Abuse-deterrent Technologies in Opioid Medications: A New Weapon in the Fight against Misuse and Abuse

Pharmaceutical manufacturers, aided by a US Food and Drug Administration (FDA) decision to expedite review of formulations designed to be tamper-resistant, have recently won approval for several such products and others are currently undergoing trials.

Initial anecdotes about the oldest of the available medications suggest they may have contributed to reductions in abuse. Unfortunately, peer-reviewed studies of individual medications may be years away. Worse, because drug users will generally choose the easiest substances to abuse, even the best studies of single medications may mean little. The only true way to test whether the new products work may be to first displace nearly all the older, cheaper medications from the market and then monitor to see whether abuse declines.

Doctors thus find themselves in a difficult position. Either they prescribe traditional medications and undermine efforts to test new products that may save thousands of lives, or they force their patients, most of whom will never misuse their medications, to spend, collectively, many billions of dollars on experimental technology that may, in the end, do little or nothing to deter abuse.

“The idea of a technical fix, something that will just make the abuse problem go away, is enormously appealing to health care professionals who just want to focus on medications,” says Mary Lynn McPherson, PharmD, Professor and Vice Chair of the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy. “But we have plenty of reason to doubt whether technical solutions will work‑‑nothing on the market can deter all manner of drug abuse‑‑and we have no reliable way to test these products without involving millions of patients and billions of dollars.”

“The idea of a technical fix, something that will just make the abuse problem go away, is enormously appealing to health care professionals who just want to focus on medications. But we have plenty of reason to doubt whether technical solutions will work.”

—Mary Lynn McPherson, PharmD, Professor and Vice Chair of the and Science at the University of Maryland School of Pharmacy

Fighting abuse on multiple fronts

Prescription drug abuse falls into two major categories. Many abusers simply take too many pills, sometimes after chewing them or using alcohol to speed the high. Other abusers manipulate a drug — often by crushing it, heating it, or bathing it with water, alcohol, or other substances — to prepare it for snorting, smoking, or injection. The former behavior, over-ingestion, is far more common than the latter, alternate delivery, but alternate delivery tends to be more dangerous and lead to a disproportionate number of deaths and other serious consequences.

In trying to prevent these behaviors, pharmaceutical companies are engineering medications with several fundamentally different technologies, each with its own strengths and weaknesses:

Tamper Resistance

impedes efforts to break an extended-release pill down and extract its active ingredients in fast-acting form. Some formulas guard only against crushing. Others resist many manipulations.

Chemical Combinations

mix standard analgesics with antidotes that block the high or irritants that annoy users. Some formulations only release the second drug if the pill is crushed or otherwise manipulated. Others are engineered to resist over-ingestion.

Pro-drugs

replace standard analgesics with chemicals that only activate when processed in the digestive system, which means they do nothing if smoked, snorted, injected, or otherwise routed around the digestive system.

Novel delivery systems

do away with pills. Patches worn on the skin can weave medication into material so that it’s very hard to extract. Implantable analgesic delivery systems would pack a month’s supply into a device inserted under the skin.

Many of the recently approved medications employ some technology or technologies from the first category, tamper resistance, to combat varying abuse strategies.

The Oxecta formulation of generic oxycodone HCI, which was approved this summer but has yet to reach stores, becomes gummy when crushed. The new formulation of Oxycontin and the Exalgo formulation of generic hydromorphone, which are both on the market, combine some crush resistance with new chemical barriers designed to ensure the slow and steady flow of medication.

Another strategy was tried by Embeda, which was approved but pulled from the market because of manufacturing difficulties. Embeda placed generic morphine around a core of naltrexone, a chemical that blocks opioid receptors. Efforts to manipulate the drug broke the barrier between the morphine and the naltrexone and, in clinical trials, created opioid withdrawal rather than a high.

In addition to recently approved drugs, there are at least three more on the market, two of which date back to the 1970s. Talwin NX and Valoron N and the newer Subutex all combine analgesics with naloxone, which counteracts some analgesic euphoria and opiate overdose.

Other formulations, using different technology, have recently made unsuccessful bids for FDA approval. The agency rejected the Remoxy formulation of oxycodone, which combined another form of crush resistance with a new time-release formula. (Many observers expect that a resubmission will soon win approval.) The Acurox formulation of oxycodone, which added enough of the anti-cholesterol drug niacin to create uncomfortable sensations in those who swallowed too many pills, was likewise rejected, on grounds that the potential for curbing oxycodone abuse, deadly as it can be, still did not justify inflicting medically benign discomfort on abusers.

The FDA has yet to review other experimental formulations that employ all four anti-abuse technologies, alone or in combination.

The most anticipated of those is a pro-drug manufactured by PharmacoFore that just completed phase 1 trials. That medication binds an opioid with a polymer that blocks opioid absorption until the medication reaches the small intestine, where exposure to the enzyme trypsin releases the drug. Smoking, snorting, or injecting the drug should thus produce no high. A further safeguard, trypsin inhibitors built into each pill, is designed to prevent the body from metabolizing more than one pill’s worth of medication in cases of over-ingestion.

Evidence of effectiveness

As pain specialists wait for information from trials of new drugs, and peer-reviewed studies of those that are on the market, there is some evidence that the new Oxycontin formulation may substantially reduce abuse. Online chatter in user forums indicates that many drug users who loved the old Oxycontin formula have abandoned the new one for other pills. Spot checks of ERs along with surveys of drug abusers have found likewise.

Historical experience with Talwin and Valoron also suggests that abuse-deterrent formulations can actually deter abuse. Both medications, upon initial introduction, were abused so frequently that authorities in various countries threatened to ban them. But the introduction of naloxone to the formulations, which created Talwin NX and Valoron N, seemed to solve much of the problem for both drugs.

“No one should expect opioid abuse statistics to plummet with the availability of abuse deterrent opioids. The promise of abuse-deterrent opioids will take years to translate into epidemiologically measured reductions in abuse.”

—Christopher Gharibo, MD, Medical Director of Pain Medicine and Associate Professor of Anesthesiology and Orthopedics at NYU Langone-Hospital for Joint Diseases

“No one should expect opioid abuse statistics to plummet with the availability of abuse deterrent opioids. The early feedback from people abusing Oxycontin is promising, as is the evidence from opioids like Embeda that these analgesics have the potential to limit euphoria and curb abuse,” says Christopher Gharibo, MD, Medical Director of Pain Medicine and Associate Professor of Anesthesiology and Orthopedics at NYU Langone-Hospital for Joint Diseases.

“The promise of abuse-deterrent opioids will take years to translate into epidemiologically measured reductions in abuse. It will take years for abuse-deterrent short- and long-acting opioids to displace current opioids. Five years would be a minimum. Five to ten years seems more likely, particularly with the understandable stance the FDA has taken on abuse-deterrent labeling,” says Gharibo.

Before approving any new formulation designed to resist manipulation or curb abuse, the FDA checks to see that it works as advertised. Still, even after confirming this, the agency will not allow any new formulation to make any claims about tamper resistance, abuse deterrence, or increased safety on its label, in advertisements, or during sales pitches. At least, not initially; the drugs must earn the right to market themselves as safer by meeting targets set as part of multi-year Risk Evaluation and Mitigation Strategy (REMS) assigned to each at approval.

The FDA’s cautious approach is designed to prevent pharmaceutical companies from marketing products on claims that are yet unfounded. But clinicians like Gharibo, who want to speed the spread of abuse deterrent formulations, worry that the FDA’s stance will greatly slow the collection of data that will demonstrate whether the new formulas work.

Without labels that proclaim greater safety, there can be little justification to force patients or insurers to pay extra for the new formulations, and yet the only way to test the new medications will be to pay more.

Is this approach cost-prohibitive?

In cases where one branded medication replaces another, the costs may be comparable, but in cases where abuse-deterrent medications seek to replace existing generics, the cost will be many times higher. A month’s supply of generic hydromorphone, for example, costs around a dollar a day. A month’s supply of Exalgo retails for $1,000 or more, depending on dosage.

Looked at on a societal scale, the potential costs are staggering. JAMA reported that doctors prescribed hydrocodone/acetaminophen 100 million times back in 2005. Multiply that figure by the cost differential between today’s generics and a hypothetical abuse-deterring replacement and the result, conservatively, runs to tens of billions per year. This would be a massive cost to impose upon insurers and patients — most of whom will never abuse a drug and won’t get any benefit whatever in exchange for spending thousands of extra dollars — even if it were certain that new medications could entirely eliminate abuse.

“The problem of abuse has grown so large that it legitimately threatens the ongoing ability of the medical profession to prescribe and ailing patients to receive vitally needed pain medication.”

—Steve Passik, PhD, Professor of Psychiatry and Anesthesiology at Vanderbilt University Medical Center

The cost appears even larger when considering that today’s experimental formulations do nothing to combat over-ingestion, which is by far the majority of the problem, and they may not even curb the alternate delivery abuse they’re targeted against. If this turns out to be the case, then how can the cost be justified?

“The problem of abuse has grown so large that it legitimately threatens the ongoing ability of the medical profession to prescribe and ailing patients to receive vitally needed pain medication,” says Steven D. Passik, PhD, Professor of Psychiatry and Anesthesiology at Vanderbilt University Medical Center. “A patient with severe pain is far better off paying more for highly effective opioid medications than getting a good deal on the less effective pain medications that will have to do if more restrictions are placed on opioid use,” he says.

Passik also says that physicians should not try to save costs by prescribing the more expensive drugs only to “high-risk” patients. Screening tools have produced mixed results when it comes to reliably identifying high-risk patients, and have an even worse record when it comes to detecting situations in which a low-risk patient shares a home with a high-risk spouse or child.

“Pain specialists will, in large part, be the ones determining how fast we adopt individual medications,” Webster said. “It’s important that they keep current so they can make wise choices.”

—Lynn Webster, MD, co-founder and chief medical director of Lifetree Clinical Research

Frontline pain practitioners are still the first line of defense

Ultimately, however, it will be up to the people who write the prescriptions to decide, at least for the next few years. “Might the FDA step in and mandate a transition? If the new medications perform well in the field but still fail to win over the marketplace, it might happen, but not for many years,” says Lynn Webster, MD, FACPM, FASAM, co-founder and chief medical director of Lifetree Clinical Research.

“Pain specialists will, in large part, be the ones determining how fast we adopt individual medications,” Webster said. “It’s important that they keep current so they can make wise choices.”