Indication: Treatment of moderate to severe chronic low back pain

Discovered by Nektar

NDA Filed

NKTR-181, a first-in-class opioid analgesic, is a new chemical entity (NCE) that 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.1

About Opioids and Pain Management

Pain is one of the most common reasons people seek medical treatment.2 Low back pain is the second most common cause of disability for adults in the U.S.3 Approximately 149 million work days are lost every year because of low back pain, with total costs estimated to be $100 to 200 billion a year (of which two-thirds is due to lost wages and lower productivity).4 A study published in the American Pain Society's The Journal of Pain in October 2014 estimated that 19 percent of the U.S. population, or 39 million people, suffer from persistent pain.5

Opioids are considered the most effective therapeutic option for pain. In 2016, 230 million opioid prescriptions were written in the U.S. 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.6 Brain imaging studies have shown that the faster a euphorigenic drug enters and leaves the brain, the stronger are its reinforcing effects.7 In 2014, nearly 2 million Americans either abused or were dependent on prescription opioid pain relievers.8 Opioid abuse is a growing epidemic in the U.S., with one in five Americans who say they have a family member who has been addicted to prescription painkillers.9

In 2015, there were nearly 22,000 deaths involving prescription opioids in the U.S.10 The health care utilization consequences are also significant; for every one death from prescription opioids, it is estimated that there are 10 treatment admissions for abuse, 32 emergency room visits for misuse or abuse, 130 people who are dependent, and 825 people who report non-medical use of these drugs.11

About NKTR-181

NKTR-181 is the first long-acting, selective mu-opioid agonist designed to provide potent pain relief without the inherent high levels of euphoria which lead to abuse and addiction with standard opioids. The novel molecular structure of NKTR-181 is designed to have low permeability across the blood-brain barrier in order to slow its rate of entry into the brain and attenuate the dopamine release that underlies euphoria. NKTR-181 is the first opioid molecule to exhibit reduction in specific CNS-mediated side effects, like euphoria and sedation, through the strategic alteration of brain-entry kinetics. In addition, NKTR-181 is designed with an inherent 12-hour elimination half-life to enable twice-daily dosing with continuous pain control.

Current strategies of abuse deterrence to address the addictive qualities of standard opioids rely on formulations alone. All abuse-deterrent formulations are limited in that once the opioid within the formulation is liberated through tampering, it can rapidly enter the brain and is highly euphorigenic. Preclinical data show that the inherent properties of NKTR-181 reduce its rate of entry into the brain compared to standard mu opioids, regardless of route of administration.12

The U.S. Food and Drug Administration (FDA) has granted NKTR-181 Fast Track designation for the treatment of moderate to severe chronic pain. NKTR-181 is an investigational product and has not been approved by the FDA or any other regulatory agencies.

SUMMIT Phase 3 Program

The SUMMIT Phase 3 program includes the SUMMIT-07 efficacy study, the SUMMIT-LTS long-term safety study and a human abuse potential (HAP) study.

The SUMMIT-07 study compared twice-daily dosing of NKTR-181 tablets to placebo in the treatment of over 600 patients with moderate to severe chronic low back pain who were new to opioid therapy (opioid-naïve). SUMMIT-07 evaluated four analgesic doses of NKTR-181 (100 mg, 200 mg, 300 mg and 400 mg). Patients in the trial achieved an average pain score reduction of over 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). Key secondary endpoints of the study also achieved high statistical significance. The study demonstrated that NKTR-181 had a favorable safety profile and was well tolerated.

The NKTR-181 HAP 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 (3 times to 12 times greater than its analgesic dose range of 100 mg to 400 mg), compared to common therapeutic doses of oxycodone (40 mg and 60 mg) in 54 healthy non-dependent recreational drug users. For the primary endpoint of Drug Liking, NKTR-181 (400 mg and 600 mg) rated less likable compared to oxycodone 40 mg and 60 mg (p<0.0001), and a supratherapeutic dose of NKTR-181 (1200 mg) rated less likable than oxycodone 60 mg (p=0.0071). Key secondary endpoints of Area Under Effect (AUE) for Drug Liking (0-1 hours, 0-2 hours, 0-3 hours), Drug High and Take Drug again were also met statistical significance for all doses of NKTR-181 (1200 mg, 600 mg, 400 mg) compared to oxycodone (60 mg).

The SUMMIT Phase 3 program also includes a 52-week long term safety study (SUMMIT-LTS). SUMMIT-LTS is evaluating the long-term safety and tolerability of NKTR-181 in 638 subjects (opioid-naïve and opioid-experienced) with moderate to severe chronic low pain or chronic non-cancer pain. Information about the SUMMIT studies can be found on clinicaltrials.gov.


1Hyman, Steven E., Harvard Review of Psychiatry. 2(1):43-46, May/June 1994.

22011 National Academy of Sciences. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research, 2010 Decision Resources, and Harstall, C. How prevalent is chronic pain? Pain Clinical Updates X, 1-4 (2003).

3Arch Intern Med 2009 February 9; 169(3): 251-258.

4World Health Organization: Priority Medicines for Europe and the World Update Report, 2013; Background Paper 6.24, Low Back Pain.


6Melnikova, I, Pain Market, Nature Reviews Drug Discovery, Volume 9, 589-90 (August 2010).

7Volkow, N., et al., Addiction: Beyond dopamine reward circuitry; PNAS, Volume 108(37), 15037-15042 (September 2011)

8Substance Abuse and Mental Health Services Administration, National Survey on Drug Use and Health, 2014.

9The Washington Post/Kaiser Family Foundation Survey of Long-Term Prescription Painkiller Users and Their Household Members: http://kff.org/other/report/the-washington-post-kaiser-family-foundation-survey-of-long-term-prescription-painkiller-users-and-their-household-members.

10CDC. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; 2016. Available at http://wonder.cdc.gov.

11Centers for Disease Control and Prevention. Policy Impact: Prescription Painkiller Overdoses. 2011 https://www.cdc.gov/drugoverdose/pdf/policyimpact-prescriptionpainkillerod-a.pdf#page=5

122010 Society of Neuroscience Annual Meeting (Nov 13-17, #HHH11).

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