it more difficult or less rewarding for a user to abuse or divert the medication’s active ingredient but maintain the drug’s analgesic effects for appropriate patients.9

Although ADFs are designed to reduce the likelihood of misuse and abuse, they do not completely eliminate their possibility because ADFs do not prevent someone from taking multiple oral doses. Therefore, a 2011 ONDCP report outlined the need for postmarketing assessment of the impact of abuse-deterrent opioid medications on public health. Evidence remains limited on the short-term and long-term impact of ADFs on clinical outcomes related to opioid abuse.10,11

There has been a significant concerted effort by the US government, regulatory agencies, and pharmaceutical companies to increase the presence of ADFs on the prescription opioid market in recent years. Despite this, many questions remain about the use of this class of medications in clinical practice. For example, the variety of technologies used in ADFs may be unclear to many prescribers, and concerns about efficacy may arise, especially when weighed against the cost of these medications.

Therefore, the objective of this review is to compare and contrast available abuse deterrent technologies and evaluate the literature related to their impact on opioid abuse and public health.

ADFs for Different Methods of Abuse
To understand the strategies employed in developing ADFs, an appreciation of the methods of opioid abuse is necessary. Abuse is defined as an intentional nontherapeutic use of a drug to achieve a desirable psychological or physiological effect.12 To achieve this psychological or “high effect,” abusers seek absorption of the highest maximum concentration of the opioid into systemic circulation and the brain in the shortest amount of time.

Although immediate-release (IR) products are the easiest to manipulate, extended-release (ER) and controlled-release dosage forms tend to have more appeal to abusers because of the large amount of active ingredient per pill that may be released at once if the drug delivery system is manipulated.13 Thus, many pharmaceutical manufacturers focus on developing ADFs of ER products instead of IR products. The ease with which a delivery system can be manipulated and the active ingredient released also are major factors that influence the likeability, or appeal, of the drug for abusers.14

Common manipulation methods to accomplish the “high effect” that abusers seek include crushing the product, dissolving it in a solvent such as ethanol, or chemically extracting the active ingredient.12 The method of manipulation may depend on the route of abuse that the user prefers. The most common routes of abuse for prescription opioids are oral ingestion (including chewing or taking multiple doses or extra doses), inhalation (snorting, smoking, or inhaling), and injection (intravenous, intramuscular, or subcutaneous).

Clinicians should be aware that the route of abuse a patient prefers may depend on a range of factors, including age, sex, geographic location, and duration of abuse.15 It has been reported that drug abuse usually begins with oral routes and transitions over time to nonoral routes, such as snorting and injecting.16 In addition, favored routes of abuse may vary based on the specific drug of abuse.12 Oxycodone tablets, for instance, have been shown to be abused primarily via oral or intranasal routes, whereas morphine tablets are preferentially abused through oral or intravenous routes. This is important because the route of abuse has a significant impact on the potential for harm to the abuser.17 Injecting and snorting are methods that are associated with an increased risk of opioid dependence and a higher fatality rate. Abuse-deterrent formulations should take into account the preferential routes of abuse for similar medications.18

Choosing an Appropriate ADF Product
Abuse-deterrent opioid products use a variety of technologies to accomplish the goal of reducing abuse while maintaining efficacy for legitimate users (Table 1).10 A familiarity with the characteristics of different ADF technologies may help practitioners choose the agent that will have the greatest potential to deter abuse in a specific patient. Many abuse-deterrent opioid products contain a combination of 2 or more abuse-deterrent technologies. There are benefits and limitations of different strategies, but no single formulation can be expected to deter all types of opioid-abuse behaviors.19, 20

Certain ADFs are better suited to prevent particular routes of abuse than others; this is largely dependent on the individual ADF’s method of deterring abuse.13,19 Abuse via crushing, extracting, or dissolving a product can be prevented with physical and chemical barriers that hinder these processes. For example, an ADF of ER morphine sulfate (MorphaBond) has physical properties that provide increased resistance to cutting and crushing, as well as chemical properties that transform the product into a viscous solution upon contact with a liquid environment.9 These barriers restrict the abuser’s ability to administer the product through intranasal or intravenous routes, but they are not sufficient barriers to prevent abuse via supratherapeutic ingestion if the product is taken orally with the tablet intact.

In contrast, products that contain aversive agents induce undesired pharmacological effects when an excessive dose is taken orally, even if the product is consumed intact. An example includes an abuse-deterrent formulation of IR oxycodone (Acurox) that contains subtherapeutic amounts of niacin as an aversive agent.21 The niacin was intended to induce flushing and other unpleasant effects when taken in excess and was demonstrated to reduce likeability scores and defer abuse of the product. However, the FDA did not approve this drug because of safety concerns.13 The disadvantage of this product and other products containing aversive agents is that they increase the risk of adverse events even in compliant patients who are taking the drug appropriately.

Regulatory Guidance for Abuse-Deterrent Opioid Formulations
In 2013, the FDA provided a guidance document for pharmaceutical manufacturers that set standards for the evaluation and regulatory approval of novel abuse-deterrent opioid analgesics.18 The guidance document outlines the quantity and quality of studies that must be conducted for the new opioid medication to be considered for FDA-approved abuse-deterrent labeling. Manufacturers are incentivized to conduct the necessary studies to seek abuse-deterrent labeling for their opioid medications because it allows them to promote and market these products as ADFs.

Four categories of studies are evaluated by FDA for products seeking ADF designation:

Preclinical in vitro manipulation and extraction studies
In vivo pharmacokinetic studies assessing manipulated or “abused” forms of the drug
Clinical studies assessing the potential for consideration of the ADF product
Postmarketing epidemiologic studies

The aim of a category 3 clinical study is to assess abuse potential outcomes of the ADF, such as drug likeability scores, and compare these to the same drug without abuse-deterrent properties to provide evidence for abuse deterrence. The aim of category 4 post-marketing studies is to determine whether a product results in meaningful reductions in abuse, misuse, overdose, and other clinical outcomes in the community. The FDA anticipates that data from some or all 3 categories of premarketing studies could support a statement that an ADF opioid has been shown to reduce abuse, although they may not fully predict abuse potential in the postmarketing setting; such a statement would require supporting data from category 4 studies.

Multiple prescription opioid medications have been approved by FDA and incorporate abuse-deterrent technologies, some of which are proprietary, to attain abuse deterrence (Table 2). However, only a subset of these meets FDA standards to be designated as an ADF.22 It is possible for an opioid product with abuse-deterrent properties to be approved by the FDA but not be approved to carry abuse-deterrent labeling if the FDA does not find that the data produced from studies demonstrate adequate abuse-deterrent potential. For example, a reformulated version of oxycodone hydrochloride and acetaminophen extended-release tablets (Xartemis XR) that employs physical and chemical abuse-deterrent technology was approved by the FDA in 2014 but was not granted official abuse-deterrent labeling.22, 23

To date, 9 opioid analgesics have FDA-approved ADF labeling—Arymo, MorphaBond, Hysingla ER, OxyContin, Troxyca ER, Targiniq ER, Embeda, Vantrela ER, and Xtampza ER. Manufacturers of these medications are encouraged by the FDA to include data on their abuse-deterrent studies in their product labeling to increase awareness among healthcare practitioners.18,22

In 2016, the FDA released a second guidance document that set forth instructions for pharmaceutical companies interested in developing generic versions of abuse-deterrent opioid products that already are on the market.24 This emphasizes that the FDA considers this area of development to be a public health priority and encourages the development of ADFs for various opioids. However, the FDA also makes it clear that non-ADFs of opioid medications must remain available on the market because there are patients who cannot tolerate ADFs, such as hospice patients requiring crushed medications.18

Impact of ADF Oxycodone on Prescription Oxycodone Abuse
The first ADF to appear on the US market was a reformulation of ER oxycodone tablets (OxyContin) in 2010.22 At this time, this ADF is the only product with published postmarketing results on its effectiveness in deterring abuse.25 Several studies have demonstrated that the reformulation has led to decreased rates of prescribing and abuse of oxycodone and oxycodone-related fatalities in the United States.25-29

The rate of abuse among patients prescribed OxyContin was 0.42 per 100 person-years of opioid use prior to release of the ADF. After the release, the rate of abuse decreased by 34%, to 0.28 per 100 person-years.25 Rates of abuse remained stable for 4 other comparator opioids that did not have abuse-deterrent versions introduced, providing evidence that the reductions were specific to ADF OxyContin and not to other opioid analgesics.

An analysis of a surveillance sample of 140,496 individuals found that abuse of ADF oxycodone was 41% lower than abuse of historical non-abuse deterrent oxycodone.26 This study found that the rates of reduction varied depending on the route of abuse, with a significant, 66% reduction for nonoral routes of oxycodone abuse (injection, snorting, and smoking) and a more modest reduction of 17% for oral abuse. This reveals that the physiochemical barriers of this ADF formulation may pose more of a deterrent to nonoral than oral routes of abuse. Anecdotal reports also suggest, however, that the reduction in OxyContin abuse also may be the result of increased regulatory surveillance, physicians’ reluctance to prescribe, and legislative changes.

Another study confirmed that the ADF of oxycodone can reduce rates of opioid abuse, but it is limited in that it does not protect against certain routes of abuse and users can overcome ADF technology.11 After a sharp, initial reduction from 45.1% to 26% in rates of oxycodone abuse after the introduction of ADF oxycodone, levels of abuse persisted from 25% to 30% in subsequent months without any further decrease.

Most participants who were able to continue abusing the ADF oxycodone stated they were able to do so either because of a transition from nonoral to oral routes of abuse (43%) or because of successful efforts to overcome ADF properties of the drug, allowing for nonoral routes of abuse (34%). Several of those who were able to overcome the ADF mechanisms consulted the internet for information on how to do so. It remains to be seen whether this issue will continue as newer ADF products with novel drug delivery systems and potentially more resistant abuse-deterrent mechanisms, such as Vantrela ER and Xtampza ER, are developed.

Impact of ADF Oxycodone on Overall Prescription Opioid Abuse
Although it is clear that the oxycodone ADF resulted in a reduction of abuse and diversion of oxycodone, many studies noted that there is limited evidence that abusers ceased their overall drug abuse as a result of the reformulation.

A study by Cicero et al, which collected data from 2,566 anonymous surveys completed by opioid users with prescription opioid dependence, found that the selection of OxyContin as a primary drug of abuse decreased from 35.6% of respondents to 12.8% just 21 months after the release of ADF oxycodone (P <0.001).27 However, during the same time frame, use of fentanyl and hydromorphone as the primary drug of abuse increased significantly. In addition, a smaller sample of patients who were individually interviewed showed that 66% switched from abusing OxyContin to abusing another opioid, with heroin being the most common agent to which abuse was diverted because it was “cheaper, easier to use, and easily available.”

An analysis by Michna et al specifically examined the degree to which any patient previously receiving non-ADF versions of prescription opioids for treatment either agreed to switch to the ADF versions of the same opioid medication or requested switching to another non-ADF opioid drug.30 After introduction of the abuse-deterrent OxyContin, 69.4% of previous OxyContin users agreed to take the abuse-deterrent medication and 25.4% chose to switch to another ER or long-acting non-abuse deterrent opioid medication.

A similar trend occurred with ADF of oxymorphone. Some patients in both groups chose to discontinue any long-acting opioid medication after the introduction of the ADF. The authors found that patients who switched to alternative non-ADFs or those who altogether discontinued using the abuse-deterrent versions of prescription opioid medications were more likely to be opioid abusers. Rates of diagnosed opioid abuse among patients treated with oxycodone who switched to non-ADF opioids or discontinued opioids altogether were 6.7% and 10.5%, respectively, while the rate of diagnosed opioid abuse in those who agreed to switch to the abuse-deterrent oxycodone was only 3.5% (relative risk, 1.9; P <0.001).

Impact of ADF Oxycodone on Heroin Abuse
Two years after the manufacturing change for ADF oxycodone, the estimated overdose rate involving prescription opioids decreased by 20%, but the rate of heroin overdose increased by 23%.31 Multiple studies have found that a decrease in prescription opioid-related deaths following the development of ADF products has been accompanied by an increase in heroin-related deaths. However, the authors of these studies noted that this correlation cannot be attributed solely to the use of ADF medications without controlling for other potential confounding factors, such as other opioid-related policies, prescription drug monitoring programs, or national trends that may have caused increases in heroin use.16, 31, 32

A recently published report from the National Bureau of Economic Research attempted to control for all of these factors and concluded that the data clearly show that “a substantial share of the dramatic increase in heroin deaths since 2010 can be linked to the reformulation of OxyContin.”33 By analyzing the pre-2010 rates of OxyContin misuse by individual state, it was discovered that states with the highest initial rates of OxyContin misuse experienced the largest reductions in OxyContin abuse and also the largest increases in heroin deaths after the reformulation.

The authors determined that the introduction of abuse-deterrent oxycodone in 2010 caused a unique supply disruption that led to a high degree of substitution with heroin. It was estimated that each percentage point reduction in the rate of OxyContin misuse due to reformulation led to 3.1 additional heroin-related deaths per 100,000 people.33 The authors emphasize that this study only evaluated short-term effects of reformulated oxycodone. They raise the possibility that long-term ADF use eventually may prove effective by deterring new cases of abuse. However, they caution against any supply-disrupting strategies to tackle opioid abuse as long as a substitute (such as heroin) remains readily available.

Impact of ADFs on Cost Savings
Prescription drug abuse has an estimated societal cost of approximately $56 billion annually in the US.34 Cost savings due to the introduction of ADFs are believed to be substantial because of reductions in both direct and indirect costs such as abuse treatment programs and medical costs for abuse-related emergency visits and hospitalizations.35 However, these cost savings depend upon a range of assumptions, including the actual cost of the ADFs and their efficacy in deterring abuse and related clinical outcomes.

To date, only 1 study has examined the postmarketing economic impact of an ADF opioid.34 This study evaluated the impact of reformulated ADF oxycodone (OxyContin) and found that its introduction resulted in significantly lower rates of diagnosed abuse in commercially-insured, Medicaid, and uninsured patients. The authors estimated that the total annual medical cost savings was $86 million and $344 million from reductions in diagnosed abuse and undiagnosed abuse, respectively. This study did not examine cost savings related to abuse-related mortality, loss in productivity, or emotional and financial burden on family members, because the evidence is still unclear on the effect of ADFs on these outcomes.

A significant limitation of the current body of literature is that a majority of the published studies on the epidemiologic impact of ADFs focus solely on the first developed ADF of OxyContin. The postmarketing impact of this single ADF cannot be generalized to all other ADFs. First, OxyContin will not necessarily have the same impact on abuse as other ADF products because of its own unique platform technology and abuse-deterrent strategy. It also is important that at the time of release of ADF OxyContin, there were no other ADF formulations on the market to provide safe and effective alternatives for patients whose abuse was not deterred by ADF OxyContin. There are 9 ADFs, and several other products contain abuse-deterrent properties but do not have the official label. Therefore, additional postmarketing studies that reflect the availability of alternative ADF opioids will be crucial to evaluate the overall societal impact of ADFs.

Financial Barriers to ADF Use
Although ADFs of opioids are predicted to be cost-effective overall, their increased average cost in comparison to the average cost of non-abuse deterrent opioids can present a financial barrier.36 One report estimates that the average cost of a tablet of an abuse-deterrent opioid ($12.24) was $9.04 higher than the average cost of a non-abuse deterrent opioid tablet ($3.20). In addition, health insurance plans that were sampled often required prior authorizations for abuse-deterrent opioids, further limiting patient access to these medications. Patients who are unwilling or unable to support these increased costs will not continue the ADF medication, and abusers may transition to more dangerous alternatives that are less expensive, such as heroin.

To address this issue, legislation has been introduced in several states requiring third-party insurers to make ADF opioids available to patients at the same cost as non-ADF versions.37 Critics of this legislation argue that there remains an evidence gap on the effectiveness of these products and such mandates will result in staggering costs to the healthcare system because insurance companies will lose the ability to negotiate with pharmaceutical manufacturers to reduce overall prices of branded ADFs. However, some have estimated that, while the costs of the abuse-deterrent products are high, an overall reduction in costs associated with opioid abuse justifies their higher expense.38

Another potential solution for this issue will be the development and approval of generic abuse-deterrent opioids, which likely will lower drug costs by introducing market competition for the current branded abuse-deterrent products.24 The FDA has shown a public commitment to the development of generic ADFs because they are predicted to increase prescribers’ uptake of abuse-deterrent products and reduce costs.39 Unfortunately, brand products have market exclusivity for several years after being approved, meaning that no identical generic versions of the products are able to be approved.40

For this time period, the increasing costs of ADFs will remain an issue for healthcare providers, patients, and third-party payers. Healthcare providers should keep open communication with patients on this issue and direct patients to financial assistance resources. Many products have savings cards or coupons provided through their respective pharmaceutical companies (Table 2). However, patients whose prescriptions are covered under Medicare, Medicaid, or other government programs are not eligible for these savings.41

Future Directions
Providing access to prescription opioid analgesics for patients with chronic pain while minimizing diversion and abuse remains a significant challenge for healthcare practitioners, pharmaceutical companies, and the FDA. Attempts to mitigate prescription and nonprescription opioid abuse will require a comprehensive approach, of which ADFs of opioids are just one component.

The use of abuse-deterrent opioids in clinical practice requires an understanding of the advantages and inherent limitations of current abuse-deterrent products and technologies as well as the financial barriers to access. The benefits of ADFs to improve abuse-related outcomes must be weighed against evolving evidence that they may have the unintended consequence of shifting potential abusers to nonoral routes of abuse, other opioid prescriptions, or non-prescription opioids such as heroin, which may pose a much greater overall risk to public health.

Expanded availability and reduced costs may improve access and favorable outcomes, but ongoing research is required to fully elucidate the net positive and negative effects of ADFs of opioids on public health.