New Opioid Receptor Agonist Approved for Pruritus in Chronic Kidney Disease: Difelikefalin (Korsuva)

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In end-stage chronic kidney disease (CKD), pruritus is a common and oftentimes exasperating symptom for patients in accompaniment to their slew of disease management complexities. What’s worse is that it is incompletely understood, and hence underestimated by both patients and healthcare professionals (HCP) alike1. Pruritus, when not managed adequately, can lead to a significant decrease in quality of life, including sleep disturbances, depression, decreased mental and physical functioning, missed dialysis sessions and the aggravating complications of an improperly managed chronic disease. 

The pathophysiology of CKD-associated pruritus (CKD-ap), or uremic pruritus, is poorly understood but there are hypotheses involving metabolic disturbances and, immunologic and opioidergic systems2. This brings us to the newly approved chemical entity, Difelikefalin, or KorsuvaTM, developed by Cara Therapeutics, Inc.  

Indication, Dosing and Administration 

Difelikefalin, has been recently approved for use in Singapore by the Health Sciences Authority in August 2022 for the treatment of moderate-to-severe pruritus in adult patients on haemodialysis (HD). Notably, this applies to patients refractory to off-label CKD-ap treatment methods like emollients, topical analgesics, oral antihistamines or a Ggabapentinoid. 

Difelikefalin is the first intravenous treatment modality for pruritus in CKD patients on haemodialysis approved by the US Food and Drug Administration (US FDA), and also the European Medicines Agency (EMA). It follows a 0.5mcg/kg target dry body weight dosing guideline and is meant to be injected as a bolus into the venous line of the dialysis circuit after each HD session3. This unique vascular requirement leaves it unstudied in the peritoneal dialysis population.  

Mechanism of Action

Difelikefalin is a selective kappa opioid receptor (KOR) agonist which acts on the peripheral sensory neurons and immune cells. The opioid hypothesis inducing uremic pruritus proposes that it is caused by an imbalance in the expression of central mu and kappa opioid receptors4, whereby pruritus increases with mu-receptor activation and kappa-receptor blockade. Conversely, it decreases with the mu-receptor blockade, and kappa-receptor activation, with which Ddifelikefalin comes into play. 

Efficacy from Clinical Studies 

The approval for Ddifelikefalin stems from two randomised, multicenter, double-blind, placebo-controlled trials, KALM-16 and KALM-27, held across North America, Europe and Asia-Pacific. Both trials saw a cumulative enrolment of 851 subjects, 18 years and above undergoing HD with moderate-to-severe pruritus, receiving either Ddifelikefalin or placebo, three times a week for a total of 12 weeks. Results were calculated based on a patient-reported, daily 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS) score with 0 being “no itch” and 10 being “worst itch imaginable”. 

In a pooled analysis8, there was an improved itch intensity observed with Ddifelikefalin compared with placebo (51.5% versus 35.2%; p< 0.001), defined as a ≥3-point reduction from baseline. This was achieved in just 12 weeks of treatment, with some results seen as early as in Week 1. With regards to ≥3-point reduction, there were similarly significant differences observed between Ddifelikefalin versus placebo (38.7% versus 23.4%; p<0.001). More importantly, there were reports of an improvement in itch-related quality of life observed through week 64 which shows sustained efficacy whilst on treatment. 

Back in Asia, a Japanese Phase III double-blind clinical study9 conducted with 178 HD patients over 6 weeks, followed by an open-label extension over 52 weeks, showed similar positive results with Ddifelikefalin compared to placebo. 

Safety from Clinical Studies 

In the same Japanese trial, Ddifelikefalin demonstrated a safe and well-tolerated safety profile. This is corroborated by the pooled safety analysis with KALM-1 and KALM-210, where 6.8% of the Ddifelikefalin arm withdrew for adverse events compared with 4% with placebo. The most common reason for discontinuation was dizziness (0.9% versus 0.2% with placebo), but its incidence did not increase with long-term use.   

Interestingly, dizziness (6.8% versus 3.8% in placebo) occurred within the first 3 weeks of treatment and was generally transient, with a median duration of 1 day. Somnolence, another commonly reported adverse effect (4.2% versus 2.4% in placebo) also occurred within the same 3- week period but was observed to subside with continued dosing. Of note, somnolence was more prevalent in patients aged 65 years and older in the dDifelikefalin-arm as compared to those younger than 65 (7.0% versus 2.8%). It is recommended to exercise greater caution with the concomitant use of centrally-acting depressants, sedating antihistamines and opioid analgesics.  

Other common adverse effects with mild to moderate in severity (incidence ≥2% and ≥1% higher than placebo), include diarrhoea, nausea, gait disturbances, hyperkalemia, headache, and changes in mental status. 


Possible extensions to the existing clinical studies such as a longer study period beyond 52 weeks, and comparisons with existing Ggabapentinoids used routinely in CKD-ap could further substantiate Ddifelikefalin’s place in therapy. Nonetheless, it still safely addresses an unmet need for HD patients suffering from this bothersome symptom without adding to their existing pill burden. 

There is little room to doubt Ddifelikefalin’s pharmacological efficacy and safety for now, but more is to be said about its cost-effectiveness which is left largely undiscussed. Hopefully, this would not become yet another hindrance for patients with regard to their access to holistic disease management. 



  1. International Comparisons of Prevalence, Awareness, and Treatment of Pruritus in People on Hemodialysis. Rayner HC, Larkina M, Wang M, Graham-Brown M, van der Veer SN, Ecder T, Hasegawa T, Kleophas W, Bieber BA, Tentori F, Robinson BM, Pisoni RL. Clin J Am Soc Nephrol. 2017;12(12):2000. Epub 2017 Sep 18.
  2. Pisoni RL, Wikström B, Elder SJ, et al. Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2006;21:3495-3505.
  3. Korsuva (difelikefalin) [prescribing information]. Stamford, CT: Cara Therapeutics Inc; December 2021.
  4. Involvement of central mu-opioid system in the scratching behavior in mice, and the suppression of it by the activation of kappa-opioid system. Umeuchi H, Togashi Y, Honda T, Nakao K, Okano K, Tanaka T, Nagase H. Eur J Pharmacol. 2003;477(1):29. 
  5. The neurobiology of itch .Ikoma A, Steinhoff M, Ständer S, Yosipovitch G, Schmelz M. Nat Rev Neurosci. 2006;7(7):535. 
  6. Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F; KALM-1 Trial Investigators. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. N Engl J Med. 2020 Jan 16;382(3):222-232. doi: 10.1056/NEJMoa1912770. Epub 2019 Nov 8. PMID: 31702883.
  7. Wooldridge T.D., Mccafferty K., Schoemig M., et al. Efficacy and safety of difelikefalin for moderate-to-severe CKD–associated pruritus: a global phase 3 study in hemodialysis patients (KALM-2) [abstract FR-OR24] J Am Soc Nephrol. 2020;31(Suppl):22–23.
  8. Topf J, Wooldridge T, McCafferty K, Schömig M, Csiky B, Zwiech R, Wen W, Bhaduri S, Munera C, Lin R, Jebara A, Cirulli J, Menzaghi F. Efficacy of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis of KALM-1 and KALM-2 Phase 3 Studies. Kidney Med. 2022 Jun 28;4(8):100512. doi: 10.1016/j.xkme.2022.100512. PMID: 36016762; PMCID: PMC9396406.
  9. Positive topline results from japanese phase iii clinical study (Double-blind period) of difelikefalin (Mr13a9) in hemodialysis patients with pruritus. KISSEI PHARMACEUTICAL CO.,LTD.

Safety and tolerability of difelikefalin for the treatment of moderate to severe pruritus in hemodialysis patients: pooled analysis from the phase 3 clinical trial program. Kidney Medicine. 2022;4(8):100513.

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