Are Abuse-Deterrent Opioid Products A Double-Edged Sword? – Practical Pain Management – May 16, 2017 – By Jasmine Shah, PharmD and Ryan W Rodriguez, PharmD, BCPS
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.
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.
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.
This is not true for some pain patients, whose digestive disturbances limit their absorption of nutrients or anything else in the best of circumstances. They may not be able to digest the abuse-resistant medications because the chemical barriers that make opioids abuse-resistant also prevent them to be digested easily.
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
Abuse is defined as an intentional nontherapeutic use of a drug to achieve a desirable psychological or physiological effect.
While this definition may apply to this particular article, “abuse” is generally defined as not taking a medication “as prescribed”. Straying the slightest bit from the prescription instructions, like taking a pill earlier (or later) than prescribed or taking more (or even less) than prescribed, is defined as abuse.
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.
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.
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
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).
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.
Regarding “agent that will have the greatest potential to deter abuse in a specific patient”:
This assumes it’s possible to know not only who will abuse but even their preferred method. This is fantasy, not policy.
Fundamentally, this assumes almost everyone will abuse and all “reasoning” springs from that premise.
Meanwhile, the real problem, people suffering from addiction, is not addressed because there are not enough resources to treat them.
If all the money being spent on the drug war were instead spent on medication and counseling for people with addiction, we could
- significantly reduce the number of people with addiction,
- reduce the demand for illicit drugs,
- cut off the money flowing to drug cartels,
- reduce the amount of drug trafficking, and
- reduce crime.
Instead, we do nothing to help those with addiction who are driving the epidemic of overdoses.
Medication-assisted treatment has been proven to be the most effective treatment, but the spiritual 12-step-based method has both the public and public funds in its grip, despite its abysmal success rate of only~10%. In fact, the 90% who fail become repeat customers of the same ineffective treatment method over and over, generating even more profit.
Even worse, the few doctors willing to treat this population are limited in what they are allowed to prescribe.
And all this effort and expense is wasted on the 95+% of patients that don’t abuse their opioids. And, while the numbers of opioids prescribed have been declining for the last years, the numbers of opioid/heroin overdoses are still skyrocketing,
None of this makes sense, but drug-warriors cling to the old (from 1935) 12-step superstitions, the public is assaulted with ubiquitous warnings that 12-setp recovery is their only hope, and the government keeps funding and guiding people into these treatments.
There are benefits and limitations of different strategies, but no single formulation can be expected to deter all types of opioid-abuse behaviors
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.
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. 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.
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.
This is like forcing all knives to be manufactured dull to prevent murder, thus making them useless even for their intended purpose.
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.
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.
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.
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.
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. At this time, this ADF is the only product with published postmarketing results on its effectiveness in deterring abuse. 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.
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.
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%).
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.
Of course not! Addiction wasn’t addressed so the user simply switched to heroin.
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 [not patients, but abusers] 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.”
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).
These ADF’s only lead to a 3.2% difference in supposed opioid abuse and are over 4 times as expensive.
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.
Should be seen as a sign that addiction is the problem, not opioids, yet this only led to “doubling down” on same ineffective policies.
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.”
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
Impact of ADFs on Cost Savings
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.
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.
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.
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.
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.
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
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.
The makers of Oxycontin have managed to keep generics out of the market since 1995.
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
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.
To any rational person, it should be obvious that Addiction is the problem, not any specific drug.
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.