Novel Opioid May Deter Abuse Through Slow-Acting Analgesia

Nancy A. Melville

September 26, 2011

September 26, 2011 (Las Vegas, Nevada) — A novel opioid drug candidate being developed to reduce the likelihood of abuse has shown safety, tolerability, and significant bioavailability in a phase 1 clinical trial. The results were presented here at the American Academy of Pain Management 22nd Annual Clinical Meeting.

The analgesic, with the investigational tag of NKTR-181 (Nektar Therapeutics), is a µ-opioid designed to treat chronic pain with technology that allows for rapid absorption into the plasma but has delayed uptake in the central nervous system (CNS). Opioid effects, therefore, emerge slowly and without the euphoria, respiratory depression, or sedation that make other opioids attractive for abuse, the researchers note in their research findings.

"What we believe is happening and what the preclinical data suggest is a slower entry of the molecule into the brain from the plasma," said Robert Medve, MD, Nektar's vice president and chief medical officer.

In the phase 1 study of the drug's safety, tolerability, pharmacokinetics, and pharmacodynamics, 7 groups of 15 healthy subjects were administered single oral doses of NKTR-181 solution, ranging from 10 to 500 mg (n = 12), or placebo (n = 3).

The results showed that although the drug was detected in the plasma within 15 minutes, miosis lagged in its time course in the plasma, consistent with the reduced rate of CNS uptake that was observed preclinically, Dr. Medve explained.

The extent and duration of the opioid effect was dose-dependent, reaching a maximum effect between 4 and 6 hours, with a duration up to about 16 hours.

The drug was well tolerated across a 50-fold range of doses, with only a few reports of adverse events until the highest dose (500 mg), Dr. Medve reported, when mild nondose-limiting adverse events were consistent with an active opioid agonist. The dose-linear pharmacokinetic profile supported a once-daily or twice-daily schedule.

Unlike other technologies designed to deter abuse, NKTR-181 is unique in that it is not a new formulation of an existing opioid prone to abuse, but a novel drug that cannot be manipulated to take immediate effect.

"What's interesting about this drug is where it goes and the rate at which it gets there," Dr. Medve said. "Right now, we don't know of any way to actually accelerate that rush into the CNS. NKTR-181 will have its own profile as a new opioid; as we go forward into development, we'll seek to explore that."

For chronic pain patients, once the drug therapy is initiated, a steady analgesic remains, without further delay, as long as dosing continues, said Lynn Webster, MD, FACPM, FASAM, cofounder and medical director of Lifetree Clinical Research in Salt Lake City, Utah.

"As clinicians who treat chronic pain, our major concern right now is the misuse and abuse of medication," Dr. Webster said.

"If you have someone who is going to need to be dosed once or twice a day, then once you've induced them and started them on an opioid, the delay doesn't matter, because they will have a blood level that will be maintained and their analgesia will occur in an acceptable period of time, without the potential of it being too rewarding for those seeking mostly rewards and not analgesia."

With prescription drug abuse reaching epidemic proportions in the United States, the premise for NKTR-181 has a unique appeal, said Gary M. Reisfield, MD, assistant professor and director of the division of pain and palliative medicine at the Department of Community Health & Family Medicine, University of Florida College of Medicine, Jacksonville.

"If its initial favorable pharmacokinetic and pharmacodynamic profiles are borne out in advanced clinical trials, NKTR-181 could be a valuable addition to our opioid armamentarium," he said.

However, developing any kind of pain drug to be truly abuse resistant is a tough challenge, Dr. Reisfield added.

"It should be noted that slow CNS penetration is not synonymous with low abuse liability, which should be assessed in clinical trials," he said. "The distinctive appeal of NKTR-181 will lie in its resistance to subversion to a rapidly acting drug, something that cannot be determined until after the drug reaches the market."

"This product, like other abuse-deterrent or tamper-resistant products, can presumably still be lethal when used in quantities larger than prescribed or when mixed with alcohol or other central nervous system depressants."

Dr. Reisfield and Dr. Webster have disclosed no relevant financial relationships.

American Academy of Pain Management (AAPM) 22nd Annual Clinical Meeting: Abstract 15. Presented September 21, 2011.


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