Novel Compound Promising Alternative to Current Opioids

Pauline Anderson

March 22, 2017

ORLANDO — New evidence suggests that a novel kappa opioid receptor agonist called CR845 relieves pain and doesn't carry many of the side effects of currently prescribed opioids.

A phase 2 proof-of-concept study found that CR845 (Cara Therapeutics), being developed for acute and chronic pain and pruritus, is safe and effective for patients with osteoarthritis pain.

But Joseph Stauffer, DO, an anesthesiologist and chief medical officer of Cara, a small biotech company, believes this new agent can play a much larger role in pain management.

He discussed his company's research at a poster session here at the American Academy of Pain Medicine (AAPM) 2017 Annual Meeting.

CR845 attaches to kappa opioid receptors in the peripheral nervous system and doesn't cross the blood-brain barrier, so it doesn't carry some of the "baggage" that currently prescribed opioids do, Dr Stauffer told Medscape Medical News.

"This drug has no abuse liability," he said, adding that it also doesn't cause respiratory depression.

He listed several other advantages, too. "The drug will not make you chronically constipated; the drug will likely not be scheduled; and the drug is excreted through the kidney so there's no chance for drug-to-drug interactions."

Main Receptors

Opioid analgesia is mediated through three main receptor types. In addition to kappa opioid receptors, there are delta opioid receptors and mu opioid receptors. Many of the opioids commonly prescribed for pain, such as morphine and oxycodone, are mediated through the mu opioid receptor.

The new study included 81 patients, mean age about 63 years, who had osteoarthritis of the hip or knee and had an average pain intensity in the index joint of at least 4 on the 0- to 10-point numeric rating scale (NRS).

Participants had to be willing to stop taking pain medications beginning 5 days before baseline and throughout the 2-week study period.

Researchers evaluated four cohorts of 20 or 21 patients sequentially at escalating oral doses of CR845 (0.25 mg, 0.5 mg, 1.0 mg, and 5.0 mg) taken twice daily.

Study patients could take acetaminophen as a rescue medication.

Of the 81 patients, 44% reported at least one adverse event, with the incidence being highest for the 1.0-mg (50%) and the 5.0-mg (85%) groups. The most common adverse events included nausea, thirst, dizziness, and headache. Most events were mild or moderate.

As for pain, Dr Stauffer's poster showed that the area under the curve for NRS pain scores was significantly less over time in the 5.0-mg group than the pooled results of the 0.25-, 0.5-, and 1.0-mg groups (P = .02).

Rescue medication was used significantly less often in the 5.0-mg group compared with pooled results of the other groups (P = .033 at 2 weeks).

The percentage of patients who rated the change in their osteoarthritis as "very much improved" or "much improved" increased with increasing doses.

Dr Stauffer referred to another study the company has carried out — a phase 2 study of the intravenous version of CR845 after laparoscopic hysterectomy. The study showed that a single postoperative dose of CR845 significantly reduced pain.

Another phase 2 trial of the drug, in patients undergoing bunionectomy, showed the drug had a significantly greater decrease in pain intensity compared with placebo.

The company is running phase 3 pivotal trials in patients having a hysterectomy and those undergoing surgery to fix a hernia in the abdomen, said Dr Stauffer.

Another advantage of this new agent is that, unlike currently available opioids, it doesn't require tapering, commented Dr Stauffer. "You can stop this drug cold turkey if you wanted to; there's zero withdrawal."

Not as Effective

Medscape Medical News approached Steven P. Cohen, MD, Colonel, US Army (retired), chief of the Pain Medicine Division and director of clinical operations and professor of anesthesiology and critical care medicine, neurology, and physical medicine and rehabilitation, Johns Hopkins School of Medicine (Baltimore, Maryland) and Uniformed Services University of the Health Sciences (Bethesda, Maryland), and director of pain research, Walter Reed National Military Medical Center (Bethesda), for comment.

It's understandable that researchers are looking for alterative pain drugs because of the side effects of the currently available opioids, said Dr Cohen. But he pointed out that it's because these opioids work on mu receptors that they're so effective as analgesics.

"It would be great if you could get a drug that worked for pain that didn't have the same side effects," said Dr Cohen. "That's why people are looking at kappa-receptor antagonists that maybe people don't develop a tolerance to, or work on the periphery nervous system so they don't have the same side effects."

The problem is that "these are definitely not as effective for pain," said Dr Cohen. 

"You give someone a pure kappa agonist and you give them oxycodone — oxycodone will win every time," when it comes to pain relief.

Dr Stauffer also reported new data from a human abuse liability trial in which recreational opioid and hallucinogen users were given placebo and three doses of intravenous CR845 — in a four-way crossover design. That study found no strong liking for the drug.

He told meeting delegates that he doesn't see CR845 replacing morphine or oxycodone. "I don't think we will ever replace mu opioids with our compound; mu opioids are necessary; they're clearly important."

During a question-and-answer period, one delegate asked when the drug would be available — "because we need it now." Dr Stauffer estimated that the drug could be approved in 2 to 3 years but that because it's a novel compound, "it will likely go to an advisory committee."

Asked whether it will be restricted, Dr Stauffer said CR845 is currently treated as a nonscheduled drug because  it doesn't cause euphoria or respiratory depression. But once approved, "the FDA might want to schedule it because it's an opioid."

Responding to a query about how the drug might fit into the setting of chronic pain that involves central sensitization, Dr Stauffer stressed that CR845 does not act centrally. It's not clear whether it would be of much help to a patient with, for example, fibromyalgia, he said.

The study was funded by Cara Therapeutics. Dr Stauffer is an employee of Cara Therapeutics and is an option holder in the company, as well as a stock shareholder.  

American Academy of Pain Medicine (AAPM) 2017 Annual Meeting. Abstract 167. Presented March 16, 2017.

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