Friday, August 12, 2011

Abuse-Deterrent Opioids; A Better Mousetrap?

Opioids With addiction reportedly on the rise due to the misuse of prescription opioid analgesics, drug makers are devising clever ways of discouraging such aberrant behaviors. Consequently, a new generation of “abuse-deterrent” opioid formulations is emerging. Questions remain, however, about whether these medications will better serve the needs of patients with pain.

According to a recent online article by Hannah Waters in Nature Medicine [August 4, 2011, here], the U.S. Food and Drug Administration (FDA) approved this past June a new abuse-deterrent formulation of short-acting oxycodone, called Oxecta®. The new pill becomes gummy if crushed, making the oxycodone ingredient harder for misusers to extract as a powder and snort or inject for a quick, potent high. “It lends itself less well to standard practices of laypeople trying to abuse it,” notes anesthesiologist Howard Smith, MD, of Albany Medical Center in upstate New York, quoted in the article.

Devising better analgesics is big business, Waters claims in her article. Healthcare providers wrote more than 200 million prescriptions for opioid medications in the U.S. during 2009. Meanwhile, the number of people entering treatment programs for opioid addiction increased 5-fold between 1998 and 2008, and “a July 2010 report from the U.S. Centers for Disease Control and Prevention points to pain killers as the leading cause of fatal drug overdoses,” she writes.

Not every “abuse-deterrent” design has received regulatory approval. Last June, a few days after the Oxecta announcement, the FDA rejected a similar product, Remoxy®, because of manufacturing problems. Remoxy combines a crush-resistant technology similar to that found in Oxecta, but with a time-release element that adds complexity.

Another analgesic in this new generation of opioid formulations has faced setbacks. King Pharmaceuticals, now a subsidiary of Pfizer, pulled its morphine formulation Embeda® off the shelves last March. Each pill has a core of naltrexone, which blocks opioid receptors and negates effects of morphine if the pill is crushed and misused. However, naltrexone also can be difficult to stabilize as a core component, so the drug has experienced repeated recalls.

While most of the new formulations target persons who snort or inject crushed pills, a group that represents 10% to 20% of all opioid abusers, according to the report in Nature, simply swallowing too many pills can be just as risky. An earlier formulation of Oxecta targeted this type of oral abuse but the FDA denied its approval in 2009.

That drug, called Acurox®, incorporated the anti-cholesterol drug niacin, which causes uncomfortable skin flushing if large amounts are ingested. 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, MD, in the Nature article. Webster is 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, a biotechnology firm in California, PharmacoFore, is developing a complex formulation containing an opioid 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 abd releases the opioid. Since trypsin isn't found in the bloodstream, snorting or injecting the medication is ineffective.

This experimental analgesic includes an interesting safety feature: each pill is co-formulated 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 in time). The drug just completed phase 1 clinical trails and, reportedly, met all of the endpoints that had been established for this stage of testing.

COMMENTARY: These days, with increasing fears and regulations surrounding opioid analgesics, this new generation of opioid formulations will be a welcome addition to the pain treatment repertoire, IF it helps to assure continued access to essential opioids for patients with pain who need them. Certainly, “abuse-deterrent” formulations have been praised by a number of authorities in the pain field, as well as U.S. government agencies, as at least part of a solution for escalating problems of opioid misuse, addiction, and overdose. However, there are a number of questions that we have not seen adequately addressed in the literature:

  • The new formulations may not confer added analgesic effectiveness, that is not their intention, but in daily practice will they provide pain relief that is at least comparable to existing opioid products?

  • Will the new formulations incur added costs — if only due to more complex manufacturing processes? And, will health insurance plans, including Medicare/Medicaid, pay for these newer medications? If not, will average patients be able to bear the added burdens of cost?

  • According to the better research data, only a relatively small population of all persons misuse opioids for nonmedical purposes — such as crushing to snort or inject, or swallowing excessive amounts for recreational use — and an even smaller percentage of legitimate patients misuse their analgesics in these ways; so, should ALL patients be prescribed the newer formulations or only those believed or known to be at special risk?

The recently released report on Relieving Pain in America from the U.S. Institute of Medicine [IOM, highlighted in UPDATES here and here] observes that, “Ironically, while many people with pain have difficulty obtaining opioid medications, nonmedical users appear to obtain them far too easily.” Will these new formulations truly be an effective and long-term deterrent to misuse and curtail increases of opioid addiction and overdose? As with all other expectedly “foolproof” mechanisms built into products to prevent misuse or harm, genuine fools seem to be very clever at circumventing them.

The IOM report also states in italics for emphasis that “the majority of people with pain use their prescription drugs properly, are not a source of misuse, and should not be stigmatized or denied access because of the misdeeds or carelessness of others.” As an unintended consequence, will the new formulations serve as a barrier to adequate pain care while doing little in themselves to stem addiction? As Steven Passik, PhD, observes in the Nature article, “Ultimately, clever pill design will need to be paired with therapy and monitoring to prevent addiction.” Passik is Associate attending psychologist, Department of Psychiatry and Behavioral Sciences at Memorial Sloan-Kettering Cancer Center in New York.

We do not have answers for the questions posed above. But they seemed worth asking. What do readers think — comment below.

Throughout this article in Nature, a very credible publication, the author used the term “pain killer” — which we changed to “pain reliever” or “analgesic” — in reference to opioid medications. This use of “killer” in conjunction with a beneficial and potentially life-saving medication is unfortunate and hopefully does not reflect a pervasively negative bias of the news media.

Secondly, the term “abuse-deterrent” used by government agencies and in this article from Nature is perhaps a misnomer, since “abuse” can have various connotations and its overall use in this context is poorly defined. “Tamper-resistant” is sometimes used to describe certain new formulations; however, this also is vague in comparison with, say, “crush-resistant.” To their credit, the term “proof,” as in “abuse- or tamper-proof,” is never used.

Finally, a complete listing of prescription opioid analgesics, including the latest FDA-approved formulations and links to associated Medication Guides and REMS programs, can be found at Opioids911-Safety [here].