Abuse-Deterrent Opioid Formulations: Purpose, Practicality, and Paradigms

When reflecting on commonly abused drugs, pharmacists generally focus attention on cocaine, amphetamines and methylphenidate, barbiturates, hallucinogens such as ketamine (“Special K”), benzodiazepines, marijuana, and designer drugs such as “bath salts." However, the standouts these days seem to be heroin and prescription opioids.

According to the National Institute on Drug Abuse, the number of deaths from prescription opioid analgesics has sky rocketed from 2001 to 2011, accounting for a 4-fold increase in the total number of deaths from opioids and creating what many claim to be an “opioid epidemic.” In 2013, the US Centers for Disease Control and Prevention (CDC) revealed that opioid analgesics including Vicodin and OxyContin caused 75% of prescription drug overdoses, outpacing both cocaine and heroin overdoses combined. The most up-to-date data is posted on the CDC's Prescription Drug Overdose in the United States: Fact Sheet.¹

While extended-release (ER) opioid analgesics are an essential component of pain management, abuse and misuse of these medications can cause substantial morbidity and mortality. Abusers often manipulate ER opioid formulations by crushing, chewing, snorting, vaping², or injecting the total dose. Drug seekers are particularly interested in the ER formulations because tampering with these products provides them with a higher maximum concentration of the drug in a small volume of powder, which is easily snorted with minimal discomfort compared to the large amount of powder (and excipients) required of standard immediate-release (IR) dosage formulations.

For this reason, at least in part, lawmakers and the FDA have assigned blame to ER formulations for the opioid epidemic and increased mortality from overdose. Without a doubt, the fire was disproportionately fueled when the FDA approved Zohydro ER, a prescription single-entity hydrocodone ER medication. Zohydro ER uses a Spheroidal Oral Drug Absorption System (SODAS), which is not an abuse-deterrent formulation (ADF). Once ingested, the hard gelatin layer dissolves and gastrointestinal fluid enters the beads. The active medication then diffuses out of the beads, allowing both immediate and time release of hydrocodone.

There have been several legislative attempts to combat the opioid epidemic over the years. For instance, Congressmen Bill Keating (D-MA) introduced the Stop the Tampering of Prescription Pills (STOPP) Act to address opioid abuse and misuse. The STOPP Act³ was the first federal legislation that directed pharmaceutical manufacturers to invest in research and production to create ADFs of opioids.

Subsequently, the FDA has tried to combat the epidemic by creating more stringent regulations regarding approval of opioid formulations. In fact, the FDA is moving towards a requirement for all future formulations of ER opioids to contain abuse-deterrent properties.

ADFs are designed to obviate tablet or capsule manipulation for dose dumping orally, crushing and/or dissolving for injection, or snorting. Various designs for ADFs have been suggested, including physical/chemical barriers, agonist/antagonist combinations, aversion properties, altered release design, or a prodrug formulation of the medication.

There are numerous opioids that have abuse-deterrent properties but have not been approved by the FDA as an ADF. These include Exalgo (hydromorphone), Nucynta ER (tapentadol), Opana ER (oxymorphone), Oxecta (oxycodone), and Xartemis (oxycodone and acetaminophen).

Nucynta ER has properties that make it difficult to crush, cut, or break. Exalgo is available in an Osmotic [Controlled] Release Oral [Delivery] System (OROS) tablet, a dosage form that renders it relatively crush resistant, allowing gradual release of the hydromorphone when used as directed. Oxecta possess 2 unique abuse deterrent properties, as its formulation contains sodium lauryl sulfate, which makes snorting the medication unpleasant, and an excipient that causes the tablet to form a gel if any attempts are made to dissolve it. Similarly, when Opana tablets are crushed, they turn into a gel that is difficult to inject.

The FDA has issued draft guidance⁴ on abuse-deterrent opioids to assist pharmaceutical manufacturers in creating formulations of opioids with ADFs. The document suggests that drugs must contain the following properties in order to be recognized as abuse deterrent opioids by the FDA:

Physical/Chemical Barrier: drugs with physical barriers that can prevent chewing, crushing, cutting, grating, or grinding of the dosage form. Dosage forms with chemical barriers should resist extraction of the opioid through use of common solvents including water, alcohol or other organic solvents.

• Agonist/antagonist combinations: An opioid antagonist is added to the formulation to interfere with the release of the opioid if the medication is taken in any other way than it was intended.
• Aversion: Substances are added to the dosage form to produce an unpleasant effect if the dosage form is manipulated prior to ingestion or if a higher dosage than directed is used.
• Delivery system: Alternative delivery systems such as a depot injectable or an implant that is more difficult to manipulate.
• Prodrug: Medication contains a prodrug that lacks opioid activity until it has been transformed in the gastrointestinal tract.
• Combination: 2 or more of the above methods can be combined to deter abuse.

The opioids that have been designed consistent with the FDA’s 2013 draft guidance and have thus been approved as ADFs include Embeda (morphine sulfate/naltrexone HCl), Hysingla (hydrocodone), a new formulation of OxyContin (oxycodone), and Targiniq ER (oxycodone/naloxone).

OxyContin reformulation contains features that make it difficult to crush, cut, or break the tablets. Embeda contains properties such that crushing or snorting the medication will release morphine sulfate with the opioid antagonist naltrexone. Targiniq ER works as an ADF similar to Embeda, except it contains naloxone which is only released if the tablet is crushed, snorted, or dissolved.

Interestingly, Targiniq ER may come with less constipation compared to most other ER formulations when used as prescribed because the naloxone is available within the gut but is poorly absorbed. This in turn will block opioid receptors within the gut that are otherwise responsible for opioid induced constipation.⁵ Although Targiniq ER is an abuse-deterrent product from the standpoint of injection, it still can be crushed and ingested orally as an IR dosage form.

Hysingla is similar to the OxyContin formulation in that its physical and chemical properties render it difficult to crush, break, or dissolve. Once crushed and placed into liquid, Hysingla forms a thick gel that makes it difficult, if not impossible, to inject.

None of the ADFs can address 1 lingering concern: all medications can be misused and abused if the user ingests medications that are not prescribed to them or ingests more tablets than prescribed, regardless of the technology. Furthermore, there are ways to circumvent some of these ADFs.

Just Google “methods to crush OxyContin.” There are several blogs and YouTube videos that offer techniques to crush the new formulation of OxyContin. A blog called Bluelight⁶ suggests that OxyContin users can place the drug into their mouths for roughly 1 to 2 minutes to dissolve the coating, and then allow it to dissolve in acidic beverages such as lemon juice or root beer. Once in the beverage, the tablets expand and start to break apart (in as little as 2 to 4 hours) and are easy to consume.

Another blog, MedsChat, lists that OxyContin can be baked⁷ for 10 minutes, then wet with water and reheated in a microwave until the pill dissolves for injection. Another user on MedsChat suggests using a nutmeg grinder with a sealed container to grind OxyContin and catch the shavings. It is inevitable that drug abusers can find ways to circumvent barriers to deter them from abusing opioids.

The government has spent millions of dollars fighting the “war on opioids”; however, little has been done to date to treat substance abuse as a disease, as opposed to criminalizing such behavior, the result of which makes it difficult for addicted patients to seek help that is needed.⁸ Moreover, it is clear that immediately following the reformulation of OxyContin, there was a surge in abuse of oxycodone IR 30 mg and generic Opana (oxymorphone) ER tablets.⁹

While ADF is a step towards combating prescription drug abuse, it is not the only solution. We must remember that a synonym for “deterrent” is “discourage,” not “prevent”. It is also important to recognize that all ADFs are brand name only, which results in the much dreaded prior approval process, non-coverage, or higher-tiered co-pays, which are all problematic in the highest -risk populations.

As health care professionals, we must seek a comprehensive method that involves not only ADFs, but also collaborative drug therapy management between providers, utilization of PDMP, and prescriber/patient education tools. While it is incumbent upon all of us to prevent opioids from getting into the wrong hands, we shouldn’t deny legitimate patients from receiving the medications they need.

This article was collaboratively written with Nabeela Ahmed, a 2015 PharmD candidate at the Albany College of Pharmacy and Health Sciences. Ahmed hopes to complete a PGY1 and PGY2 Pharmacy Residency and become a clinical pharmacy specialist in the future. Her focused areas of interest include critical care and cardiology. She is currently under the mentorship of Dr. Fudin while studying pain management.

This article is the sole work of the authors and stated opinions/assertions do not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies listed.

References:

• Prescription Drug Overdose in the United States: Fact Sheet [internet]. 2015. [Accessed 2015 January 26]. Available from:www.cdc.gov/homeandrecreationalsafety/overdose/facts.html
• Police Warn of New Way to Use Drugs in Plain Sight [internet].2013. [Accessed 2015 January 26]. Available from: http://www.10tv.com/content/stories/2013/10/01/Columbus_Electronic_Cigarettes.html
• Keating Introduces Bipartisan STOPP Act to promote abuse-deterrent technologies in addictive painkillers [internet].2013. [Accessed 2015 January 26]. Available from: http://keating.house.gov/index.php?option=com_content&view=article&id=225:keating-introduces-bipartisan-stopp-act-to-promote-abuse-deterrent-technologies-in-addictive-painkillers&catid=14&Itemid=13
• Guidance for Industry: Abuse-Deterrent Opioids- Evaluation and Labeling. 2013. [Accessed 2015 January 26]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf
• Kominek C, Fudin J. Overview and Novel Therapies for Opioid induced Constipation [internet]2014. Available from: http://paindr.com/overview-and-novel-therapies-for-opioid-induced-constipation
• OxyContin (OP Formulation) Questions [internet]. 2011. [Accessed 2015 January 26]. Available from: http://www.bluelight.org/vb/archive/index.php/t-576055.html
• Baking Op [internet]. 2014. [Accessed 2015 January 26]. Available from: http://www.medschat.com/topics/baking-op/
• Gerritt J. Criminalizing addiction: Whether drug users go to prison depends on where they live. [internet]. 2014. [Accessed 2015 January 26]. Available from:http://www.toledoblade.com/Courts/2014/09/07/Criminalizing-addiction-1.html
• Leger DL. Opana abuse in USA overtakes OxyContin.[internet] 2012. Available from: http://usatoday30.usatoday.com/news/nation/story/2012-07-10/opana-painkiller-addiction/56137086/1