With painkiller addiction on the rise, drugmakers have come up with clever ways to discourage such behavior. As recently as 20 June, the US Food and Drug Administration (FDA) approved a new abuse-deterrent formulation of oxycodone called Oxecta, developed by Pfizer and Acura Pharmaceuticals of Palatine, Illinois. The new pill becomes gummy when crushed, making the oxycodone harder for addicts to extract as a powder and snort for a quick, potent high. “It lends itself less well to standard practices of laypeople trying to abuse it,” explains anesthesiologist Howard Smith of Albany Medical Center in upstate New York.

Devising a better painkiller is big business. Doctors wrote more than 200 million prescriptions for opioid medications in the US during 2009. Meanwhile, the number of people entering substance abuse programs for opioid addiction increased fivefold between 1998 and 2008, and a July 2010 report from the US Centers for Disease Control and Prevention points to painkillers as the leading cause of fatal drug overdoses.

But not every 'abuse-deterrent' design has received a regulatory thumbs-up. On 23 June, only a few days after the Oxecta approval, the FDA rejected Remoxy because of manufacturing problems. Remi Barbier, president and chief executive officer of Pain Therapeutics in Austin, Texas, which developed the drug with Pfizer, says the companies are now working to resolve those issues.

Remoxy combines a crush-resistant technology similar to that found in Oxecta with a time-release element, so the pill is “trying to do a lot all at once,” says Sidney Schnoll, vice president of pharmaceutical risk management services at Pinney Associates in Bethesda, Maryland. “These are difficult products to produce.”

And Remoxy isn't the first abuse-resistant painkiller to face manufacturing setbacks. King Pharmaceuticals, a subsidiary of Pfizer based in Bristol, Tennessee, pulled its formulation of morphine—called Embeda—off the shelves in March. Each pill had a core of naltrexone, which blocks opioid receptors, thus negating the morphine if the pill is crushed, but can also be difficult to stabilize as a core component.

Tough to swallow

Many of the new painkiller formulations target addicts who snort or inject crushed pills, a group that represents 10–20% of all opioid abusers. But simply swallowing too many pills can be just as risky. An earlier formulation of Oxecta targeted this type of oral abuse, but the FDA rejected the drug in 2009. The pill, dubbed Acurox, incorporated the cholesterol drug niacin, which causes uncomfortable skin flushing. However, the FDA “didn't feel that the added potential side effects of niacin, though benign, were worth the potential benefit in deterrence,” says Lynn Webster, medical director and founder of Lifetree Clinical Research in Salt Lake City, Utah.

Rather than adding a deterrent ingredient or changing a pill's response to crushing, the Californian biotechnology company PharmacoFore is developing a biochemically complex opioid formulation. The active drug compound is attached to a polymer that prevents the drug from binding to cell receptors until it reaches the small intestine. Once there, the digestive enzyme trypsin activates the molecule, releasing the drug. Trypsin isn't found in the bloodstream, so snorting and injecting the medicine is ineffective. As a coup de grace against painkiller abuse, each pill is coformulated with a trypsin inhibitor that can block overdose if too many pills are taken at once (as the intestine only has a limited amount of trypsin at any given point). The drug just completed phase 1 clinical trails and “met all the endpoints that we had set,” according to Greg Sturmer, PharmacoFore's chief financial officer.

Ultimately, clever pill design will need to be paired with therapy and monitoring to prevent addiction, says Steven Passik, a psychiatrist and anesthesiologist at Vanderbilt University School of Medicine in Nashville, Tennessee: “At the end of the day, you can develop a drug that's like Fort Knox, but it's still meant to deliver [relief] to people in pain.”