Friday, July 13, 2012

Abuse-Deterrent Opioids Spawn Upsurge in Heroin

Opioid FearsChanges in the formulations of OxyContin and Opana, making them less subject to misuse, ironically have former abusers of those drugs turning to deadly heroin, according to reports in the New England Journal of Medicine and USA Today. Meanwhile, as another unintended consequence, some patients with chronic pain say the newly formulated opioids do not work for them as well as before.

Researchers at Washington University School of Medicine in St. Louis report a study of OxyContin® (controlled-release oxycodone from Purdue Pharma LP) based on information gathered from patients entering drug abuse treatment during nearly 3 years [Cicero et al. 2012]. More than 2,500 patients from 150 treatment centers in 39 states answered survey questions about their drug use with a particular focus on the reformulated OxyContin.

“Our data show that OxyContin use by inhalation or intravenous administration has dropped significantly since that abuse-deterrent formulation came onto the market,” says principal investigator Theodore J. Cicero, PhD, in a news release on the study [here]. “In that sense, the new formulation was very successful.”

However, while many substance abusers shunned the new OxyContin, they did not stop their aberrant behavior. “The most unexpected, and probably detrimental, effect of the abuse-deterrent formulation was that it contributed to a huge surge in the use of heroin,” Cicero and colleagues observed. “We’re now seeing reports from across the country of large quantities of heroin appearing in suburbs and rural areas. Unable to use OxyContin easily, which was a very popular drug in suburban and rural areas, drug abusers who prefer snorting or IV drug administration now have shifted either to more potent opioids, if they can find them, or to heroin.”

The study found that, during the past few years, the number of participants who selected OxyContin as their primary drug of abuse decreased from 36% of respondents before the release of the abuse-deterrent formulation to 13% percent now. When users were asked about which opioid they used to get “high” in the “past 30 days at least once,” OxyContin decreased by 37% — whereas, during the same time period, reported use of heroin nearly doubled.

More in-depth interviews with a select group of patients revealed that two-thirds had switched to an opioid other than OxyContin, with heroin mentioned most prominently. A typical response from drug abusers was: “Most people that I know don’t use OxyContin to get high anymore. They have moved on to heroin [because] it is easier to use, much cheaper, and easily available.”

Many of those who moved on from OxyContin apparently went to Opana ER® (extended-release oxymorphone from Endo Health Solutions), according to a recent article in USA Today [“Opana abuse in USA overtakes OxyContin,” July 10, 2012, here]. Reporter Donna Leger observes that the dangerous popularity of Opana around the country sprang directly from drug abusers switching from OxyContin. Opana — a semisynthetic opioid analgesic that is more potent than OxyContin — was, until recently, available in a formulation that could be crushed for snorting or injecting.

In some locales, Opana emerged as a key drug of choice among substance abusers and addicts, the news article notes. The street price for a single 40 mg tablet soared to $65, compared with less than 1/8th of that price when purchased legitimately at a pharmacy. Along with abuse of the drug, came reports of increases in Opana-related overdoses and deaths.

However, like OxyContin, Opana was reformulated recently with abuse-deterrent features. Opana had come on the market in 2006 and the manufacturer developed a crush-resistant version in 2010, but that was not approved by the FDA until late 2011. By last month, June 2012, all strengths of the original formulation of Opana had been replaced by the newer crush-resistant tablet.

According to the USA Today report, the street price for remnants of the old Opana formulation has skyrocketed to $185 for a 40 mg tablet. That price has been off-putting to drug abusers and sparked a surge in heroin use, which law enforcement and addiction experts expect will grow worse as the last supplies of the old formulation are depleted and heroin fills the void.

COMMENTARY: We have previously lamented in these Pain-Topics UPDATES — most recently last month [here] — how the desperate drive to stem problems associated with the misuse and abuse of prescription analgesics may be headed in the wrong direction and provoking unintended consequences. These latest articles, above, reaffirm that heroin, with its attendant threats of morbidity and mortality, is reappearing with a vengeance.

Prior to approval, as with all pharmaceutical products, both OxyContin and Opana underwent extensive clinical testing to demonstrate that they were relatively safe and quite effective IF prescribed and used as directed. Because of their slow-release formulations the products could contain more active ingredient allowing less frequent dosing and added convenience for patients.

In the case of OxyContin, for example, Cicero and colleagues observe in their journal article that it was originally thought to be a solution to the abuse of opioid analgesics, because the slow release of its active ingredient, oxycodone, would not produce an immediate “high” favored by drug abusers. Unfortunately, drug abusers soon learned to evade the slow-release mechanism by crushing the pills and inhaling (snorting) the powder or dissolving it in water for injection; thereby, getting an immediate and powerful “rush.”

Additionally, the large amounts of oxycodone in each pill made OxyContin even more attractive to abusers, since standard oxycodone tablets contained smaller amounts of the drug and did not produce as big a rush or high when snorted or injected. Apparently, the experience among drug abusers had been similar with Opana and its oxymorphone active ingredient.

Then, in 2010, a new formulation of OxyContin was introduced, with a covering on each pill that is extremely difficult to crush. Plus, if the abuser is successful in extracting any ingredients, it becomes a sticky glob in the nose if snorted or if liquid is added, making it impossible to inject. As noted above, a similarly abuse-deterrent formulation of Opana was shipped to pharmacies this year, 2012.

It seems that these abuse-deterrent formulations have largely achieved their purpose in that substance abusers are turning away from OxyContin and Opana, but this has not meant that they are discontinuing their drug abuse. Unfortunately, a new drug of choice is an old scourge that never completely disappeared from the scene — heroin, which poses a far greater risk to individuals and public health.

There also may be another unintended consequence. There have been anecdotal reports from patients (often in comments to our various UPDATES articles) that the new formulations of OxyContin and Opana are not providing the same pain relief as before or, worse, causing adverse effects that patients did not experience with the original products. This is difficult to understand and, to our knowledge, there has been no research to confirm these effects.

The FDA requires that reformulated drugs must be biologically equivalent to the original versions; for example, a new 20 mg liquid formulation of a drug must be demonstrated as bioequivalent to an original 20 mg tablet version. Still, there have been examples of where patient responses to different formulations of some drugs have varied substantially and, usually, for reasons that are unknown. In the case of OxyContin and Opana, the active ingredients and their amounts are the same, but the packaging and some excipients (inactive pharmaceutical ingredients) were modified.

So, why were OxyContin and Opana changed? (And, we should add that some other analgesics also have been developed or modified to have abuse-deterrent features as well [see UPDATE here].)

Our understanding is that the new formulations were developed for one primary purpose: to satisfy pressures coming from government agencies that manufacturers must take actions to quell the misuse and abuse of their products. Improving the care of legitimate patients with pain as a result of the changes was not an objective of those directives. Indirectly, however, there was the threat that, if abuse of the products continued unabated, the government might impose restrictions on their prescribing and distribution that would limit access to those analgesics — which would be detrimental to both manufacturers and patients.

In retrospect, changing products to integrate abuse-deterrent features with no therapeutic benefits probably was not the best solution. In their New England Journal of Medicine article, Cicero and colleagues conclude, “abuse-deterrent formulations may not be the ‘magic bullets’ that many hoped they would be in solving the growing problem of opioid abuse.”

In the press release, Cicero compares attempts to limit drug abuse to a levee holding back floodwaters. “Where the new formulation of OxyContin may have made it harder for abusers to use that particular drug, the ‘water’ of illicit drug use simply has sought out other weak spots in the ‘levee’ of drug policy,” he says.

In the USA Today article, Jeffrey Reynolds, executive director of the Long Island Council on Alcoholism and Drug Dependence, describes the dilemma like a game of Whac-a-Mole: “You get a handle on OxyContin, they switch to Opana. My guess is it will be something new tomorrow.”

In our opinion, the problem is that this “game” is deadly… tomorrow has come…. and the “something new” is heroin. And, unless better strategies are developed to get at the roots of substance abuse in society, all other efforts at deterrence will be like putting short-lived patches on the levee to stop the flood.

REFERENCE: Cicero TJ, Ellis MS, Surrat HL. Effect of abuse-deterrent formulation of OxyContin. New Engl J Med. 2012(Jul);367(2):187-189 [abstract here].

Proviso: Pain Treatment Topics is supported in part by educational grants from Purdue Pharma LP, maker of OxyContin, and Endo Pharmaceuticals, maker of Opana ER. Neither of those organizations had any role in the initiation, development, or review of this UPDATE article and they are in no way responsible for its content; all facts are from the sources cited, all opinions are expressly those of the author.

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