Mu-Opioid Analgesic in Phase III Offers Hope for the Management of Chronic Pain Without Addictive Side Effects

Dissociating dopamine-mediated euphoria and analgesia by slowing the rate of entry of opioid-like compounds through the blood-brain barrier.
Dissociating dopamine-mediated euphoria and analgesia by slowing the rate of entry of opioid-like compounds through the blood-brain barrier.

Opioid agonists that mediate analgesia through activation of µ-opioid receptors are associated with a number of adverse effects, which include respiratory depression, sedation, euphoria, abuse and addiction. In view of the ongoing opioid epidemic, much effort is devoted to developing improved analgesics with reduced adverse events.

Among the drugs in the pipeline at Nektar Therapeutics, a biotechnology company based in San Francisco, CA, is NKTR-181, currently in Phase III. Clinical Pain Advisor interviewed Stephen Doberstein, PhD, Nektar's Senior Vice President and Chief Scientific Officer.

The Science Behind NKTR-181

Research studies indicate a correlation between the rate of entry of traditional opioids into the brain and their abuse liability.1 Drugs commonly used for pain management, including morphine, fentanyl and semi-synthetic opioids such as oxycodone and hydrocodone, display fast kinetics across the BBB.2,3 The rapid increase in opioid concentration in the brain that ensues leads to a burst of dopamine (DA) release that has been associated with reinforcing behavior.4

Concentration of analgesic compounds in the brain-not their rate of entry through the BBB-is correlated with level of analgesia. Scientists at Nektar therefore hypothesized that, by slowing the rate of entry of opioid-like compounds through the BBB, they might be able to dissociate DA-mediated euphoria from analgesic effect, and achieve reduced abuse liability.5

NKTR-181, is a full agonist for the µ-opioid receptor, belongs to the same class as morphine and oxycodone.  In NKTR-181, a functional group (a polyethylene glycol [PEG] polymer) has been attached to the multiple ring structure. This technology developed at Nektar, allows to modulate the rate of entry across the BBB.

Pre-clinical testing of NKTR-181 showed high efficacy in animal models of visceral pain, as well as in models of peripherally mediated heat-type pain, convincing physiological effects associated with µ-opioid receptors, as well as reduced abuse liability.

Phase I

For the development of any analgesic drug, evoked pain models are used in phase I. Healthy subjects were given a clinical dose of NKTR-181; the time they could hold their hand in a cold water bath was measured, and compared to that of subjects not having received the compound. Patients administered with NKTR-181 maintained their hand in the cold water for significantly longer periods of time, indicating centrally mediated analgesia.

Binding of agonists to µ-opioid receptors leads to pupil constriction (miosis), offering a direct way to monitor the central effects of opioid compounds. Peak of oxycodone blood concentration and maximal pupil constriction almost overlap, with a delay of ~11 minutes, indicating rapid transport of the drug to the brain, in stark contrast with the 2.8 h delay observed with NKTR-181.

Another interesting attribute of NKTR-181 is its very long half life -particularly when compared to traditional opioids like vicodin or percocet which have a half life of 4h - precluding the need for an extended release version of the compound.

In addition, kinetics of NKTR-181 do not rely on formulation characteristics, but rather, are inherent to the molecule in which the PEG polymer is strongly linked to the opioid backbone. This property renders useless any attempt by prospective abusers to modify the conjugate for faster entry into the brain.

Human Abuse Liability Study

Recreational drug abusers not physically dependent on opioids, but for whom opioids are the drug of choice, were chosen as NKTR-181 study participants. Subjects were asked to tell the difference between opioids in a controlled clinical setting. Participants were given 5 different administrations (placebo, oxycodone  as a positive control, and 3 different doses of NKTR-181 [100, 200, 400 mg]) in a random order. They were then asked to assess their experience in a blinded manner.

In the next 24 h, subjects were asked to rate their drug-related experience, by answering questions such as “How high do you feel right now?”, “How much do you like the experience you are having right now?”, as well as some secondary questions, “How much would you pay for this experience?”

Every study participant could correctly identify the oxycodone dose, for which they rated the peak of “feeling high” at ~80 on a 1 to 100 scale. The 100 and 200 mg arms of NKTR-181 were indistinguishable from placebo, and the 400 mg dose had a modest peak with a score of ~20, occurring with a 1 to 2 h delay compared to the oxycodone peak.

Efficacy Trial

An efficacy clinical trial for NKTR-181 is ongoing, with opioid-naïve patients experiencing low back pain, and asked to provide pain scores on a 1 to 10 scale several times a day.6 Patients coming out of the phase III efficacy trial and wishing to continue on NKTR-181, can enroll on a 52-week-long safety study.7

Next steps will require a large, well-controlled and well-executed study, to assess whether NKTR-181 provides potent analgesia. This, in combination with the 52-week study should reveal any potential NKTR-181-related adverse effects (constipation and slight lightheadedness are already known to be associated with NKTR-181 treatment).

Death from opioid abuse is due to respiratory depression, rendering assessment of this adverse event essential for NKTR-181. “So far, it looks quite promising in that regard,” noted Dr Doberstein “but that's something we want to understand better, because if there is an advantage here for having a relatively slow rate of entry causing less respiratory depression, that would really be remarkable.”

Dr Doberstein also mentioned the very high standards held throughout the clinical trials, aimed at minimizing the placebo effect, an important component of any drug development effort, particularly in human pain studies, which are highly subjective—subjectivity is known to enhance the placebo effect.

 “Other than that, if we have really managed to do what we think we may have done, which is separate the euphoria from analgesia for chronic pain patients, that's a really game-changing proposition,” added Dr Doberstein. “I hope we are on a path to being able to control that and still being able to maintain good pain control,” he added.


  1.  NKTR-181, Nektar Therapeutics. Available at: Accessed July 21, 2016.
  2. Boström E, Hammarlund-udenaes M, Simonsson US. Blood-brain barrier transport helps to explain discrepancies in in vivo potency between oxycodone and morphine. Anesthesiology. 2008;108(3):495-505.
  3. Stanski DR. Narcotic pharmacokinetics and dynamics: the basis of infusion applications. Anaesth Intensive Care. 1987;15(1):23-6.
  4. Jones JD, Comer SD. A review of pharmacogenetic studies of substance-related disorders. Drug Alcohol Depend. 2015;152:1-14.
  5. Di chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 1988;85(14):5274-5278.
  6. Efficacy and Safety Study of NKTR-181 in Opioid-Naive Subjects With Low Back Pain (SUMMIT-07). Available at: Accessed July 21, 2016.
  7. Long-Term Safety and Tolerability Study of NKTR-181 in Subjects With Chronic Low Back Pain or Chronic Non-Cancer Pain (SUMMIT-LTS). Available at: Accessed July 21, 2016.
You must be a registered member of Clinical Pain Advisor to post a comment.