Abuse-Deterrent Hydrocodone Passes Phase 3

Pauline Anderson

March 14, 2014

Patients with chronic low back pain taking a once-daily extended-release (ER) single-entity hydrocodone formulation experienced a statistically significant reduction in pain compared with those taking placebo, according to new topline phase 3 study results.

If approved, the agent (hydrocodone bitartrate, Purdue Pharma LP) would be the first ER hydrocodone product with abuse-deterrent properties, the company said in a statement issued earlier this week. Although not totally abuse-proof, the product contains a polymer that makes it difficult to crush; it becomes gummy, which prevents it from being easily snorted or drawn into a syringe to inject.

The company also has an approved abuse-deterrent formulation of oxycodone (OxyContin).

Small Step

Development of such products is an "important but small step forward" in tackling the widespread problem of abuse and misuse of opioid drugs, according to Lynn R. Webster, MD, immediate past president, American Academy of Pain Medicine, and vice president of scientific affairs, PRA International, Salt Lake City, Utah. He would like to see these drugs replaced with "nonrewarding" analgesics.

Pressure has been building from government and consumer and specialty groups to offer abuse-deterrent pain medications to combat what some call an "epidemic" of abuse related to opioid drugs.

Purdue has invested considerable resources into developing a portfolio of such agents, said Gary Stiles, MD, senior vice president of research and development. "Purdue believes that products with abuse-deterrent characteristics provide a societal benefit and should be increasingly adopted into clinical practice of pain management."

The double-blind, randomized, multicenter study of the new ER product evaluated 588 opioid-naive and opioid-experienced patients with moderate to severe chronic low back pain (average pain score of 7.4 on a scale of 0 to 10, with 0 being no pain) over 12 weeks. The primary endpoint was the mean pain intensity over a 24-hour period recorded daily during the last week of the double-blind period.

To achieve adequate pain control before randomization, the dose for hydrocodone bitartrate ER was increased once every 3 to 5 days, if necessary, until a stabilized once-daily dose (20 to 120 mg) was identified.

The study showed that most patients treated with hydrocodone experienced at least a 30% improvement in pain intensity. Nearly half (48%) achieved a 50% improvement with hydrocodone bitartrate. The most common adverse events were constipation, nausea, vomiting, dizziness, and headache.

In addition to this safety and efficacy study, Purdue has conducted a series of laboratory manipulation and extraction studies, pharmacokinetic studies, and clinical abuse potential studies with this investigational medication, the company notes. Purdue announced plans to file a New Drug Application with the US Food and Drug Administration (FDA) later this year requesting approval to market this medication.

Chronic pain conditions affect more than 100 million US adults. The annual cost to the US economy is estimated to be as much as $635 billion in direct healthcare expenses and lost productivity.

In the United States, hydrocodone products are the most commonly prescribed opioid analgesics. However, they're also the most widely abused in terms of nonmedical use, according to the Substance Abuse and Mental Health Services Administration, the Purdue release notes.

Introducing opioids with abuse-deterrent properties is among the strategies being developed to tackle this growing problem. Last fall, the FDA announced stricter labeling on ER/long-acting (ER/LA) opioids and plans to change the scheduling for hydrocodone combination medications, such as Vicodin (a combination of hydrocodone and acetaminophen), from Schedule III to Schedule II to increase security measures.

As part of its label change plans, the FDA said it will remove the indication of moderate pain and replace it with pain "severe enough" to warrant ER/LA opioids. As well, the FDA clarified that ER/LA opioids should be used only if alternative treatment options, including nonopioid analgesics or immediate-release opioids, have been ineffective or not tolerated or would be otherwise inadequate.

The FDA also outlined steps to acquire additional data on the use, misuse, abuse, addiction, and overdose of opioids, and suggested that industry players work together to accomplish this end.

Unusual Move

However, at about the same time that the FDA announced these changes, it approved a single-entity ER hydrocodone product (Zohydro ER, Zogenix Inc), which doesn't have abuse-deterrent technology. Many in the pain management field found that move unusual not only given the proposed schedule change for hydrocodone combination products but also because its own advisory panel had recommended against approving the drug.

The approval sparked a call for its reversal by 29 state attorneys general and a coalition of groups calling itself FedUp!: A Coalition to End the opioid Epidemic.

Zogenix has since announced it has entered into an agreement to develop abuse-deterrent formulations of Zohydro ER.

In addition to this new ER form of hydrocodone and oxycodone, other abuse-deterrent products are coming down the pipeline, so there should eventually be several options. "Not all patients respond the same way to, or can tolerate, a particular medication," commented Dr. Stiles. "That is why clinicians need an array of therapeutic options, including medications and other treatment modalities, so that they can tailor the care of their individual patients."

However, the technology being used in these new products doesn’t erase the potential for abuse by swallowing multiple intact pills. "As long as opioids are available, they are going to be abused, people are going to take them in excess of what’s been prescribed, and they are going to die," commented Dr. Webster. "There is such a significant public health problem around these prescription drugs that something has to be done to make the formulation safer."

He said he wants to see the National Institutes of Health fund more research to develop nonrewarding analgesics. "We need to have analgesics that don’t have rewarding properties and that are as powerful and effective as an opioid."


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