Continuing Education Activity

Difelikefalin is a medication used to treat and manage uremic pruritis and postoperative pain, affecting patients' quality of life. Difelikefalin is in the opioid class of drugs and works as 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, CKD-943, MR13A9, FE202845, and CR 845. Since difelikefalin is peripherally selective, it is unlikely to cause lethal central nervous system adverse effects such as respiratory depression. IV dosing schedule after dialysis sessions enhances treatment logistics and patient outcomes. Moreover, difelikefalin presents as a safer alternative for managing postoperative pain amid the opioid crisis, offering decreased abuse potential and promising results in early trials. However, further research is needed to validate its efficacy and safety, especially in patients with diabetes and end-stage renal disease. This activity describes the mechanism of action, indications, administration, adverse effects, monitoring, and contraindications for difelikefalin therapy pertinent for interprofessional team members in treating patients with uremic pruritis or postoperative pain.

Objectives:

• Identify patients with uremic pruritus and post-operative pain who may benefit from difelikefalin therapy.

• Screen patients for contraindications, potential drug interactions, and other factors that may impact the safe and effective use of difelikefalin.

• Assess the effectiveness of difelikefalin therapy in managing uremic pruritus and postoperative pain, monitoring treatment response, and adjusting the treatment plan as needed.

• Collaborate with other healthcare professionals, such as nephrologists, anesthesiologists, and pain management specialists, to ensure coordinated care and optimize the use of difelikefalin in managing uremic pruritus and post-operative pain.

Indications

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 (IV) to provide analgesia in patients suffering from neuralgia. In the 1990s, various extended-release oral opioid formulations were introduced to the market.

These oral formulations made available in high doses marked the beginning of the opioid crisis in the United States today. When combined with tolerance and lethal central nervous system (CNS) adverse effects, the euphoric effects of these medications pose a dangerous situation for patients seeking pain relief. The opioid crisis has made the transition to illegal drug use and death by overdose, with oral formulations, commonplace. In the United States, in 2016, over 230 million opioid prescriptions were written to treat acute and chronic pain. The survey showed that 1 in every 3 Americans had been prescribed an opioid medication. Safe and effective pain management remains challenging for the clinician and interprofessional healthcare team. The market for novel opioid medications with less abuse potential and fewer dangerous adverse effects is vast.[1][2]

Kappa, delta, and mu-opioid receptors are present in various human tissues and can be targeted in treating 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.[3] 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, and it offers the opportunity to treat the etiology of itch that patients with end-stage renal disease may suffer from. 

Difelikefalin is indicated for treating moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis and is FDA-approved for that purpose.[1][4][5]  In phase 3 clinical trials, IV difelikefalin showed analgesic efficacy in treating post-operative pain and uremic pruritus in patients with end-stage renal disease who require hemodialysis.[5][6][1] Phase 2 clinical trials examining off-label utilization of difelikefalin for notalgia paresthetica and paroxysmal neuropathic pruritus in pediatric patients with Type I Chiari malformations suggest the utility of the kappa opioid receptor for pruritis of neuropathic etiology.[7][8]

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.[4][9] Difelikefalin is peripherally selective due to its small hydrophilic peptide structure. This drug is not able to cross the blood-brain barrier. Therefore, unlike many other opioid medications, it does not cause lethal CNS adverse effects such as respiratory depression.[10] 

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 CNS, negligible abuse potential is apparent for this novel agent.[9] This medication selectively acts on kappa opioid receptors in peripheral tissues, contributing to pruritis and nociception. Activating opioid receptors in peripheral neurons and keratinocytes reduces afferent (sensory) impulses toward the CNS, 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.[11][12][13]

Administration

Difelikefalin can be administered via the oral or IV route. IV dosing is weight-based.[11][10] IV dosings and administration for uremic pruritus:

• 0.5 mcg per kg IV bolus 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 appropriate weight-based dose is determined by the clinician and is based on the prescription dry body weight of the patient with end-stage renal disease, where the patient is considered normovolemic.[11][14][11]

Pharmacokinetics

Difelikefalin showed a dose-proportional response over a single dosage range from 1 to 3 mcg/kg and multiple IV dosage range from 0.5 to 2.5 mcg/kg in chronic kidney disease patients undergoing hemodialysis. A steady-state plasma concentration was reached after the second administered dosage, and the mean accumulation ratio was up to 1.6.

• Bioavailability: 100%

• Distribution: The mean volume of distribution is approximately 238 mL/kg, and human plasma protein binding in dialysis patients is 23% to 28%.[15]

• Metabolism: Not metabolized by cytochrome P450 (CYP) enzymes presents in human hepatic microsomes CYP1A2, CYP2C19, CYP2C8, CYP2C9, CYP2D6 or CYP3A or in in-vitro hepatocytes; excreted unchanged in urine and bile.

• Elimination half-life: 2 hours

• Duration of action: 12 hours after a single IV dose[9]

Specific Patients Population 

Hepatic impairment: No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. However, the impact of the pharmacokinetics of difelikefalin has not been evaluated in patients with severe hepatic impairment; therefore, the use of difelikefalin is not recommended in this patient population. 

Renal impairment: The manufacturer label provides no dose adjustment data for patients with renal impairment. Difelikefalin has not been studied in patients on peritoneal dialysis and has no recommendations for use in this patient population.

Pregnant women: Difelikefalin is considered a pregnancy category B medicine. Limited data on the use of difelikefalin in pregnant women is insufficient to assess a drug-associated risk for significant congenital disabilities or miscarriage.

Breastfeeding women: The manufacturer labels do not provide data regarding the presence of difelikefalin in human milk, its effects on the breastfed infant, and/or milk production.

Pediatric patients: The safety and efficacy of difelikefalin are not established in pediatric patients. 

Older patients: The safety and efficacy of difelikefalin were studied on 848 subjects in the placebo-controlled trial.[16] In this study, 278 subjects (32.8%) and 98 subjects (11.6%) were 65 and 75 years of age or older, respectively. No overall differences in the safety or efficacy of difelikefalin have been observed between older and adult patient populations. The incidence of somnolence was 7% higher in older patients than in adult patients. No difference in plasma concentrations of difelikefalin has been observed between older and adult patient populations.

Adverse Effects

Phase 3 clinical trials involving patients with end-stage renal disease requiring dialysis suffering from uremic pruritus involved a study design. Patients received IV difelikefalin at weight-based doses of 1.0 mcg per kg 3 times a week in the venous circuit of their dialysis machine for 12 weeks.[5] This study demonstrated the following most common adverse effects:

• Diarrhea

• Vomiting

• Dizziness

A double-blind, randomized study assessed the potential of difelikefalin to cause respiratory depression in healthy patients compared to a 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, which 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 IV doses of 1.0 and 5.0 mcg per kg.[10] The following adverse effects were reported in 20% to 60% of participants:

• Paresthesia

• Hypoesthesia

• Somnolence

When study subjects experienced these adverse effects, the persistence of the symptoms ranged from less than 1 minute to less than 90 minutes and did not require any intervention.[10]

Contraindications

No published contraindications exist for difelikefalin. Phase 3 clinical trials involved 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.[11] Of note, clinical trials have only included adult patients. Difelikefalin should not be administered to children or adolescents.

Warnings and Precautions

Risk of driving and operating machinery

Patients who take difelikefalin may experience dizziness, somnolence, and mental status changes. The possibility exists that difelikefalin may impair the physical or mental abilities needed to perform potentially hazardous activities such as driving a car and operating machinery. Therefore, patients are advised not to drive or operate dangerous machinery until the effect of difelikefalin on their ability to drive or operate machinery is known.

Dizziness, somnolence, mental status changes, and gait disturbances

Patients who take difelikefalin may experience mental status changes, dizziness, somnolence, and gait disturbances, including falls. However, these adverse reactions may subside over time with continued treatment. In clinical trials, more patients who received difelikefalin reported at least 1 of these adverse reactions compared to those who received a placebo. The incidence of somnolence was higher in patients aged 65 years and older than those younger. Patients should use caution when taking difelikefalin with centrally-acting depressant medications, sedating antihistamines, and opioid analgesics.

Monitoring

Supportive treatment for the more commonly experienced adverse effects of difelikefalin, including vomiting and diarrhea, will increase positive patient outcomes. The health care team must avoid dehydration, acid-base disturbances, or an electrolyte imbalance when managing patients receiving difelikefalin. Clinicians should ensure adequate hydration status and assess patients with routine labs, administering electrolyte repletion as indicated.[1] If the adverse effect of dizziness is experienced in patients taking difelikefalin, fall risk measures must be taken to avoid injury, especially in older or frail patients. Opioid withdrawal symptoms were not observed after the cessation of treatment with difelikefalin.[11]

Toxicity

At supratherapeutic levels (15 mcg per mL), concern for respiratory depression or euphoric effects has not been demonstrated.[1][10] Difelikefalin has been studied in rats and determined to cause diuresis by activating central kappa opioid receptors.[17] Mild to moderate hypernatremia has been reported at supratherapeutic doses of 1.0, 2.0, and 5.0 mcg per kg. 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-limiting at supratherapeutic doses.[10]

No documented antidote for difelikefalin is currently in use. Considering the reassuring safety profile, the lack of activity in the CNS, and the more common adverse effects of difelikefalin subsiding without intervention, the clinical utility of naloxone in suspected supratherapeutic or toxic levels of difelikefalin is unlikely to be relevant. Phase 3 double-blind, randomized, placebo-controlled clinical trials have been conducted to study the use of difelikefalin for up to 8 and 12 weeks. The potential long-term effects of difelikefalin remain unclear.

Enhancing Healthcare Team Outcomes

The utility of a selective peripheral kappa opioid receptor agonist in treating uremic pruritis is emerging.[11] Patients with 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 clinicians is necessary to address the uremic pruritis often experienced by these patients appropriately so that the negative impact on the patient is diminished.[18] Common practice can evolve from current therapy for uremic pruritis, which often ineffectively utilizes antihistamines or involves off-label use of gabapentin.[19][20][21] 

Understanding the mechanism of difelikefalin and how it effectively addresses the nonhistaminergic pathway that 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.[19][5] The IV dosing of difelikefalin, typically 3 times a week in IV bolus form after completing dialysis sessions, is logistically ideal, enhancing team performance and subsequent patient outcomes when rendering this treatment.[4] 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.[22][21] 

The opioid crisis facing the healthcare industry today requires the introduction of safer postoperative pain medications with decreased abuse potential. Surgeons and primary care clinicians can initiate IV or oral difelikefalin for patients with acute postoperative pain or sub-acute and chronic pain, without significant concerns for lethal overdose or euphoric effects, even at supratherapeutic doses.[1] The extensive development of safer formulations of traditional oral opioid medications for pain management without the risk of misuse potential demonstrates a need that the novel difelikefalin oral formulation would fulfill through widespread implementation by healthcare providers.[21][1][14] Trials are currently underway to test difelikefalin for use in controlling postoperative pain; early results have shown promise regarding cost-effectiveness, clinical efficacy, and adverse event profile, but more research is necessary.[2]