Widespread abuse of medicines that treat chronic non-malignant pain has led to the development of abuse-deterrent opioid formulations. Paul Titley, Director of Business and Commercial Development, Aesica Pharmaceuticals, looks at the challenges
Prescription drug abuse has emerged as a major epidemic in the US and now accounts for 75% of all overdose deaths, with opioids alone accounting for 75% of those fatalities. Opioid abuse costs the US healthcare system $72.5 billion annually.
There is huge healthcare demand for effective treatment of chronic non-malignant pain disorders. Statistics suggest that this is a silent epidemic sweeping the US, affecting approximately 116 million citizens. It is now one of the most common reasons why patients seek medical care. It is estimated that this costs the US economy more than $600bn per annum when measured in medical costs and decreased work productivity.
Chronic pain has been clearly identified as a disorder associated with many psychosocial conditions including appetite loss, depression and sleep disturbances. As a consequence of this, the use of multimodal therapeutic plans have become imperative for the effective treatment of patients suffering such pain. This includes interventional therapies, such as injectable medications, nerve blocks and transcutaneous electrical nerve stimulation (TENS) which are used in multiple situations. Such therapeutic plans will typically employ the use of both opioid and non-opioid analgesics to help control the pain.
There is at present a great deal of discussion about the long-term use of opioids in the treatment of chronic non-malignant pain. Some of this discussion stems from the lack of data supporting supporting long-term opioid use due to a lack of efficacy, on-going concerns about adverse effects, but of most critical concern is the issue of the serious potential for opioid misuse and abuse.
Pressure for solutions is also coming from the US Food & Drug Administration (FDA). In this context, the FDA has looked actively into ways of addressing this drug abuse problem, with members of the US Congress considering introducing legislation that would limit opioid use.
The regulatory authority started requiring risk mitigation strategies of extended-release and long-acting opioids
In April of this year, the FDA took the unusual step of banning any generics of the original long-acting formulation of a well-known drug in the category OxyContin. It stated that the danger of abuse outweighed the benefits of a cheaper version of the product. But most positively, it also, for the first time, gave OxyContin maker Purdue Pharma the right to put a specific claim on its new version of the drug that it is abuse-deterrent. Furthermore, the regulatory authority is encouraging the development of new tamper-resistant products and started ‘requiring risk mitigation strategies of extended-release and long-acting opioids.’
In such an environment, doing nothing is not an option for pharmaceutical drug manufacturers.
Abuse and misuse of these medications remains a serious public health challenge, with abuse rates quadrupling during the period 1990 to 2000. Moreover, it is estimated that 70% of illegal users obtain opioids by stealing them, purchasing them illegally, or receiving them from family or friends. These individuals seek to obtain a high from prescription medications by taking an excess number of pills orally or by crushing the pills, followed by snorting, smoking, or injecting the new altered formulation.
By altering the prescribed formulation, many abusers seek to create what is known as the ‘dump’ effect, or an acceleration associated with a rapid ‘high’. This effect results in a much higher peak serum concentration (Cmax) over a shorter period of time (Tmax). This pharmacokinetic change results in a pharmacodynamic response or in the abuser’s desired ‘reward’ of euphoria. Consequently, each opioid should be examined for its potential abuse quotient (AQ = Cmax/Tmax). The abuse quotient can be reviewed to calculate the rate of rise achieved by the drug in either the blood or the brain when the formulation is manipulated by the abuser.
Extended-release formulations hold a greater attraction for abusers than immediate-release formulations because of their pre-dose level of drug
Critically, extended-release (ER) formulations hold a greater attraction for abusers than immediate-release (IR) formulations because of their pre-dose level of drug. ER opioid formulations provide much higher drug concentrations that can be manipulated. When ER formulations are altered, there are two important effects. There is a more rapid onset of action (a shorter Tmax) than that proposed by the manufacturer. Equally, there is a greater euphoria or anxiolysis, an effect that abusers desire.
Abuse deterrent formulations (ADF) are developed with a number of specific goals in mind. These general goals include producing a drug that is safe and effective for the intended population, one that does not easily cause serious harm to the potential abuser, and a medication that is economically feasible. The additional component added to the development of an ADF is that it must also deter abuse by potential abusers.
Research aimed at finding reliable data on the most commonly abused drugs and their preferred routes of administration by abusers can be extremely helpful in determining which drugs need an ADF and which characteristics the new drug will most likely exhibit.
Indeed, the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) database was created to track drugs of abuse, their current popularity and their preferred method of use by abusers. The database further breaks down each drug of abuse into percentages that show the drug’s use within the previous months and the routes by which it is most often abused. A thorough examination of this database would assist the pharmaceutical industry to focus on the drugs of abuse that generate the most concern and to identify the delivery routes that new formulations should specifically strive to deter.
For example, a review of the database would lead to a simple conclusion that investing large amounts of time and money into the development of new formulations of hydrocodone that deters injection would be a clear waste of resources, because just 1% of hydrocodone users inject the drug.
Explicit claims may be made when clinical trials establish that the new formulation has been shown to deter abuse
As soon as an innovation for an ADF is under development, the next crucial step is to show that the drug is safe and effective for the treatment of pain and that it deters abuse. The current ‘gold standard’ in clinical trials is to compare the abuse liability of a new opioid or opioid formulation with that of an opioid of known abuse liability in volunteers that have a history of past drug abuse. If the trial shows a low abuse liability within this population, the abuse liability in the general population can be expected to be low.
Clinical trials can lead manufacturers to make FDA-approved implicit or explicit claims, which can be included in the product’s labelling. Implicit claims may indicate that the new formulation might have some impact on the abuse but has not yet been proven. Explicit claims may be made when clinical trials establish that the new formulation has been shown to deter abuse. These claims and any materials promoting the new formulation are closely monitored by the FDA, and serve as incentives that drugs companies receive for investing their time and money in products that some would consider unnecessary or that would serve only to protect the public from itself.
Aesica Pharmaceuticals, is collaborating with QRxPharma on the development of new treatments for pain management using abuse-deterrence technology
One effective method for creating an ADF is to add a pharmaceutical or chemical component to the opioid. A strong example is the addition of naloxone to decrease the user’s response to an abused substance or to provide an adverse reaction when the user alters the formulation. This type of modification is made to try and decrease the abuse quotient of the particular opioid formulation. Another method is to deter the user’s ability physically to alter the drugs original manufactured form to extract the active ingredient through various methods, such as crushing, chewing, or mixing with a solvent, such as alcohol.
Industry collaborations are actively in place to meet the challenge and to develop abuse-deterrent solutions that meet with the pressing demands of the market. For example, Aesica Formulation Development, a subsidiary of Aesica Pharmaceuticals, formed an industry collaboration with QRxPharma for the development of new treatments for pain management using QRxPharma’s proprietary abuse-deterrence technology, known as Stealth Beadlets.
In response to clinical concerns and pressures concerning drug abuse, many manufacturers are now actively developing opioid products with abuse-deterrent qualities
Stealth Beadlets may be incorporated into almost any potentially abused drug (e.g. opioids, amphetamines, sedatives, etc.) that is sold in solid dosage forms (e.g. tablet, capsule, sachet). They provide significant resistance to the extraction of active ingredients if crushed, solubilised or heated. Stealth Beadlets have no effect on the active ingredient release profile and consist entirely of patient-safe, low-cost, excipients that have GRAS (Generally Regarded As Safe) status with the FDA. Patent applications for the ADF technology are currently under review at the US patent office, and, if granted, will provide for product exclusivity until 2029.
This programme is ready for Phase 2 studies and has shown that the incorporation of Stealth Beadlets into a formulation is a relatively simple task.
The various types of pain and treatment options pose a huge challenge to the international healthcare markets. Opioids can provide effective therapies for various chronic non-malignant pain conditions. In response to clinical concerns and pressures concerning drug abuse, many manufacturers are now actively developing opioid products with abuse-deterrent qualities.
Clinicians need fully to understand the characteristics of these agents if they are to improve the care of their patients with chronic non-malignant pain. The introduction of new formulations has improved management options for clinicians who develop treatment plans.