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Continuing Education Activity

Difelikefalin is a medication used to treat and manage uremic pruritis and post-operative pain, which affect the quality of life. It is in the opioid class of medications. This activity describes the mechanism of action, indications, administration, adverse effects, monitoring, and contraindications for difelikefalin therapy pertinent for interprofessional team members in the treatment and management of patients suffering from uremic pruritis or post-operative pain.


  • To describe the mechanism of action of difelikefalin.
  • Identify the indications of difelikefalin therapy.
  • Explain key points in the administration of difelikefalin.
  • Review the most common adverse effects associated with difelikefalin therapy.


The use of opioid medication for analgesia dates back to the 1800s. One of the original opioid medications, morphine, named after Morpheus, the god of dreams, was extracted from opium plants and injected intravenously for providing analgesia in patients suffering from neuralgia. In the 1990s, various extended-release oral opioid formulations were introduced into the market.

These oral formulations available in high doses marked the beginning of the opioid crisis in the United States today.  Euphoric effects of these medications, when combined with tolerance, and lethal central nervous system side effects, pose a dangerous situation for patients seeking pain relief. The opioid crisis has made the transition to illegal drug use and death by overdose, even with oral formulations, commonplace.  In the United States in 2016, over 230 million opioid prescriptions were written to treat acute and chronic pain. At that time, it was surveyed that one in every three adult Americans had currently been prescribed an opioid medication. Safe and effective pain management persists as a challenge for the physician and interprofessional health care team. The market for novel opioid medications with less abuse potential and fewer dangerous side effects is vast.[1] 

Kappa, delta, and mu-opioid receptors are present in various human tissues and can be targeted, not only in the treatment of acute and chronic pain. Opioid receptor distribution in patients with end-stage renal disease requiring hemodialysis plays a role in the chronic itch that they can experience. Polypharmacy is commonly involved in managing these patients, who often have many comorbidities and decreased quality of life. The potential for selective opioid medications to target specific receptors in peripheral tissues is groundbreaking. It offers the opportunity to treat the etiology of itch that patients with end-stage renal disease may suffer from. 

Difelikefalin is under development by Cara Therapuetics, Inc and is currently awaiting FDA approval.[2] Indications for difelikefalin are the following:[2][1][3]

  • Uremic pruritus
  • Post operative pain

Intravenous treatment of moderate to severe uremic pruritus has been conditionally accepted by the FDA.

In phase III clinical trials, intravenous dIfelikefalin has shown analgesic efficacy in treating post-operative pain and in the treatment of uremic pruritus in patients with end-stage renal disease who require hemodialysis.[3][4][1]

Mechanism of Action

Difelikefalin is a selective kappa-opioid receptor agonist. Alternative names for difelikefalin include 4-amino-1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl) piperidine-4-carboxylic acid,  KORSUVA, CKD-943, MR13A9, FE202845, and CR 845.[2][5] Difelikefalin is peripherally selective, which is due to its small hydrophilic peptide structure. It is not able to cross the blood-brain barrier. Therefore, unlike many other opioid medications, it does not cause lethal central nervous system side effects such as respiratory depression.[6] 

Difelikefalin has no action at the mu-opioid receptor, which is responsible for the euphoric effects of traditional opioid medications. Without activity at the mu-opioid receptors in the central nervous system, there is negligible abuse potential for this novel agent.[5] 

Difelikefalin selectively acts on kappa opioid receptors in peripheral tissues, which contribute to pruritis and nociception. The activation of opioid receptors in peripheral neurons and keratinocytes reduces afferent (sensory) impulses towards the central nervous system, decreasing pain signals. Activating kappa opioid receptors on immune cells, including monocytes and T lymphocytes, decreases the release of pro-inflammatory chemicals such as prostaglandins.[7][8][9]


Difelikefalin can be administered via the oral or intravenous (IV) route.

IV dosing is weight-based.

IV dosing and administration for uremic pruritus:[7]

  • 0.5 mcg per kg IV bolus three times weekly into the venous port of the dialysis circuit immediately following dialysis.
  • Weight-based dosing in the treatment of uremic pruritus should be taken into careful consideration when rendering this medication. The appropriated weight-based dose is determined by the physician and is based on the prescription dry bodyweight of the patient with end-stage renal disease, where the patient is considered normovolemic.[7]

IV dosing and administration for postoperative pain:[6]

  • 0.5 mcg per kg IV bolus once before surgery and once after surgery

Oral formulations and dosing:[10]

  • Tablet: 0.25 mg, 0.5 mg, 1mg BID


  • Bioavailability: 100%
  • Elimination half-life: 2 hours
  • Metabolism: Not metabolized, excreted unchanged in urine and bile
  • Duration of action: 12 hours after a single IV dose[5]

Adverse Effects

Phase III clinical trials involving patients with end-stage renal disease requiring dialysis who were suffering from uremic pruritus involved a study design. Patients received intravenous difelikefalin at weight-based doses of 1.0 mcg per kg three times a week into the venous circuit of their dialysis machine for twelve weeks. This study demonstrated the following most common adverse side effects:[3]

  • Diarrhea
  • Vomiting
  • Dizziness

A double-blind, randomized study assessed the potential of difelikefalin to cause respiratory depression in healthy patients compared to placebo. The lowest observed respiratory rate in study subjects in both groups was 14 breaths per minute. This respiratory rate is well above the 10 breaths per minute respiratory rate that qualified as respiratory depression for this study. Additionally, no significant differences in pulse oximetry readings were observed in subjects receiving placebo versus those receiving IV difelikefalin. This study utilized supratherapeutic intravenous doses of  1.0 mcg per kg and then 5.0 mcg per kg. The following adverse effects were reported in 20 to 60% of participants:[6]

  • Paresthesia
  • Hypoesthesia
  • Somnolence

When these adverse effects were experienced by study subjects, the persistence of the symptom ranged from less than one minute to less than ninety minutes and did not require any intervention.[6]


No published contraindications exist for difelikefalin. Phase III clinical trials were conducted involving patients with comorbidities and polypharmacy, demonstrating promise for difelikefalin to have generalized applicability with low risk for drug-drug interactions. Difelikefalin does not interfere with liver enzymes.[7] Of note, clinical trials have only included adult patients. Do not administer difelikefalin to a child or adolescent.


Therapeutic levels: 5 mcg per mL[1]

Supportive treatment for the more commonly experienced adverse side effects of difelikefalin, including vomiting and diarrhea, will increase positive patient outcomes. The health care team needs to avoid dehydration, acid-base disturbances, or an electrolyte imbalance when managing patients receiving difelikefalin. Providers should ensure adequate hydration status and assess patients with routine labs, administering electrolyte repletion as indicated.

If the adverse effect of dizziness is experienced in patients taking difelikefalin, fall risk measures must be taken to avoid injury, especially in patients who are elderly or frail.

Opioid withdrawal symptoms were not observed after the cessation of treatment with difelikefalin.[7]


At supratherapeutic levels (15 mcg per mL), concern for respiratory depression or euphoric effects has not been demonstrated.[1][6]

At supratherapeutic doses of 1.0 mcg per kg, 2.0 mcg per kg, and 5.0 mcg per kg, mild to moderate hypernatremia has been reported. Any induced electrolyte imbalance observed during treatment should be managed per the standard of care, in conjunction with the termination of medication administration and identification of any additional etiologies for the electrolyte disturbance. 

The adverse effects mentioned previously, including hypoesthesia, paresthesia, and somnolence, are self-limited at supratherapeutic doses.[6]

There is no documented antidote for difelikefalin.

Considering the reassuring safety profile, the lack of activity in the central nervous system, and the more common adverse side effects of difelikefalin subsiding without intervention, the clinical utility of naloxone in suspected supratherapeutic or toxic levels of difelikefalin is unlikely relevant.

Phase III double-blind, randomized, placebo-controlled clinical trials have been conducted over the course of up to eight and twelve weeks. Potential long-term effects of difelikefalin remain unclear.

Enhancing Healthcare Team Outcomes

The utility of a selective peripheral kappa opioid receptor agonist in the treatment of uremic pruritis is emerging.[7] [Level 1] Patients with an end-stage renal disease requiring dialysis face many challenges in preserving their quality of life. A coordinated effort by the nephrologist, dialysis nursing staff, patient family members, and primary care providers is necessary to ensure that the uremic pruritis often experienced by these patients is addressed appropriately so that the negative impact on the patient is diminished.[11] Common practice has the opportunity to evolve from current therapy for uremic pruritis, which often ineffectively utilizes antihistamines or involves off-label use of gabapentin.[12][13][14] 

Understanding the mechanism of difelikefalin and how it effectively addresses the nonhistaminergic pathway, which causes uremic pruritus, is essential for the healthcare team to ensure that itching and the associated emotional distress often experienced by patients requiring dialysis may appropriately be addressed.[12][3] The intravenous dosing of difelikefalin, typically 3 times a week in intravenous bolus form once dialysis sessions are completed, is logistically ideal, which can enhance team performance and subsequent patient outcomes when rendering this treatment.[2] Further research clarifying the efficacy of difelikefalin in diabetes and end-stage renal disease patients would provide valuable insight for clinical decision-making as these conditions often co-exist.[15][14] 

The opioid crisis facing the healthcare industry today requires the introduction of safer post-operative pain medications with decreased abuse potential. Surgeons and primary care clinicians are in a position to initiate intravenous or oral difelikefalin for patients with acute postoperative pain, or sub-acute and chronic pain, without the fear of lethal overdose or euphoric effects, even at supratherapeutic doses.[1] [Level I]

The extensive development of safer formulations of traditional oral opioid medications for pain management without the risk of abuse potential demonstrates the need that the novel difelikefalin oral formulation would fulfill with widespread implementation by healthcare providers.[14][1][10] [Level 1] Trials are currently underway to test difelikefalin for use in controlling post-operative pain; early results have shown promise regarding both clinical efficacy and adverse event profile, but more research is necessary.

Article Details

Article Author

Julianne Pilla

Article Editor:

Pavan Devulapally


5/1/2022 9:08:12 AM

PubMed Link:




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