New Pain Medication Shows Less Abuse Potential in Study

NKTR-181 is a first-in-class investigational opioid to treat chronic pain

As researchers look for pain-relief solutions that don’t fuel the opioid epidemic, a new study of one contender appears to show that it has less potential for abuse and addiction.

Nektar Therapeutics announced positive topline results from an oral human abuse potential study of NKTR-181, a first-in-class opioid analgesic. NKTR-181 is the first full mu-opioid agonist molecule designed to provide potent pain relief without the high levels of euphoria that can lead to abuse and addiction with standard opioids. The FDA has granted the investigational drug fast-track designation for the treatment of moderate to severe chronic pain.

The new study was designed to confirm and assess the relative oral abuse potential of NKTR-181 at its maximum analgesic or therapeutic dose (400 mg) and at a supratherapeutic dose (three to 12 times greater than its analgesic dose range of 100 mg to 400 mg) compared to common therapeutic doses of oxycodone.

The primary endpoint of the study was “drug liking.” NKTR-181 400 mg had a significantly lower rating of peak liking compared to oxycodone 40 mg (62.0 versus 76.6, P < 0.0001) and oxycodone 60 mg (62.0 versus 81.5, P < 0.0001). Liking was based on a subject-reported 100-point bipolar liking/disliking visual analog scale (VAS).

On secondary endpoints, NKTR-181 400 mg had significantly lower ratings of peak drug high compared to both oxycodone 40 mg and 60 mg (P < 0.0001). In area under effect (AUE) for drug liking following dosing (0-1 hours, 0-2 hours, 0-3 hours), NKTR-181 400 mg had significantly lower AUE for all timepoints compared to both oxycodone 40 mg and 60 mg (P < 0.0001). And NKTR-181 400 mg had significantly lower ratings of peak “take drug again” compared to the 40 mg and 60 mg oxycodone (P < 0.0001).

Opioids act on specific receptors in the brain to provide pain relief, but they also target the dopamine reward system in the brain to produce euphoria and other psychoactive effects, which leads to addiction and abuse. 

"Getting very high, very fast, is a mark of conventional high-risk, abused opioids," said Jack Henningfield, PhD, vice president at Pinney Associates and adjunct professor at The Johns Hopkins University School of Medicine. "NKTR-181 represents a meaningful advance in the treatment of pain as the first opioid analgesic with inherent brain-entry kinetics that avoids this addictive quality of traditional opioids. This prevents the rapid 'rush' that abusers seek during the critical period immediately after dosing. Importantly, these properties of NKTR-181 are inherent to its molecular structure and are not changed through tampering or route of administration."

In March 2017, NKTR-181 completed a phase 3 efficacy trial (SUMMIT-07) in 610 patients with moderate to severe chronic low back pain who were opioid-naïve.  SUMMIT-07 evaluated four analgesic doses of NKTR-181 (100 mg, 200 mg, 300 mg, and 400 mg).  Patients achieved an average pain score reduction of more than 65% (from 6.73 at screening to 2.32 at randomization) during the dose titration period.   The primary efficacy endpoint of the study demonstrated significantly improved chronic back pain relief with NKTR-181 compared to placebo (P = 0.0019).

Source: Nektar Therapeutics; July 18, 2017.