April 27, 2011 -- When the oxycodone brand called OxyContin was introduced in the late 1990s, its maker claimed that the drug's controlled-release mechanism would make it less likely to be abused.
The idea was that if it released its opioid slowly, rather than all at once, abusers wouldn't find the immediate rush they crave.
But it didn't take long for drug seekers to devise a workaround that foiled that plan.
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Chewing the tablet, crushing it, or dissolving and injecting it -- all destroyed the timed-release mechanism, which unpacked the full opioid punch faster than you could say, "Your brain on drugs."
Since that failed attempt at making a "safe" opioid, researchers have been experimenting with ways to make all prescription painkillers "abuse-resistant."
Although OxyContin maker Purdue had its "tamper-proof" version approved last year, few other attempts to abuse-proof these drugs have made it on the market.
In June, however, the FDA is expected to issue a decision about another oxycodone product -- Acurox, Pfizer's attempt (through the acquisition of King Pharmaceuticals) at entry into the abuse-proof market.
And a handful of other companies are pursuing a pharmacological solution to help mitigate what the federal government has described as an epidemic of prescription painkiller abuse.
Some are attempting to prevent abusers not only from inhaling and injecting the drug, but also from taking multiple pills all at once.
What's Out There
When the goal is making an opioid impenetrable to abuse, there are a host of tacks to take -- adding physical barriers to chewing, crushing, or mixing with alcohol or another liquid to separate out the active ingredient is the first line of strategy.
Another option is to combine agonists with antagonists, like adding naltrexone to oxycodone, or combining the opioid with aversive agents, like niacin.
OxyContin version 2.0 is a good example of the physical barrier strategy. It's resin-based, which not only makes it harder to pound into powder, but also makes it tougher to dissolve in water.
Another entry into the abuse-proof market, an agonist-antagonist, is the morphine sulfate-naltrexone combo marketed as Embeda. The antagonist naltrexone -- which blocks opioid receptors -- remains latent if the drug is taken as prescribed, but can reduce the effects of the morphine, or even lead to withdrawal, if crushed.
But Embeda was recently pulled from the market because of stability problems and will likely remain unavailable for many months, according to reports.
A handful of other long-acting opioids, including Tramadol, Exalgo, and Opana use other capsule manufacturing technologies to make pills crush resistant.
Next in Line
With Acurox, Pfizer tried to combine both a physical barrier and an aversive agent.
The barrier was not only designed to make the drug break down into crumbled chunks instead of powder if crushed, but also to make the drug become "sudsy" if it is mixed with liquid and drawn into a syringe, according to Dr. Gail Cawkwell, vice president of medical affairs at Pfizer.
It also contains an irritant that will affect the nose if inhaled, she said.
This is the second go-round for the Pfizer anti-abuse drug.
Last year an FDA advisory committee gave a thumbs-down to a version that also contained niacin as a means of preventing oral abuse.
Niacin, which can induce a chemical flush, was added as an extra disincentive, but critics said the flushing, could be easily defeated by taking an aspirin or even just food with the drug. Also there was concern that niacin could cause flush even among people who took the medicine as directed.
Yet the addition of niacin has been one of few means of addressing abusers who take handfuls of pills, which is particularly a problem with short-acting opioids like hydrocodone (Vicodin).
Cawkwell says the company is exploring other alternatives, and last December it submitted a new drug application (NDA) for a niacin-free version of Acurox. The FDA has fast-tracked this version and the company anticipates a final decision in June.
Pfizer has another abuse-resistant drug -- Remoxy, a gelatinous form of long-acting oxycodone -- also under FDA review.
In this case the formulation -- think molasses -- makes it impossible to crush or chew. Likewise it is too viscous to be drawn into a syringe and Cawkwell said that mixing it with alcohol to release the full potency of the opioid -- a popular technique used by abusers -- doesn't work.
She said that FDA is expected to rule on the Remoxy NDA later this year.
Other companies have pursued the agonist-antagonist route -- including Elite Pharmaceuticals with OxyNal and Pain Therapeutics with Oxytrex -- but the status of these products remains unclear. That may be related to troubles with Embeda, the other agonist-antagonist combination; it could also have to do with the fact that more companies are pursuing molecular-based solutions instead.
Collegium Pharmaceuticals has received FDA fast-track status to develop two long-acting opioids incorporating its DETERx technology, which involves a "multi-particulate matrix formation in a capsule."
Essentially, that's beads of gelatin oxycodone that are hard to crush and won't release a punch if pulverization is attempted, according to Dr. Lynn Webster, of Lifetree Pain Clinic in Salt Lake City, who is a consultant to various companies developing tamper-resistant drugs.
The bead-filled capsule is also intended to prevent overdose in patients who can't swallow pills and need to mix the contents with food or water.
Other companies are targeting the chemistry of opioids themselves and hoping to alter chemical structure to short circuit abuse.
Nektar Therapeutics said it has modified an opiate with a permanently bound polymer that slows the rate at which the drug can cross the blood-brain barrier. Dr. Lorianne Masuoka, chief medical officer for Nektar, told MedPage Today, "there's nothing you can do to make it enter the brain more quickly."
"This feature is inherent to the molecule," Masuoka added. "There's no coating, no polymer matrix. It's part of the chemistry itself."
The compound, NKTR-181, has just entered a phase-I trial that will enroll 75 patients.
Taking a similar path, PharmacoFore is using an amino acid to mask opioid molecules. Once the compound PF329 hits the small intestine, the amino acid is cleaved off by the digestive enzyme trypsin, activating controlled release of the drug.
No crushing or dissolving can sever the bonds of the molecule, according to PharmacoFore chief financial officer Greg Sturmer.
And because the key "unlocking" enzyme isn't in the blood, injecting or snorting the drug won't do the user any good.
The company thinks PF329 may also be effective at curbing oral, multiple-pill abuse. Sturmer said an additional investigative technology specific to PF329's chemistry can control the biological mechanism that modulates the release of the opioid.
"There's a progressive inhibition of the release of the drug," Sturmer said. "The more you take, the less ability your body has to activate the delivery system."
Data from human trials have demonstrated the efficacy of the molecular delivery system, although data on the oral, multi-pill abuse technology have been limited to animal models.
Physicians Play a Role
Webster, from the Salt Lake City pain clinic, recently described the PPF329 mechanisms in a presentation at the American Academy of Pain Medicine meeting in Washington. He noted that he serves as a consultant to PharmacoFore, but maintained that the technology was promising and could be a new approach to safer opioid prescribing.
Although making drugs less abusive would be helpful, it's unlikely to prove a panacea for the epidemic of painkiller abuse.
"The biggest problem we have is that there are too many people on opiates for pain when there's no evidence whatsoever that they work," said Dr. Richard Ries, professor of psychiatry at the University of Washington, referring to a lack of long-term data on long-acting opioids.
"It's great to have different opiates that people can't abuse," Ries added. "That will protect against some diversion. But it's really a fraction of the huge population of opiate-dependent people we have in the U.S."
Dr. Charles Argoff, a neurologist at Albany Medical Center, agreed that more effective physician prescribing is key to any hope of mitigating the nation's addiction issues.
"A drug can be designed more safely," Argoff said, "but we really have to use this class of drugs in a more optimal way."