Abuse-Deterrent Opioids (ADOs) have been the focus of recent pharmaceutical research both in the United States and internationally. The impetus for this research is that most of the currently available extended-release opioids, indicated for individuals requiring around-the-clock analgesia, do not provide sufficient deterrence to disruption of the extended-release mechanism. So check out this video about the Development of Abuse-Deterrent Opioids:
This disruption of delivery system integrity may be intentional (by misusers), or unintentional (inadvertently done by patients or family caregivers). Intentional disabling of the extended-release systems for misuse may lead to physical and psychological dependence.
Moreover, both forms of disruption to the delivery system may lead to acute toxicity from exposure to supratherapeutic opioid doses, potentially causing overdose and even death. It is imperative to understand the means by which these drugs are misused in order to understand the approaches being taken to thwart such efforts.
The primary means of opioid abuse is simply over-consumption of an intact product. Abuse also occurs when individuals physically crush the product and then swallow the medication. Abusers may also inhale or smoke the active agent extracted from the crushed product or inject the drug after combining it with a simple solvent. Strategies are being developed to deter these efforts at misuse.
Two strategies have been employed in the effort to create more difficult-to-abuse formulations. There are, of course, clinical and ethical quandaries posed by ADOs. The first strategy is for opioids to have either antagonist agents (i.e. naltrexone or naloxone), or aversive elements that are included with the analgesic agents.
The second strategy utilizes specialized physical barriers to the various forms of disruption of the extended-release mechanism. These are so-called tamper-resistant or extraction-resistant formulations.
In the United States, the FDA has approved an extended-release formulation of morphine with sequestered naltrexone. This is a prototypical formulation containing an antagonist — in this case, naltrexone — sequestered within the nucleus of the formulation. When the medication is taken as directed, the opioid effect is not affected by the antagonist and there are clinical strategies in place to minimize the risk of prescription drug abuse and diversion.
However, disruption of the delivery system can liberate the naltrexone. Clinical trials have demonstrated that the product is an effective analgesic when used as directed. However, in preclinical studies of drug liking and euphoria, significant reductions in additional drug liking were observed and subjective reports of euphoria were diminished with the increase in naltrexone that was released.
It is unclear whether such effects will be of benefit in reducing misuse of this analgesic. There are two case reports of the intentional crushing of the product by opioid-dependent individuals who experienced significant withdrawal. Epidemiologic studies regarding prescribing ADOs have been proposed and are in review with the FDA to determine whether or not claims towards a reduction in misuse, abuse, and diversion can be substantiated.
Tamper Resistant/Extraction Resistant
Another abuse-deterrent approach attempts to create physical barriers or other means to frustrate efforts to disrupt the extended-release mechanisms. These drugs include different matrices in which the opioid cannot be easily separated from the extended-release formulation. See also this article about the Mayday Project and prescribing ADOs.
A new extended-release oxycodone delivery system has been formulated to resist simple crushing and has been made with a barrier that cannot easily be dissolved or chemically manipulated to cause the release of the opioid. Similarly, osmotic technology has been applied to an extended-release hydromorphone product, such that a simple extraction of the opioid cannot be easily accomplished, although it can still be crushed.
Both of these products have been available in the United States since 2010. Abuse is not limited to extended-release opioids. Immediate-release medications are frequently cited as major sources of misuse. Some work is being done in the immediate-release opioid categories. Currently, the FDA is considering a formulation of oxycodone immediate release that will be more difficult to make into an injectable or inhaled formulation.
The techniques involved in the development of these new abuse-deterrent formulations in pain management are not likely to deter all forms of abuse. None of the formulations offer a solution to over-consumption of the medication. Therefore, the need remains for additional types of innovative solutions to address the serious problem of drug abuse.
Ethical Considerations in the Use of Abuse-Deterrent Formulations
Prescribers may justifiably be concerned about the ethical issues surrounding the adoption of ADOs into clinical practice. These issues raise justice-based concerns about the increased cost of drug therapy due to the choice of a more expensive ADO product as an alternative to the standard product without ADO features.
Such a choice may unnecessarily increase health care costs or decrease access to needed medications. Incorporation of therapeutically unnecessary chemical moieties that deter abuse may have a beneficial impact on the public health due to the potential for the prevention of abuse or diversion, but offer limited or no benefit for the actual patient to whom the medication is prescribed.
This is difficult to justify according to the traditional responsibility of clinicians to act only so as to promote the patient’s well-being. Some ADO formulations may even have the potential to be harmful or unpleasant if the products are used incorrectly in non-abuse scenarios. Healthcare professionals who don’t feel comfortable anymore in their line of work may want to take a look at his article with some pretty unusual nursing jobs you may not have considered
The use of ADOs in the high-risk pain patient is clearly an ethically defensible aspect of prescribing, perhaps more so than is every day prescribing of non-ADO formulations for this population. The ethical principle of non-maleficence is placed in jeopardy of daily violation within this subgroup of high-risk patients.
Such an ethical dilemma is raised despite the prescribers intention to relieve the patients suffering due to pain when providing opioids inasmuch as such patients may actually be exposed to harm given this access (putting into conflict the principles of autonomy and beneficence on the one hand and non-maleficence on the other).
The suffering due to unchecked or re-kindled addiction in the provision of opioid therapy has only recently entered the dialogue surrounding opioid prescribing and is a serious argument for the adoption of the ADOs as they become available.
In the lower risk patient groups, ethical problems are raised when increased economic costs are to be incurred and/or patients are to be exposed to even minute amounts of chemical moieties that they do not need, or from which there is no potential to accrue benefit.
Clinicians are often wrong in their assessment of risk. Indeed, a recent study suggested that of the patients believed by their clinicians to be adherent to their opioid-based regimen, only 40% in fact were. These data suggesting an inability to detect risk correctly support the argument that ADOs should be adopted into widespread use just in case the assessment of low risk is inaccurate. And many clinics and hospitals have taken tentative measures to deal with not only EMR procedures but also on ADOs to be sure to comply with FDA requirements and regulations.
An increasing number of pain management clinicians routinely rather than selectively employ risk management tools. The use of these tools implies an advanced and more accurate understanding of risk stratification. Indeed, in such circumstances, the ethical conflict between the social justice concerns related to stemming the tide of opioid misuse may conflict with the ethical aspects of the patient’s individual healthcare.
While these are difficult issues, the placing of society’s well-being ahead of that of the individual patient’s healthcare rights is not unprecedented in the recent history of medicine, although it is highly controversial. For example, directly observed therapy to ensure compliance with a full course of anti-tuberculosis treatment to prevent the development of resistant strains violates the autonomy and privacy of the individual.
The same might be said of the periodic use of quarantine. These issues are far from settled in the use of ADOs, though a dialogue in the healthcare community should seek to clarify a position on such matters.