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17 Articles in Volume 20, Issue #1
20/20 with Lynn Webster, MD
Analgesics of the Future: Peripheral Kappa Opioid Receptor Agonists
Correspondence: Opioid-Induced Hyperalgesia; Pain Care in Older Adults
Don’t Discount the Role of Diet for Chronic Pain Relief
Editorial: Why Haven’t There Been More Breakthrough Analgesics?
Gasping for Air: Sleep-Disordered Breathing and Chronic Opioids
How can botulinum toxin be used in chronic pain syndromes?
Neurodestructive Interventions for Cancer Pain
Obesity and Pain Care: Multifaceted Considerations for Treatment
Obesity and Rheumatoid Arthritis: What Clinicians Should Know
Sickle Cell Pain Crisis: Clinical Guidelines for the Use of Oxygen
The Complexity of Sickle Cell Pain: An Overview
The Perseverance Loop: The Psychology of Pain and Factors in Pain Perception
The Rapid Rise of Non-Opioid Pain Policies
Treating Pain by Overcoming Communication Barriers
Visual Artists Tackle What Pain Looks Like
Will 2020 Be the Year of Patient Education?

Analgesics of the Future: Peripheral Kappa Opioid Receptor Agonists

The breakthrough therapy difelikefalin may change approaches to treating inflammatory pain as well as chronic kidney disease-associated pruritis.
Pages 23-27


The search for an analgesic agent that has the efficacy of traditional mu-opioid agonists but is not accompanied by the well-known adverse effects has been a goal for researchers and pharmaceutical manufacturers for decades. One ideal target that has had a lot of attention is the kappa opioid receptor agonist. It has been shown that the kappa opioid receptor plays a role in analgesia, however, it comes with its own adverse effects that may limit its potential. To limit these possible adverse effects, researchers began to target peripheral kappa opioid receptors.

Many companies have worked to develop peripherally selective kappa opioid agonists, however, none have shown as much promise as CR845, developed by Cara Therapeutics (Stamford, CT). Although there have been multiple early trials with this agent as a potential analgesic, it seems as if the Cara Therapeutics focus has changed to another novel indication with an unmet need – intractable pruritis – which interestingly appears to be modulated by the kappa opioid receptor.

Snapshot of Korsuva

  • Class: peripheral kappa opioid receptor agonists 
  • Products: CR845/difelikefalin (Korsuva) IV and oral, from Cara Therapeutics 
  • Potential indications: post-surgical pain, osteoarthritic pain, hemodialysis- induced pruritis 
  • Features: high selectivity for kappa receptors, no affinity for non-opioid receptors, limited CNS exposure across blood-brain barrier, analgesic, anti- inflammatory, anti-itching, low abuse potential 
  • Pipeline: CR845 is completing Phase 2 studies for acute and chronic pain; received FDA “breakthrough therapy” designation for the treatment of chronic kidney disease associated pruritis.
  • Star rating: 4.5 out of 5 stars - see full review below 

Peripheral Opioid Receptors and Their Pathways

Opioid receptors are located throughout the body, including in the brain, spinal cord, peripheral sensory nerves, and immune cells.1 A majority of opioids activate receptors in the central nervous system (CNS). Activation of opioid receptors in the CNS causes analgesia, but also leads to a majority of known adverse effects, such as respiratory depression, sedation, dependence, and euphoria and/or dysphoria. As opioids and the opioid pathways have been further studied, more has been discovered about peripheral pathways, making them a target for opioid development in an attempt to minimize negative CNS side effects.

Peripheral sensory nerves transmit pain signals to the CNS when activated by noxious mechanical, chemical, or heat stimuli.1 Opioid receptors are located on peptidergic and nonpeptidergic C fibers of afferent peripheral sensory nerves and, when agonized by endogenous or exogenous ligands, produce analgesia by preventing the activation of these fibers and the subsequent transmission of the pain signal.1,2

Peripheral opioid receptors have also become an important target for relieving inflammatory tissue pain. During periods of inflammation, there is an upregulation of opioid receptors in the dorsal root ganglion (DRG).1 A release of cytokines and nerve growth factor at the site of inflammation leads to an increase in the number of opioid receptors being transported from the DRG to the peripheral sensory nerves at the site of damage.1,2 Immune cells at the site of inflammation also have opioid receptors, mainly kappa receptors, present on their surface; these receptors, when activated, have an immunomodulatory function that controls the release of cytokines at the area, helping to decrease inflammation.2

The Kappa Opioid Receptor

The kappa opioid receptor is one of the four main opioid receptors. Its activation causes analgesia, but activation in the CNS leads to unpleasant side effects, including dysphoria, sedation, and diuresis.3 An important note is that kappa agonism is not associated with common mu-receptor side effects including dependence and respiratory depression.4 There are three known kappa receptor subtypes: kappa 1, kappa 2, and kappa 3. Most of the information known is in regard to kappa 1 and kappa 3, with little known about kappa 2 as there is no known selective ligand for this receptor. Previous studies have shown that kappa 3 is the primary receptor involved in analgesia.

The kappa opioid receptor is not a new target for the treatment of pain. Other opioids which have shown sufficient analgesic effect (eg, levorphanol, pentazocine, and butorphanol) are known to have agonistic activity at the kappa receptor but also have activity at the mu receptor. Researchers have continued to pursue the development of a kappa selective opioid agonist to mitigate mu receptor related adverse effects. Selective kappa agonists previously developed, such as enadoline and spiradoline, did not make it to the market due to the unpleasant dysphoric side effects experienced by trial participants.3 Since then, there has been a new focus to selectively target peripheral kappa opioid receptors, negating the potential for the unpleasant CNS side effects.

The Data

CR845/difelikefalin (Korsuva) is a peripheral kappa opioid receptor agonist developed by Cara Therapeutics that is reported to have high kappa selectivity over other opioid receptors and no known affinity for non-opioid receptors.5 Another important feature of CR845 is that it is stated to have poor penetration of the blood-brain barrier.5 CR845 has been developed as an oral and IV formulation and is currently undergoing studies for acute post-operative pain, chronic pain, and pruritis.

According to clinical trials.gov, there are a total of 17 studies that are completed, active, or recruiting (see Table I). These studies are evaluating the use for acute post-operative pain following abdominal surgery, hysterectomies, and bunionectomies, the efficacy for chronic pain with osteoarthritis of the hips and knees, and the effect on moderate-to-severe pruritis in hemodialysis patients and in patients with dermatitis.6 The indication getting the most attention at this time is the treatment of chronic kidney disease-associated pruritis as the FDA gave this specific indication “breakthrough therapy” designation in 2017.7

To date, no completed studies of CR845, for any indication, have been published, however, reports of preliminary results are promising. A Phase 2 study evaluating the analgesic effect of IV CR845 for pain following bunionectomy surgery used 0.005 mg/kg IV CR845 matched to placebo. The primary endpoint was pain intensity differences over 24 hours following administration of the drug and found CR845 decreased pain about six times more than placebo in that time period (P < 0.05). The most common adverse effects experienced by the study group included nausea, dizziness, paresthesia, and somnolence, all occurring in more than 10% of the population.6

Another study evaluating the analgesic effect of IV CR845 for hysterectomy surgery used a single dose of 0.04 mg/kg IV CR845 pre-operatively and post-operatively matched to placebo. The primary outcome was total consumption of morphine in the first 24 hours after drug administration and found that the study group required 13.9 mg morphine while the placebo group required 21.9 mg morphine (P < 0.05). The most common adverse events in the study group were nausea, increase sodium and chloride, hypotension, and headache, all occurring in more than 10% of the population.6

A Cara Therapeutics news release about its Phase 2b study for the treatment of patients with chronic pain due to osteoarthritis stated that the observed reduction in the mean pain score was promising, and more importantly reported that the medication was well-tolerated with no dysphoric or psychomimetic side effects reported. The most common adverse effects reported for this study included dry mouth and constipation, both having an incidence of greater than 5%.8 Another company release stated that its Phase 3 trial for dialysis-related itching had met primary endpoints and was found tolerable, with the most common side effects being diarrhea, dizziness, nasopharyngitis, and vomiting.9

The manufacturer completed a human abuse liability study that found CR845 unlikely to be abused and showed statistically significant reductions in: “drug liking,” “feeling high,” “overall liking,” and “take drug again” scores in comparison to IV pentazocine, a medication with kappa agonist activity.5 While other peripheral kappa opioid agonists, such as asimadoline, have been developed and entered clinical trials for indications such as irritable bowel syndrome and dyspepsia, trials for these products have been halted due to lack of efficacy data or adverse effects such as dose-related hyperalgesia.10


While much of the focus and media attention surrounding CR845 in the public has been on its use in hemodialysis-related itching, this development holds a lot of potential for the treatment of acute and chronic pain management as well. Researchers have been working to create an analgesic devoid of the negative CNS side effects for decades, and peripherally selective kappa opioid receptor agonists are an attractive target. Thus far, researchers have been met with impediments such as molecules that continue to cross the blood-brain barrier and questionable analgesic efficacy. Results released for CR845 appear positive with efficacy not just in hemodialysis-related pruritis, but also in acute and pain management. Findings to date have also supported the notion that CR845 has poor blood-brain barrier penetration as no serious adverse events such as dysphoria have been reported.

If results and published studies continue to support the preliminary data that has been released, this product could have a significant impact on the standard practice of pain management. An opioid that is an effective analgesic and anti-inflammatory, that is also lacking CNS side effects, and has low abuse potential, is an ideal agent that has been sought after for generations. If approved for the treatment of pain this class of drug could become a first-line treatment option for many acute and chronic pain indications, replacing some of the more traditional mu-opioid agonists with their associated abuse potential. Its potential impact is widened by the fact that it has been formulated as an IV and oral formulation.

Conclusion: Revisit Analgesic Trials?

While CR845 shows much promise, its introduction to the world of pain management is most likely several years away. In addition to the fact that much attention has been turned to a pruritis indication, more robust later phase clinical trials in pain are needed in order to demonstrate safety and efficacy. One factor that may positively impact the review and approval timeline for CR845 in pain management is that it received a breakthrough therapy designation, which expedites this review process, specifically for the treatment of chronic kidney disease-associated pruritis.7 The fact that CR845 gained this designation by the FDA shows the amount of promise and potential that this class of drug holds. (More on modern analgesic trials.)


Experts Weigh In: by PPM Editors-at-Large Jeff Gudin, MD, and Jeffrey Fudin, PharmD

Although centrally acting kappa agonists have been scrutinized for many years for their potential analgesic benefits, developing a product that targets peripheral kappa receptors is a relatively novel approach which can help to avoid many of the adverse effects we have seen to date from centrally acting kappa agonists. Crossover of these agents into the blood-brain barrier is in large part responsible for intolerable side effects and the abandonment of research heretofore on kappa agonists. 

The risk-benefit ratio for peripheral kappa agonists in comparison to centrally acting kappa agonists could be a game-changer for opioid therapeutics, if significant analgesic benefit pans out in larger-scale studies. Furthermore, when considering the pathophysiology, combining agents such as nerve growth factor inhibitors with peripheral kappa agonists could be a rational polypharmacy approach to treating certain resistant pain types. 

The actual clinical utility of these agents as analgesics is still somewhat undefined, but could be elucidated with larger studies. Nevertheless, the market potential of an efficacious peripherally acting kappa agonist is tremendous, especially in the current opioid environment where there are limited, potentially less toxic alternatives that have a lesser effect on respiratory depression compared to traditional opioids. Considering the potential attributes of CR845 as described in the main review herein, and the above points, we give this a 4.5 star rating. 

*Star-rating based on: novelty, risk-benefit ratio, clinical utility, scientific rigor of studies, and market potential, along with the reviewer’s expertise and opinion. 


Prior Analgesics of the Future Columns

Last updated on: September 8, 2021
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