NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential

Miyazaki, Takahiro; Choi, Irene; Rubas, Werner; Anand, Neel K.; Ali, Cherie F.; Evans, Juli; Gursahani, Hema; Hennessy, Marlene; Kim, Grace; McWeeney, Daniel; Pfeiffer, Juergen; Quach, Phi; Gauvin, David V.; Riley, Timothy A.; Riggs, Jennifer A.; Gogas, Kathleen R.; Zalevsky, Jonathan; Doberstein, Stephen K.

doi:10.1124/jpet.117.243030

Cited by 38 publications

(36 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Its side effect profile was improved compared to oxycodone, although at the most effective analgesic doses NKTR-181 induced mild muscle rigidity and motor impairment. Compared to cocaine and oxycodone, it did not produce reward in self-administration paradigm ( Miyazaki et al, 2017 ) (Table 3 ). In healthy, non-physically dependent recreational opioid users, single oral application of NKTR-181 (in doses used in ongoing phase 3 trials) induced significantly lower drug liking effects (indicative of lower abuse potential) and smaller changes in the pupil diameter (indicative of less robust CNS actions) relative to oxycodone.…”

Section: Other Approachesmentioning

confidence: 99%

“…Still, the effects of the highest NKTR-181 dose used were significantly higher vs. placebo ( Webster et al, 2018 ). The compound is considered to be resistant to physical or chemical tampering, albeit the data were not shown ( Miyazaki et al, 2017 ), and the possibility of taking it at high doses to achieve high CNS levels cannot be excluded, as in case of abuse-deterrent opioids. The company sponsored completed phase 2 trial in patients with osteoarthritis (NCT02367820) and phase 3 trial in patients with chronic low back pain (NCT02362672; both at ClinicalTrials.gov ), but the peer reviewed data are not available yet (Table 1 ).…”

Section: Other Approachesmentioning

confidence: 99%

See 1 more Smart Citation

Advances in Achieving Opioid Analgesia Without Side Effects

2018

View full text Add to dashboard Cite

Opioids are the most effective drugs for the treatment of severe pain, but they also cause addiction and overdose deaths, which have led to a worldwide opioid crisis. Therefore, the development of safer opioids is urgently needed. In this article, we provide a critical overview of emerging opioid-based strategies aimed at effective pain relief and improved side effect profiles. These approaches comprise biased agonism, the targeting of (i) opioid receptors in peripheral inflamed tissue (by reducing agonist access to the brain, the use of nanocarriers, or low pH-sensitive agonists); (ii) heteromers or multiple receptors (by monovalent, bivalent, and multifunctional ligands); (iii) receptor splice variants; and (iv) endogenous opioid peptides (by preventing their degradation or enhancing their production by gene transfer). Substantial advancements are underscored by pharmaceutical development of new opioids such as peripheral κ-receptor agonists, and by treatments augmenting the action of endogenous opioids, which have entered clinical trials. Additionally, there are several promising novel opioids comprehensively examined in preclinical studies, but also strategies such as biased agonism, which might require careful rethinking.

show abstract

Section: Other Approachesmentioning

confidence: 99%

Section: Other Approachesmentioning

confidence: 99%

Advances in Achieving Opioid Analgesia Without Side Effects

2018

View full text Add to dashboard Cite

show abstract

“…One notable example is NKTR-181, a compound that contains a five-ring morphine-like scaffold bonded to a short-chain poly(ethylene glycol). 38 , 39 This functional group has previously been shown to reduce oral bioavailability and transmission rate across the BBB. 40 , 41 Through this mechanism, NKTR-181 provides analgesia in humans and is currently in Phase III clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“… 35 Similarly, NKTR-181, the five-ring morphine-like scaffold bonded to a short-chain PEG produced analgesic-like effects for only up to 4-h post-administration in the hot-plate test in mice, this being similar to the effects of free opioids. 39 …”

Section: Discussionmentioning

confidence: 99%

PolyMorphine provides extended analgesic-like effects in mice with spared nerve injury

Lax

Chen²,

Leep

et al. 2017

Mol Pain

View full text Add to dashboard Cite

Morphine is a well-characterized and effective analgesic commonly used to provide pain relief to patients suffering from both acute and chronic pain conditions. Despite its widespread use and effectiveness, one of the major drawbacks of morphine is its relatively short half-life of approximately 4 h. This short half-life often necessitates multiple administrations of the drug each day, which may contribute to both dependence and tolerance to morphine. Here, we tested the analgesic properties of a new polymer form of morphine known as PolyMorphine. This polymer has monomeric units of morphine incorporated into a poly(anhydride-ester) backbone that has been shown to hydrolyze into free morphine in vitro. Using an animal model of chronic pain, the spared nerve injury surgery, we showed that PolyMorphine is able to block spared nerve injury-induced hypersensitivity in mice for up to 24-h post-administration. Free morphine was shown to only block spared nerve injury-induced hypersensitivity for up to 2-h post-injection. PolyMorphine was also shown to act through the mu opioid receptor due to the ability of naloxone (a mu opioid receptor antagonist) to block PolyMorphine-induced analgesia in spared nerve injury animals pretreated with PolyMorphine. Additionally, we observed that PolyMorphine causes similar locomotor and constipation side effects as free morphine. Finally, we investigated if PolyMorphine had any effects in a non-evoked pain assay, conditioned place preference. Pretreatment of spared nerve injury mice with PolyMorphine blocked the development of conditioned place preference for 2-methyl-6-(phenylethynyl)pyridine (MPEP), a short-lasting mGluR5 antagonist with analgesic-like properties. Free morphine does not block the development of preference for MPEP, suggesting that PolyMorphine has longer lasting analgesic effects compared to free morphine. Together, these data show that PolyMorphine has the potential to provide analgesia for significantly longer than free morphine while likely working through the same receptor.

show abstract

“…The positive correlation between BBB permeability/transport with abuse liability is the cornerstone of the strategically designed novel mu-opioid agonist, NKTR-181, which is analgesic but has limited abuse liability in humans ( 208 , 209 ). This compound has a poly-ethylene glycol side chain and shows delayed transfer across the BBB ( 208 ). It is currently in Phase III clinical trials to treat chronic lower back pain or non-cancer pain (NCT02367820).…”

Section: Not All Opioid Analgesics Are the Same: Exploring Novel Pharmentioning

confidence: 99%

Pain Therapy Guided by Purpose and Perspective in Light of the Opioid Epidemic

et al. 2018

View full text Add to dashboard Cite

Prescription opioid misuse is an ongoing and escalating epidemic. Although these pharmacological agents are highly effective analgesics prescribed for different types of pain, opioids also induce euphoria, leading to increasing diversion and misuse. Opioid use and related mortalities have developed in spite of initial claims that OxyContin, one of the first opioids prescribed in the USA, was not addictive in the presence of pain. These claims allayed the fears of clinicians and contributed to an increase in the number of prescriptions, quantity of drugs manufactured, and the unforeseen diversion of these drugs for non-medical uses. Understanding the history of opioid drug development, the widespread marketing campaign for opioids, the immense financial incentive behind the treatment of pain, and vulnerable socioeconomic and physical demographics for opioid misuse give perspective on the current epidemic as an American-born problem that has expanded to global significance. In light of the current worldwide opioid epidemic, it is imperative that novel opioids are developed to treat pain without inducing the euphoria that fosters physical dependence and addiction. We describe insights from preclinical findings on the properties of opioid drugs that offer insights into improving abuse-deterrent formulations. One finding is that the ability of some agonists to activate one pathway over another, or agonist bias, can predict whether several novel opioid compounds bear promise in treating pain without causing reward among other off-target effects. In addition, we outline how the pharmacokinetic profile of each opioid contributes to their potential for misuse and discuss the emergence of mixed agonists as a promising pipeline of opioid-based analgesics. These insights from preclinical findings can be used to more effectively identify opioids that treat pain without causing physical dependence and subsequent opioid abuse.

show abstract

NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential

Cited by 38 publications

References 27 publications

Advances in Achieving Opioid Analgesia Without Side Effects

Advances in Achieving Opioid Analgesia Without Side Effects

PolyMorphine provides extended analgesic-like effects in mice with spared nerve injury

Pain Therapy Guided by Purpose and Perspective in Light of the Opioid Epidemic

Contact Info

Product

Resources

About