Roadblocks to Opiate Abuse

Many individuals live with pain, either chronic or acute. An estimated 100 million Americans suffer from chronic pain.¹ Pain causes stress and suppresses immune responses, which make medical problems worse. The use of opiates to manage pain has increased. Unfortunately, along with the rise in opiate prescriptions is the increase in abuse. By 2012, 2.1 million Americans were addicted to prescription opiates.² Opiates for pain relief were involved in 14,800 drug overdose deaths in 2008 versus 11,500 in 2007.³

To combat opiate abuse and its dire consequences, drug makers developed many strategies. Some formulations allow active medicine for pain relief while blocking excessive blood levels at receptors. Other strategies alter opiate availability in a physical manner, so that drugs can no longer be snorted, injected, or dissolved.⁴

Opiates act on specific receptors that evolved to respond to endogenous opiates such as dynorphin and enkephalin. Receptors include μ, δ, and Κ, distributed at γ-aminobutyric acid (GABA)-releasing axons. They can inhibit GABA release onto dopamine-producing neurons in the nucleus accumbens, increasing dopamine-induced pain relief. Unfortunately, in addition to relieving pain, dopamine is also heavily implicated in addiction. Many newer opiate formulations are designed to achieve a balance at receptors, relieving pain but blocking excessive levels associated with abuse and addiction.

Partial blocking with naloxone

Approved in 2002 for opiate dependence, Suboxone is a combination of buprenorphine and naloxone in a 4:1 ratio. In addition to treating abuse, it is used as therapy for chronic pain. Buprenorphine is a partial opioid agonist at μ-opioid receptors and an antagonist at κ-opioid receptors. By itself, buprenorphine relieves pain, but because it is an antagonist at higher doses, it can prevent abuse. The addition of naloxone adds further abuse prevention, as an opioid antagonist with no agonist activity.

Naltrexone combinations

Embeda, a morphine/naltrexone analgesic, is a gelatin capsule of the μ-opioid antagonist naltrexone within a morphine-containing pill. The naltrexone is released if the tablet is crushed, blocking the opiate effects of morphine. If the pill is taken as intended, naltrexone has a minimal effect.

Another medication, under development with Elite Pharmaceuticals, is ELI-216, which is a combination of oxycodone and naltrexone. ELI-216 is similar to Embeda in that naltrexone is only released when the medication is crushed, dissolved, or otherwise extracted. Naltrexone in this case is sequestered within small beads placed inside the gel capsule.

Resisting manipulation

Drug manufacturers have developed several different technologies that allow for pain management but deter abuse on the basis of their physical properties alone. For example, Opana ER, marketed by Endo Pharmaceuticals, is a controlled-release oxymorphone in a drug matrix called INTAC Technology, created by the company Grünenthal. INTAC makes a drug resistant to crushing, dissolving, cutting, and chewing. Even when the medication has been tampered with, release properties stay the same. According to an informational brochure released by Grünenthal, this is based on “polyethylenoxide (PEO) of high molecular weight and a proprietary hot-melt extrusion process that combines the two factors of heat and pressure.”

With similar intentions to prevent pill manipulation, Acura Pharmaceuticals has developed Aversion technology. Three different strategies prevent abuse, although all are not incorporated into one medication. For example, if the medication is crushed, it turns into nasal cavity irritating chunks. When mixed with liquid, it becomes a difficult-to-inject gel. The third strategy is the addition of niacin to an opiate, which causes itching, headache, and chills when too much is ingested. Symptoms go away after about 90 minutes.

As an example, Acuracet uses Aversion technology. It is an immediate-release oxycodone/acetaminophen combination, with deterred nasal inhalation and intravenous injection. However, in a recent phase 2 trial, the technology did not elicit a negative enough response in users who snorted the medication, and the FDA requested further information from Acura. Vycavert is another opioid analgesic developed by Acura, which contains hydrocodone and acetaminophen. It also uses Aversion technology to prevent nasal inhalation and intravenous injection.

Remoxy is an oxycodone developed by Durect, Pain Therapeutics, and Pfizer. It is resistant to injection and snorting because of its Oradur technology. In a statement on their Web site, Durect states that Oradur “uses a high-viscosity base component such as sucrose acetate isobutyrate to provide controlled release.” They further claim that this component makes it more difficult to abuse medications containing Oradur technology by crushing or dissolving them. Remoxy is currently in phase 2 clinical trials.

Slow on the uptake

Maintaining gradual, consistent drug release properties is another way to keep opiates from being abused. NkTR-181 is a μ-opioid agonist for chronic pain currently in phase 2 trials with Nektar Therapeutics. Its reduced abuse potential is based on slower entry into the CNS, because it is conjugated to small polymers. Slower entry also reduces euphoric effects and potential for respiratory depression.

Exalgo contains hydromorphone and is delivered via the OROS (osmotic extended-release oral delivery system). The slow controlled-release mechanism and crush-resistant nature of the tablet and makes it difficult to abuse. The ALZA company developed OROS, and tablets consist of a rigid shell with one or more holes drilled into them. After ingestion, water enters the tablet. Osmotic force gradually pushes the active drug through holes in the tablet.

COL-003 is an oxycodone that uses DETERx technology, which maintains the medication’s extended-release qualities even if the medication has been crushed or dissolved. Collegium Pharmaceutical developed both the medication and the technology. The medication consists of beads within a capsule. Active molecules are contained within a matrix, in a fatty acid-ionic complex. The matrix contains the extended-release mechanism at a microscopic level, so crushing a pill does not change release, even when the medication is sprinkled on food.

Dr Barry Setlow of the University of Florida College of Medicine Center for Addiction Research and Education commented on the new opiate formulations. He states, “Addiction is a heterogeneous disorder, and different prevention approaches will be effective in different individuals. Just as reducing easy access to prescription opiates has proven effective in reducing abuse, minimizing the abuse liability of opiates once they are prescribed should further reduce abuse, allowing for safer and more effective pain management.”

July 9, 2014, marked the release of the President’s drug policy blueprint. In contrast to waging a war on drugs, it emphasizes understanding addiction as a brain disease. Perhaps consistent with this idea, current opiates contain roadblocks to actively stop addiction from developing, rather than leaving it up to human will alone.

References:

1. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011. http://books.nap.edu/openbook.php?record_id=13172&page=1. Accessed August 19, 2014.

2. National Institute on Drug Abuse. National RX Drug Abuse Summit. April 21, 2014. http://www.drugabuse.gov/about-nida/noras-blog/2014/04/national-rx-drug-abuse-summit. Accessed August 19, 2014.

3. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers-United States, 1999-2008. MMWR Morb Mortal Wkly Rep. 2011;60:1487-1492.

4. Moorman-Li R, Motycka CA, Inge LD, et al. A review of abuse-deterrent opioids for chronic nonmalignant pain. Pharm Ther. 2012;37:412-418.